DOI: 10.1111/jdv.

12943 JEADV

ORIGINAL ARTICLE

Etanercept for patients with psoriasis who did not respond

or who lost their response to adalimumab or iniximab
R. Bissonnette,1,* C. Maari,1 K. Barber,2 C.W. Lynde,3 R. Vender4
1
Innovaderm Research, Montreal, QC, Canada
2
Kirk Barber Research, Calgary, AB, Canada
3
Lynderm Research, Markham, ON, Canada
4
Dermatrials Research, Hamilton, ON, Canada
*Correspondence: R. Bissonnette. E-mail: rbissonnette@innovaderm.ca

Abstract
Background There is a paucity of data on the use of etanercept in patients who have previously failed a different
tumour necrosis factor (TNF) alpha antagonist.
Objectives To study etanercept in patients who did not achieve a satisfactory response to adalimumab or who lost
their response to adalimumab or iniximab and to explore the role of anti-adalimumab and anti-iniximab antibodies in
etanercept response.
Methods Patients with psoriasis who did not achieve a satisfactory response to adalimumab or who lost their response
to adalimumab or iniximab were included. All patients received etanercept 50 mg twice a week for 12 weeks followed
by 50 mg once a week for 12 more weeks. Anti-iniximab and anti-adalimumab antibodies were measured at baseline.
The primary objective was to study the efcacy of etanercept using the proportion of patients who achieved a physician
global assessment (PGA) of 0 or 1.
Results A total of 81 patients were included. The proportion of patients who achieved a PGA of 0 or 1 after 24 weeks
of etanercept was 20.0% (95% CI 4.835.2%) for patients who had an unsatisfactory response to adalimumab, 35.1%
(95% CI 19.051.3%) and 35.7% (95% CI 7.064.4%) for patients who lost their response to adalimumab and iniximab
respectively. The proportion of patients who achieved a PGA of 0 or 1 at week 24 was numerically higher for patients
who had anti-adalimumab or anti-iniximab antibodies (36.5%) as compared to those without (17.2%; P = 0.08).
Conclusions Etanercept can be effective in patients with psoriasis who failed a previous TNF alpha antagonist.
Received: 5 September 2014; Accepted: 28 November 2014

Conicts of interest
Robert Bissonnette has received honoraria for participation in advisory boards and/or research grants from Abbvie,
Amgen, Celgene, Eli-Lilly Galderma, Incyte, Janssen, Leo Pharma, Merck, Novartis, Pzer and Tribute. Catherine Maari
has been an advisory board member, investigator and or speaker for Abbvie, Amgen, Celgene, Eli Lilly, Galderma, Leo
Pharma, Merck, Novartis, and/or Tribute. Kirk Barber has received compensation for participation in Advisory Boards
and/or research support and/or grants from Amgen, Abbvie and/or Janssen. Charles W. Lynde has been a Speaker,
Consultant and/or Principal Investigator for: Abbvie, Amgen, Janssen, Celgene, Eli Lilly. Novartis, Merck, Leo Pharma,
Pzer and/or Tribute. Ronald Vender has received funds from AMGEN for advisory Boards, speaking, clinical trials, and
educational travels grants.

Funding sources
This study has been funded with a research grant from Amgen.

Introduction ongoing treatment.13 Therefore, physicians regularly need to

Tumour necrosis factor alpha antagonists are frequently used for
the treatment of moderate to severe psoriasis. However, <25% of
patients achieve complete clearance, as defined by psoriasis
assessment severity index (PASI) 100, with these agents.13
Moreover, some patients lose their response over time despite
consider other treatment options for patients who did not have
a good response or who lost their response to a TNF alpha
antagonist.
Etanercept is a soluble TNF alpha receptor that is approved
in several countries for the treatment of moderate to severe

JEADV 2015 2015 European Academy of Dermatology and Venereology

2 Bissonnette et al.
psoriasis. There a paucity of data on the efficacy of etanercept in
patients with psoriasis who had an unsatisfactory response or
lost their response to another TNF alpha antagonist. A pilot
study conducted with patients who did not achieve a physicians
global assessment (PGA) of clear or almost clear after 12 weeks
of adalimumab showed that 50% achieved a PGA of clear or
almost clear after 12 weeks of treatment with etanercept.4 How-
ever, this study was small (10 patients) and enrolled only
patients who were biologically naive before receiving ada-
limumab.4 The present study explores the response to etanercept
of patients who have not shown a satisfactory response to ada-
limumab, have lost a satisfactory response to adalimumab or
who have lost a satisfactory response to infliximab. Anti-ada-
limumab and anti-infliximab antibody levels were measured to
compare etanercept response in patients with and without anti-
drug antibodies.
Materials and methods
Patients
This open label study was approved by an ethics research com-
mittee and informed consent was obtained from each subject.
To be eligible, patients 18 years and older with moderate to
severe psoriasis had to either: (i) have had an unsatisfactory
response to adalimumab defined as failure to achieve a PGA of 0
or 1 despite treatment with adalimumab at 40 mg every other
week (EOW) for at least 12 weeks; or (ii) have lost their satisfac-
tory response to adalimumab defined as patients who achieved a
PGA of 0 or 1 after at least 12 weeks of adalimumab at 40 mg
EOW but lost this PGA response at any time after 12 weeks of
adalimumab; or (iii) have lost their satisfactory response to inf-
liximab defined patients who achieved a PGA of 0 or 1 after at
least three infusions of infliximab at 5 mg/kg but lost this PGA
response at any time after the third infusion. Patients who were
currently on adalimumab or infliximab and patients who had
already stopped but had historical documentation of previous
unsatisfactory response or failure were included. Washout peri-
ods were 14 days for adalimumab and infliximab, 4 weeks for
methotrexate, cyclosporine and acitretin, 8 weeks for etanercept
and 2 weeks for UVB phototherapy and topical treatment.
Etanercept treatment
All patients received etanercept 50 mg twice a week for 12 weeks
followed by once a week for an additional 12 weeks. Patients
who were on topical treatment during the last 4 weeks of the
period when they failed to achieve a satisfactory response to ada-
limumab were required to use the same topical treatment
throughout the entire study.
Efcacy and safety evaluations
Psoriasis severity was evaluated with the psoriasis area and sever-
ity index (PASI), a 5-grade PGA (from clear to severe) and with
JEADV 2015
estimation of the body surface area (BSA) involved with psoria-
sis. Safety was assessed by evaluation of adverse events, physical
examinations and routine chemistry and haematology analyses.
Immunogenicity
Pre-etanercept dosing of antibodies against adalimumab was
performed for patients enrolled based on an unsatisfactory
response or loss of response to adalimumab, whereas dosing of
antibodies against infliximab was performed for patients
enrolled based on a loss of response to infliximab. Dosing of
antibodies was performed at the end of the study by the Sanquin
Blood Supply Laboratory (Amsterdam, the Netherlands) using a
previously published method and patients were considered posi-
tive if their titre was 12 AU/mL or more.5,6 This method detects
all antibodies directed against the Fab portion of the ada-
limumab or infliximab monoclonal antibody. Analyses using the
level of antibodies were performed for patients with low
(12100 AU/mL) and high (100 AU/mL) antibody titres using
as previously described.7
Statistical analysis
The proportion of patients who achieved a PGA of clear or
almost clear, change from baseline in PASI and dermatology life
quality index (DLQI) at week 12 and 24 are presented as per-
centage with 95% confidence interval. An intent-to-treat
approach with non-responder imputation was used for PGA
analysis for patients who missed week 12 and/or week 24 visits.
For PASI, BSA and PASI evaluations, an intent-to-treat analysis
with last observation carried forward (LOCF) was used. For
immunogenicity analyses, the proportion of patients achieving a
PGA of clear or almost clear with or without the presence of
anti-adalimumab or anti-infliximab antibodies was compared
using the Fishers exact test. The level of significance was 0.05.
No adjustment for multiplicity was performed.
Results
Efcacy
A total of 81 patients were enrolled in this study: 30 who had an
unsatisfactory response to adalimumab, 37 who lost their satis-
factory response to adalimumab and 14 who lost their satisfac-
tory response to infliximab. Demographic information and
patient disposition are provided in Table 1 and Fig. 1. The pro-
portion of patients who achieved a PGA of 0 or 1 at week 12 was
20% (95 confidence interval (CI) 4.835.2%) for patients who
had an unsatisfactory response to adalimumab, 37.8% (95% CI
21.454.2%) for patients who lost their satisfactory response to
adalimumab and 35.7% (95% CI 7.064.4%) for patients who
lost their satisfactory response to infliximab. At 24 weeks after
initiation of etanercept the proportion of patients who achieved
a PGA of 0 or 1 was 20.0% (95 CI 4.835.2%) for patients who
had an unsatisfactory response to adalimumab, 35.1% (95% CI
2015 European Academy of Dermatology and Venereology
Etanercept after a biologic in psoriasis 3

19.051.3%) for patients who lost their satisfactory response to 15.00% to 6.10%) for patients who lost their satisfactory
adalimumab and 35.7% (95% CI 7.064.4%) for patients who response to adalimumab and 17.20 (95% CI 28.63% to
lost their satisfactory response to infliximab. 5.77%) for patients who lost their satisfactory response to inf-
Mean BSA progressively decreased after initiation of etaner- liximab. Mean PASI also progressively decreased after initiation
cept (Fig. 2a). The change from baseline in BSA at week 24 was of etanercept. The change from baseline in PASI at week 24 was
4.56 (95 CI 6.79% to 2.33%) for patients who had an 4.13 (95% CI 5.98 to 2.28) for patients who had an unsat-
unsatisfactory response to adalimumab, 10.55 (95% CI isfactory response to adalimumab, 8.32 (95% CI 10.75 to
5.90) for patients who lost their satisfactory response to ada-
limumab and 8.92 (95% CI 13.66 to 4.19) for patients who
Table 1 Demographics and baseline disease characteristics lost their satisfactory response to infliximab (Fig. 2b). Mean
Unsatisfactory Loss of Loss of DLQI also progressively decreased after initiation of etanercept
response to satisfactory satisfactory (Fig. 2c). The change from baseline in DLQI at week 24 was
adalimumab response to response to 3.47 (95% CI 6.32 to 0.61) for patients who had an unsat-
(N = 30) adalimumab iniximab
(N = 37) (N = 14) isfactory response to adalimumab, 6.43 (95% CI 8.95 to
3.92) for patients who lost their satisfactory response to ada-
Age, mean (SD) 47.0 (13.1) 50.6 (10.6) 46.2 (12.4)
limumab and 6.71 (95% CI 11.09 to 2.34) for patients who
Weight in kg, 96.9 (23.2) 94.4 (20.2) 84.3 (18.6)
mean (SD) lost their satisfactory response to infliximab.
Sex, n (%)
Male 21 (70) 28 (75.7) 11 (78.6) Safety
Race/Ethnicity, n (%) The median time between the last adalimumab and the last inf-
Asian 1 (3.3) 3 (8.1) 0 (0.0) liximab dose and the first etanercept dose was 7.1 weeks. The
Black 0 (0.0) 1 (2.7) 1 (7.1) proportion of patients who received their last dose of ada-
Caucasian 27 (90.0) 32 (86.5) 13 (92.9) limumab or infliximab <6 weeks, 612 weeks, 1224 weeks and
Hispanic 0 (0.0) 1 (2.7) 0 (0.0) more than 24 weeks before Day 0 was: 34.6%, 28.4%, 7.4% and
Indian 2 (6.7) 0 (0.0) 0 (0.0) 29.6% respectively. Some patients had their last dose of ada-
Body surface 12.0 (9.2) 15.9 (16.2) 24.6 (27.0) limumab more than 24 weeks before Day 0 as patients could be
area, mean (SD)
enrolled based on historical documentation of lack of satisfac-
Physician global assessment, n (%)
tory or loss of satisfactory response. Two serious adverse events
3 Moderate 18 (60.0) 23 (62.2) 8 (57.1)
were observed in this study: a case of cellulitis and a case of
4 Severe 10 (33.3) 13 (35.1) 6 (42.9)
encephalitis. Both adverse events were evaluated as possibly
5 Very severe 2 (6.7) 1 (2.7) 0 (0.0)
related to etanercept.

Figure 1 Flow diagram and patient disposition.

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4 Bissonnette et al.

60 (a) Unsatisfactory response to adalimumab PGA of 0 or 1 with and without antibodies to adalimumab was
50
Loss of satisfactory response to adalimumab
Loss of satisfactory response to infliximab very similar (P = 1.0; Fig. 3a). For patients who lost their satis-
factory response to infliximab, the proportion of patients achiev-
40
ing a PGA of 0 or 1 at week 12 was numerically higher (50.0%)
BSA (%)

30 for patients with anti-infliximab antibodies than for patients

20 without anti-infliximab antibodies (16.7%; P = 0.301; Fig. 3a).
10
Similar results were obtained at week 24 (Fig. 3b). At week 24
the proportion of patients achieving a PGA of 0 or 1 was numer-
0
Day 0 Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 ically higher for patients with anti-drug antibodies (36.5%) as
Visit compared to patients without (17.2%; P = 0.08).

25 (b) Discussion
Unsatisfactory response to adalimumab

20
Loss of satisfactory response to adalimumab This study showed that 38 and 36% of patients who had lost
Loss of satisfactory response to infliximab
their response to adalimumab and infliximab respectively were
15 able to achieve a clear or almost clear status after 12 weeks of
PASI

etanercept. This is lower than the proportion of patients who

10
were reported to achieve a clear or almost clear status in phase
5 III studies with etanercept (49%) but suggests that etanercept is
still an interesting treatment option for patients who have lost
0
Day 0 Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 their response to another TNF alpha antagonists.2,3 The lower
Visit response rate for patients who have failed a previous TNF alpha
antagonist is expected and has been reported for other TNF
Unsatisfactory response to adalimumab
20 (c) alpha antagonists when used to treat psoriasis.8,9 This lower
Loss of satisfactory response to adalimumab
18 Loss of satisfactory response to infliximab
16 response is also seen in patients with rheumatoid arthritis or
14 ankylosing spondylitis when a second TNF alpha antagonist is
12
used.10,11
DLQI

10
8 For patients who never responded to adalimumab, the pro-
6 portion of patients who were clear or almost clear with etaner-
4
2
0 patients who had an unsatisfactory response to adalimumab and
Day 0 Week 12
Visit
Figure 2 Body surface area (BSA) (a) psoriasis area and severity
index (PASI) (b) and dermatology life quality index (DLQI) (c)
according to time for patients with an unsatisfactory response to
adalimumab, a loss of satisfactory response to adalimumab and a
loss of satisfactory response to iniximab (LSRI) Last observation
carried forward imputation (n = 81).
Immunogenicity
At baseline 64.2% of patients had anti-drug antibodies: (63.3%
of patients who had an unsatisfactory response to adalimumab,
67.6% of patients who lost their response to adalimumab and
57.1% of patients who lost their response to infliximab). For
patients with an unsatisfactory response to adalimumab, the
proportion of patients achieving a PGA of 0 or 1 at week 12 was
numerically higher (26.3%) for patients with anti-adalimumab
antibodies than for patients without anti-adalimumab antibod-
ies (9.1%; Fig. 3a). However, this difference was not statistically
significant (P = 0.372). For patients who lost their satisfactory
response to adalimumab, the proportion of patients achieving a
cept in the current trial was 20%. Interestingly, only 9% of
Week 24 who did not have anti-adalimumab antibodies responded to eta-
nercept as compared to 26% of patients with anti-adalimumab
antibodies who responded to etanercept. The presence of
adalimumab antibodies may explain the absence of response to
adalimumab for some of these patients. The onset of anti-ada-
limumab antibodies after initiation of adalimumab has been
studied in patients with rheumatoid arthritis. Most patients will
develop anti-adalimumab antibodies within the first 24 weeks of
therapy and more than 50% of patients who will eventually
develop antibodies become positive by week 16,6 The presence
of anti-adalimumab antibodies is associated with a lower
response rate but many patients still respond very well despite
the presence of these antibodies.6 Anti-adalimumab antibodies
have been reported to be associated with lower adalimumab lev-
els and lower response in patients with psoriasis.7 Unfortunately,
we did not study adalimumab or infliximab levels in the current
study as patients eligibility was based on historical documenta-
tion and many patients had stopped their previous biologic
many months or even years prior to the study. Taken together,
this pattern of anti-adalimumab antibody production and our
observations on response to etanercept suggest that for patients
who never respond to adalimumab, some may have an early rise

JEADV 2015 2015 European Academy of Dermatology and Venereology

Etanercept after a biologic in psoriasis 5

60% (a)

50%

% of Patients with PGA 0 or 1 at Wk 12

Without antibodies
40% With antibodies

30%

20%

10%

0%
Unsatisfactory response Loss of response Loss of response
to adalimumab to adalimumab to infliximab

60% (b)
% of Patients with PGA 0 or 1 at Wk 24

50%

Without antibodies
40% With antibodies

30%

20%
Figure 3 Proportion of patients with a
physician global assessment of clear or
10%
almost clear at (a) week 12 and (b) week 24
according to presence or absence of anti-
drug antibodies at baseline Non- 0%
responder imputation (n = 81). Unsatisfactory response Loss of response Loss of response
to adalimumab to adalimumab to infliximab

in anti-adalimumab antibodies preventing improvement in pso-
riasis. Many of these patients are TNF alpha responders and will
respond to a second TNF blocker such as etanercept. However,
patients who fail to respond to adalimumab and do not have
anti-adalimumab antibodies may be mostly non-responders to
TNF alpha antagonist as shown by the low proportion (9%)
who responded to etanercept in the current study. For these
patients, a TNF alpha antagonist may be a less interesting option
as their psoriatic disease may not be mainly driven by TNF
alpha. Etanercept may still be an interesting option to consider
for patients who have a primary failure to adalimumab, if they
have anti-adalimumab antibodies, as 26% of these patients
achieved the clear or almost clear status in the current study.
Further studies are needed on the efficacy of non-TNF alpha
blocking agents (such as ustekinumab or IL-17 antagonists) in
patients who had an unsatisfactory response to adalimumab in
order to determine if these patients would benefit from being
switched to a non-TNF alpha blocking agent.
For patients who responded to adalimumab but lost their
response over time, the presence of anti-adalimumab antibodies
did not seem to have an influence on the likelihood or
responding to etanercept. The proportion of patients who
responded to etanercept was approximately similar for patients
with and patients without antibodies for those who lost their
response to adalimumab. These patients may have lost their
response overtime because of disease progression or non-adher-
ence to treatment rather than the presence of anti-adalimumab
antibodies. As patients could be included based on the loss of
response observed in routine dermatology practice, no data are
available on adalimumab treatment adherence. A prospective
study of patients treated with adalimumab would be ideal to
address this question.
The proportion of patients with anti-adalimumab or anti-inf-
liximab antibodies observed in this study is slightly higher than
what has been previously reported in previous studies using a
similar analytical method for antibody measurement.12 This
could be due to the fact that the current study only recruited
patients who did not respond or lost their response to another
TNF alpha antagonist. The presence of antibodies against ada-
limumab or infliximab has been shown to be associated with
lower trough adalimumab or infliximab levels and lower clinical
response in patients with psoriasis.7,12,13 Jamnitski et al.11

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6 Bissonnette et al.
studied the response to etanercept of 292 patients with rheuma-
toid arthritis including 89 who were switched from adalimumab
or infliximab. They found that improvement in arthritis, as mea-
sured by DAS 28, was lower for patients previously treated with
adalimumab or infliximab who did not have antibodies against
adalimumab or infliximab than for switchers who had antibod-
ies. These results are similar to our findings in patients with pso-
riasis and suggest that patients switching form one TNF alpha
antagonist will have a lower response if they do not have anti-
bodies.
Limitations of the current study include the fact that docu-
mentation of unsatisfactory response or loss of response to ada-
limumab or infliximab was not systematically obtained in a
clinical study. Therefore, no detailed documentation of adher-
ence to adalimumab and infliximab treatment was available. In
addition, the presence and levels of anti-drug antibodies could
be influenced by the fact that these levels were measured more
than 6 months after treatment cessation for 29.6% of patients.
Other limitations include the small sample size, specifically for
the infliximab cohort and the fact that adalimumab and inflix-
imab drug levels could not be measured as many patients had
stopped their treatment several months before being included in
the study.
In conclusion, a good proportion of patients who lost their
response to adalimumab or infliximab achieved a PGA of clear
or almost clear after being treated with etanercept. This propor-
tion was lower for patients who had an unsatisfactory primary
response to adalimumab suggesting that some of these patients
may be TNF alpha non-responders. Etanercept is a treatment
option to consider for patients who have failed adalimumab or
who have lost their response to adalimumab or infliximab.
Acknowledgements
We thank Philippe Marchessault for his assistance with figure
generation and manuscript preparation and Miguel Chagnon for
his assistance with statistical analysis.
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References
1 Menter A, Tyring SK, Gordon K et al. Adalimumab therapy for moderate
to severe psoriasis: a randomized, controlled phase III trial. J Am Acad
Dermatol 2008; 58: 106115.
2 Papp KA, Tyring S, Lahfa M et al. A global phase III randomized con-
trolled trial of etanercept in psoriasis: safety, efficacy, and effect of dose
reduction. Br J Dermatol 2005; 152: 13041312.
3 Reich K, Nestle FO, Papp K et al. Infliximab induction and maintenance
therapy for moderate-to-severe psoriasis: a phase III, multicentre, dou-
ble-blind trial. Lancet 2005; 366: 13671374.
4 Vender R. An open-label, prospective cohort pilot study to evaluate the
efficacy and safety of etanercept in the treatment of moderate to severe
plaque psoriasis in patients who have not had an adequate response to
adalimumab. J Drugs Dermatol 2011; 10: 396402.
5 Vande Casteele N, Buurman DJ, Sturkenboom MG et al. Detection of
infliximab levels and anti-infliximab antibodies: a comparison of three
different assays. Aliment Pharmacol Ther 2012; 36: 765771.
6 Bartelds GM, Krieckaert CL, Nurmohamed MT et al. Development of
antidrug antibodies against adalimumab and association with disease
activity and treatment failure during long-term follow-up. JAMA 2011;
305: 14601468.
7 Lecluse LL, Driessen RJ, Spuls PI et al. Extent and clinical consequences
of antibody formation against adalimumab in patients with plaque psori-
asis. Arch Dermatol 2010; 146: 127132.
8 Bissonnette R, Bolduc C, Poulin Y, Guenther L, Lynde CW, Maari C. Effi-
cacy and safety of adalimumab in patients with plaque psoriasis who have
shown an unsatisfactory response to etanercept. J Am Acad Dermatol
2010; 63: 228234.
9 Gottlieb AB, Kalb RE, Blauvelt A et al. The efficacy and safety of inflix-
imab in patients with plaque psoriasis who had an inadequate response
to etanercept: results of a prospective, multicenter, open-label study.
J Am Acad Dermatol 2012; 67: 642650.
10 Lie E, van der Heijde D, Uhlig T et al. Effectiveness of switching between
TNF inhibitors in ankylosing spondylitis: data from the NOR-DMARD
register. Ann Rheum Dis 2011; 70: 157163.
11 Jamnitski A, Bartelds GM, Nurmohamed MT et al. The presence or
absence of antibodies to infliximab or adalimumab determines the out-
come of switching to etanercept. Ann Rheum Dis 2011; 70: 284288.
12 Bito T, Nishikawa R, Hatakeyama M et al. Influence of neutralizing anti-
bodies to adalimumab and infliximab on the treatment of psoriasis. Br
J Dermatol 2014; 170: 922929.
13 Menter A, Feldman SR, Weinstein GD et al. A randomized comparison
of continuous vs. intermittent infliximab maintenance regimens over
1 year in the treatment of moderate-to-severe plaque psoriasis. J Am Acad
Dermatol 2007; 56: 31 e115.
2015 European Academy of Dermatology and Venereology