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ORIGINAL ARTICLE

A consensus report on appropriate treatment optimization


and transitioning in the management of moderate-to-severe
plaque psoriasis
U. Mrowietz,
1,
* E.M.G.J. de Jong,
2
K. Kragballe,
3
R. Langley,
4
A. Nast,
5
L. Puig,
6
K. Reich,
7
J. Schmitt,
8
R.B. Warren
9
1
Department of Dermatology, Psoriasis-Center, University Medical Center, Schleswig-Holstein (Campus Kiel) Kiel, Germany
2
Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
3
Department of Dermatology,

Arhus University Hospital,

Arhus, Denmark
4
Division of Dermatology, Dalhousie University, Halifax, NS, Canada
5
Division of Evidence Based Medicine, Klinik f ur Dermatologie, Venerologie und Allergologie Charite-Universit atsmedizin Berlin, Berlin,
Germany
6
Hospital de la Santa Creu i Sant Pau, Universitat Aut onoma de Barcelona, Barcelona, Spain
7
Dermatologikum Hamburg, Hamburg
8
Centre for evidence-based healthcare, Technische Universit at, Dresden, Germany
9
Dermatology Centre, Manchester Academic Health Sciences Centre, Salford Royal Foundation Trust, the University of Manchester
Manchester, UK
*Correspondence: U. Mrowietz. E-mail: umrowietz@dermatology.uni-kiel.de
Abstract
Background There is limited information on systemic and biological treatment optimization and transitioning in routine
clinical practice.
Objective To provide practical guidance on treatment optimization and transitioning for moderate-to-severe plaque
psoriasis.
Methods Dermatologists from 33 countries contributed to the Transitioning Therapies programme. Fourteen questions
were identied. Answers were drafted based on systematic literature reviews (7/14 questions) and expert opinion (7/14
questions). Using a modied Delphi procedure, dermatologists from 30 countries voted on their level of agreement with
each draft answer (scale: 19, strong disagreement to strong agreement). Consensus was dened as 75% of partici-
pants scoring within the 79 range.
Results Consensus was achieved on the answers to all questions. Recommendations for the use of cyclosporine and
methotrexate were agreed. Transitioning from a conventional systemic therapy to a biological agent may be done
directly or with an overlap (if transitioning is required because of lack of efcacy) or potentially with a treatment-free inter-
val (if transitioning is required for safety reasons). Combination therapy may be benecial. Continuous therapy for
patients on biologicals is strongly recommended. However, during successful maintenance with biological monotherapy,
a dosage reduction may be considered to limit drug exposure, although this may carry the risk of decreased efcacy.
Switching biologicals for reasons of efcacy should be done without a washout period, but switching for reasons of
safety may require a treatment-free interval.
Conclusion This consensus provides practical guidance on treatment optimization and transitioning for moderate-to-
severe plaque psoriasis, based on literature reviews and the expert opinion of dermatologists from across the globe.
Received: 19 October 2012; Accepted: 21 January 2013
Conict of interest
UM has been a consultant and/or speaker and/or participant in clinical trials and/or received grants from the following
companies that manufacture drugs for the treatment of psoriasis including Abbott, Almirall-Hermal, BiogenIdec, Cel-
gene, Centocor, Forward Pharma, Janssen, Leo Pharma, Medac, MSD Sharp & Dohme, Novartis, Pzer. EdeJ has acted
as consultant and/or paid speaker and/or participated in research sponsored by companies that manufacture drugs used
for the treatment of psoriasis including Abbott, Janssen-Cilag, MSD and Pzer. KK has declared no conicts of interest.
RL has served as a scientic advisory board advisor (SAB), investigator (I) or speaker (Sp) for Abbott (SAB, I, Sp), Amgen
(SAB, I, Sp), Centocor (SAB, I), Pzer (SAB, I) and Celgene (SAB, I). AN has received honoraria for CME certied educa-
tional talks that received indirect sponsorship from Abbott and Janssen-Cilag; the deBM (his employer) has received
2013 The Authors
Journal of the European Academy of Dermatology and Venereology 2013 European Academy of Dermatology and Venereology JEADV 2013
DOI: 10.1111/jdv.12118 JEADV
research grants from Wyeth (now Pzer). LP has served as consultant and/or paid speaker for and/or participated in clini-
cal trials sponsored by companies that manufacture drugs used for the treatment of psoriasis including Abbott, Celgene,
Centocor, Janssen-Cilag, Leo, Merck, MSD (formerly Schering-Plough), Novartis, Pzer (formerly Wyeth). KR has
received honoraria as a consultant and/or advisory board member and/or acted as a paid speaker and/or participated in
clinical trials sponsored by Abbott, Amgen, Biogen-Idec, Centocor, MSD (formerlyEssex Pharma, Schering Plough),
UCB, Janseen-Cilag, Celgene, Pzer (formerly Wyeth), Novartis, LEO Pharma, Basilea, Forward Pharma, Medac and
Ocean Pharma. JS has acted as a paid speaker for Novartis and Abbott, and received research grants from Pzer (for-
merly Wyeth) and from Novartis. RBW has acted a consultant and/or speaker for Abbott, Pzer, Janssen, Leo and Scher-
ing Plough (now MSD).
Funding sources
This study was funded through an educational grant to the Psoriasis-Center, Department of Dermatology, University
Medical Center Schleswig-Holstein, Campus Kiel, Germany, from Abbott.
Introduction
Patients with psoriasis remain undertreated, as illustrated in a sur-
vey of dermatological practices in Germany, which showed that
29.5% of 1341 patients with psoriasis had moderate disease [Pso-
riasis Area Severity Index (PASI): 1120] and 19.4% had severe
disease (PASI: >20), but only 31% received systemic treatment.
1
Treatment goals, which supplement existing guidelines,
25
have been developed by a European Consensus Group to pro-
mote the consistent use of available therapies to improve patient
care.
6
However, while treatment goals provide guidance on when
to modify treatment, there are few data in the literature, and
limited information in guidelines, to guide physicians on treat-
ment optimization of conventional systemic and biological ther-
apies and how and when to transition from one treatment to
another in routine clinical practice.
7
Furthermore, there is ongo-
ing debate on whether a successful therapy should be continued
and, if so, for how long. Criteria on which to base the decision
to terminate or interrupt treatment have not been elaborated
but are of signicant clinical importance.
Here, we report on the Transitioning Therapies programme,
which was established to provide practical, evidence-based,
expert-agreed guidance on appropriate treatment optimization
and transitioning in the management of moderate-to-severe pla-
que psoriasis.
Materials and methods
Thirty-three countries were involved in the Transitioning Thera-
pies programme. The programme took place between May 2011
and June 2012 and was overseen by a Steering Committee (SC)
of nine dermatologists from Europe and Canada (the authors of
this article). The programme was conducted as a modied Del-
phi procedure and consisted of several stages (Fig. 1). Similar
methodology has been employed in development of other con-
sensus-based guidelines.
8,9
The participating dermatologists were asked to suggest clini-
cally relevant questions, covering optimization of conventional
systemic therapies, transitioning from conventional systemic
therapies to biological therapy and transitioning from one biolo-
gical agent to another. These suggestions were assembled into a
list of 93 questions. The questions were sent back to the partici-
pating dermatologists with a question prioritization form. The
group consisted of a total of 147 dermatologists (referred to as
the national faculty members), who were selected based on their
expertise in treating patients with moderate-to-severe psoriasis.
The results from the question prioritization stage enabled
questions to be ranked and critical clinical questions to be
identied. Fourteen key questions (some of which had several
sub-sections, resulting in 25 components) were agreed at a face-
to-face meeting of the SC in October 2011 to be taken forward
to the next stage.
Draft answers to the 14 questions were developed by the SC.
The feasibility of answering the questions based on a systematic
literature search was assessed by the SC and, when possible, draft
answers were developed for 7/14 questions (questions 1B, 2B, 7,
8, 11, 13, 14) based on the results of systematic literature review.
For the systematic literature search each question was rephrased
according to the PICO method.
10
Details of the systematic
searches, which were conducted with pre-dened search strings,
are listed in Table 1, with the outcomes listed in Table 2. The
evidence was graded using the classication of the Oxford Cen-
tre for Evidence-Based Medicine: Level 1 (highest level of evi-
dence based on randomized controlled trials); Level 2 (high
quality cohort studies and poor quality randomized controlled
trials); Level 3 (high quality case-control studies); Level 4 (case
series or poor quality cohort or case-control studies); Level 5
(lowest evidence based on expert opinion) (see http://www.
cebm.net/index.aspx?o=1025). The remaining seven questions
were answered based on non-systematic literature review and
expert opinion; these draft answers were not assigned an
evidence level.
Using a structured, iterative process draft answers were sent
to the national faculties to be discussed during national
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2 Mrowietz et al.
meetings. Feedback was returned to the SC and was consolidated
into revised answers, taking into account consistency between
countries, alternative views and the opinions of the SC.
The revised answers were discussed again (and amended when
this was thought to be necessary) at an international meeting of
103 participants from 30 of 33 invited countries which was held
in Frankfurt, Germany on 21 and 22 June 2012. Each country
had between 1 and 5 dermatologists participating in the interna-
tional meeting with the exception of Canada (9 participants)
and Italy (10 participants). Two thirds of the participants at the
international meeting had previously participated in both the
question prioritization phase of the programme and the national
2012
2011
International: steering
committee
National: faculty
Question
development
Answer
development
Consensus
Finalise questions
Refine & rank questions
Draft questions
Literature research &
consolidated report
Finalise consolidated
report
National meeting
International meeting
Publication National cascade
May Jul
Sep - Oct
Oct
Nov Jan
Feb Mar
May
Jun
Sep
onward
Figure 1 Workow of Transitioning Therapies programme.
Table 1 Summary of the systematic literature searches
Databases searched Medline (search date: 28.10.2011)
Medline in Process (search date: 28.10.2011)
Embase (search date: 28.10.2011)
Cochrane Library (search date: 31.10.2011)
Limits 2000 present
Humans
English, French or German
Hand searches
(2007 onwards)
Journals:
J Invest Dermatol
Brit J Dermatol
J Am Acad Dermatol
Arch Dermatol
J Eur Acad Dermatol Venereol
Abstracts:
German Dermatological Society meetings
2007, 2009 and 2011
American Academy of Dermatology meetings
20092011
European Academy of Dermatology and
Venereology meetings 20052011
From Gene to Clinic meeting London 2005
and 2008
Congress of the Psoriasis International
network, Paris 2010
Inclusion criteria Randomized controlled studies
Case-control studies
Case series
Prospective and retrospective studies
Studies with >5 patients treated with the
same medication
Exclusion criteria False topics
No original data
No relevant outcome data
Fewer than 5 patients
Table 2 Summary of references retrieved in systematic literature
searches
Question Number of
references
retrieved by
systematic
searches
Final number
of articles
included in
the systematic
reviews
Additional
abstracts/
articles
identied
by hand
searches
Q1B/2B 150 17 in total:
10 cyclosporine
7 methotrexate
0
Q7 809 2 0
Q8 8 1
Q11 8 2
Q13 8 0
Q14 13 0
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Optimizing and transitioning psoriasis treatment 3
meetings. The participants were reminded that the recommen-
dations refer to plaque psoriasis unless otherwise stated.
Voting was performed using hand-held electronic voting
devices. Each participant had one vote per component or
question. Participants indicated their level of agreement with
each draft answer using a voting scale of 19 (where
1 = strong disagreement and 9 = strong agreement). Each
voting score was allocated to one of three ranges: 13, 46
and 79. Consensus was dened as 75% of participants
scoring within the 79 range. If <75% of participants scored
within this range, the answer was debated and revised, and a
second vote took place, with consensus based on the criteria
above.
Results
At the question prioritization stage, 110 of 147 invited dermatol-
ogists responded (with at least 1 valid form from each participat-
ing country), with 107 completed valid forms (73% response
rate). In total, 14 key questions were identied, some of which
had several sub-sections, resulting in 25 components.
Following development of the draft answers, feedback was
generated at national meetings of the national faculty members
from 32 of the 33 participating countries, and consolidated into
revised answers as described above.
The revised answers were discussed and voted upon at the
international meeting. Consensus was achieved on all 25 compo-
nents at the international meeting with only one component
(Q13) requiring a second vote. The consensus-agreed answers
are presented in Tables 39.
Optimization of conventional systemic therapies
Cyclosporine Consensus recommendations on optimizing
therapy with cyclosporine are presented in Table 3. Treatment
with cyclosporine should generally only be used for short peri-
ods to induce a clinical response. Clinically meaningful
responses (50% reduction in mean PASI in a population of
patients) have been observed after 46 weeks of cyclosporine
(starting dosages of 2.53 mg/kg/day) (Level of evidence 2),
1117
with a more rapid onset of response (within 34 weeks) with
higher starting dosages ( 5 mg/kg/day) (Level of evidence 2),
1720
although this may be associated with greater toxicity. Clinical
response to cyclosporine 2.55 mg/kg/day can be expected to
reach a maximum within 512 weeks (Level of evidence 2).
1323
When necessary for medical reasons, cyclosporine may be
given to responding patients for up to 2 years. In exceptional
cases, where no other treatment options are available, cyclospor-
ine may be given for longer than 2 years but caution is advised
because of the signicant risk of renal toxicity, the development
of arterial hypertension and the increased risk of skin cancer
(especially in patients with extensive previous phototherapy, e.g.
>200 PUVA treatments).
24
Special caution is also recommended
for patients with a history of cancer or in those who are immu-
nosuppressed. Changes in the risk-benet prole for cyclospor-
ine can occur early after treatment onset and this should be
taken into account when considering treatment options.
25,26
Patients on cyclosporine therapy should be monitored regularly
according to the existing guidelines and examination for skin
cancer should be undertaken.
Table 3 Recommendations on optimizing conventional systemic
therapies: cyclosporine
Q1A What is the maximum period for which conventional systemic
therapies should be given to patients responding to treatment?
1 Treatment with cyclosporine is generally used intermittently
for inducing a clinical response with one or several courses
over 36 months.
2 When necessary, cyclosporine may be given to patients
responding to treatment continuously for up to 2 years.
In exceptional cases, where no other treatment options are
available, treatment with cyclosporine can be extended for
longer than 2 years with adequate monitoring. However,
changes in the risk-benet prole for cyclosporine can
already occur from an early stage of treatment and this
should be borne in mind when considering treatment
options.
25,26
3 The long-term use of cyclosporine should be considered
with caution because of the signicant risk of renal toxicity,
the development of arterial hypertension and the increased
risk of skin cancer
24
especially in patients with extensive
previous phototherapy (e.g. >200 PUVA treatments).
Long-term cyclosporine use should be considered with
particular caution in patients with a history of cancer or
who are immunosuppressed.
4 Regular monitoring should be performed according to the
existing guidelines; skin examination to check for skin
cancer is also recommended.
99% consensus agreement on rst vote; median score = 8
Q1B Following treatment with conventional systemic therapy,
during what time period should we expect to see a clinical
response? At what time points should we monitor patients for
treatment response, for example, with PASI 75?
1 In clinical trials with cyclosporine starting dosages of
2.53 mg/kg/day, clinically meaningful responses (50%
reduction in the mean PASI) have been observed after 46
weeks.
1117
(Level of evidence 2)
2 Higher starting dosages ( 5 mg/kg/day) lead to a more
rapid onset of response (50% reduction in mean PASI
within a mean time of 34 weeks)
1720
(Level of evidence 2)
although this may be associated with greater toxicity than
starting at a lower dosage.
3 The clinical response to cyclosporine in a patient population
with dosages of 2.55 mg/kg/day can be expected to reach a
maximum within 512 weeks.
1323
(Level of evidence 2)
100% consensus agreement on rst vote; median score = 9
PASI, Psoriasis Area Severity Index; PUVA, psoralen plus ultraviolet A;
clinically meaningful response, a 50% reduction in the mean PASI in a
population of patients.
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Methotrexate There is no evidence-based study directly
addressing the question of how long methotrexate can be
administered to patients. However, there is a wealth of expert
experience suggesting that methotrexate therapy is effective for
long periods of time (1015 years) in appropriate patients and
with regular safety monitoring. Therefore, methotrexate may be
given to patients for as long as it remains effective and well toler-
ated (Table 4).
In clinical trials, clinically meaningful responses (50% reduc-
tion in mean PASI in a population of patients) have been
observed after 713 weeks of oral methotrexate (57.5 mg
weekly starting dose, escalating),
11,2731
with a reduction in mean
PASI by 75% occurring within 14 weeks (Level of evidence 2).
27
Higher oral starting doses (1522.5 mg weekly) produce a more
rapid onset of response (50% reduction in mean PASI within a
mean of 34 weeks
12,32
; and 75% reduction in mean PASI within
7 weeks
32
) (Level of evidence 2). The clinical response to oral
methotrexate can be expected to reach a maximum within
1220 weeks (Level of evidence 2).
12,2729,32,33
There are few evidence-based studies on the pattern of
treatment of psoriasis with methotrexate and treatment deci-
sions have often been a matter of judgement and best practice.
Nonetheless, we recommend that oral methotrexate can be
initiated at dosages of 515 mg/week with early monitoring
Table 4 Recommendations on optimizing conventional systemic therapies: methotrexate
Q2A What is the maximum period for which conventional systemic therapies should be given to patients responding to treatment?
1 Methotrexate may be given to patients for as long as it remains effective and well-tolerated.
2 Screening and monitoring of patients according to the existing guidelines is required.
3 In most cases, the risk of liver toxicity with methotrexate therapy is low; however, the impact of additional risk factors such as baseline liver
disease (including HBV or HCV), alcohol intake, obesity and type 2 diabetes and the use of concomitant medications should be taken into
account.
36,39,40
The risk of liver toxicity may increase with cumulative doses of methotrexate.
4 There is no clear evidence for or against increased risk of malignancies
82
or serious infections with methotrexate therapy in patients with
psoriasis.
97% consensus agreement on rst vote; median score = 9
Q2B Following treatment with conventional systemic therapy, during what time period should we expect to see a clinical response? At what time
points should we monitor patients for treatment response, for example, with PASI 75?
1 In clinical trials with oral methotrexate (57.5 mg weekly starting dose, escalating), clinically meaningful responses (50% reduction in the
mean PASI) have been observed after 713 weeks.
11,2731
A reduction of the mean PASI by 75% has been observed within 14 weeks.
27
(Level of evidence 2)
2 Higher oral starting doses (1522.5 mg weekly) lead to more rapid onset of response (50% reduction in the mean PASI within a mean
time of 34 weeks
12,32
and 75% reduction in the mean PASI within 7 weeks).
32
(Level of evidence 2)
3 The clinical response to oral methotrexate in a patient population can be expected to reach a maximum within 1220 weeks.
12,2729,32,33
(Level of evidence 2)
98% consensus agreement on rst vote; median score = 9
Q3 If a patient does not respond to methotrexate within 1624 weeks, should we increase the dose? What is the maximum dose we should
use before considering treatment failure?
1 Oral methotrexate therapy can be initiated at dosages between 5 and 15 mg/week with early monitoring (before the second dose). If a
low starting dose is selected, rapid dosage escalation to 15 mg/week by week 3 can be considered.
2 If at week 8 the response is insufcient, an increase in the dosage to 20 mg/week can be considered.
3 For patients who are non-responders to 20 mg oral methotrexate treatment at 1624 weeks the effect of further increasing the dose
remains unclear.
29,31,34
4 There is evidence for oral methotrexate only; increased efcacy and tolerability may be achievable by subcutaneous administration.
95% consensus agreement on rst vote; median score = 9
Q4 What is the optimal safety monitoring (clinical, laboratory) of patients receiving methotrexate? How often?
1 Current guidelines provide monitoring recommendations for screening, initiation and maintenance with methotrexate therapy.
2,3
For
methotrexate-naive patients, it is particularly important to assess for early signs of toxicity before administering the second dose of
methotrexate.
2 In addition to guideline recommendations, monitoring for liver toxicity may include measurement of PIIINP every 36 months in the
same laboratory and assessment of the liver using transient elastography, if these tests are available.
3 Liver biopsy is not routinely indicated but may be considered in specic clinical circumstances following discussion with a hepatologist.
88% consensus agreement on rst vote; median score = 8
HBV, hepatitis B virus; HCV, hepatitis C virus; PASI, Psoriasis Area Severity Index; PASI 75, a 75% reduction in PASI; PIIINP, procollagen III N-terminal
peptide; clinically meaningful response, a 50% reduction in the mean PASI in a population of patients.
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Optimizing and transitioning psoriasis treatment 5
(before the second dose) (Table 4). If a low starting dose is
selected, rapid dosage escalation to 15 mg/week by week 3 can
be considered. A further increase in dosage to 20 mg/week is
an option if response is insufcient at week 8. In non-
responders to 20 mg oral methotrexate at 1624 weeks (the
timeframe established in the European treatment goals) the
effect of further dose increases remains unclear,
29,31,33
although a formal dose escalation study to establish an upper
dose limit has not been performed. Furthermore, there is no
evidence that splitting the dose provides an increase in ef-
cacy. Increased efcacy and tolerability may be achievable with
subcutaneous administration, as shown in patients with rheu-
matoid arthritis;
35
however, to date, no study data comparing
oral vs. subcutaneous methotrexate have been published for
psoriasis.
36
Although supplementation with folic acid is often
recommended,
36
there is little evidence about its pharmacolog-
ical effects on tolerability of methotrexate.
There was some debate at the international meeting on the
monitoring recommendations for methotrexate therapy which
reected the inter-country variation in access to specic tests.
Despite this, consensus was achieved on monitoring recommen-
dations for screening, initiation and maintenance with metho-
trexate therapy. Patients for whom methotrexate is considered
should be monitored according to existing guidelines.
2,3
In
methotrexate-nave patients, it is important to assess for early
signs of bone marrow toxicity before administering the second
dose.
37,38
In addition, it is important to take account of the
impact of risk factors for liver toxicity (e.g. baseline liver disease
[including HBV or HCV], alcohol intake, obesity, type 2 diabe-
tes and the use of concomitant medications).
36,39,40
In most
cases, the risk of liver toxicity with methotrexate is low, although
risk may increase with cumulative doses; it is not possible to
provide an absolute threshold value for cumulative dose as there
is limited evidence in the literature. Physicians may also perform
the PIIINP test every 36 months (using the same laboratory),
which is considered the best non-invasive test for liver brosis;
however, PIIINP levels can be difcult to interpret in patients
with active psoriatic arthritis or lung brosis or in other situa-
tions in which broneogenesis occurs. Assessment of the liver
using transient elastography may also be considered, if available,
but further studies are required to fully evaluate the diagnostic
properties of this test. Liver biopsy is not routinely indicated
2
but may be considered in specic clinical circumstances follow-
ing discussion with a hepatologist.
There was considerable debate at the international meeting on
whether testing for tuberculosis (including chest X-ray, skin
and/or blood tests) should be performed prior to initiating
methotrexate therapy as recommended in guidelines
2,5
as there
is no evidence for an increased risk of latent TB reactivation by
the drug. In the case of a positive history of TB substantiated by
positive skin or blood testing (interferon gamma release assay)
and/or positive chest X-ray, therapy for latent TB with drugs
such as isoniazide may increase the risk of liver toxicity when
given together with methotrexate.
Stopping conventional therapy
In most patients with moderate-to-severe psoriasis, continuous
therapy is required to achieve long-term disease control and
stopping therapy is not generally recommended (Table 5).
Nonetheless, stopping therapy (either abruptly or by tapering)
with careful follow-up may be considered in patients with pro-
longed clinical and quality of life (QoL) response. There is little
evidence to suggest the subgroups of patients in which therapy
can be interrupted or stopped, with the exception of patients
with guttate psoriasis. The course of the disease is important
when considering treatment interruption. In many patients who
do discontinue therapy, disease recurrence can be expected
within 26 months.
Following cessation of conventional systemic therapy, there
are no standard criteria for treatment reintroduction. There-
fore, it is important that decision making is shared between
the physician and patient, taking into account that patients
who have experienced prolonged disease control may become
less tolerant of disease recurrence. It should also be noted
that more rapid loss and more severe recurrence of disease is
likely to limit the probability of re-establishing effective dis-
ease control when treatment is reintroduced. As a practical
guide, the reintroduction of conventional systemic therapy
may be considered if there is a PGA >2 and/or PASI 5
and/or DLQI 5 or if there is rapid disease recurrence. Fur-
thermore, the early reintroduction of therapy is required if a
patient develops psoriatic arthritis after stopping conventional
systemic therapy.
Transitioning from conventional systemic therapy to
biological therapy
There is limited evidence in the literature on the effect of
overlapping the different treatments or the methods of transi-
tioning. However, the possibility of overlapping therapies
during transitioning can be implied from studies that report
on combination therapy. Recommendations for transitioning
will differ depending on the reason for transitioning, for
example, in the case of safety, a treatment-free interval may
be necessary, whereas in response to lack of efcacy, transi-
tioning directly or with an overlap period can be considered
(Table 6). Importantly, if a patient develops psoriatic arthri-
tis, transitioning to an agent that is efcacious in both psori-
asis and psoriatic arthritis is required. Irrespective of the
reason for transitioning, the new drug should be given at the
approved induction dosage.
Guidance on transitioning (with overlap and washout period
recommendations) from specic conventional systemic therapies
to each of the TNF antagonists or ustekinumab is provided in
Table 6.
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Combining conventional systemic therapy with biological
therapy
There is no approved indication for any combination of a biolo-
gical with conventional systemic therapies in psoriasis (Table 7).
However, combination therapy is often used to improve efcacy,
optimize the risk-benet prole, reduce the risk of immunoge-
nicity (with methotrexate) and improve long-term disease man-
agement.
The safety (Level of evidence 4) and efcacy (Level of evidence 3)
of methotrexate (515 mg/week) combined with the TNF antago-
nists etanercept and iniximab has been demonstrated,
4145
but
data were not identied for methotrexate combined with ada-
limumab nor ustekinumab. Nonetheless, this latter combination
may be considered (Level of evidence 5). Since the systematic
search was conducted, a retrospective case note review of
ustekinumab use in real-life settings in 10 centres in the United
Kingdom and Ireland has been published, which includes informa-
tion on combination therapy.
46
In addition, a case series of ada-
limumab with methotrexate has been published very recently.
47
TNF antagonists or ustekinumab should be used with caution
in combination with cyclosporine because of a lack of evidence
on efcacy and the potential for increased toxicity (e.g. an
increased risk of skin cancer) (Level of evidence 5). Etanercept
25 mg/week in combination with acitretin has a similar efcacy
(Level of evidence 2) and safety prole (Level of evidence 3) to
etanercept 25 mg twice weekly.
48
Adalimumab may be also
considered in combination with acitretin (Level of evidence 4).
In contrast, data for acitretin combined with iniximab or
ustekinumab are not currently available, although an increased
clinical response might also be expected (Level of evidence 5).
The optimal safety monitoring for combination therapy has
not been determined. We recommend monitoring as for mono-
therapy, with the monitoring frequency dened by the drug with
the most stringent monitoring criteria. If synergistic toxicity is
suspected, more frequent monitoring intervals may be required
and additional monitoring parameters added.
When combining therapies, the conventional systemic ther-
apy should be added to a biological beginning with the lowest
recommended dosage (e.g. 510 mg/week for methotrexate). If
adequate response is not achieved with combination therapy,
consider optimizing the current therapy or switching to another
biological (Table 7).
Table 5 Recommendations on stopping conventional therapy
Q5 Can conventional systemic therapy be stopped in cases of sustained response/clearance using monotherapy? If so, how many months of
sustained clearance should we see before stopping therapy?In which patient groups can we stop conventional systemic therapies (e.g. all
patients, only those with previous slow relapses following discontinuation)?
1 Continuous therapy is required to achieve long-term disease control. Therefore, stopping therapy is not generally recommended. However,
if agreed with the patient, and after achieving a clinical response of clear or almost clear with good QoL for a prolonged period of time, for
example, a minimum of 1 year, stopping conventional systemic therapy can be considered with careful follow-up.
2 Consideration of stopping therapy in patients with well-controlled psoriasis should be based on:
Patient preference
Presence of individual risk factors with an impact on the long-term benet-risk prole
Prior course of disease including pattern of ares/rebound
Presence of comorbidity
Presence of PsA
Disease phenotype, severity and impact on QoL
Availability of treatment options in case of disease recurrence
Type of treatment
3 Recurrence of the disease can be expected within 26 months in many patients discontinuing therapy.
4 There is little evidence to suggest the subgroups of patients in which therapy can be interrupted or stopped.
98% consensus agreement on rst vote; median score = 9
Q6 In patients who have stopped conventional systemic therapy, what criteria should we use to determine when therapy should be reintroduced
(e.g. loss of PASI 75, loss of PASI 50 (relapse), loss of DLQI<5 response, loss of PGA <2, loss of PGA <3)?
1 There are no standard criteria for treatment reintroduction.
2 Shared decision making between physician and patient is important.
3 Patient management should take into account that after having experienced disease control for some time, patients may become less
tolerant
of disease recurrence.
4 Recurrence of limited disease may be controlled with topical therapy or phototherapy.
5 As a practical guide, consider reintroducing systemic therapy if there is a PGA >2 and/or PASI 5 and/or DLQI 5 or if there is rapid
disease recurrence.
98% consensus agreement on rst vote; median score = 9
DLQI, Dermatology Life Quality Index; PASI 50, a 50% reduction on the Psoriasis Area Severity Index; PASI 75, a 75% reduction in PASI; PGA, Physi-
cians Global Assessment; PsA, psoriatic arthritis; QoL, quality of life.
2013 The Authors
Journal of the European Academy of Dermatology and Venereology 2013 European Academy of Dermatology and Venereology JEADV 2013
Optimizing and transitioning psoriasis treatment 7
Adjusting biological therapy
There is no published data addressing dose adjustment protocols
in a formal fashion. A dosage reduction to limit drug exposure
may be considered during successful maintenance with biologi-
cal monotherapy, although there is a theoretical risk that this
may decrease efcacy and some evidence that extended intervals
of administration may increase the risk of anti-drug antibody
formation.
4952
Nonetheless, decreasing the dosage (decreasing
the dose or extending the dosing interval) of biological therapy
below the recommended range may be considered in patients on
combination therapy (see Table 8 for specic recommendations)
(Level of evidence 5).
Furthermore, dosing intervals may be increased with some
biologicals, such as adalimumab (Level of evidence 5) and eta-
nercept (Level of evidence 2),
5358
but not with iniximab
monotherapy (Level of evidence 2).
49
Theoretically, the dose for
a patient responding to ustekinumab may be reduced from 90 to
45 mg (Level of evidence 5).
Stopping biological therapy voluntarily (as opposed to stopping
for medical reasons which may include elective surgery, pregnancy
or serious infection) is generally not recommended and treatment
administration should be continuous and uninterrupted.
49,50,53,5964
These recommendations are based on data that show that greater
efcacy occurs with continuous biological therapy than with inter-
mittent therapy,
49,50,53,5964
up to 20% of patients fail to regain a
PASI 75 response after reintroduction of the same biological mono-
therapy,
49,50,53,5964
and signicant therapeutic breaks are difcult to
achieve without a high risk of disease recurrence.
Nonetheless, if agreed with the patient, and after achieving a
clinical response of clear or almost clear with good QoL for a
prolonged period, stopping biological therapy can be considered
with careful follow-up (Table 8).
Table 6 Recommendations for transitioning from conventional systemic therapy to biological therapy
Q7 In cases of non-response to conventional systemic therapies, should transitioning to a biological agent be done sequentially without a
washout period, sequentially with a washout period, or should treatments be overlapped? What is the appropriate dosing schedule in
each of these scenarios?
General
1 Recommendations for transitioning therapies will differ depending on the reason for transitioning. When transitioning from conventional
systemic therapy to another drug for safety reasons, a treatment-free interval may be necessary until the safety parameter has normalized or
stabilized.
2 When transitioning due to lack of efcacy, transitioning directly or with an overlap period can be considered.
3 When transitioning from conventional systemic treatments to biological treatments, approved induction dosages should be used.
99% consensus agreement on rst vote; median score = 9
Acitretin to a biological agent
1 Treatment transitioning from acitretin to TNF antagonists can be performed without a washout period or with an overlap.
48,83
(Level of
evidence 3)
2 Treatment transitioning from acitretin to ustekinumab can be performed without a washout period or with an overlap. (Level of
evidence 5)
3 However, women of child-bearing age should continue with contraception for 2 years as recommended for the use of acitretin.
94% consensus agreement on rst vote; median score = 9
Cyclosporine to a biological agent
1 Treatment transitioning from cyclosporine to TNF antagonists can be performed without a washout period.
84,85
(Level of evidence 4)
2 Treatment transitioning from cyclosporine to ustekinumab may be performed without a washout period. (Level of evidence 5)
3 A short overlap period (e.g. 28 weeks) of cyclosporine with TNF antagonists or ustekinumab can be considered in order to reduce the
risk of rebound in partial responders but the overlap period should be minimized and the dose of cyclosporine tapered down as soon as
possible. (Level of evidence 5)
92% consensus agreement on rst vote; median score = 9
Methotrexate to a biological agent
1 Treatment transitioning from methotrexate to TNF antagonists can be performed without a washout period.
33,74
(Level of evidence 2)
2 Treatment transitioning from methotrexate to ustekinumab can be performed without a washout period. (Level of evidence 5)
3 Methotrexate can be overlapped or used concurrently with TNF antagonists
4145,86
(level of evidence 2) or ustekinumab (level of
evidence 5).
87,88
98% consensus agreement on rst vote; median score = 9
TNF, tumour necrosis factor; partial responder (or intermediate responder), dened in the European treatment goals as achievement of an intermediate
response of change in PASI 50 but <75 (as compared with disease severity at the time of treatment initiation), where DLQI 5 has not been achieved
or where DLQI<5 has been achieved.
2013 The Authors
Journal of the European Academy of Dermatology and Venereology 2013 European Academy of Dermatology and Venereology JEADV 2013
8 Mrowietz et al.
In cases of temporary interruption of therapy, a major impact
on efcacy is not expected, that is, skipping one dose is not gen-
erally considered treatment interruption (with the exception of
etanercept, due to the dosing schedule). When considering
treatment interruption, it is important to be aware that there
are fewer treatment options available during treatment
re-introduction following biological failure, and the risk of anti-
body formation against biologicals increases with intermittent
therapy, particularly with iniximab monotherapy.
50
There is
little evidence to suggest the patient subgroups in which biologi-
cal therapy can be interrupted or stopped. Where therapy has
been withdrawn and restarted, an induction dosing schedule
should be used for re-introduction of the biological agent, with
the possible exception of iniximab (because of the increased
risk of infusion reactions).
There is no established denition of inadequate clinical
response to biological therapy, although in published clinical tri-
als, a primary non-response was dened as not achieving PASI
50 (Table 9).
55,6571
Strategies for primary and secondary non-
responders can include dosage increases or a reduction in dosing
intervals (Table 9),
55,6571
and combination therapy with con-
ventional treatments, as detailed above (Level of evidence 5). If
these approaches are unsuccessful, the patient may be switched
to a different biological therapy.
Table 7 Recommendations on combining conventional systemic therapy with biological therapy
Q8 Is it efcacious to combine biological therapy with conventional systemic therapy? Is it safe to combine biological therapy with conventional
systemic therapy?
1 There is no approved indication for any combination of a biological with conventional systemic therapies in psoriasis.
2 A conventional systemic therapy can be added to biological monotherapy with the intention to improve efcacy, optimize the risk-benet
prole, reduce the risk of immunogenicity (with methotrexate) and enhance long-term disease management.
3 For the TNF antagonists, combination with methotrexate (515 mg/week) is safe (Level of evidence 4) and increases the long-term efcacy
of the treatment regimen.
4145
(Level of evidence 3)
4 Due to the lack of evidence and the potentially increased toxicity, for example, an increased skin cancer risk, the combination of TNF
antagonists or ustekinumab with cyclosporine should be used with caution. (Level of evidence 5)
5 The combination of etanercept 25 mg/week with acitretin showed similar efcacy as 2x25 mg/week etanercept monotherapy.
48
(Level of evidence 2) The combination of acitretin with lower doses of etanercept 25 mg/week has a safety prole comparable to the
monotherapy.
48
(Level of evidence 3)
6 The combination of adalimumab with acitretin may be considered. (Level of evidence 4)
7 A treatment combination of methotrexate with ustekinumab may be used, but there is limited data on safety and efcacy
(Level of evidence 5).
8 Data for the combination of acitretin with iniximab or ustekinumab are not currently available but an increased clinical response might
also be expected. (Level of evidence 5)
97% consensus agreement on rst vote; median score = 9
Q9 What is the optimal safety monitoring (clinical, laboratory) of patients receiving combination therapy with a conventional systemic agent
and a biological therapy? How often?
1 The optimal safety monitoring for combination therapy has not been determined.
2 All parameters recommended to be monitored for each drug as monotherapy should be assessed.
3 As a practical guide, the monitoring interval should be dened by the drug with the most stringent monitoring criteria.
4 If synergistic toxicity is suspected, monitoring intervals may need to be reduced and additional parameters may need to be added.
95% consensus agreement on rst vote; median score = 9
Q10 If there is no response or insufcient response when combining a conventional systemic therapy with a biological agent, should we
increase the dose of the conventional systemic therapy? Increase the dose of the biological? Reduce time intervals of the biological?
Change to another biological?
1 The combination of a biological with a conventional systemic therapy is an option in the treatment of psoriasis; however, there is no clinical
trial evidence on which to provide answers to these questions.
2 Conventional systemic therapy with methotrexate or acitretin can be added to a biological monotherapy with the intention to improve
efcacy, optimize the risk-benet prole, reduce the risk of immunogenicity (with methotrexate) and enhance long-term disease
management. The conventional systemic therapy should be added beginning with the lowest recommended dosage, for example,
510 mg/week for methotrexate. The combined use of cyclosporine and a biological raises safety concerns.
3 If adequate response is still not achieved:
Optimize the current therapy (e.g. increase the dosage of the conventional systemic therapy; increase the dose or decrease the
treatment interval of the biological)
Consider switching to another biological drug
93% consensus agreement on rst vote; median score = 9
TNF, tumour necrosis factor.
2013 The Authors
Journal of the European Academy of Dermatology and Venereology 2013 European Academy of Dermatology and Venereology JEADV 2013
Optimizing and transitioning psoriasis treatment 9
Transitioning from one biological therapy to another
None of the trials identied in the literature search compared
the safety and efcacy of transitioning with or without a washout
period. We recommend that switching between biologicals due
to failure of efcacy is performed without a washout period at
the time of the next scheduled dose, using the standard induc-
Table 8 Recommendation on adjusting biological therapy
Q11 In a patient who is responding to a biological agent, can the dosing interval be increased or the dosage reduced?
1 During successful maintenance with biologicals as monotherapy, a dosage reduction can be considered to limit drug exposure. However,
long-term efcacy and safety data has only been generated for the approved dosage and there is a theoretical risk of decreased efcacy
when using reduced dosages. In addition, there is some evidence to suggest that a lower dosage of a biological drug may increase the risk
of anti-drug antibody formation.
2 Decreasing the dosage of biological therapy below the recommended range may be considered in patients on combination therapy,
that is, methotrexate + TNF antagonists. (Level of evidence 5)
3 In clinical practice, dosing intervals have been increased with adalimumab and etanercept
5358
while maintaining clinical response.
(Level of evidence 5 for adalimumab; Level of evidence 2 for etanercept)
4 With iniximab monotherapy, dosing intervals should not be increased over the intervals generally recommended.
49
(Level of evidence 2)
5 The dosage of iniximab may be reduced from 5 mg/kg bodyweight to a minimum of 3 mg/kg bodyweight particularly if combined
with methotrexate. (Level of evidence 5)
6 With ustekinumab, increasing the injection intervals beyond 12 weeks does not appear meaningful, but theoretically, the dose for a
responding patient may be reduced from 90 to 45 mg. (Level of evidence 5)
96% consensus agreement on rst vote; median score = 9
Q12A Can biological therapy be stopped or interrupted in cases of sustained response/clearance? If so, how many months of sustained
clearance should we see before stopping therapy?
1 Stopping biological therapy is not generally recommended. In patients with moderate-to-severe psoriasis, signicant therapeutic breaks
are difcult to achieve without risk of recurrence or an impact on efcacy following re-initiation of therapy biological therapy should
generally be administered using a continuous uninterrupted treatment regimen.
49,50,53,5964
2 However, if agreed with the patient, and after achieving a clinical response of clear or almost clear with good QoL for a prolonged period
of time, for example, a minimum of 1 year, stopping biological therapy can be considered with careful follow-up.
3 There is little evidence to suggest the subgroups of patients in which therapy can be interrupted or stopped. However, subgroups in which
this might be considered include patients with:
Patient preference
Patients with a history of disease-free intervals or previously stable plaque-type psoriasis
Absence of signicant comorbidities
Absence of PsA
Low impact of disease on QoL
No worsening of disease after previous dose reductions and treatment withdrawals
4 However, because biological therapies are typically considered for patients with more severe disease, and come after failed conventional
systemic therapy, patients on biologicals are less likely to full these criteria. Furthermore, fewer treatment options are available for these
patients during treatment re-introduction following treatment failure.
5 Another consideration is that the risk of antibody formation against biological therapies increases with intermittent therapy. This is
particularly important for the use of iniximab monotherapy where a higher risk of infusion reactions has been observed with
intermittent therapy.
50
79% consensus agreement on rst vote; median score = 8
Q12B Can efcacy with biological therapy be regained following therapeutic interruption and re-initiation using the same therapy? How long
can the therapeutic interruption last without losing efcacy?
1 Continuous biological therapy generally results in greater improvements in efcacy over time compared with intermittent
therapy.
49,50,53,5964
2 In clinical trials with primary responding patients, up to 20% fail to regain a PASI 75 response after the rst reintroduction of the same
biological monotherapy.
49,50,53,5964
This decrease in efcacy may be greater with intermittent use of the drug.
3 In patients receiving biological therapy, there is a high likelihood of disease recurrence within several months of cessation of treatment
although some patients may maintain disease control for a prolonged period of time.
4 Where therapy has been withdrawn and restarted, an induction dosing schedule should be used for re-introduction of the biological
agent, with the possible exception of iniximab (because of the increased risk of infusion reactions).
81% consensus agreement on rst vote; median score = 8
PASI 75, a 75% reduction in Psoriasis Area Severity Index; PsA, psoriatic arthritis; QoL, quality of life; TNF, tumour necrosis factor.
2013 The Authors
Journal of the European Academy of Dermatology and Venereology 2013 European Academy of Dermatology and Venereology JEADV 2013
10 Mrowietz et al.
Table 9 Recommendations on transitioning from one biological therapy to another
Q13 In the case of inadequate response to a biological therapy (etanercept, iniximab, adalimumab and ustekinumab), should we increase the
dose or reduce treatment intervals before switching? Which is preferable?
1 There is no established denition of inadequate clinical response. In published clinical trials with the biological agents a primary
non-response was dened as not achieving PASI 50.
2 Strategies for primary and secondary non-responders, include:
For adalimumab, an increase of the dosage from 40 mg every other week to 40 mg/week.
65,66
(Level of evidence 3)
For etanercept, an increase of the dosage from 50 mg/week to 2 9 50 mg/week.
55,67,68
(Level of evidence 4)
For ustekinumab, with primary partial responders, the dose can be increased from 45 to 90 mg with 12 week dosing intervals.
If this is unsuccessful, the dose can be further increased to 90 mg at 8 week intervals.
69
(Level of evidence 2)
For iniximab, a reduction of the dosing intervals from every 8 weeks to every 6 weeks with 5 mg/kg can be considered in secondary
non-responders, dened as the loss of at least 50% of the initial improvement.
70,71
(Level of evidence 4). In special cases an increase of
the dosage > 5 mg/kg can be considered (Level of evidence 5).
Alternatively, combination strategies with conventional treatments can be considered. (Level of evidence 5)
3 If at the end of the induction phase there is an inadequate clinical response (primary inadequate response), or in the case of secondary
non-response to biological monotherapy, and if the aforementioned strategies have been considered, it is recommended to switch to
another drug.
79% consensus agreement on second vote; median score=8
Q14 When transitioning from one biological therapy to another, for whatever reason, should transitioning to a different biological agent be done:
sequentially without a washout period?
sequentially with a washout period? If so, how long should we wait before giving the new biological therapy? What
factors should inuence this decision (dosing interval, elimination half-life, potential for rebound, other)?
What is the appropriate dosing schedule for the second biological?
Should we use the maintenance dose or the loading dose?
General
1 In the situation where switching biologicals has been decided due to failure of efcacy, switching is advisable without a washout period at
the time of the next scheduled dose, using the standard induction dose, followed by the maintenance dose.
2 If switching is necessary for reasons of safety, a treatment-free interval may be necessary until the safety parameter has normalized or stabilized.
94% consensus agreement on rst vote; median score = 9
Adalimumab ?another biological agent
1 Administer the rst treatment with etanercept after a treatment transitioning from adalimumab at the time point of the next scheduled
drug dosage (typically 2 weeks).
72
(Level of evidence 3)
2 Administer the rst treatment with iniximab after a treatment transitioning from adalimumab at the time point of the next scheduled
drug dosage (typically 2 weeks). (Level of evidence 5)
3 Administer the rst treatment with ustekinumab after a treatment transitioning from adalimumab at the time point of the next scheduled
drug dosage (typically 2 weeks).
73
(Level of evidence 4)
97% consensus agreement on rst vote; median score = 9
Etanercept ?to another biological agent
1 Administer the rst treatment with adalimumab after a treatment transitioning from etanercept at the time point of the next scheduled
drug dosage (typically 1 week).
66,74,75
(Level of evidence 3)
2 Administer the rst treatment with iniximab after a treatment transitioning from etanercept at the time point of the next scheduled
drug dosage (typically 1 week).
76,77
(Level of evidence 4)
3 Administer the rst treatment with ustekinumab after a treatment transitioning from etanercept at the time point of the next scheduled
drug dosage (typically 1 week).
73,78
(Level of evidence 2)
99% consensus agreement on rst vote; median score = 9
Iniximab ?to another biological agent
1 Initiation of the rst treatment with adalimumab after a treatment transitioning from iniximab can be considered as early as
24 weeks after the last iniximab dose, particularly in cases of treatment failure. (Level of evidence 5)
2 Initiation of the rst treatment with etanercept after a treatment transitioning from iniximab can be considered early as
24 weeks after the last iniximab dose, particularly in cases of treatment failure.
79
(Level of evidence 4)
3 Initiation of the rst treatment with ustekinumab after a treatment transitioning from iniximab can be considered as early as
24 weeks after the last iniximab dose, particularly in cases of treatment failure.
73
(Level of evidence 4)
99% consensus agreement on rst vote; median score = 9Ustekinumab ?to another biological agent
2013 The Authors
Journal of the European Academy of Dermatology and Venereology 2013 European Academy of Dermatology and Venereology JEADV 2013
Optimizing and transitioning psoriasis treatment 11
tion dose, followed by the maintenance dose (Table 9). When
switching for reasons of safety, it may be necessary to delay
introduction of the new biological until the safety parameter has
normalized or stabilized. Switching recommendations for
individual biologicals are presented in Table 9.
66,7279
The sec-
ond biological should be used starting with the pharmaco
kinetically dened induction dosage followed by the mainte-
nance dosage.
7274,7779
Discussion
Evidence-based guidelines provide useful information about sys-
temic anti-psoriatic drugs, but they often provide very little
information on key questions that have not been addressed in
clinical trials. A number of important questions including the
length of continuous therapy, criteria for treatment cessation
and possible re-introduction as well as transitioning from one
drug to another for various medical reasons and patient-related
factors are often discussed among clinicians taking care of
psoriasis patients. It was therefore the aim of the programme to
address these issues by dening key questions and answering
these in the best possible way by systematic or non-systematic
literature search and expert opinion.
This programme included an academically rigorous process,
supported by a large number of dermatologists worldwide,
representing a broad range of clinical opinion from diverse
geographical regions and a variety of clinical practices.
The programme does have several limitations. Although sys-
tematic literature searches were conducted for some questions,
this was not possible for other questions. In these instances, rec-
ommendations were based on the clinical experience and opinion
of the participating dermatologists. It should also be acknowl-
edged that experience with the TNF antagonists is much more
extensive than that with the more recently licensed ustekinumab.
Despite these limitations, consensus agreement on all of the rec-
ommendations (with consensus of at least 90% achieved for most
of the 25 components) was gained from a large group of clinicians
representing a broad scope of clinical opinion.
This consensus process has highlighted areas requiring further
research. There are only limited data in the literature on combi-
nations of conventional systemic therapies and biologicals in
patients with moderate-to-severe psoriasis, and recommenda-
tions for dosages could not be given on an evidence-based level.
In addition, there were insufcient data to comment on the
safety of combination therapy or to propose an optimal safety
monitoring schema; although data for the safety of methotrexate
and TNF antagonists can be derived from studies in patients
with psoriatic or rheumatoid arthritis.
80
Data for combination treatment with ustekinumab are lim-
ited, with no evidence for combination therapy with conven-
tional systemic therapies, or for efcacy and safety when
overlapped with cyclosporine during treatment transitioning. In
addition, the recommendation allowing overlap with
ustekinumab and acitretin is based on information from combi-
nation trials, which only imply that overlap is allowable.
Although we recommend that continuous systemic treatment
for psoriasis should be maintained, treatment interruption may
Table 9 (Continued)
Initiation of the rst treatment with adalimumab, etanercept or iniximab after a treatment transitioning from ustekinumab
should be performed at 812 weeks but can be considered as early as 24 weeks after the initial biological dose in cases of treatment failure.
(Level of evidence 5)
89% consensus agreement on rst vote; median score = 9
Dosing schedule for the second biological
The second biological should be used starting with the dened induction dosage and followed by the maintenance dosage.
96% consensus agreement on rst vote; median score = 9
Level of evidence
Adalimumab ?etanercept 3
72
Adalimumab ?iniximab 5
Adalimumab ?ustekinumab 4
73
Etanercept ?adalimumab 3
74
Etanercept ?iniximab 3
77
Etanercept ?ustekinumab 2
73, 78
Iniximab ?adalimumab 5
Iniximab ?etanercept 4
79
Iniximab ?ustekinumab 4
73
Ustekinumab ?adalimumab/etanercept/iniximab 5
PASI 50, a 50% reduction in the Psoriasis Area Severity Index; partial responder (or intermediate responder), dened in the European treatment goals as
achievement of an intermediate response of change in PASI 50 but <75 (as compared with disease severity at the time of treatment initiation), where
DLQI 5 has not been achieved or where DLQI<5 has been achieved; Treatment failure (or inadequate response), failure to achieve or maintain an
improvement of PASI 50 (as compared with disease severity at the time of treatment initiation).
2013 The Authors
Journal of the European Academy of Dermatology and Venereology 2013 European Academy of Dermatology and Venereology JEADV 2013
12 Mrowietz et al.
be considered in some circumstances. However, it is important
to note that the criteria for dening the duration of sustained
response before stopping therapy have not been dened; neither
have data on the duration of treatment cessation before reintro-
duction of the same therapy.
Differing resource settings, reimbursement for long-term man-
agement, access to care, the type of treatment centre, concomitant
therapies (except where specied) or the co-existence of other
disease have not been taken into consideration when formulating
these recommendations. As such, it may not be possible for all
physicians to apply all aspects of the guidance within their prac-
tice. For example, not all tests for monitoring methotrexate ther-
apy are available in all countries, and in some instances, country-
specic regulations may not allow off-label approaches to therapy
optimization. In addition, the recommendations do not take into
account the potential impact of compliance or adherence which
should be explored prior to making transitioning decisions.
2,3
A recent study by Augustin and colleagues outlined specic
issues in psoriasis and suggested goals and actions to address
these needs.
81
It specically highlighted the need for guidance on
treatment optimization and treatment switching which is not
provided by the current guidelines. The Transitioning Therapies
programme addresses this need by providing practical consen-
sus-agreed guidance on appropriate treatment optimization and
transitioning in the clinical management of moderate-to-severe
plaque psoriasis.
Acknowledgements
This article summarizes the results of the International Consen-
sus meeting on Progressive Psoriasis Initiative (PPI) Transition-
ing Therapies, which was held in Frankfurt, Germany on 21-22
June 2012.
Abbott solely funded the Progressive Psoriasis Initiative pro-
gramme. The PPI programme and all content was funded by
Abbott through an educational grant to the Medical Center
Schleswig-Holstein, Campus Kiel, Germany. The PPI pro-
gramme was led by a Steering Committee whose goal was to
dene and gain European consensus on treatment goals and gain
international consensus on how to optimize treatment transi-
tioning for patients with moderate-to-severe plaque psoriasis.
Abbott provided funding to the medical communications
agency Lucid, Burleigheld House, Loudwater, UK, to manage
the PPI programme that led to the development of this manu-
script. Abbott paid consultancy fees to members of the Steering
Committee for their participation at Steering Committee meet-
ings and reimbursed travel costs.
Abbott provided funding to Lucid to manage the interna-
tional Consensus meeting that also led to the development of
this manuscript. Abbott reimbursed travel costs for participants
of the International Consensus meeting.
No payments were made to the authors for the writing of this
manuscript. Abbott had no inuence on the development of the
manuscript nor did it review the content of the manuscript. The
authors (all of whom are members of the PPI Steering Commit-
tee) determined and approved the nal content of the manu-
script. Elaine Bell of Lucid provided editorial support for the
authors in the development of this manuscript. Abbott paid
Lucid for this study.
We thank all the participants in the Transitioning Therapies
programme. The people listed below have participated at various
stages in the programme (suggesting questions and/or question
prioritization and/or review of draft answers at national meet-
ings and/or participation at the international consensus meet-
ing):
Bashar Abbasi, Jordan; Hussain Abdel Dayem, UAE; Moham-
med Ahmed, UAE; Laith Akkash, Jordan; Melih Akyol, Turkey;
Ali Al Amir, Saudi Arabia; Anwar Al Hammadi, UAE; Abdullah
AL Khalifa, Saudi Arabia; Amna Al Muhairi, UAE; Maryam Al
Obad, UAE; Ali Al Radadi, Saudi Arabia; Abdullah Al Rakban,
Saudi Arabia; Hala Al Shaikh Ali, Syria; Mouza Al Suwaidi,
UAE; Ali Al-Nahdi, Saudi Arabia; Sibel Alper, Turkey; Mario
Amaya-Guerra, Mexico; Paolo Amerio, Italy; Alfred Ammoury,
Lebanon; Salem Antaby, Syria; Christina Antoniou, Greece; Petr
Arenberger, Czech Republic; Nilg un Atakan, Turkey; Luna Azu-
lay, Brazil; Christopher Baker, Australia; Flora Balieva, Norway;
Bo Bang, Denmark; Federico Bardazzi, Italy; Hugues Barthele-
my, France; Maria Rita Bongiorno, Italy; Hugo Boonen, Bel-
gium; Marc Bourcier, Canada; Emel B ulb ul Baskan, Turkey;
Matilda Bylaite, Lithuania; Marzia Caproni, Italy; Andre Carv-
alho, Brazil; J.

Cesien_ e, Lithuania; Petra Cetkovska, Czech
Republic; Arnon Cohen, Israel; Curdin Conrad, Switzerland;
Osvaldo Correia, Portugal; Antonio Costanzo, Italy; Tomas
Dam, Denmark; Esteban Dauden, Spain; Michael David, Israel;
Christa De Cuyper, Belgium; Clara De Simone, Italy; Pierre-Luc
Dion, Canada; Jan Dutz, Canada; Cristina Echeverra, Argentina;
Claes Enk, Israel; Lorena Estrada-Aguilar, Mexico; Lincoln Fab-
ricio, Brazil; Mohammed Fatani, Saudi Arabia; Carlos Ferrandiz,
Spain; Ana Ferreira, Portugal; Paulo Filipe, Portugal; Peter Foley,
Australia; Lars French, Switzerland; Humaid Ghanem Khalfan,
UAE; Pierre-Dominique Ghislain, Belgium; Samer Ghosn,
Lebanon; Paolo Gisondi, Italy; Calin Giurcaneanu, Romania;
I. Glazauskiene, Lithuania; Wieslaw Glinski, Poland; Minerva
G omez-Flores, Mexico; Catherine Goujon Henry, France; Esther
Guevara-Sangines, Mexico; Wayne Gulliver, Canada; Mehmet
Ali G urer, Turkey; Rolland Gyulai, Hungary; Ingo Haase,
Germany; Dafna Halel-halevy, Israel; Anna Hallander, Sweden;
Issam Hamadah, Saudi Arabia; Peter Hausermann, Switzerland;
Jose Manuel Hernanz-Hermosa, Spain; Emmilia Hodak, Israel;
Peter Holl o, Hungary; Chih-ho Hong, Canada; Jamal Ibrahim,
UAE; Arieh Ingber, Israel; Dimitrios Ioannidis, Greece; Lars
Iversen, Denmark; Fermin Jurado-Santacruz, Mexico; Razan
Kadry, UAE; Nouraldeen Kassar, Syria; Norito Katoh, Japan;
Andreas Katsambas, Greece; Lajos Kemeny, Hungary; K ulli
Kingo, Estonia; Brian Kirby, Ireland; Erol Koc, Turkey; Martina
2013 The Authors
Journal of the European Academy of Dermatology and Venereology 2013 European Academy of Dermatology and Venereology JEADV 2013
Optimizing and transitioning psoriasis treatment 13
Kojanova, Czech Republic; Aotonios Kolios, Switzerland; Pille
Konno, Estonia; Gertraud Krahn-Senftleben, Germany; Sabine
Krueger, Greece; Vesta Kucinskiene, Lithuania; Natalia Kuzmin-
a, Sweden; Morad Lahfa, France; Jo Lambert, Belgium; Elisavet
Lazaridou, Greece; Francesco Loconsole, Italy; Adriana Lopeztel-
lo-Santillan, Mexico; Charles Lynde, Canada; Francois Maccari,
France; Renata Magalh~aes, Brazil; Soa Magina, Portugal;
Emmanuel Mahe, France; Sameer Mahfoud, Syria; Piergiorgio
Malagoli, Italy; Cesar Maldonado-Garca, Mexico; Tarja
Malk onen, Finland; I. Marciukaitiene, Lithuania; Trevor
Markham, Ireland; Gabriela Marques Pinto, Portugal; Hagit
Matz, Israel; Sandy McBride, UK; Akimichi Morita, Japan; Cato
Mrk, Norway; Nils-Jrgen Mrk, Norway; Michelle Murphy,
Ireland; Hidemi Nakagawa, Japan; Joanna Narbutt, Poland; Alex
Navarini, Switzerland; Alin Nicolescu, Romania; Mamitaro
Ohtsuki, Japan; Nahide Onsun, Turkey; Isam Oumeish, Jordan;
G uzin

Ozarmagan, Turkey; Pantelis Panagakis, Greece; Felix
Pavlotsky, Israel; Thanasis Petridis, Greece; Stefano Piaserico,
Italy; Yves Poulin, Canada; Errol Prens, the Netherlands; Feras
Qarqaz, Jordan; Marc Radtke, Germany; Michal Ramon, Israel;
Tapio Rantanen, Finland; Ashraf Reda, UAE; Adam Reich,
Poland; Hassan Riad, Qatar; Dimitrios Rigopoulos, Greece;
Monica Rivera, Mexico; Norma Rodrguez-Martnez, Mexico;
Ricardo Romiti, Brazil; Lidia Rudnicka, Poland; Ousama
Sammak, Syria; Jose Luis Sanchez-Carazo, Spain; Shigetoshi
Sano, Japan; Tore Sarnhult, Sweden; Hugo Sch onenberger de
Oliveira, Portugal; Gordon Searles, Canada; Nilg un Sent urk,
Turkey; Marieke Seyger, the Netherlands; Nemer Shehadeh,
Syria; Dorit Shapiro, Israel; Stephen Shumack, Australia; Shireen
Sidhu, Australia; R. Sidlauskiene, Lithuania; Lone Skov, Den-
mark; Dimitrios Sotiriadi, Greece; Peter Soyer, Australia; Eli
Sprecher, Israel; Phyllis Spuls, the Netherlands; D. Staniene,
Lithuania; Farid Stephan, Lebanon; Michael Sticherling, Ger-
many; Klaus Str omer, Germany; I. Sutaite, Lithuania; Andrea
Szegedi, Hungary; Jacek Szepietowski, Poland; Toomas Talme,
Sweden; Diamant Thaci, Germany; Bing Thio, the Netherlands;
George Sorin Tiplica, Romania; Anne Marie Tobin, Ireland;
Tiago Torres, Portugal; Androniki Toska, Greece; Tsen-Fang
Tsai, Taiwan; Skaidra Valiukeviciene, Lithuania; Paulo Varela
Fernandes, Portugal; Luis Vega, Mexico; Annie Vermersch Lang-
lin, France; Ralph von Kiedrowski, Germany; Ben Walker, UK;
Norbert Wikonkal, Hungary; Fabienne Willaert, Belgium;
Birgitta Wilson Clareus, Sweden; Nikhil Yawalkar, Switzerland;
Savas Yayl, Turkey; Jensen Yeung, Canada; Mouna Yousef,
UAE; Bosmat Zamir, Israel; Michael Ziv, Israel [Correction
added on 25 March 2013, after rst online publication: Tore
Sarnhult, Sweden was added to the list of participants.].
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2013 The Authors
Journal of the European Academy of Dermatology and Venereology 2013 European Academy of Dermatology and Venereology JEADV 2013
16 Mrowietz et al.

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