British Association of Dermatologists guidelines for use of biological interventions in psoriasis 2005.

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GUIDELINESDOI 10.1111/j.1365-2133.2005.06893.x
British Association of Dermatologists guidelines for use of
biological interventions in psoriasis 2005
C.H. Smith, A.V. Anstey,* J.N.W.N. Barker, A.D. Burden,? R.J.G. Chalmers,? D. Chandler,§ A.Y. Finlay,–
C.E.M. Grifitths,? K. Jackson, N.J. McHugh,** K.E. McKenna,?? N.J. Reynolds?? and A.D. Ormerod§§ (Chair of
Guideline Group)
St John’s Institute of Dermatology, GKT School of Medicine, St Thomas’ Hospital, London SE1 7EH, U.K.
*Department of Dermatology, Royal Gwent Hospital, Newport NP20 2UB, U.K.
?Department of Dermatology, Western Infirmary, Glasgow G11 6NT, U.K.
?The Dermatology Centre, Hope Hospital, Salford, Manchester M6 8HD, U.K.
§Psoriatic Arthropathy Alliance, PO Box 111, St Albans AL2 3JQ, U.K.
–Department of Dermatology, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, U.K.
**Royal National Hospital for Rheumatic Diseases, Upper Borough Walls, Bath BA1 1RL, U.K.
??Department of Dermatology, Belfast City Hospital, Belfast BT9 7AB, U.K.
??Department of Dermatology, University of Newcastle Medical School, Newcastle upon Tyne NE2 4HH, U.K.
§§Department of Dermatology, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN, U.K.
Correspondence
Catherine H. Smith,
E-mail: Catherine.smith@kcl.ac.uk
or Anthony Ormerod,
E-mail: a.d.ormerod@arh.grampian.scot.nhs.uk
Accepted for publication
20 June 2005
Key words:
biologics, efalizumab, etanercept, guideline,
infliximab, psoriasis
Conflicts of interest:
C.H.S., grant ⁄research trial support Wyeth,
Serono, Schering Plough, consultant for Novartis;
A.V.A., consultant for Schering Plough;
J.N.W.N.B., consultant for Schering Plough,
Wyeth, Biogen, Serono Novartis; grant ⁄research
trial support Schering Plough, Wyeth, Biogen,
Serono; A.D.B., consultant for Wyeth, Serono,
Schering Plough; grant ⁄research trial support
Wyeth, Serono; R.J.G.C., none; D.C., none;
A.Y.F., consultant for Wyeth, Novartis, Serono,
Amgen, Abbott; trial support; C.E.M.G.,
grant ⁄research support Biogen, Serono, Amgen,
Centocor; previous consultant for Serono, Wyeth,
Schering Plough; K.J., none; N.J.McH., consultant
for Aventis, Abbott; grant research support Wyeth;
K.E.McK., none; N.J.R., grant ⁄research support
Serono; A.D.O., grant ⁄research support Wyeth,
Serono.
Introduction
Background
Psoriasis is a common, persistent, relapsing inflammatory
skin disease that can be associated with significant morbid-
ity. Quality of life studies in psoriasis reveal a negative
impact on patients comparable with that seen in cancer,
arthritis and heart disease.1–5Patients with severe disease
constitute approximately 20–30% of all patients with psori-
asis, often require systemic treatment, and represent a major
economic burden to the Health Service.
All standard systemic therapies for severe disease are asso-
ciated with the potential for major long-term toxicity, many
are expensive, and a proportion of patients has treatment-
resistant disease.6Biological therapies or ‘biologics’ describe
agents designed to block specific molecular steps important
in the pathogenesis of psoriasis and have emerged over the
last 3–5 years as potentially valuable alternative therapeutic
options.
Currently, biological therapies for psoriasis comprise two
main groups: (i) agents targeting the cytokine tumour
necrosis factor (TNF)-a (e.g. etanercept, infliximab, adal-
imumab) and (ii) agents targeting T cells or antigen-present-
ingcells(e.g. efalizumab,
etanercept(Enbrel?) andefalizumab
licensed in 2004 in the U.K. for patients with moderate to
severe psoriasis.
alefacept). Two
(Raptiva?)
ofthese,
were
Need for a guideline
These new treatments are relatively expensive and, given the
widespread patient dissatisfaction with standard treatments,2
demand is likely to be high. Clinical experience of biologi-
cal therapies in dermatology is relatively limited and their
486
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role in the context of existing standard systemic therapies,
particularly with respect to efficacy and long-term toxicity,
is uncertain. These guidelines have been developed to
ensure that this new class of therapy is introduced in a sys-
tematic and planned way to achieve the greatest possible
benefit to people with psoriasis, to facilitate safe and effect-
ive prescribing and to endorse the use of the British Associ-
ation of Dermatologists (BAD) Biological Therapy Register as
a mechanism for collecting long-term safety and efficacy
data. The guideline group has sought to provide useful,
evidence-based guidance based on systematic review of
available literature, but acknowledges that additional funding
may be required to implement guideline recommendations
fully.
Scope
These guidelines were developed in accordance with a
predetermined scope, agreed by the guideline working
group, and are as detailed below. For practical reasons,
guidance is given only on those treatments that are currently
licensed for use in psoriasis in the U.K. (etanercept,
efalizumab) and infliximab. Although infliximab is currently
unlicensed for use in psoriasis, a licence is anticipated in
the near future, it is widely available, and it is currently the
most extensively used biological therapy in dermatology
clinical practice.
Inclusions
Specific, evidence-based, recommendations cover the follow-
ing clinical areas:
• Use of infliximab, etanercept and efalizumab in adult
patients with psoriasis and, when relevant, psoriatic arthritis
• Which patients should be considered eligible for treatment
• Who should prescribe therapy and how to do so
• Definition of disease response and indications for stopping
therapy
Exclusions
• Agents licensed for use outside the U.K. (e.g. alefacept) or
in clinical development for psoriasis (e.g. adalimumab)
• Use of biological therapies in children
• Use of biological therapies for indications other than psori-
asis
Methods
This guideline has been developed using BAD recommended
methodology and the AGREE (Appraisal of Guidelines for
Research and Evaluation) instrument. The guideline working
group represents all relevant stakeholders including nurses,
rheumatologists and patients. Draft guidance was made avail-
able for consultation and review by patients and the BAD
membership prior to publication.
A literature review was performed by searching EMBASE
and Medline databases (1990 to April 2005) for clinical trials
involving efalizumab, etanercept and infliximab using an
agreed protocol. Two reviewers screened all titles and
abstracts independently, and full papers of relevant material
were obtained wherever possible. Papers included as evidence
were scored for strength of evidence using the instruments
currently recommended by the Scottish Intercollegiate Guide-
lines Network and the National Institute for Clinical Excel-
lence (Appendix 1). Additional ad hoc searches were done to
address clinical questions that arose during the development
of the guideline, and evidence was appraised in the same
manner.
Limitations of the guideline
These guidelines have been prepared for dermatologists on
behalf of the BAD and reflect the best data available at the
time the report was prepared. Caution should be exercised
in interpreting the data; the results of future studies may
require alteration of the conclusions or recommendations in
this report. It may be necessary or even desirable to depart
from the guidelines in the interests of specific patients and
special circumstances. Just as adherence to guidelines may
not constitute defence against a claim of negligence, so
deviation from them should not necessarily be deemed
negligent.
Plans for guideline revision
This field of therapeutics is in a rapid phase of development,
and revision of the scope and content of these guidelines will
therefore occur on an annual basis.
Which patients should be considered for
biological therapy?
Most patients with moderate to severe disease achieve satisfac-
tory disease control (i.e. significant or complete clearing of
disease) in the short term with at least one of the systemic
agents currentlyavailable.6
frequently requires some form of continuous therapy and
consequent, predictable risks of toxicity. At present, the risks
and benefits of anti-TNF agents, or efalizumab, relative to
standard systemic therapy, are unknown. Early, widespread
use of these agents in uncomplicated moderate to severe pso-
riasis is inappropriate and is not supported by the licensed
indications for etanercept or efalizumab.
To draw up eligibility criteria, ‘severe’ disease requires defi-
nition and should encompass objective measures of disease
severity and the impact the disease has on quality of life.
All existing disease severity assessment tools are imper-
fect,7,8and most require some training to complete. The
Psoriasis Area and Severity Index (PASI) score has been
chosen for the purposes of this guideline as it has been
widely used in clinical trials including those investigating
Long-termdisease control
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Biological interventions for psoriasis, C.H. Smith et al. 487

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biological therapies. Furthermore, it is a validated measure
of disease severity in chronic plaque psoriasis and is also
appropriate to use as an objective measure of disease
response.7A PASI score of > 10 (range 0–72) has been
shown to correlate with a number of indicators commonly
associated with severe disease such as need for hospital
admission or use of systemic therapy.8Where the PASI
is not applicable (e.g. pustular psoriasis), affected body
surface area (BSA) should be used, with severe disease
defined as > 10% area affected.8
The Dermatology Life Quality Index (DLQI) is a validated
tool for the measurement of quality of life across all skin
diseases in both trial and clinical practice settings9and a score
of > 10 (range 0–30) has been shown to correlate with at
least ‘a very large effect’ on an individual’s quality of
life.7,8,10
Patients with psoriasis may be considered eligible to receive
treatment with a biological intervention when they fulfil the
eligibility criteria as set out. However, the decision to proceed
with treatment must be made in collaboration with the patient
and must include a careful assessment of the associated risks
and benefits.
Who should prescribe biological therapy?
These treatments should be made available to all those
patients fulfilling the currently recommended eligibility cri-
teria. However, given (a) that few dermatologists have experi-
ence of their use in clinical practice, (b) the need to ensure
collection of long-term data on efficacy and safety, and, (c)
in the short term at least, to ensure that these agents are only
used when alternative standard therapies are inappropriate, it
is essential that all those which prescribed strictly to guide-
lines on prescribing practice and participate in the registration
process.
Treatment should be initiated and monitored by consultant
dermatologists experienced in managing difficult psoriasis.
This should include knowledge and experience of standard
therapies and management of those who fail to respond.
They must be familiar with, and⁄or have access to health
care professionals trained in the use of the tools recommen-
dedfordetermining treatment
response.
Supervising consultants will be responsible for ensuring
that all patients receiving therapy are registered with the
BAD Biological Therapy Register throughout the treatment
period.
eligibilityanddisease
Antitumour necrosis factor therapies
There are two anti-TNF agents in current use for psoriasis in
the U.K., U.S.A. and Europe: etanercept (Enbrel?, Wyeth) and
infliximab (Remicade?, Schering-Plough).
Pharmacology
Etanercept is a human recombinant TNF receptor p75 fusion
protein, formed by the fusion of the extracellular ligand-bind-
ing domain of human TNF receptor-2 (TNFR2⁄p75) to the Fc
domain of human IgG1. It also binds soluble and membrane-
bound TNF-a with high specificity and affinity, preventing its
binding to cell surface receptors and thus inhibiting its proin-
flammatory effects. In comparison with infliximab, etanercept
forms less stable complexes with membrane-bound TNF and
monomeric TNF, but it does bind significantly with the tri-
meric forms of soluble TNF.
Eligibility criteria
To be considered eligible for treatment, patients must have severe
disease as defined in (a) and fulfil one of the clinical categories
outlined in (b):
(a) Severe disease is defined as a PASI score of 10 or more (or a
BSA of 10% or greater where PASI is not applicable) and a DLQI >
10. Disease should have been severe for 6 months, resistant to
treatment and the patient should be a candidate for systemic ther-
apy. In exceptional circumstances (for example, disabling acral
disease), patients with severe disease may fall outside this defini-
tion but may be considered for treatment. (Strength of recommendation
D, level of evidence 3).
AND
(b) fulfil at least one of the following clinical categories (Strength
of recommendation B, level of evidence 1++ and formal consensus):
(i) have developed or are at higher than average risk of devel-
oping clinically important drug-related toxicity and where alter-
native standard therapyacannot be used
(ii) are or have become intolerant to or cannot receive standard
systemic therapy
(iii) are or have become unresponsive to standard therapyb
(iv) have disease that is only controlled by repeated inpatient
management
(v) have significant, coexistent, unrelated comorbidity which
precludes use of systemic agents such as ciclosporin or metho-
trexate
(vi) have severe, unstable, life-threatening disease (erythroder-
mic or pustular psoriasis)
(vii) have psoriatic arthritis fulfilling the British Society for
Rheumatology (BSR) eligibility criteria for treatment with anti-
TNF agents,11in association with skin disease
astandard systemic therapy includes acitretin, ciclosporin, metho-
trexate, narrowband ultraviolet (UV) B and psoralen + UVA
photochemotherapy (PUVA)
bunresponsive to standard therapy is defined as an unsatisfactory
clinical response (a less than 50% improvement in baseline PASI
score or percentage BSA where the PASI is not applicable, and a
less than 5-point improvement in DLQI) to at least 3 months of
treatment in the therapeutic dose range to the following treat-
ments: ciclosporin 2Æ5–5 mg kg)1
weekly dose (oral, subcutaneous, intramuscular) 15 mg, max 25–
30 mg; acitretin 25–50 mg daily; narrowband UVB or psoralen
photochemotherapy (nonresponse, rapid relapse or exceeding
recommended maximum doses) 150–200 treatments for PUVA,
350 treatments for narrowband UVB.12,13
daily; methotrexate single
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488 Biological interventions for psoriasis, C.H. Smith et al.

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Infliximab is a human murine (25% murine) chimeric
monoclonal IgG1 isotype antibody with a high binding affin-
ity, avidity and specificity for TNF-a. It forms stable com-
plexes with all forms of soluble and transmembrane TNF-a.
Clinical effectiveness: etanercept
Induction and maintenance of remission
Several small phase II studies14,15and two key phase III16,17
randomized controlled trials (RCTs) involving over 1000
patients with moderate to severe chronic plaque psoriasis, the
majority of whom had received previous systemic treatment or
PUVA, indicate that etanercept is an effective treatment for
chronic plaque psoriasis. Efficacy is dose related, with 34% and
49% of patients receiving 25 mg and 50 mg twice weekly,
respectively, achieving > 75% improvement in PASI (PASI 75
response) after 12 weeks of treatment. Continued treatment
appears to improve response rates further, so that at 24 weeks,
44% and 59% of patients receiving 25 mg and 50 mg twice
weekly, respectively, achieved a PASI 75 response. Studies up
to a year show sustained efficacy over time, with no evidence
of loss of efficacy with interrupted, repeat dosing.
Time to relapse, when defined as a 50% drop in the
improvement in PASI achieved after 24 weeks of therapy, ran-
ged from 70 to 91 days and appeared to be dose related (i.e.
remission was maintained for slightly longer in the high dose
group as compared with the low dose group). Of patients
achieving a PASI 75 response at 24 weeks of therapy, 11%
remained in remission at 1 year.
Treatment response in severe, recalcitrant disease, erythro-
dermic, pustular or other forms of psoriasis is unknown.
Dosing regimens
Etanercept is given as a self-administered subcutaneous injec-
tion and is licensed for use at both 25 mg and 50 mg twice
weekly. Although the percentage of patients achieving and
maintaining remission is greater with the higher dose, this
needs to be balanced against increased cost and risk of toxic-
ity.
All the trials in psoriasis have been performed as mono-
therapy. In rheumatoid arthritis, however, etanercept has been
safely combined with methotrexate.
Clinical effectiveness: infliximab
Induction and maintenance of remission
Two randomized, placebo-controlled trials have been conduc-
ted in patients with moderate to severe, stable chronic plaque
psoriasis. The larger study included patients who had received
at least one systemic therapy prior to study entry.18,19Both
trials demonstrated infliximab therapy to be highly effective at
inducing disease remission. The onset of improvement occurs
within the first 2–4 weeks of treatment and reaches maximum
benefit by week 10 in the majority. Of patients receiving a
standard induction course of therapy (5 mg kg)1at weeks 0,
2 and 6) 87% achieved a PASI 75 response. Time to relapse
following successful ‘induction’ therapy is highly variable
between individuals, and may depend on the initial dose
given: 73% of those given 10 mg kg)1during induction
maintained at least a 50% improvement in PASI scores at week
26 compared with 40% of those given 5 mg kg)1.18,20
There are no RCTs or other controlled trials examining treat-
ment efficacy of infliximab in patients with recalcitrant disease
or in other forms of psoriasis. Nevertheless, several case series
indicate infliximab monotherapy to be of benefit in patients
previously resistant to multiple systemic therapies21–25and
there are several case reports documenting efficacy in severe
unstable psoriasis and generalized pustular psoriasis.26,27Clin-
ical experience within the guideline group further supports the
value of infliximab in these clinical circumstances.
Dosing regimens
Infliximab is given by intravenous infusion over a period of
2 h. Dosing schedules vary according to the disease being
treated, and have not been optimized for psoriasis. A standard
induction course (5 mg kg)1at weeks 0, 2 and 6) may be
followed by repeat single infusions at 8–12-week intervals.28
No studies have established the optimal frequency or dose of
repeat infusions required to achieve disease control. There is a
suggestion, however, that once significant disease relapse has
occurred, repeat infusions do not achieve the same rate of dis-
ease clearance as that seen on the initial three-dose induction
treatment.18,20This latter possibility is supported by findings
in Crohns disease, where the risk of developing treatment
resistance to infliximab is reduced with maintenance (rather
than as-required) infusions. In clinical practice, the risks of
maintenance infusions must be balanced against the risks asso-
ciated with disease relapse. For those patients with, for exam-
ple, severely unstable disease, the benefits of maintaining
Etanercept: Clinical effectiveness
• Etanercept is effective in the treatment of chronic plaque psori-
asis, with 38% and 54% of patients clear or nearly clear of disease
after 12 weeks of treatment (25 mg twice weekly, 50 mg twice
weekly, respectively). (Strength of recommendation A, level of evidence
1++).
• The current licence recommends intermittent courses no longer
than 24 weeks, with the time to relapse being variable (around
12 weeks) and with similar response rates achieved with repeat
dosing.
• Treatment should normally be initiated at 25 mg subcutane-
ously, twice weekly. However, response is dose dependent and the
chances of responding to treatment are greater with 50 mg twice
weekly. The choice of the higher dose should be made based on an
individual patient basis. (Strength of recommendation B extrapolated from level
of evidence 1++).
• Treatment may be continued according to clinical need, although
long-term efficacy is only established in psoriasis for up to 2 years.
(Strength of recommendation D, level of evidence 3).
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Biological interventions for psoriasis, C.H. Smith et al. 489

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disease control may outweigh risks associated with continued
therapy.
In combination with other therapies
Large trials in rheumatoid arthritis have demonstrated thera-
peutic benefits of infliximab in combination with methotrex-
ate. The benefit of infliximab in combination with other agents
in psoriasis is not established. Evidence from case series and
clinical experience in psoriasis suggest that it can be given in
combination with a number of systemic agents including met-
hotrexate, ciclosporin, acitretin and hydroxycarbamide.21,23
Circumstances where combination therapy may be used
include when infliximab monotherapy has proved ineffective
or, on initiation of therapy, where suddenly discontinuing
existing standard therapy might result in unstable disease.
Infliximab: Clinical effectiveness
• Infliximab is effective in the treatment of chronic plaque psori-
asis, with 90% of patients becoming clear or minimally affected at
10 weeks following 5 mg kg)1at weeks 0, 2 and 6. (Strength of
recommendation A, level of evidence 1++).
• Infliximab therapy may be initiated at a dose of 5 mg kg)1at
weeks 0, 2 and 6 and subsequent maintenance infusions (either
5 mg kg)1or 3 mg kg)1) given at 8-week intervals depending on
clinical need and circumstances. (Strength of recommendation A, level of
evidence 1++).
• In those patients who respond to therapy, regular maintenance
infusions may avoid the risk of loss of efficacy seen in some
patients receiving intermittent as-required repeat infusions on dis-
ease relapse. (Strength of recommendation D, level of evidence 3).
• Infliximab may also be of value in recalcitrant or unstable dis-
ease and in generalized pustular psoriasis. (Strength of recommendation
D, level of evidence 3).
• Concomitant systemic therapies may be indicated for some pati-
ents with very severe or unstable psoriasis, although doses of these
should be minimized. (Strength of recommendation D, level of evidence 3).
Adverse effects and toxicity: Anti-TNF therapies
In general, infliximab and etanercept are well tolerated;
detailed information on side-effects can be found in the rele-
vant summary of product characteristics (SPC).28,29
Infections and malignancy are a significant clinical concern
although the actual associated risks are unknown, particularly
in psoriasis. Previous or concomitant immunosuppressant
treatment and PUVA therapy may compound such risks. Addi-
tional, serious potential toxicities include demyelinating dis-
ease and heart failure.
Allergic reactions (infusion⁄injection site reactions) and
antibody development
Etancercept. Injection site reactions are the most frequently reported
adverse event, and occur in 10–20% of patients.29,30These
comprise erythema, oedema and bruising, resolve spontane-
ously within 2–3 days, and tend to occur in the first month
of therapy. Tolerance develops in most patients with contin-
ued use.
Antibodies to etanercept may develop in up to 6% of patients but
data on the clinical relevance of these are scarce.29
Infliximab. Infusion reactions occurring during or within 1–2 h of
treatment affect up to 20% of all patients treated and rarely
may result in anaphylactic shock. Management of reactions
will depend on the degree of severity. For mild to moderate
reactions, the infusion rate may be slowed or temporarily
interrupted until symptoms disappear, and symptomatic treat-
ment given as appropriate (antihistamines, hydrocortisone,
paracetamol). For more severe reactions, further infliximab is
contraindicated, but does not necessarily preclude treatment
with other anti-TNF agents.31
Antibodies to infliximab may develop during therapy. The fre-
quency of infusion reactions is approximately 2–3 times
higher in those with antibodies compared with those without,
although overall, the presence of antibodies is poorly predic-
tive of infusion reactions. The clinical significance of antibody
development with respect to treatment outcome, and factors
that increase risk of their development, are not established in
psoriasis.19,20In other diseases, antibodies have been asso-
ciated with a poorer therapeutic outcome, and risk of
their development is reduced by giving continuous therapy
(as opposed to episodic treatments), and concomitant metho-
trexate.
Serious infections
Data
although infections are common, overall the rates of infec-
tion with these agents are no greater than with placebo.
However, serious and opportunistic infections have been
reported.32–37
Tuberculosis may be a risk particularly associated with
anti-TNF agents, as TNF-a plays a key role in host defence
against mycobacterial infection, particularly in granuloma
formation (and hence containment of Mycobacterium) and
inhibition of bacterial dissemination.38A postmarketing sur-
veillance report in 200133,39identified 70 cases of tubercu-
losisaftertreatment with
arthritis, other forms of arthritis and Crohns disease out of
an estimated total of 147 000 people treated. Onset of
infection occurred early in treatment, with 48 of 70
patients developing infection within the first three infusions.
Most patients were also receiving one or more immunosup-
pressive agents (methotrexate, ciclosporin, azathioprine or
corticosteroids). More than half had extrapulmonary disease,
and a quarter disseminated disease. Atypical and extensive
infection were thought to account for the high morbidity
with at least four deaths directly attributed to tuberculosis
infection. Most were assumed to be due to reactivation of
latent infection as only a minority reported exposure to
fromclinicaltrials inalldiseasesindicatethat
infliximabfor rheumatoid
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490 Biological interventions for psoriasis, C.H. Smith et al.