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A consensus report on appropriate treatment optimization and transitioning in the management of moderate-to-severe plaque psoriasis

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    ORIGINAL ARTICLE

    A consensus report on appropriate treatment optimization

    and transitioning in the management of moderate-to-severe

    plaque psoriasisU. Mrowietz,1,* E.M.G.J. de Jong,2 K. Kragballe,3 R. Langley,4A. Nast,5 L. Puig,6 K. Reich,7 J. Schmitt,8

    R.B. Warren9

    1Department of Dermatology, Psoriasis-Center, University Medical Center, Schleswig-Holstein (Campus Kiel) Kiel, Germany2Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands3Department of Dermatology, Arhus University Hospital, Arhus, Denmark4Division of Dermatology, Dalhousie University, Halifax, NS, Canada5Division of Evidence Based Medicine, Klinik fur Dermatologie, Venerologie und Allergologie Charite-Universitatsmedizin Berlin, Berlin,

    Germany6Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain7Dermatologikum Hamburg, Hamburg8Centre for evidence-based healthcare, Technische Universitat, Dresden, Germany9

    Dermatology Centre, Manchester Academic Health Sciences Centre, Salford Royal Foundation Trust, the University of ManchesterManchester, UK

    *Correspondence: U. Mrowietz. E-mail: [email protected]

    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: 1

    9, strong disagreement to strong agreement). Consensus was de

    ned 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 AuthorsJournal of the European Academy of Dermatology and Venereology 2013 European Academy of Dermatology and VenereologyJEADV 2013

    DOI: 10.1111/jdv.12118 JEADV

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    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 toanother 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 significant 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 modified 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

    identified. 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-defined search strings,

    are listed in Table 1, with the outcomes listed in Table 2. The

    evidence was graded using the classification 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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    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

    2011International: steeringcommittee

    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

    NovJan

    FebMar

    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 2000present

    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 2011American Academy of Dermatology meetings

    20092011

    European Academy of Dermatology andVenereology meetings 20052011

    From Gene to Clinic meeting London 2005

    and 2008

    Congress of the Psoriasis Internationalnetwork, Paris 2010

    Inclusion criteria Randomized controlled studiesCase-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

    Questi on 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 cyclosporine7 methotrexate

    0

    Q7 809 2 0

    Q8 8 1

    Q11 8 2

    Q13 8 0

    Q14 13 0

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    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 witheach 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 defined as 75% of participants

    scoring within the 79 range. If 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-benefit profile 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 intermittentlyfor 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-benefit profile 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 significant risk of renal toxicity,

    the development of arterial hypertension and the increasedrisk of skin cancer24 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 first 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 of2.53 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 first 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 weeks12,32; and 75% reduction in mean PASI within

    7 weeks

    32

    ) (Level of evidence 2). The clinical response to oralmethotrexate 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 malignancies82 or serious infections with methotrexate therapy in patients with

    psoriasis.

    97% consensus agreement on first 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 (15

    22.5 mg weekly) lead to more rapid onset of response (50% reduction in the mean PASI within a mean

    time of 34 weeks12,32 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 first 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 insufficient, 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 efficacy and tolerability may be achievable by subcutaneous administration.

    95% consensus agreement on first 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 specific clinical circumstances following discussion with a hepatologist.

    88% consensus agreement on first 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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    (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 insufficient at week 8. In non-

    responders to 20 mg oral methotrexate at 16

    24 weeks (thetimeframe 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 effi-

    cacy. Increased efficacy 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 themonitoring recommendations for methotrexate therapy which

    reflected the inter-country variation in access to specific 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 mostcases, 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 fibrosis;

    however, PIIINP levels can be difficult to interpret in patients

    with active psoriatic arthritis or lung fibrosis or in other situa-

    tions in which fibroneogenesis 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 indicated2

    but may be considered in specific 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 guidelines2,5 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, continuoustherapy 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 conventionalsystemic 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 efficacy, 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 efficacious 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 specific 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 efficacy,

    optimize the risk-benefit profile, reduce the risk of immunoge-

    nicity (with methotrexate) and improve long-term disease man-

    agement.

    The safety (Level of evidence 4) and efficacy (Level of evidence 3)

    of methotrexate (515 mg/week) combined with the TNF antago-

    nists etanercept and infliximab has been demonstrated,4145 but

    data were not identified 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 efficacy 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 efficacy

    (Level of evidence 2) and safety profile (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 infliximab 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 defined 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 benefit-risk profile

    Prior course of disease including pattern of flares/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 first vote; median score=

    9Q6 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

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    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 efficacy 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 specific 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 infliximab

    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

    efficacy 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 significant therapeutic breaks are difficult 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 conventionalsystemic 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 efficacy, 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 first 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 first vote; median score = 9Cyclosporine 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 first 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 antagonists4145,86 (level of evidence 2) or ustekinumab (level of

    evidence 5).

    87,88

    98% consensus agreement on first 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

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    In cases of temporary interruption of therapy, a major impact

    on efficacy 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 infliximab 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 infliximab (because of the increased

    risk of infusion reactions).

    There is no established definition of inadequate clinical

    response to biological therapy, although in published clinical tri-

    als, a primary non-response was defined 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 ef cacious 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 efficacy, optimize the risk-benefitprofile, 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 efficacy

    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 efficacy 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 profile 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 efficacy

    (Level of evidence 5).

    8 Data for the combination of acitretin with infliximab or ustekinumab are not currently available but an increased clinical response might

    also be expected. (Level of evidence 5)

    97% consensus agreement on first vote; median score = 9Q9 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 defined 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 first 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 improveefficacy, optimize the risk-benefit profile, 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 first vote; median score = 9

    TNF, tumour necrosis factor.

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    Transitioning from one biological therapy to another

    None of the trials identified in the literature search compared

    the safety and efficacy of transitioning with or without a washout

    period. We recommend that switching between biologicals due

    to failure of efficacy 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 efficacy and safety data has only been generated for the approved dosage and there is a theoretical risk of decreased efficacy

    when using reduced dosages. In addition, there is some evidence to suggest that a lower dosage of a biological drug may increase the riskof 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 etanercept5358 while maintaining clinical response.

    (Level of evidence 5 for adalimumab; Level of evidence 2 for etanercept)

    4 With infliximab monotherapy, dosing intervals should not be increased over the intervals generally recommended.49 (Level of evidence 2)

    5 The dosage of infliximab 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 first 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, significant therapeutic breaks

    are difficult to achieve without risk of recurrence or an impact on efficacy following re-initiation of therapybiological 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 significant 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 fulfil 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 infliximab monotherapy where a higher risk of infusion reactions has been observed with

    intermittent therapy.50

    79% consensus agreement on first 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 efficacy 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 first reintroduction of the same

    biological monotherapy.49,50,53,5964 This decrease in efficacy 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 infliximab (because of the increased risk of infusion reactions).

    81% consensus agreement on first 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.

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    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 thedose or reduce treatment intervals before switching? Which is preferable?

    1 There is no established definition of inadequate clinical response. In published clinical trials with the biological agents a primary

    non-response was defined 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 29 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 infliximab, 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, defined 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? Whatfactors should influence 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 efficacy, 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 first vote; median score = 9

    Adalimumab? another biological agent

    1 Administer the first treatment with etanercept after a treatment transitioning from adalimumab at the time point of the next scheduleddrug dosage (typically 2 weeks).72 (Level of evidence 3)

    2 Administer the first treatment with infliximab 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 first 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 first vote; median score = 9

    Etanercept? to another biological agent

    1 Administer the first 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 first treatment with infliximab 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 first 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 first vote; median score = 9

    Iniximab? to another biological agent

    1 Initiation of the first treatment with adalimumab after a treatment transitioning from infliximab can be considered as early as

    24 weeks after the last infliximab dose, particularly in cases of treatment failure. (Level of evidence 5)

    2 Initiation of the first treatment with etanercept after a treatment transitioning from infliximab can be considered early as

    24 weeks after the last infliximab dose, particularly in cases of treatment failure. 79 (Level of evidence 4)

    3 Initiation of the first treatment with ustekinumab after a treatment transitioning from infliximab can be considered as early as

    24 weeks after the last infliximab dose, particularly in cases of treatment failure. 73 (Level of evidence 4)

    99% consensus agreement on first vote; median score = 9Ustekinumab? to another biological agent

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    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 pharmacokinetically defined 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 defining 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 insufficient 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 efficacy 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 first treatment with adalimumab, etanercept or infliximab 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 first vote; median score = 9

    Dosing schedule for the second biological

    The second biological should be used starting with the defined induction dosage and followed by the maintenance dosage.

    96% consensus agreement on first vote; median score = 9

    Level of evidence

    Adalimumab?etanercept 372

    Adalimumab?iniximab 5

    Adalimumab?ustekinumab 473

    Etanercept?adalimumab 374

    Etanercept?iniximab 377

    Etanercept?ustekinumab 273, 78

    Iniximab?adalimumab 5

    Iniximab?etanercept 479

    Iniximab?ustekinumab 473

    Ustekinumab?adalimumab/etanercept/iniximab 5

    PASI 50, a 50% reduction in the Psoriasis Area Severity Index; partial responder (or intermediate responder), de ned in the European treatment goals as

    achievement of an intermediate response of change in PASI 50 but

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    be considered in some circumstances. However, it is important

    to note that the criteria for defining the duration of sustained

    response before stopping therapy have not been defined; 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 specified) 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-

    specific 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 specificissues in psoriasis and suggested goals and actions to address

    these needs.81 It specifically 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

    define 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, Burleighfield 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 influence 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 final content of the manu-

    script. Elaine Bell of Lucid provided editorial support for the

    authors in the development of this manuscript. Abbott paidLucid 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; Nilgun 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 Bulbul 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; TomasDam, 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

    Gomez-Flores, Mexico; Catherine Goujon Henry, France; Esther

    Guevara-Sangines, Mexico; Wayne Gulliver, Canada; Mehmet

    Ali Gurer, 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 Hollo, 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; Kulli

    Kingo, Estonia; Brian Kirby, Ireland; Erol Koc, Turkey; Martina

    2013 The AuthorsJournal of the European Academy of Dermatology and Venereology 2013 European Academy of Dermatology and VenereologyJEADV 2013

    Optimizing and transitioning psoriasis treatment 13

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    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; Sofia Magina, Portugal;

    Emmanuel Mahe, France; Sameer Mahfoud, Syria; Piergiorgio

    Malagoli, Italy; Cesar Maldonado-Garca, Mexico; Tarja

    Malkonen, 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;

    Guzin 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 Schonenberger de

    Oliveira, Portugal; Gordon Searles, Canada; Nilgun Senturk,

    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 Stromer, 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 first online publication: Tore

    Sarnhult, Sweden was added to the list of participants.].

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