Effective and sustainable biologic treatment of psoriasis: what can we learn from new clinical data?

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REVIEW ARTICLE Effective and sustainable biologic treatment of psoriasis: what can we learn from new clinical data? R.G. Langley* Queen Elizabeth II Health Sciences Centre, Division of Dermatology, Department of Medicine, Dalhousie University, Halifax, Canada *Correspondence: R. Langley. E-mail: [email protected] Abstract The introduction of the biologic agents, adalimumab, etanercept, infliximab and ustekinumab, has provided more options for the short- and long-term treatment of patients with psoriasis. Physicians are now able to achieve and maintain effective disease control in more patients using biologic therapies. Newly published clinical data support the introduction of novel optimization strategies to further improve outcomes in patients with psoriasis. Recent randomized controlled clinical trials have provided data on the efficacy of conventional therapies, including systemic agents, and biologics at specific time points. Switching from methotrexate to a tumour necrosis factor (TNF)-a antagonist after 16 weeks can improve response rates, as demonstrated in a study of patients with moderate-to- severe psoriasis, while the benefit of long-term methotrexate use remains unclear. In a separate study, psoriasis area and severity index (PASI) 75 response rates were maintained over time (>3 years for adalimumab), suggesting that long-term biologic therapy is an effective and sustainable treatment option for psoriasis. For each individual patient, the benefit of a particular treatment needs to be balanced with the risks. The lack of head-to-head trials of antipsoriatic therapies, particularly biologic therapies, does not help with making individualized treatment decisions. However, a benefit–risk assessment of TNF-a antagonists calculated from an integrated analysis of published literature in moderate-to-severe psoriasis can be used to aid clinical practice. The number needed to treat, number needed to harm and number of patient years of observation to detect an adverse event have been determined for adalimumab, etanercept and infliximab. The benefit–risk profiles generated demonstrated that, during the initial year of treatment, likelihood of success with TNF-a antagonists was several orders of magnitude greater than the likelihood of serious toxicity. Received: 22 November 2011; Accepted: 28 November 2011 Conflicts of interest R.G.L. has served as consultant and or paid speaker for and or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis including Abbott, Amgen, Astellas, Boehringer Ingelheim, Celgene, Centocor, Genentech, Merck, Novartis and Pfizer. Funding statement The writing of this supplement article was sponsored by an educational grant from Abbott Immunology. Introduction The development of biologic therapies has provided dermatolo- gists with an increasing repertoire of treatments with which to treat psoriasis, in both the short- and long-term. Biologic thera- pies fall into two main categories: the tumour necrosis factor-a (TNF-a) antagonists and interleukin (IL)-12 23 monoclonal anti- bodies (mAbs). TNF-a antagonists (adalimumab, etanercept and infliximab) block the binding of TNF-a to its receptor, interrupt- ing the subsequent signalling and inflammatory pathways driven by TNF-a. This suppresses inflammation and the increased activa- tion of T cells that are characteristic of psoriasis. IL-12 23 mAbs (ustekinumab) inhibit the activity of IL-12 and IL-23, cytokines that drive the inflammatory processes which can cause psoriatic lesions. Several randomized controlled clinical trials have demonstrated the efficacy of biologic therapies in the first year of psoriasis treatment. 1–11 A summary of the key outcomes of these trials is provided in Table 1. The TNF-a antagonists (adalimumab, etaner- cept and infliximab) and ustekinumab provide efficacious therapy, with high rates of psoriasis area and severity index (PASI) 75 response being achieved by patients in all trials. These trials also illustrated the safety and tolerability of biologic therapies, ª 2012 The Author JEADV 2012, 26 (Suppl. 2), 21–29 Journal of the European Academy of Dermatology and Venereology ª 2012 European Academy of Dermatology and Venereology DOI: 10.1111/j.1468-3083.2011.04412.x JEADV

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Effective and sustainable biologic treatment of psoriasis: what can we learn from new clinical data?

Transcript of Effective and sustainable biologic treatment of psoriasis: what can we learn from new clinical data?

  • REVIEW ARTICLE

    Effective and sustainable biologic treatment of psoriasis:what can we learn from new clinical data?

    R.G. Langley*

    Queen Elizabeth II Health Sciences Centre, Division of Dermatology, Department of Medicine, Dalhousie University, Halifax,

    Canada

    *Correspondence: R. Langley. E-mail: [email protected]

    AbstractThe introduction of the biologic agents, adalimumab, etanercept, infliximab and ustekinumab, has provided more

    options for the short- and long-term treatment of patients with psoriasis. Physicians are now able to achieve and

    maintain effective disease control in more patients using biologic therapies. Newly published clinical data support

    the introduction of novel optimization strategies to further improve outcomes in patients with psoriasis. Recent

    randomized controlled clinical trials have provided data on the efficacy of conventional therapies, including systemic

    agents, and biologics at specific time points. Switching from methotrexate to a tumour necrosis factor (TNF)-a

    antagonist after 16 weeks can improve response rates, as demonstrated in a study of patients with moderate-to-

    severe psoriasis, while the benefit of long-term methotrexate use remains unclear. In a separate study, psoriasis

    area and severity index (PASI) 75 response rates were maintained over time (>3 years for adalimumab), suggestingthat long-term biologic therapy is an effective and sustainable treatment option for psoriasis. For each individual

    patient, the benefit of a particular treatment needs to be balanced with the risks. The lack of head-to-head trials of

    antipsoriatic therapies, particularly biologic therapies, does not help with making individualized treatment decisions.

    However, a benefitrisk assessment of TNF-a antagonists calculated from an integrated analysis of published

    literature in moderate-to-severe psoriasis can be used to aid clinical practice. The number needed to treat, number

    needed to harm and number of patient years of observation to detect an adverse event have been determined for

    adalimumab, etanercept and infliximab. The benefitrisk profiles generated demonstrated that, during the initial year

    of treatment, likelihood of success with TNF-a antagonists was several orders of magnitude greater than the

    likelihood of serious toxicity.

    Received: 22 November 2011; Accepted: 28 November 2011

    Conflicts of interestR.G.L. has served as consultant and or paid speaker for and or participated in clinical trials sponsored bycompanies that manufacture drugs used for the treatment of psoriasis including Abbott, Amgen, Astellas, Boehringer

    Ingelheim, Celgene, Centocor, Genentech, Merck, Novartis and Pfizer.

    Funding statementThe writing of this supplement article was sponsored by an educational grant from Abbott Immunology.

    IntroductionThe development of biologic therapies has provided dermatolo-

    gists with an increasing repertoire of treatments with which to

    treat psoriasis, in both the short- and long-term. Biologic thera-

    pies fall into two main categories: the tumour necrosis factor-a(TNF-a) antagonists and interleukin (IL)-12 23 monoclonal anti-bodies (mAbs). TNF-a antagonists (adalimumab, etanercept andinfliximab) block the binding of TNF-a to its receptor, interrupt-ing the subsequent signalling and inflammatory pathways driven

    by TNF-a. This suppresses inflammation and the increased activa-tion of T cells that are characteristic of psoriasis. IL-12 23 mAbs

    (ustekinumab) inhibit the activity of IL-12 and IL-23, cytokines

    that drive the inflammatory processes which can cause psoriatic

    lesions.

    Several randomized controlled clinical trials have demonstrated

    the efficacy of biologic therapies in the first year of psoriasis

    treatment.111 A summary of the key outcomes of these trials is

    provided in Table 1. The TNF-a antagonists (adalimumab, etaner-cept and infliximab) and ustekinumab provide efficacious therapy,

    with high rates of psoriasis area and severity index (PASI) 75

    response being achieved by patients in all trials. These trials also

    illustrated the safety and tolerability of biologic therapies,

    2012 The AuthorJEADV 2012, 26 (Suppl. 2), 2129 Journal of the European Academy of Dermatology and Venereology 2012 European Academy of Dermatology and Venereology

    DOI: 10.1111/j.1468-3083.2011.04412.x JEADV

  • during these periods, an important concept when considering

    treatment decisions.

    Role of conventional systemic therapies

    Despite the encouraging results seen in response to biologic thera-

    pies, conventional treatments continue to play a major role in der-

    matology and should still be considered for use in patients with

    psoriasis. As psoriasis is a chronic disease, long-term maintenance

    requires continued use of therapy. Systemic therapies have been in

    use for decades and are well established in treatment regimens,

    and dermatologists are better positioned to make long-term deci-

    sions on the use of such conventional therapies. For example,

    methotrexate has been successfully used for the treatment of psori-

    asis since the 1950s.12,13 Methotrexate has been combined with

    Table 1 Results of pivotal randomized controlled clinical trials of biologic therapies for the treatment of psoriasis

    Treatment schedule Number of patientsreceiving biologictherapy

    PASI 75 responserate (%) at1016 weeks*

    Complete ornear-completeclearance (%)

    Adalimumab

    CHAMPION1 80 mg at week 0 then 40 mg e.o.w.from week 1

    108 79.6 16.7 (PASI 100)

    51.3 (PASI 90)

    73.1 (PGA 0 1)REVEAL2 80 mg at week 0 then 40 mg e.o.w.

    from week 1814 71 20 (PASI 100)

    45 (PASI 90)

    60 (PGA 0 1)BELIEVE3 80 mg at week 0 then 40 mg e.o.w.

    from week 1364 70.9 24.2 (PASI 100)

    50.8 (PASI 90)

    64.4 (PGA 0 1)Gordon et al.7 80 mg at weeks 0, 1; then 40 mg q.w. 50 80 26 (PASI 100)

    33 (PASI 90)

    76 (PGA 0 1)Etanercept

    Leonardi et al.4 50 mg b.i.w. 164 49 22 (PASI 90)

    49 (PGA 0 1)Papp et al.5 50 mg b.i.w. 194 49 21 (PASI 90)

    57 (PGA 0 1)Tyring et al.45 50 mg b.i.w. 311 47 21 (PASI 90)

    Gottlieb et al.46 25 mg b.i.w. 57 30 >50 (PGA 0 1)van de Kerkhof et al.47 50 mg q.w. 37.5 64 (PGA 0 1)Infliximab

    EXPRESS 18 5 mg kg at weeks 0, 2, 6; then every 8 weeks 301 80 57 (PASI 90)83 (PGA 0 1)

    EXPRESS 29 5 mg kg at weeks 0, 2, 6 314 75.5 45.2 (PASI 90)76.0 (PGA 0 1)

    Ustekinumab

    PHOENIX 110 45 mg at weeks 0, 4; then every 12 weeks 255 67.1 12.5 (PASI 100)

    41.6 (PASI 90)

    60.4 (PGA 0 1)90 mg at weeks 0, 4; then every 12 weeks 256 66.4 10.9 (PASI 100)

    36.7 (PASI 90)

    61.7 (PGA 0 1)PHOENIX 211 45 mg at weeks 0, 4; then every 12 weeks 409 66.7 18.1 (PASI 100)

    42.3 (PASI 90)

    68.0 (PGA 0 1)90 mg at weeks 0, 4; then every 12 weeks 411 75.5 18.2 (PASI 100)

    50.9 (PASI 90)

    73.5 (PGA 0 1)

    *These trials were not conducted in a head-to-head fashion and differing methods of statistical anaysis and study designs do not make comparisons

    possible.

    b.i.w., twice per week; e.o.w., every other week; PASI, psoriasis area and severity index; PGA, physicians global assessment; q.w., once per week.

    2012 The AuthorJEADV 2012, 26 (Suppl. 2), 2129 Journal of the European Academy of Dermatology and Venereology 2012 European Academy of Dermatology and Venereology

    22 Langley

  • psoralen and ultraviolet A (PUVA), ultraviolet B (UVB), etretinate

    and cyclosporine with the aim of improving efficacy, reducing

    dosage and limiting associated toxicity.1421 Methotrexate and

    cyclosporine have been particularly successful in achieving this,

    although long-term use has not been reported.21 The efficacy of

    cyclosporine in the treatment of psoriasis has been investigated

    and established in randomized controlled trials (RCTs). These

    studies have been of short duration and the approved use of this

    agent in most countries is for a limited period due to concerns

    over toxicity.2227 However, short intermittent courses of cyclo-

    sporine are effective and have been adopted in clinical practice.25,26

    Retinoids are a group of natural and synthetic therapies closely

    related to vitamin A. They are also well established in the treat-

    ment of dermatological conditions: acitretin, an oral retinoid, is

    currently used for moderate-to-severe psoriasis.28 Despite these

    agents being in use for over 50 years, there are few RCTs that

    address the dosing and treatment regimen of retinoids.2932 The

    combination of retinoids with topical or phototherapies has

    proved effective for psoriasis treatment and can be more successful

    than retinoid monotherapy.3338

    Conventional systemic agents remain important therapies in the

    management of patients with psoriasis. The use of conventional

    therapies, however, must be monitored regularly and modified if

    the treatment goal is not reached.39 For treatment to achieve maxi-

    mal benefit and optimal patient outcomes, it must be initiated

    and modified in a timely and appropriate manner. Although RCTs

    continue to demonstrate the efficacy and safety of biologic thera-

    pies, there has been less systematic investigation regarding conven-

    tional therapies. Despite the proven efficacy and safety of biologic

    agents in the treatment of psoriasis, there appears to be a general

    reluctance among dermatologists to prescribe them.40 This article

    aims to address this discrepancy and provide evidence for the

    effective and sustainable use of biologics in psoriasis.

    Optimization strategies for systemic and biologictherapiesOptimizing results with systemic or biologic agents may enhance

    the efficacy achieved with these agents. It is important to be aware

    of what responses may be expected and when efficacy may be

    observed. Specific guidelines have been developed which summa-

    rize this information and can assist clinicians in the decision to

    switch or modify treatment regimens, as appropriate.39 As new

    treatments are introduced, it is important that dermatologists are

    aware of the best use of therapies through the analysis of evidence-

    based clinical data. Recent clinical studies have investigated opti-

    mization strategies to define such areas, and these are reviewed

    below.

    Optimization of conventional therapies

    Conventional therapies range in their probability of achieving an

    adequate clinical response and in the level of efficacy attained.41,42

    Methotrexate provides an example of a drug that is well estab-

    lished in the treatment of psoriasis, but lacks an evidence-based

    approach to optimizing dose. The lack of evidence-based strategies

    has, in part, led to an experience-based approach, with a subse-

    quent lack of standardized, evidence-based treatment guidelines,

    which has contributed to a large variety of treatment regimens.

    Three recent Phase 3 clinical trials have been performed in

    which methotrexate was compared with biologic agents.1,43,44 The

    initial trial, CHAMPION, randomized 271 patients to receive ada-

    limumab, methotrexate or placebo for 16 weeks.1 RESTORE ran-

    domized 868 patients to receive infliximab or methotrexate for

    16 weeks, after which treatment switch was permitted.44 A third

    Phase 3 trial randomized 317 patients to receive briakinumab or

    methotrexate over 52 weeks (M10-255).43 RESTORE and M10-

    255 indicated that if a PASI 75 response is not achieved by week

    16, then it is not likely to occur and treatment discontinuation or

    modification should be considered.43,44 Switching from metho-

    trexate to a TNF-a antagonist after 16 weeks can improve theresponse.44 In CHAMPION, the methotrexate dose was started at

    7.5 mg orally and sequentially increased in subsequent weeks,

    depending on clinical response and the presence of adverse

    events.1 The methotrexate dose was increased to 20 mg week ifPASI 50 response had not been reached by week 8 and it was fur-

    ther increased to 25 mg week if PASI 50 had not been reached byweek 12. Results at week 16 showed that PASI 75 was achieved by

    79.6% of patients who received adalimumab, compared with

    35.5% of patients who received methotrexate. Conclusions drawn

    from this information are limited because methotrexate was

    started and maintained at a relatively low dose compared with

    clinical practice and dose increases were not appropriate in the

    achievement of a high PASI response (only increased if response

    was

  • trexate had a PASI 75 response. The results from this trial demon-

    strate the benefit of appropriate dose escalation of oral methotrex-

    ate until 20 mg week. Patients with a sub-optimal response at thisstage receive little further benefit from increasing the dose to

    25 mg.43 This response-guided therapeutic approach increasingly

    reflects current practice, as depicted by the European Consensus

    Programme on goals for the treatment of psoriasis, and shows the

    importance of regular monitoring.39

    Optimization of biologic therapies

    The expected short-term efficacy of different biologic agents has

    been described in several RCTs15,711,4547 and the European goals

    were recently set out by the European Consensus Programme.39

    Patients who have not achieved an adequate response by a defined

    endpoint may be considered primary failures. Patients who reach

    a specified endpoint but who then lose response are considered

    secondary failures.48 Following primary or secondary failure, it is

    important to clinically address why these patients failed to respond

    or lost response. Factors which may be considered include adher-

    ence compliance, confounding factors (infection, natural variationin disease, exogenous stress) or inadequate drug levels. Before dose

    optimization, it is crucial to determine whether any of these con-

    founding factors led to primary or secondary failure. In the

    absence of a confounding variable that would explain failure to

    achieve an immediate response (primary) or later response (sec-

    ondary), clinicians can attempt to optimize therapy.

    The long-term use of biologic therapy was addressed in the

    Phase 3 REVEAL trial, which examined the extended efficacy and

    safety of adalimumab. Following the initial 52-week trial period,

    patients were able to enter an open-label extension trial to receive

    adalimumab for a total of 3 years. The PASI response rates

    achieved by patients treated with adalimumab were compared

    with patients who received placebo.49 During the initial Phase 3

    trial, 71% patients who received adalimumab achieved PASI 75

    response. Approximately 60% of patients who entered the ada-

    limumab arm became sustained responders, achieving a PASI 75

    response at weeks 16 and 33. At 100 weeks and 160 weeks of con-

    tinuous therapy, PASI 75 was retained by 83% and 76% of these

    initial responders, respectively. Some patients with

  • 40 mg week), infliximab (from a dose every 8 weeks to a doseevery 6 weeks) and ustekinumab (45 or 90 mg every 12 weeks to

    45 or 90 mg every 8 weeks). To ensure the optimal efficacy of ada-

    limumab, it is important to include an induction dose of 80 mg at

    baseline. A recent study has shown that failing to provide this

    loading dose can result in inferior efficacy and is less cost-effec-

    tive.50 A small study has shown that increasing infliximab dose

    beyond 5 mg does not improve the efficacy; rather, shortening the

    time between dose intervals may be a more appropriate modifica-

    tion.51

    Weight is an important factor for consideration when making

    therapeutic decisions in the use of biologic agents. A study that

    examined the effect of weight on the efficacy of biologic therapy

    showed that weight-based regimens do not result in reduced effi-

    cacy in heavier patients.52 An analysis of the PHOENIX trials

    investigated how the optimal dose of ustekinumab is affected by

    weight. The study analysed weight in 10 kg increments and found

    that weight-based fixed dosing gives improved efficacy to patients.

    This study is potentially limited by a cut-off of 100 kg, which may

    not be reflected in clinical practice.53 A comparison of week 12

    data by weight was carried out using data from two clinical trials

    of adalimumab and one of etanercept. Patients were divided into

    100 kg groups. The adjusted outcome showed that

    both drugs have a reduced efficacy in heavier patients.54

    Modification and transitioning of therapies

    Novel optimization strategies can provide a standardized basis for

    the development of patient treatment, ensuring that the most ben-

    eficial outcomes can be reached. The modification of treatment is

    crucial to achieving the treatment goal following initial failure.

    The transitioning of treatments may take a number of forms,

    including direct switching to a new therapy and the overlap or

    temporary permanent addition of a new therapy. The successfultransitioning from methotrexate to biologic therapy has been

    demonstrated in other clinical trials.44,55

    Efficacy may also be achieved with the use of concomitant ther-

    apy. Topicals such as corticosteroids, calcipotriene and other

    agents (i.e. coal tar, anthralin) may be used as monotherapy or

    combination therapy [for example, betamethasone and calcipotriol

    (Dovobet)] in psoriasis treatment. Topical therapy is usually the

    initial therapy used in psoriasis treatment and can be added to

    biologic therapies to optimize results.56 Acitretin is a retinoid that

    may be combined with biologic agents to increase efficacy and

    reduce side-effects compared with retinoid monotherapy, includ-

    ing a possible reduction in the risk of skin cancer.57,58

    Combined treatment with topical therapies and biologic agents

    can be used in clinical practice and may serve to maximize thera-

    peutic outcome. The BELIEVE study compared the efficacy of

    adalimumab in combination with a topical versus adalimumab

    with vehicle only. After 4 weeks of therapy, PASI 75 rate was

    achieved by 40.7% versus 32.4% in the adalimumab + topical

    group compared with the adalimumab + vehicle group, respec-

    tively. This demonstrated that a rapid and higher efficacy was

    achieved with the combination therapy within the first 4 weeks of

    treatment. This was not sustained: by 16 weeks, 64.8% and 70.9%

    of patients receiving combination treatment compared with ada-

    limumab + vehicle, respectively, had achieved a PASI 75

    response.3 However, after 4 weeks of treatment, the use of topical

    therapy changed from once daily to as required, and this may

    have introduced adherence as a confounding factor in the inter-

    pretation of these data.

    Methotrexate has been utilized in combination with TNF-aantagonists routinely in the management of psoriatic arthritis and

    rheumatoid arthritis.5961 More recently, the systemic agent has

    been combined with biologics in the treatment of psoriasis. The

    NORDIC study compared a combination of etanercept with con-

    tinuous methotrexate versus etanercept with tapered and discon-

    tinued methotrexate in patients with psoriasis. Significantly more

    patients achieved a physicians global assessment score of clear al-most clear in the continuous therapy group compared with the

    methotrexate tapered group (66.7% versus 37.0%, respectively).62

    This was supported by data from a more recent larger, random-

    ized, double-blind, placebo-controlled Phase 3b study that com-

    pared the responses of patients who received methotrexate and

    etanercept compared with etanercept alone. After 24 weeks of

    treatment, significantly more patients receiving combination treat-

    ment achieved PASI 50, 75 and 90 responses compared with those

    receiving etanercept monotherapy.55

    Benefitrisk profiles of biologic therapiesIn making treatment decisions, there may be a tendency for per-

    sonal experiences or perception of riskbenefit to positively or

    negatively influence the use of therapies. There may be some con-

    flict between evidence-based data and the personal preferences of

    the dermatologist and or patient. Treatment guidelines and goalsare designed to facilitate such decisions, and the benefitrisk pro-

    files of therapies provide dermatologists with important and acces-

    sible information regarding therapy options and outcomes.

    In the absence of head-to-head trials comparing the safety and

    efficacy of different TNF-a antagonists, a benefitrisk assessmentof agents based on published data can be used to aid clinical deci-

    sions. This may come from RCTs, postmarketing data or registry

    data. Clinical trials provide high quality data but are often based

    on short-term use of treatments and may not reflect clinical prac-

    tice. There can be caveats to consider when analysing longer-term

    studies with methodological shortcomings, the optimization of

    treatments and criteria for patient inclusion, as well as methods of

    statistical analysis. Postmarketing data can provide access to large

    numbers of patients, but may not be high quality and do not

    include controls. Registries are an important source of data,

    providing long-term information on large numbers of patients,

    although information from psoriasis-specific registries is limited.

    When assessing benefitrisk profiles, one approach considers

    the number of patients needed to treat (NNT) and number of

    2012 The AuthorJEADV 2012, 26 (Suppl. 2), 2129 Journal of the European Academy of Dermatology and Venereology 2012 European Academy of Dermatology and Venereology

    Effective, sustainable biologic treatment of psoriasis 25

  • patients needed to harm (NNH), together with the number of

    patient years of observation required before the detection of an

    adverse outcome. The NNT is a measure used to determine the

    efficacy of a given therapy defining the number of patients who

    need to receive the assessed treatment for one benefit to be

    observed, compared with a control group. The NNH is a measure

    of how many patients need to be exposed to a risk factor over a

    specified time frame in order for one patient to experience harm

    that would not otherwise have occurred. Such analyses are based

    on published data from trials of psoriatic treatments

    (Table 2).63,64

    A meta-analysis and literature review of 22 trials that compared

    the efficacy of psoriasis treatments showed that TNF-a antagonistswere most likely to achieve a PASI 75 response. The relative risk of

    achieving a PASI 75 response for TNF-a antagonists was 15.57,compared with 9.24 and 5.65 for systemic and T-cell therapies,

    respectively.41 A comparison of the benefits and risks of TNF-aantagonists is shown in Table 3.

    Another meta-analysis comparing TNF-a antagonists and sys-temic therapies used in the treatment of moderate-to-severe psori-

    asis also demonstrated the high efficacy and tolerability of TNF-aantagonists. Low rates of adverse events were seen in patients

    receiving TNF-a antagonists, and these were comparable to equiv-alent rates observed in patients on systemic therapies (Table 4).63

    Due to their mode of action, there is concern that patients

    receiving TNF-a antagonists may become more susceptible toinfection. This is an issue that may restrict the use of biologic

    therapy but, in so doing, limit the potential for optimal patient

    outcome. The meta-analysis of trial data of TNF-a antagonistsshowed low serious infection rates among patients on biologic

    therapy (Fig. 2). The rates of infection ranged from 0.1 to 1.0% of

    patients across the trials, compared with 0 to 0.9% of patients in

    the placebo groups.64 An analysis comparing serious adverse

    events across different indications of adalimumab indicated that

    these are particularly low when compared with the equivalent

    infection rates exhibited by patients who received adalimumab for

    rheumatoid arthritis. The rates of serious infection in this analysis

    were nearly three times greater in patients being treated for rheu-

    matoid arthritis than in those treated for psoriasis (4.65 versus

    1.32, respectively).65 Although such data may have raised concerns

    among dermatologists regarding the use of biologics, these patient

    groups cannot be compared directly because patients with rheu-

    matoid arthritis may have different co-morbidities, and commonly

    receive multiple therapies, including steroids, which have an

    impact on their susceptibility to infection. The best predictors of

    serious infection events for patients with rheumatoid arthritis can

    include the severity of rheumatoid arthritis or the disease activity,

    the use of corticosteroid therapy, the presence of co-morbidities

    and the presence of skin infection and joint surgery.66,67 The use

    of biologics should also be taken into consideration. These predic-

    tors are useful indicators for physicians in controlling infection,

    and similar parameters may prove useful for the treatment of pso-

    riasis with biologic therapies.

    Essentially, the benefitrisk profiles generated for antiTNF-atherapies demonstrate a benefit to patients in the first year of

    treatment that greatly outweighs the risk of serious toxicity.64 This

    is an important message that must be appropriately conveyed to

    patients when discussing treatment options. The risk of developing

    adverse events, including infection, is low.

    ConclusionsConventional therapies remain important treatment options for

    patients with psoriasis. They continue to play a central role in

    developing therapy regimens, whether alone or in combination

    with biologic treatments. The advent of biologics has provided

    new options for dermatologists and patients with psoriasis. These

    therapies have been extensively studied in RCTs and show high

    efficacy rates as monotherapy in the majority of patients.64

    Although biologic therapies have shown high efficacy, in certain

    patients, optimization of therapy may be required to achieve an

    initial response or regain disease control when response has been

    lost. To optimize patient outcomes, it is vital to monitor the effec-

    tiveness of treatment and modify the dose or therapy as appropri-

    ate. Before optimizing treatment, it is important that any

    confounding factors are addressed and that patients are assessed

    with a careful history and clinical exam. Understanding new clini-

    cal data and guidelines may facilitate optimal patient management,

    in addition to enabling timely and appropriate decisions to be

    made with regard to treatment modification and switching. Opti-

    mization strategies can include an increase of dose, a decrease in

    dose interval, or modification of the treatment regimen to include

    a conventional topical or systemic agent.

    The rates of adverse events are low for conventional psoriatic

    treatments, including those for biologic therapies. The high effi-

    Table 2 An evidence-based comparison from clinical trials: number of patients needed to treat with a specified biologic agent tosee a benefit compared with patients in a control group.64

    Drug Dose Treated patientswho achievedPASI 75 (%)

    Placebo patientswho achievedPASI 75 (%)

    Number needed totreat (95%confidence interval)

    Adalimumab 80 mg at week 0 then 40 mg e.o.w. for 16 weeks 72.1 8.0 1.6 (1.51.7)

    Etanercept 50 mg b.i.w. for 12 weeks 48.4 4.1 2.3 (2.12.5)

    Infliximab 5 mg kg at weeks 0, 2, 6; then every 8 weeks to 24 weeks 75.4 3.9 1.4 (1.31.5)

    b.i.w., twice per week; e.o.w., every other week.

    2012 The AuthorJEADV 2012, 26 (Suppl. 2), 2129 Journal of the European Academy of Dermatology and Venereology 2012 European Academy of Dermatology and Venereology

    26 Langley

  • cacy demonstrated by biologic therapies greatly outweighs the low

    risk of experiencing adverse events. The risks and side effects asso-

    ciated with treatment are an important consideration and should

    be taken into account when defining therapeutic strategies. The

    benefitrisk profile of biologic therapies favours the appropriate

    use of biologics for the treatment of moderate-to-severe psoriasis,

    and effective disease control can now be achieved and maintained

    through the appropriate use of such therapies.

    AcknowledgementsThe author would like to thank Facilitate Ltd, funded by Abbott

    Immunology, for editorial assistance in the production of this

    manuscript.

    References1 Saurat JH, Stingl G, Dubertret L et al. Efficacy and safety results from

    the randomized controlled comparative study of adalimumab vs.

    Table 4 Adverse event rates from a meta-analysis of 16double-blind, placebo-controlled trials that were reviewed for

    treatment efficacy and tolerability63

    DrugNumber ofstudies

    Number ofpatients

    Adverseevents*,%

    Seriousadverseevents*,%

    Cyclosporine2.55 mg kg

    3 318 16.1 (n = 503) 2.3

    Methotrexate15 mg q.w.

    1 43 17.7 0

    Infliximab5 mg kg

    3 711 17.8 1.1

    Etanercept50 mg b.i.w.

    1 311 17.6 0.6

    Adalimumab80 mg at week 0then 40 mg e.o.w.

    1 814 16.6 0.5

    *Average monthly incidence rate.

    b.i.w., twice per week; e.o.w., every other week; q.w., once per week.

    Figure 2 A comparison of serious infection rates from a meta-analysis of patients with psoriasis who received different TNF-aantagonist therapies. Point estimates for the NNHs, with 95% CIlower (NNH 2.5) and upper (NNH 97.5) bounds are provided.64

    b.i.w., twice per week; e.o.w., every other week; NNH, number

    needed to harm; q.w., once per week.

    Ta

    ble

    3AcomparisonofbenefitriskprofilesofTNF-a

    antagonists

    64

    Ad

    alim

    um

    ab

    1,2

    ,7E

    tan

    erc

    ep

    t4,5

    ,4547,6

    8,6

    9In

    flix

    ima

    b8,9

    Ad

    alim

    um

    ab

    *(n

    =921)

    Pla

    ce

    bo

    (n=

    451)

    Eta

    ne

    rce

    pt

    (n=

    511)

    Pla

    ce

    bo

    (n=

    460)

    Eta

    ne

    rce

    pt

    (n=

    669)

    Pla

    ce

    bo

    (n=

    665)

    Infl

    ixim

    ab

    (n

    =301)

    Pla

    ce

    bo

    (n=

    77)

    Infl

    ixim

    ab

    (n

    =314)

    Pla

    ce

    bo

    (n=

    208)

    Ben

    efiteffica

    cyprofile

    PASI75,%

    72.1

    8.0

    34.2

    3.0

    48.4

    4.1

    75.4

    3.9

    75.5

    1.9

    PASI90,%

    45.8

    2.9

    11.5

    0.7

    21.1

    0.9

    53.5

    1.3

    45.2

    0.5

    PASI100,%

    19.7

    0.9

    NA

    NA

    NA

    NA

    NA

    NA

    NA

    NA

    Riskad

    verseev

    entprofile

    AE

    63.6

    58.5

    56.0

    (n=415)

    51.0

    (n=414)

    47.5

    (n=670)

    48.3

    (n=270)

    82.0

    (n=298)

    71.0

    (n=76)

    68.8

    56.0

    (n=207)

    AEleadingto

    discontinuation,%

    1.6

    2.2

    2.3

    2.8

    1.2

    2.1

    9.1

    6.6

    5.1

    2.4

    SeriousAE,%

    1.8

    1.8

    2.1

    (n=96)

    6.5

    (n=46)

    NA

    NA

    5.7

    2.6

    2.9

    2.4

    Seriousnon-infectiousAE,%

    1.3

    0.9

    1.6

    1.5

    1.5

    1.0

    NA

    NA

    NA

    NA

    SeriousinfectiousAE,%

    0.5

    0.9

    0.2

    0.9

    0.1

    0.7

    1.0

    0NA

    NA

    *40mgevery

    otherweek.

    50mgweekly.

    50mgtw

    iceweekly.

    5mgkgatweeks

    0,2,6,thenevery

    8weeks.

    AE,adverseevent;NA

    ,notavailable;PASI,pso

    riasisareaandse

    verity

    index.

    2012 The AuthorJEADV 2012, 26 (Suppl. 2), 2129 Journal of the European Academy of Dermatology and Venereology 2012 European Academy of Dermatology and Venereology

    Effective, sustainable biologic treatment of psoriasis 27

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