银屑病治疗指南-英国银屑病协会2005年最新版

GUIDELINES DOI 10.1111/j .1365-2133.2005.06893.x British Association of Dermatologists guidelines for use of biological interventions in psoriasis 2005 C.H. Smith, A.V. Anstey,* J.N.W.N. Barker, A.D. Burden,� R.J.G. Chalmers,� D. Chandler,§ A.Y. Finlay,– C.E.M. Grifitths,� K. Jackson, N.J. McHugh,** K.E. McKenna,�� N.J. Reynolds�� and A.D. Ormerod§§ (Chair of Guideline Group) St John’s Institute of Dermatology, GKT School of Medicine, St Thomas’ Hospital, London SE1 7EH, U.K. *Department of Dermatology, Royal Gwent Hospital, Newport NP20 2UB, U.K. �Department of Dermatology, Western Infirmary, Glasgow G11 6NT, U.K. �The Dermatology Centre, Hope Hospital, Salford, Manchester M6 8HD, U.K. §Psoriatic Arthropathy Alliance, PO Box 111, St Albans AL2 3JQ, U.K. –Department of Dermatology, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, U.K. **Royal National Hospital for Rheumatic Diseases, Upper Borough Walls, Bath BA1 1RL, U.K. ��Department of Dermatology, Belfast City Hospital, Belfast BT9 7AB, U.K. ��Department of Dermatology, University of Newcastle Medical School, Newcastle upon Tyne NE2 4HH, U.K. §§Department of Dermatology, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN, U.K. Correspondence Catherine H. Smith, E-mail: Catherine.smith@kcl.ac.uk or Anthony Ormerod, E-mail: a.d.ormerod@arh.grampian.scot.nhs.uk Accepted for publication 20 June 2005 Key words: biologics, efalizumab, etanercept, guideline, infliximab, psoriasis Conflicts of interest: C.H.S., grant ⁄ research trial support Wyeth, Serono, Schering Plough, consultant for Novartis; A.V.A., consultant for Schering Plough; J.N.W.N.B., consultant for Schering Plough, Wyeth, Biogen, Serono Novartis; grant ⁄ research trial support Schering Plough, Wyeth, Biogen, Serono; A.D.B., consultant for Wyeth, Serono, Schering Plough; grant ⁄ research trial support Wyeth, Serono; R.J.G.C., none; D.C., none; A.Y.F., consultant for Wyeth, Novartis, Serono, Amgen, Abbott; trial support; C.E.M.G., grant ⁄ research support Biogen, Serono, Amgen, Centocor; previous consultant for Serono, Wyeth, Schering Plough; K.J., none; N.J.McH., consultant for Aventis, Abbott; grant research support Wyeth; K.E.McK., none; N.J.R., grant ⁄ research support Serono; A.D.O., grant ⁄ research support Wyeth, Serono. Introduction Background Psoriasis is a common, persistent, relapsing inflammatory skin disease that can be associated with significant morbid- ity. Quality of life studies in psoriasis reveal a negative impact on patients comparable with that seen in cancer, arthritis and heart disease.1–5 Patients with severe disease constitute approximately 20–30% of all patients with psori- asis, often require systemic treatment, and represent a major economic burden to the Health Service. All standard systemic therapies for severe disease are asso- ciated with the potential for major long-term toxicity, many are expensive, and a proportion of patients has treatment- resistant disease.6 Biological therapies or ‘biologics’ describe agents designed to block specific molecular steps important in the pathogenesis of psoriasis and have emerged over the last 3–5 years as potentially valuable alternative therapeutic options. Currently, biological therapies for psoriasis comprise two main groups: (i) agents targeting the cytokine tumour necrosis factor (TNF)-a (e.g. etanercept, infliximab, adal- imumab) and (ii) agents targeting T cells or antigen-present- ing cells (e.g. efalizumab, alefacept). Two of these, etanercept (Enbrel�) and efalizumab (Raptiva�) were licensed in 2004 in the U.K. for patients with moderate to severe psoriasis. Need for a guideline These new treatments are relatively expensive and, given the widespread patient dissatisfaction with standard treatments,2 demand is likely to be high. Clinical experience of biologi- cal therapies in dermatology is relatively limited and their 486 � 2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp486–497 role in the context of existing standard systemic therapies, particularly with respect to efficacy and long-term toxicity, is uncertain. These guidelines have been developed to ensure that this new class of therapy is introduced in a sys- tematic and planned way to achieve the greatest possible benefit to people with psoriasis, to facilitate safe and effect- ive prescribing and to endorse the use of the British Associ- ation of Dermatologists (BAD) Biological Therapy Register as a mechanism for collecting long-term safety and efficacy data. The guideline group has sought to provide useful, evidence-based guidance based on systematic review of available literature, but acknowledges that additional funding may be required to implement guideline recommendations fully. Scope These guidelines were developed in accordance with a predetermined scope, agreed by the guideline working group, and are as detailed below. For practical reasons, guidance is given only on those treatments that are currently licensed for use in psoriasis in the U.K. (etanercept, efalizumab) and infliximab. Although infliximab is currently unlicensed for use in psoriasis, a licence is anticipated in the near future, it is widely available, and it is currently the most extensively used biological therapy in dermatology clinical practice. Inclusions Specific, evidence-based, recommendations cover the follow- ing clinical areas: • Use of infliximab, etanercept and efalizumab in adult patients with psoriasis and, when relevant, psoriatic arthritis • Which patients should be considered eligible for treatment • Who should prescribe therapy and how to do so • Definition of disease response and indications for stopping therapy Exclusions • Agents licensed for use outside the U.K. (e.g. alefacept) or in clinical development for psoriasis (e.g. adalimumab) • Use of biological therapies in children • Use of biological therapies for indications other than psori- asis Methods This guideline has been developed using BAD recommended methodology and the AGREE (Appraisal of Guidelines for Research and Evaluation) instrument. The guideline working group represents all relevant stakeholders including nurses, rheumatologists and patients. Draft guidance was made avail- able for consultation and review by patients and the BAD membership prior to publication. A literature review was performed by searching EMBASE and Medline databases (1990 to April 2005) for clinical trials involving efalizumab, etanercept and infliximab using an agreed protocol. Two reviewers screened all titles and abstracts independently, and full papers of relevant material were obtained wherever possible. Papers included as evidence were scored for strength of evidence using the instruments currently recommended by the Scottish Intercollegiate Guide- lines Network and the National Institute for Clinical Excel- lence (Appendix 1). Additional ad hoc searches were done to address clinical questions that arose during the development of the guideline, and evidence was appraised in the same manner. Limitations of the guideline These guidelines have been prepared for dermatologists on behalf of the BAD and reflect the best data available at the time the report was prepared. Caution should be exercised in interpreting the data; the results of future studies may require alteration of the conclusions or recommendations in this report. It may be necessary or even desirable to depart from the guidelines in the interests of specific patients and special circumstances. Just as adherence to guidelines may not constitute defence against a claim of negligence, so deviation from them should not necessarily be deemed negligent. Plans for guideline revision This field of therapeutics is in a rapid phase of development, and revision of the scope and content of these guidelines will therefore occur on an annual basis. Which patients should be considered for biological therapy? Most patients with moderate to severe disease achieve satisfac- tory disease control (i.e. significant or complete clearing of disease) in the short term with at least one of the systemic agents currently available.6 Long-term disease control frequently requires some form of continuous therapy and consequent, predictable risks of toxicity. At present, the risks and benefits of anti-TNF agents, or efalizumab, relative to standard systemic therapy, are unknown. Early, widespread use of these agents in uncomplicated moderate to severe pso- riasis is inappropriate and is not supported by the licensed indications for etanercept or efalizumab. To draw up eligibility criteria, ‘severe’ disease requires defi- nition and should encompass objective measures of disease severity and the impact the disease has on quality of life. All existing disease severity assessment tools are imper- fect,7,8 and most require some training to complete. The Psoriasis Area and Severity Index (PASI) score has been chosen for the purposes of this guideline as it has been widely used in clinical trials including those investigating � 2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp486–497 Biological interventions for psoriasis, C.H. Smith et al. 487 biological therapies. Furthermore, it is a validated measure of disease severity in chronic plaque psoriasis and is also appropriate to use as an objective measure of disease response.7 A PASI score of > 10 (range 0–72) has been shown to correlate with a number of indicators commonly associated with severe disease such as need for hospital admission or use of systemic therapy.8 Where the PASI is not applicable (e.g. pustular psoriasis), affected body surface area (BSA) should be used, with severe disease defined as > 10% area affected.8 The Dermatology Life Quality Index (DLQI) is a validated tool for the measurement of quality of life across all skin diseases in both trial and clinical practice settings9 and a score of > 10 (range 0–30) has been shown to correlate with at least ‘a very large effect’ on an individual’s quality of life.7,8,10 Patients with psoriasis may be considered eligible to receive treatment with a biological intervention when they fulfil the eligibility criteria as set out. However, the decision to proceed with treatment must be made in collaboration with the patient and must include a careful assessment of the associated risks and benefits. Who should prescribe biological therapy? These treatments should be made available to all those patients fulfilling the currently recommended eligibility cri- teria. However, given (a) that few dermatologists have experi- ence of their use in clinical practice, (b) the need to ensure collection of long-term data on efficacy and safety, and, (c) in the short term at least, to ensure that these agents are only used when alternative standard therapies are inappropriate, it is essential that all those which prescribed strictly to guide- lines on prescribing practice and participate in the registration process. Treatment should be initiated and monitored by consultant dermatologists experienced in managing difficult psoriasis. This should include knowledge and experience of standard therapies and management of those who fail to respond. They must be familiar with, and ⁄or have access to health care professionals trained in the use of the tools recommen- ded for determining treatment eligibility and disease response. Supervising consultants will be responsible for ensuring that all patients receiving therapy are registered with the BAD Biological Therapy Register throughout the treatment period. Antitumour necrosis factor therapies There are two anti-TNF agents in current use for psoriasis in the U.K., U.S.A. and Europe: etanercept (Enbrel�, Wyeth) and infliximab (Remicade�, Schering-Plough). Pharmacology Etanercept is a human recombinant TNF receptor p75 fusion protein, formed by the fusion of the extracellular ligand-bind- ing domain of human TNF receptor-2 (TNFR2 ⁄p75) to the Fc domain of human IgG1. It also binds soluble and membrane- bound TNF-a with high specificity and affinity, preventing its binding to cell surface receptors and thus inhibiting its proin- flammatory effects. In comparison with infliximab, etanercept forms less stable complexes with membrane-bound TNF and monomeric TNF, but it does bind significantly with the tri- meric forms of soluble TNF. Eligibility criteria To be considered eligible for treatment, patients must have severe disease as defined in (a) and fulfil one of the clinical categories outlined in (b): (a) Severe disease is defined as a PASI score of 10 or more (or a BSA of 10% or greater where PASI is not applicable) and a DLQI > 10. Disease should have been severe for 6 months, resistant to treatment and the patient should be a candidate for systemic ther- apy. In exceptional circumstances (for example, disabling acral disease), patients with severe disease may fall outside this defini- tion but may be considered for treatment. (Strength of recommendation D, level of evidence 3). AND (b) fulfil at least one of the following clinical categories (Strength of recommendation B, level of evidence 1++ and formal consensus): (i) have developed or are at higher than average risk of devel- oping clinically important drug-related toxicity and where alter- native standard therapya cannot be used (ii) are or have become intolerant to or cannot receive standard systemic therapy (iii) are or have become unresponsive to standard therapyb (iv) have disease that is only controlled by repeated inpatient management (v) have significant, coexistent, unrelated comorbidity which precludes use of systemic agents such as ciclosporin or metho- trexate (vi) have severe, unstable, life-threatening disease (erythroder- mic or pustular psoriasis) (vii) have psoriatic arthritis fulfilling the British Society for Rheumatology (BSR) eligibility criteria for treatment with anti- TNF agents,11 in association with skin disease astandard systemic therapy includes acitretin, ciclosporin, metho- trexate, narrowband ultraviolet (UV) B and psoralen + UVA photochemotherapy (PUVA) bunresponsive to standard therapy is defined as an unsatisfactory clinical response (a less than 50% improvement in baseline PASI score or percentage BSA where the PASI is not applicable, and a less than 5-point improvement in DLQI) to at least 3 months of treatment in the therapeutic dose range to the following treat- ments: ciclosporin 2Æ5–5 mg kg)1 daily; methotrexate single weekly dose (oral, subcutaneous, intramuscular) 15 mg, max 25– 30 mg; acitretin 25–50 mg daily; narrowband UVB or psoralen photochemotherapy (nonresponse, rapid relapse or exceeding recommended maximum doses) 150–200 treatments for PUVA, 350 treatments for narrowband UVB.12,13 � 2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp486–497 488 Biological interventions for psoriasis, C.H. Smith et al. Infliximab is a human murine (25% murine) chimeric monoclonal IgG1 isotype antibody with a high binding affin- ity, avidity and specificity for TNF-a. It forms stable com- plexes with all forms of soluble and transmembrane TNF-a. Clinical effectiveness: etanercept Induction and maintenance of remission Several small phase II studies14,15 and two key phase III16,17 randomized controlled trials (RCTs) involving over 1000 patients with moderate to severe chronic plaque psoriasis, the majority of whom had received previous systemic treatment or PUVA, indicate that etanercept is an effective treatment for chronic plaque psoriasis. Efficacy is dose related, with 34% and 49% of patients receiving 25 mg and 50 mg twice weekly, respectively, achieving > 75% improvement in PASI (PASI 75 response) after 12 weeks of treatment. Continued treatment appears to improve response rates further, so that at 24 weeks, 44% and 59% of patients receiving 25 mg and 50 mg twice weekly, respectively, achieved a PASI 75 response. Studies up to a year show sustained efficacy over time, with no evidence of loss of efficacy with interrupted, repeat dosing. Time to relapse, when defined as a 50% drop in the improvement in PASI achieved after 24 weeks of therapy, ran- ged from 70 to 91 days and appeared to be dose related (i.e. remission was maintained for slightly longer in the high dose group as compared with the low dose group). Of patients achieving a PASI 75 response at 24 weeks of therapy, 11% remained in remission at 1 year. Treatment response in severe, recalcitrant disease, erythro- dermic, pustular or other forms of psoriasis is unknown. Dosing regimens Etanercept is given as a self-administered subcutaneous injec- tion and is licensed for use at both 25 mg and 50 mg twice weekly. Although the percentage of patients achieving and maintaining remission is greater with the higher dose, this needs to be balanced against increased cost and risk of toxic- ity. All the trials in psoriasis have been performed as mono- therapy. In rheumatoid arthritis, however, etanercept has been safely combined with methotrexate. Clinical effectiveness: infliximab Induction and maintenance of remission Two randomized, placebo-controlled trials have been conduc- ted in patients with moderate to severe, stable chronic plaque psoriasis. The larger study included patients who had received at least one systemic therapy prior to study entry.18,19 Both trials demonstrated infliximab therapy to be highly effective at inducing disease remission. The onset of improvement occurs within the first 2–4 weeks of treatment and reaches maximum benefit by week 10 in the majority. Of patients receiving a standard induction course of therapy (5 mg kg)1 at weeks 0, 2 and 6) 87% achieved a PASI 75 response. Time to relapse following successful ‘induction’ therapy is highly variable between individuals, and may depend on the initial dose given: 73% of those given 10 mg kg)1 during induction maintained at least a 50% improvement in PASI scores at week 26 compared with 40% of those given 5 mg kg)1.18,20 There are no RCTs or other controlled trials examining treat- ment efficacy of infliximab in patients with recalcitrant disease or in other forms of psoriasis. Nevertheless, several case series indicate infliximab monotherapy to be of benefit in patients previously resistant to multiple systemic therapies21–25 and there are several case reports documenting efficacy in severe unstable psoriasis and generalized pustular psoriasis.26,27 Clin- ical experience within the guideline group further supports the value of infliximab in these clinical circumstances. Dosing regimens Infliximab is given by intravenous infusion over a period of 2 h. Dosing schedules vary according to the disease being treated, and have not been optimized for psoriasis. A standard induction course (5 mg kg)1 at weeks 0, 2 and 6) may be followed by repeat single infusions at 8–12-week intervals.28 No studies have established the optimal frequency or dose of repeat infusions required to achieve disease control. There is a suggestion, however, that once significant disease relapse has occurred, repeat infusions do not achieve the same rate of dis- ease clearance as that seen on the initial three-dose induction treatment.18,20 This latter possibility is supported by findings in Crohns disease, where the risk of developing treatment resistance to infliximab is reduced with maintenance (rather than as-required) infusions. In clinical practice, the risks of maintenance infusions must be balanced against the risks asso- ciated with disease relapse. For those patients with, for exam- ple, severely unstable disease, the benefits of main