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Sussexcds.co.ukD O I 1 0 . 1 1 1 1 / j . 1 3 6 5 - 2 1 3 3 . 2 0 0 5 . 0 6 8 9 3 . x British Association of Dermatologists guidelines for use ofbiological interventions in psoriasis 2005C.H. Smith, A.V. Anstey,* J.N.W.N. Barker, A.D. Burden, R.J.G. Chalmers,à D. Chandler,§ A.Y. Finlay,–C.E.M. Griﬁtths,à K. Jackson, N.J. McHugh,** K.E. McKenna, N.J. Reynoldsàà and A.D. Ormerod§§ (Chair ofGuideline 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.
àThe 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.
ààDepartment 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.
E-mail: firstname.lastname@example.org Psoriasis is a common, persistent, relapsing inflammatoryskin 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- biologics, efalizumab, etanercept, guideline, 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 C.H.S., grant ⁄ research trial support Wyeth, are expensive, and a proportion of patients has treatment- Serono, Schering Plough, consultant for Novartis; resistant disease.6 Biological therapies or ‘biologics’ describe J.N.W.N.B., consultant for Schering Plough, agents designed to block specific molecular steps important Wyeth, Biogen, Serono Novartis; grant ⁄ research in the pathogenesis of psoriasis and have emerged over the trial support Schering Plough, Wyeth, Biogen, last 3–5 years as potentially valuable alternative therapeutic Serono; A.D.B., consultant for Wyeth, Serono, Schering Plough; grant ⁄ research trial support Currently, biological therapies for psoriasis comprise two Wyeth, Serono; R.J.G.C., none; D.C., none; main groups: (i) agents targeting the cytokine tumour A.Y.F., consultant for Wyeth, Novartis, Serono, necrosis factor (TNF)-a (e.g. etanercept, infliximab, adal- imumab) and (ii) agents targeting T cells or antigen-present- grant ⁄ research support Biogen, Serono, Amgen, Centocor; previous consultant for Serono, Wyeth, Schering Plough; K.J., none; N.J.McH., consultant licensed in 2004 in the U.K. for patients with moderate to 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, These new treatments are relatively expensive and, given thewidespread patient dissatisfaction with standard treatments,2demand is likely to be high. Clinical experience of biologi-cal therapies in dermatology is relatively limited and their Ó 2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp486–497 Biological interventions for psoriasis, C.H. Smith et al. 487 role in the context of existing standard systemic therapies, A literature review was performed by searching EMBASE particularly with respect to efficacy and long-term toxicity, and Medline databases (1990 to April 2005) for clinical trials is uncertain. These guidelines have been developed to involving efalizumab, etanercept and infliximab using an ensure that this new class of therapy is introduced in a sys- agreed protocol. Two reviewers screened all titles and tematic and planned way to achieve the greatest possible abstracts independently, and full papers of relevant material benefit to people with psoriasis, to facilitate safe and effect- were obtained wherever possible. Papers included as evidence ive prescribing and to endorse the use of the British Associ- were scored for strength of evidence using the instruments ation of Dermatologists (BAD) Biological Therapy Register as currently recommended by the Scottish Intercollegiate Guide- a mechanism for collecting long-term safety and efficacy lines Network and the National Institute for Clinical Excel- data. The guideline group has sought to provide useful, lence (Appendix 1). Additional ad hoc searches were done to evidence-based guidance based on systematic review of address clinical questions that arose during the development available literature, but acknowledges that additional funding of the guideline, and evidence was appraised in the same may be required to implement guideline recommendations These guidelines have been prepared for dermatologists on These guidelines were developed in accordance with a behalf of the BAD and reflect the best data available at the predetermined scope, agreed by the guideline working time the report was prepared. Caution should be exercised group, and are as detailed below. For practical reasons, in interpreting the data; the results of future studies may guidance is given only on those treatments that are currently require alteration of the conclusions or recommendations in licensed for use in psoriasis in the U.K. (etanercept, this report. It may be necessary or even desirable to depart efalizumab) and infliximab. Although infliximab is currently from the guidelines in the interests of specific patients and unlicensed for use in psoriasis, a licence is anticipated in special circumstances. Just as adherence to guidelines may the near future, it is widely available, and it is currently the not constitute defence against a claim of negligence, so most extensively used biological therapy in dermatology deviation from them should not necessarily be deemed Specific, evidence-based, recommendations cover the follow- This field of therapeutics is in a rapid phase of development, and revision of the scope and content of these guidelines will • 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 stoppingtherapy Most patients with moderate to severe disease achieve satisfac-tory disease control (i.e. significant or complete clearing ofdisease) in the short term with at least one of the systemic • Agents licensed for use outside the U.K. (e.g. alefacept) or frequently requires some form of continuous therapy and in clinical development for psoriasis (e.g. adalimumab) consequent, predictable risks of toxicity. At present, the risks • Use of biological therapies in children and benefits of anti-TNF agents, or efalizumab, relative to • Use of biological therapies for indications other than psori- 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 licensedindications for etanercept or efalizumab.
To draw up eligibility criteria, ‘severe’ disease requires defi- This guideline has been developed using BAD recommended nition and should encompass objective measures of disease methodology and the AGREE (Appraisal of Guidelines for severity and the impact the disease has on quality of life.
Research and Evaluation) instrument. The guideline working All existing disease severity assessment tools are imper- group represents all relevant stakeholders including nurses, fect,7,8 and most require some training to complete. The rheumatologists and patients. Draft guidance was made avail- Psoriasis Area and Severity Index (PASI) score has been able for consultation and review by patients and the BAD chosen for the purposes of this guideline as it has been widely used in clinical trials including those investigating Ó 2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp486–497 488 Biological interventions for psoriasis, C.H. Smith et al.
biological therapies. Furthermore, it is a validated measure The Dermatology Life Quality Index (DLQI) is a validated of disease severity in chronic plaque psoriasis and is also tool for the measurement of quality of life across all skin appropriate to use as an objective measure of disease diseases in both trial and clinical practice settings9 and a score response.7 A PASI score of > 10 (range 0–72) has been of > 10 (range 0–30) has been shown to correlate with at shown to correlate with a number of indicators commonly least ‘a very large effect’ on an individual’s quality of associated with severe disease such as need for hospital admission or use of systemic therapy.8 Where the PASI Patients with psoriasis may be considered eligible to receive is not applicable (e.g. pustular psoriasis), affected body treatment with a biological intervention when they fulfil the surface area (BSA) should be used, with severe disease eligibility criteria as set out. However, the decision to proceed with treatment must be made in collaboration with the patientand must include a careful assessment of the associated risksand benefits.
To be considered eligible for treatment, patients must have severe These treatments should be made available to all those disease as defined in (a) and fulfil one of the clinical categories patients fulfilling the currently recommended eligibility cri- teria. However, given (a) that few dermatologists have experi- (a) Severe disease is defined as a PASI score of 10 or more (or a ence of their use in clinical practice, (b) the need to ensure BSA of 10% or greater where PASI is not applicable) and a DLQI > collection of long-term data on efficacy and safety, and, (c) 10. Disease should have been severe for 6 months, resistant to in the short term at least, to ensure that these agents are only treatment and the patient should be a candidate for systemic ther- used when alternative standard therapies are inappropriate, it apy. In exceptional circumstances (for example, disabling acraldisease), patients with severe disease may fall outside this defini- is essential that all those which prescribed strictly to guide- tion but may be considered for treatment. (Strength of recommendation lines on prescribing practice and participate in the registration Treatment should be initiated and monitored by consultant dermatologists experienced in managing difficult psoriasis.
(b) fulfil at least one of the following clinical categories (Strength This should include knowledge and experience of standard of recommendation B, level of evidence 1++ and formal consensus): therapies and management of those who fail to respond.
(i) have developed or are at higher than average risk of devel- They must be familiar with, and ⁄ or have access to health oping clinically important drug-related toxicity and where alter-native standard therapya cannot be used care professionals trained in the use of the tools recommen- (ii) are or have become intolerant to or cannot receive standard (iii) are or have become unresponsive to standard therapyb Supervising consultants will be responsible for ensuring (iv) have disease that is only controlled by repeated inpatient that all patients receiving therapy are registered with the BAD Biological Therapy Register throughout the treatment (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 There are two anti-TNF agents in current use for psoriasis in Rheumatology (BSR) eligibility criteria for treatment with anti- the U.K., U.S.A. and Europe: etanercept (EnbrelÒ, Wyeth) and TNF agents,11 in association with skin disease infliximab (RemicadeÒ, Schering-Plough).
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 Etanercept is a human recombinant TNF receptor p75 fusion clinical response (a less than 50% improvement in baseline PASI protein, formed by the fusion of the extracellular ligand-bind- score or percentage BSA where the PASI is not applicable, and aless than 5-point improvement in DLQI) to at least 3 months of ing domain of human TNF receptor-2 (TNFR2 ⁄ p75) to the Fc treatment in the therapeutic dose range to the following treat- domain of human IgG1. It also binds soluble and membrane- ments: ciclosporin 2Æ5–5 mg kg)1 daily; methotrexate single bound TNF-a with high specificity and affinity, preventing its weekly dose (oral, subcutaneous, intramuscular) 15 mg, max 25– binding to cell surface receptors and thus inhibiting its proin- 30 mg; acitretin 25–50 mg daily; narrowband UVB or psoralen flammatory effects. In comparison with infliximab, etanercept photochemotherapy (nonresponse, rapid relapse or exceeding forms less stable complexes with membrane-bound TNF and recommended maximum doses) 150–200 treatments for PUVA, monomeric TNF, but it does bind significantly with the tri- Ó 2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp486–497 Biological interventions for psoriasis, C.H. Smith et al. 489 Infliximab is a human murine (25% murine) chimeric weekly. Although the percentage of patients achieving and monoclonal IgG1 isotype antibody with a high binding affin- maintaining remission is greater with the higher dose, this ity, avidity and specificity for TNF-a. It forms stable com- needs to be balanced against increased cost and risk of toxic- plexes with all forms of soluble and transmembrane TNF-a.
All the trials in psoriasis have been performed as mono- therapy. In rheumatoid arthritis, however, etanercept has been 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, themajority of whom had received previous systemic treatment or Two randomized, placebo-controlled trials have been conduc- PUVA, indicate that etanercept is an effective treatment for ted in patients with moderate to severe, stable chronic plaque chronic plaque psoriasis. Efficacy is dose related, with 34% and psoriasis. The larger study included patients who had received 49% of patients receiving 25 mg and 50 mg twice weekly, at least one systemic therapy prior to study entry.18,19 Both respectively, achieving > 75% improvement in PASI (PASI 75 trials demonstrated infliximab therapy to be highly effective at response) after 12 weeks of treatment. Continued treatment inducing disease remission. The onset of improvement occurs appears to improve response rates further, so that at 24 weeks, within the first 2–4 weeks of treatment and reaches maximum 44% and 59% of patients receiving 25 mg and 50 mg twice benefit by week 10 in the majority. Of patients receiving a weekly, respectively, achieved a PASI 75 response. Studies up standard induction course of therapy (5 mg kg)1 at weeks 0, to a year show sustained efficacy over time, with no evidence 2 and 6) 87% achieved a PASI 75 response. Time to relapse of loss of efficacy with interrupted, repeat dosing.
following successful ‘induction’ therapy is highly variable Time to relapse, when defined as a 50% drop in the between individuals, and may depend on the initial dose improvement in PASI achieved after 24 weeks of therapy, ran- given: 73% of those given 10 mg kg)1 during induction ged from 70 to 91 days and appeared to be dose related (i.e.
maintained at least a 50% improvement in PASI scores at week remission was maintained for slightly longer in the high dose 26 compared with 40% of those given 5 mg kg)1.18,20 group as compared with the low dose group). Of patients There are no RCTs or other controlled trials examining treat- achieving a PASI 75 response at 24 weeks of therapy, 11% ment efficacy of infliximab in patients with recalcitrant disease or in other forms of psoriasis. Nevertheless, several case series Treatment response in severe, recalcitrant disease, erythro- indicate infliximab monotherapy to be of benefit in patients dermic, pustular or other forms of psoriasis is unknown.
previously resistant to multiple systemic therapies21–25 andthere are several case reports documenting efficacy in severeunstable psoriasis and generalized pustular psoriasis.26,27 Clin- ical experience within the guideline group further supports the Etanercept is given as a self-administered subcutaneous injec- value of infliximab in these clinical circumstances.
tion and is licensed for use at both 25 mg and 50 mg twice Infliximab is given by intravenous infusion over a period of • Etanercept is effective in the treatment of chronic plaque psori- 2 h. Dosing schedules vary according to the disease being asis, with 38% and 54% of patients clear or nearly clear of diseaseafter 12 weeks of treatment (25 mg twice weekly, 50 mg twice treated, and have not been optimized for psoriasis. A standard weekly, respectively). (Strength of recommendation A, level of evidence 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 • The current licence recommends intermittent courses no longer No studies have established the optimal frequency or dose of than 24 weeks, with the time to relapse being variable (around repeat infusions required to achieve disease control. There is a 12 weeks) and with similar response rates achieved with repeat suggestion, however, that once significant disease relapse has occurred, repeat infusions do not achieve the same rate of dis- • Treatment should normally be initiated at 25 mg subcutane-ously, twice weekly. However, response is dose dependent and the ease clearance as that seen on the initial three-dose induction chances of responding to treatment are greater with 50 mg twice treatment.18,20 This latter possibility is supported by findings weekly. The choice of the higher dose should be made based on an in Crohns disease, where the risk of developing treatment individual patient basis. (Strength of recommendation B extrapolated from level resistance to infliximab is reduced with maintenance (rather than as-required) infusions. In clinical practice, the risks of • Treatment may be continued according to clinical need, although maintenance infusions must be balanced against the risks asso- long-term efficacy is only established in psoriasis for up to 2 years.
ciated with disease relapse. For those patients with, for exam- (Strength of recommendation D, level of evidence 3).
ple, severely unstable disease, the benefits of maintaining Ó 2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp486–497 490 Biological interventions for psoriasis, C.H. Smith et al.
disease control may outweigh risks associated with continued comprise erythema, oedema and bruising, resolve spontane- ously within 2–3 days, and tend to occur in the first monthof therapy. Tolerance develops in most patients with contin-ued use.
Antibodies to etanercept may develop in up to 6% of patients but Large trials in rheumatoid arthritis have demonstrated thera- data on the clinical relevance of these are scarce.29 peutic benefits of infliximab in combination with methotrex-ate. The benefit of infliximab in combination with other agents Infliximab. Infusion reactions occurring during or within 1–2 h of in psoriasis is not established. Evidence from case series and treatment affect up to 20% of all patients treated and rarely clinical experience in psoriasis suggest that it can be given in may result in anaphylactic shock. Management of reactions combination with a number of systemic agents including met- will depend on the degree of severity. For mild to moderate hotrexate, ciclosporin, acitretin and hydroxycarbamide.21,23 reactions, the infusion rate may be slowed or temporarily Circumstances where combination therapy may be used interrupted until symptoms disappear, and symptomatic treat- include when infliximab monotherapy has proved ineffective ment given as appropriate (antihistamines, hydrocortisone, or, on initiation of therapy, where suddenly discontinuing paracetamol). For more severe reactions, further infliximab is existing standard therapy might result in unstable disease.
contraindicated, but does not necessarily preclude treatmentwith other anti-TNF agents.31 Antibodies to infliximab may develop during therapy. The fre- quency of infusion reactions is approximately 2–3 times higher in those with antibodies compared with those without, • Infliximab is effective in the treatment of chronic plaque psori- although overall, the presence of antibodies is poorly predic- asis, with 90% of patients becoming clear or minimally affected at tive of infusion reactions. The clinical significance of antibody 10 weeks following 5 mg kg)1 at weeks 0, 2 and 6. (Strength of development with respect to treatment outcome, and factors recommendation A, level of evidence 1++).
• Infliximab therapy may be initiated at a dose of 5 mg kg)1 at that increase risk of their development, are not established in weeks 0, 2 and 6 and subsequent maintenance infusions (either psoriasis.19,20 In other diseases, antibodies have been asso- 5 mg kg)1 or 3 mg kg)1) given at 8-week intervals depending on ciated with a poorer therapeutic outcome, and risk of clinical need and circumstances. (Strength of recommendation A, level of their development is reduced by giving continuous therapy (as opposed to episodic treatments), and concomitant metho- • In those patients who respond to therapy, regular maintenance infusions may avoid the risk of loss of efficacy seen in somepatients receiving intermittent as-required repeat infusions on dis-ease relapse. (Strength of recommendation D, level of evidence 3).
• Infliximab may also be of value in recalcitrant or unstable dis-ease and in generalized pustular psoriasis. (Strength of recommendation although infections are common, overall the rates of infec- • Concomitant systemic therapies may be indicated for some pati- tion with these agents are no greater than with placebo.
ents with very severe or unstable psoriasis, although doses of these However, serious and opportunistic infections have been should be minimized. (Strength of recommendation D, level of evidence 3).
Tuberculosis may be a risk particularly associated with anti-TNF agents, as TNF-a plays a key role in host defence Adverse effects and toxicity: Anti-TNF therapies against mycobacterial infection, particularly in granulomaformation (and hence containment of Mycobacterium) and In general, infliximab and etanercept are well tolerated; inhibition of bacterial dissemination.38 A postmarketing sur- detailed information on side-effects can be found in the rele- veillance report in 200133,39 identified 70 cases of tubercu- vant summary of product characteristics (SPC).28,29 Infections and malignancy are a significant clinical concern arthritis, other forms of arthritis and Crohns disease out of although the actual associated risks are unknown, particularly an estimated total of 147 000 people treated. Onset of in psoriasis. Previous or concomitant immunosuppressant infection occurred early in treatment, with 48 of 70 treatment and PUVA therapy may compound such risks. Addi- patients developing infection within the first three infusions.
tional, serious potential toxicities include demyelinating dis- Most patients were also receiving one or more immunosup- pressive agents (methotrexate, ciclosporin, azathioprine orcorticosteroids). More than half had extrapulmonary disease, Allergic reactions (infusion ⁄injection site reactions) and and a quarter disseminated disease. Atypical and extensive infection were thought to account for the high morbiditywith at least four deaths directly attributed to tuberculosis Etancercept. Injection site reactions are the most frequently reported infection. Most were assumed to be due to reactivation of adverse event, and occur in 10–20% of patients.29,30 These latent infection as only a minority reported exposure to Ó 2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp486–497 Biological interventions for psoriasis, C.H. Smith et al. 491 tuberculosis and all had been living in the U.S.A. for at for heart disease were absent in 50% of cases, and complete least 10 years. Based on this report, the risk of tuberculosis resolution or substantial improvement of symptoms seen on with infliximab has been estimated to be approximately six withdrawal of drug in younger patients (< 50 years).
times that of untreated patients.39 Risks of tuberculosis withetanercept may be less.36,37 Only nine cases had beenreported to the U.S. Food and Drug Administration (FDA) at the time of the report, with similar total numbers of • Anti-TNF agents should be avoided in patients with severe patients receiving treatment. Although no cases of tuber- (NYHA class III or IV) congestive heart failure. (Strength of recommen- culosis have been reported in clinical trials of either inflix- imab or etanercept in psoriasis, this probably reflects the • Those with milder disease should be carefully assessed prior to limited numbers of patients treated and, possibly, mono- treatment, and treatment withdrawn at the onset of new symp- toms or worsening of pre-existing heart failure. (Strength of recom- Other serious infections reported include sepsis secondary to Listeria monocytogenes35 and histoplasmosis.34,36,37 Most ofthese cases have occurred in association with infliximab treat-ment and, in most instances, additional immunosuppressant Safety data so far do not indicate increased rates of malig- Risks of anti-TNF treatment in the context of human immu- nancy, including lymphoproliferative disorders, over the nodeficiency virus (HIV) infection are unknown, but severe normal rates in the population. Patients who have received disseminated opportunistic infections have been reported in PUVA therapy may represent a particular at-risk group.
TNF blockers as a class may be associated with the develop-ment of, or worsening of demyelinating disease. Lenercept, • Actual risks of serious infections are unknown, particularly in a soluble p55 receptor developed for the treatment of mul- those with psoriasis. Concomitant treatment with immunosuppres-sants or HIV infection may increase any risk. (Strength of recommenda- tiple sclerosis, was withdrawn from further development due to increasing severity and duration of symptoms in clinical • Reactivation of tuberculosis may occur following treatment trial subjects. Worsening of multiple sclerosis with inflixim- with anti-TNF agents, and the risks are greatest with infliximab.
ab and at least four cases of demyelination with etanercept There appears to be a disproportionate risk of nonpulmonary and (all of which resolved on drug cessation) have also been disseminated infection. (Strength of recommendation D, level of evidence 3).
• Patients with evidence of either active tuberculosis or previous,inadequately treated tuberculosis should receive antituberculoustreatment prior to anti-TNF therapy.41,42 (Strength of recommendation Table 1 New York Heart Association classification of heart failure No limitations. Ordinary physical activity does not cause fatigue, breathlessness or palpitations (asymptomatic left Possible risks of anti-TNF therapy in the context of heart fail- ventricular dysfunction is included in this category) ure were first highlighted when trials in severe congestive car- Slight limitation of physical activity. Such patients are comfortable at rest. Ordinary physical activity results in diac failure [New York Heart Association (NYHA) class III and fatigue, palpitation, breathlessness or angina pectoris IV, left ventricular ejection fraction < 35%; Table 1] were (symptomatically ‘mild’ heart failure) prematurely discontinued due to failure to show benefit in the Marked limitation of physical activity. Although patients case of the etanercept studies, and an excess mortality with are comfortable at rest, less than ordinary physical high-dose infliximab.43 Clinical trial data in psoriasis and activity will lead to symptoms (symptomatically other diseases show no excess risk of heart failure although selection bias (i.e. exclusion of those at risk) may account for Inability to carry on any physical activity without discomfort. Symptoms of congestive cardiac failure are this. Forty-seven spontaneous reports to the FDA of new onset present even at rest. With any physical activity increased or worsening of pre-existing heart failure following either inf- discomfort is experienced (symptomatically ‘severe’ liximab or etanercept were recently reviewed in detail.44 The possibility of drug-induced pathology was supported by an apparent temporal association between introduction of drug Patients with heart failure may have a number of symptoms, and onset of symptoms (median onset 3 months with inflix- the most common being breathlessness, fatigue, exercise intoler-ance and fluid retention.
imab, 8Æ5 months with etanercept). Pre-existing risk factors Ó 2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp486–497 492 Biological interventions for psoriasis, C.H. Smith et al.
to LFA-1, efalizumab inhibits multiple pathogenic steps in psoriasis: T-cell activation, cutaneous T-cell trafficking and • Infliximab and etanercept should not be given to people with a history of demyelinating disease or optic neuritis and treatmentshould be withdrawn if neurological symptoms develop. (Strengthof recommendation D, level of evidence 4).
Antinuclear antibodies and lupus–like syndromes Four large phase III studies involving over 2000 patients with Antinuclear antibodies and, less commonly, anti-double-stran- moderate to severe plaque psoriasis, most of whom had ded DNA antibodies may develop during therapy, but do not received previous systemic therapy for psoriasis, have been seem to be associated with symptoms or signs of lupus in the published in full.49–52 Overall, efalizumab appears to be vast majority. Syndromes resembling drug-induced lupus have effective in chronic plaque psoriasis, with 27% of patients been reported and usually resolve on treatment withdrawal.
receiving efalizumab 1 mg kg)1 weekly achieving a PASI 75response vs. 4% in the placebo group by week 12, and19–32% achieving a physician’s global assessment of clear or almost clear. Continuing therapy beyond 12 weeks may Rare cases of severe hepatitic reactions following infliximab increase the response rate further.51,52 In one study, 20% of therapy have been reported to the FDA (35 spontaneous patients who failed to achieve a PASI 75 response following reports received up to December 2004), with the onset of 12 weeks of treatment did so after a further 12 weeks of treat- symptoms or signs occurring from 2 weeks to more than a ment as compared with 7% who received placebo.
year after initiation of treatment. A safety alert issued in Duration of remission following discontinuation of therapy December 2004 by Centocor recommends that infliximab is variable. In one study approximately 30% of patients main- treatment be stopped in the event of jaundice and ⁄ or marked tained at least a 50% improvement in PASI score for the elevations (> 5 times upper limit of normal) in liver enzymes.
12-week follow-up period. Discontinuation of treatment may The safety of TNF blockers in patients with chronic hepatitis be associated with an exacerbation of psoriasis including B and C is not known.46,47 Two limited studies of anti-TNF development of pustular or erythrodermic disease.
therapy in hepatitis C infection (a retrospective study of inflix-imab in 24 patients with rheumatoid arthritis and a phase II study examining efficacy of etanercept as an adjuvant to inter-feron and ribavirin in the treatment of hepatitis C infection46) The licensed dose of efalizumab is 1 mg kg)1 weekly as a did not demonstrate any significant adverse effects on viral subcutaneous self-administered injection for 12 weeks follow- load or liver function tests. Data on use of TNF blockers in ing a first conditioning dose of 0Æ7 mg kg)1, with the recom- the context of hepatitis B infection are limited to case reports, mendation that treatment be continued only in those who where concomitant or prior antiviral treatment was reported respond (defined in the SPC as a physician’s global evaluation to be of benefit. However, recent consensus guidelines on use of good or better). Doses of 2 mg and 4 mg have also been of immunosuppressant therapy (not specifically anti-TNF investigated but do not confer any additional benefit. There is agents) in the context of hepatitis B recommend antiviral little information on the optimal dosing regimen for mainten- therapy prior to initiation of therapy or during treatment if ance of remission, although one long-term open-label study demonstrated maintenance of efficacy over a period of up to27 months with once-weekly doses of 1 mg kg)1.53 • The safety of TNF blockers in patients with chronic hepatitis B • Efalizumab is effective in the treatment of moderate to severe and C is not known. For patients known to be hepatitis B or C chronic plaque psoriasis, with approximately one third of patients positive, advice from a hepatologist should be sought prior to ini- treated becoming clear or almost clear after 12 weeks. (Strength of tiation of therapy. (Strength of recommendation D, level of evidence 4).
recommendation A, level of evidence 1++).
• Duration of remission is variable on discontinuing therapy andmay be associated with disease rebound. (Strength of recommendation D, level of evidence 4).
• The licensed weekly dose (1 mg kg)1) should be used andtreatment discontinued after 12 weeks in those who do not respond. (Strength of recommendation A, level of evidence 1++).
• Therapy may be continued according to clinical need although Efalizumab is a humanized form of a murine antibody direc- data on long-term efficacy are limited to 27 months. (Strength of ted against CD11a, the a subunit of leucocyte function-associ- recommendation D, level of evidence 4).
ated antigen-1 (LFA-1). In vitro studies indicate that by binding Ó 2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp486–497 Biological interventions for psoriasis, C.H. Smith et al. 493 mainly in nonresponders on discontinuation of treatment. Usu- ally this requires some systemic therapy for 6–8 weeks: for Safety data for efalizumab are more limited in terms of numbers speed of action ciclosporin has been recommended although of patients treated and duration of therapy when compared with other second-line modalities have been used. The flare usually what is known about anti-TNF therapies. However, in contrast settles and intervention for this can then be safely withdrawn.
to the safety data for infliximab and etanercept, all the informa-tion accrued for efalizumab is in patients with psoriasis.
Overall, efalizumab is well tolerated; detailed information on reported and potential adverse events are available in the There are no studies directly comparing the efficacy of SPC.54 As with any drug of this class, clinical concern exists infliximab, etanercept and efalizumab. Extrapolating data from over the potential risk of serious infection and malignancy.
short-term, placebo-controlled studies of each individual drug There is no evidence so far that the rates of serious infection suggests a possible rank order of efficacy, with infliximab being are increased. Similarly, rates of malignancy are no greater in the most effective and efalizumab the least effective at 12 weeks.
those treated compared with controls, but the data are too Over longer time periods, there is no robust evidence to indicate limited to assess this risk properly.
which agent is superior in terms of overall efficacy or safety,nor is there evidence to indicate that failure to respond to onebiological therapy precludes response to another.
Headache, fever, chills and myalgia commonly occur during the first few weeks of treatment but tend to resolve by thethird or fourth week of therapy.49–54 Safe prescribing of biological therapies requires good infra- structure and specialist nursing personnel. With additional This occurs uncommonly (between 1 in 500 and 1 in 1000 training a nurse may take responsibility for a number of the patients), so platelet counts should be monitored.
tasks outlined in the patient pathway including screening, treat-ment administration, patient education, prescription coordina-tion for home drug delivery, patient support, monitoring and data collection, e.g. PASI. A list of core competencies including A transient, acute, pruritic eruption occurs commonly between cannulation skills is suggested by the Royal College of Nursing weeks 4 and 10 in previously uninvolved flexural sites, and on for rheumatology nurses involved in biological therapies.55 the arms, neck and trunk. The eruption may be sudden andresemble pustules joining into plaques. This eruption is self- limiting and should be treated with topical steroids and notmistaken for a psoriasis flare. Flares of psoriasis are found Patients should be fully informed of the risks and benefits ofbiological therapies through detailed, collaborative discussionwith the supervising consultant and clinical nurse specialist.
Written information should be provided (available on theBAD website) and patients given adequate time to consider • Choice of agent efalizumab, etanercept or infliximab, will their decision. In clinical circumstances where these therapies depend on the clinical pattern of psoriasis, pre-existing comorbidi- are being used outside their licensed indications, written con- ty, patient preference, prescriber preference and local facilities.
• Etanercept should be considered first choice for patients with sig- nificant, uncontrolled psoriatic arthritis (refer to BSR guidelineshere,11 but for this guideline skin disease identifies patient need).
(Strength of recommendation D, level of evidence 4).
• For patients with stable psoriasis where a decision has been In the interest of acquiring long-term safety data a compre- made to treat with an anti-TNF agent, etanercept should be used hensive national register is proposed. Once this is operative unless there are clear reasons not to do so. (Strength of recommendation (expected in early 2006), all patients should be registered and D, level of evidence 4).
• Infliximab is useful in clinical circumstances requiring rapid dis- ease control, e.g. in unstable erythrodermic or pustular psoriasis,due to its very rapid onset of action and high response rate. (Strength of recommendation D, level of evidence 4).
• For patients with a high risk of latent tuberculosis (and therefore All patients should undergo a full clinical history, physical requiring tuberculosis prophylaxis) or with evidence of demyelinat- examination and further investigations as required, with par- ing disease, efalizumab should be considered first choice. (Strength of ticular reference to the known toxicity profile of the agent recommendation D, level of evidence 4).
Ó 2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp486–497 494 Biological interventions for psoriasis, C.H. Smith et al.
Table 2 Exclusion criteria for antitumour necrosis factor (TNF) agents Monitoring and assessment of disease response Patients should be seen at 12 weeks to determine whethertherapy should be continued, and thereafter at 3–6-monthly intervals. The need for monitoring biochemistry and haema- Active infections. High risk include:• chronic leg ulcers tology is less than that required for conventional drug therap- • persistent or recurrent chest infections ies (Table 3) with the exception of platelet counts for patients on efalizumab. However, regular review of the clinical status of the patient is essential to ensure early detection of adverse Malignancy or premalignancy states excluding: • adequately treated non-melanoma skin cancer• malignancies diagnosed and treated more than 10 years previously (where the probability of total cure is very high) Demyelinating diseaseaCongestive cardiac failurea This is defined as a 50% or greater reduction in baseline PASI (New York Heart Association grade III or IV, see Table 1) score (or percentage BSA where the PASI is not applicable) and a 5-point or greater improvement in DLQI within • Psoralen + ultraviolet A therapy > 200 treatments, especially 3 months of initiation of treatment.7,9,10 Where arthritis has determined eligibility for treatment, • Human immunodeficiency virus-positive or AIDS please refer to the BSR guideline for psoriatic arthritis for the aThese apply to anti-TNF agents only.
Specific exclusion criteria and recommended pretreatment Therapy should be withdrawn after 3 months if there has not investigations are listed in Tables 2 and 3. Assessment for risk been at least a 50% improvement in baseline PASI score (or of tuberculosis in patients considered for anti-TNF therapy is percentage BSA where the PASI is not applicable) and a 5-point or greater improvement in DLQI.
Table 3 Recommended pretreatment and monitoring investigations DemyelinationbHeart failurebMalignancy (including skin) PASI, Psoriasis Area and Severity Index; DLQI, Dermatology Life Quality Index; BSR, British Society for Rheumatology. aAdditional assessmentand monitoring may be required in patients on concomitant therapy or in certain clinical circumstances. bApplies to tumour necrosis factorblockers only.
Ó 2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp486–497 Biological interventions for psoriasis, C.H. Smith et al. 495 Abnormal CXR suggestive of TB or
Requires stratification for
TB risk. Refer to British
Guidelines and/or refer to
for TB risk
for TB risk
Adapted from guidelines issued by Joint Tuberculo sis Committee of the British Thoracic Society42 The three most important risk factors for TB infection are ethnicity, age (> 55 years) and, for those born outside the U.K., the length of time since first entry to the U.K. 2.
Although the summary of product characteristics for infliximab (but not that for etanercept) recommends skin testing prior to therapy, tuberculin skin testing may be unreliable (i.e. falsely negative) in those who are immunocompromised and/or systemically unwell. In this instance the risk of chemoprophylaxis (principally hepatitis) has to be balanced against the risk of developing TB during the therapy and should be assessed by a thoracic or infectious disease physician. 3. Clinical awareness of the possibility of TB should be maintained throughout anti-TNF therapy and for a period of 6 months after cessation.
CXR, chest X-ray; BCG, bacille Calmette-Guérin vaccination. Fig 1. Algorithm for assessment and management of tuberculosis (TB) in patients scheduled for antitumour necrosis factor (TNF) therapy.
Withdrawal of therapy is also indicated due to the develop- ment of a serious adverse event. Adverse events which mayjustify the withdrawal of treatment include the following: The guideline was produced by the BAD independently malignancy (excluding nonmelanoma skin cancer); severe of any funding body although the BAD does receive fund- drug-related toxicity; pregnancy (temporary withdrawal); ing for its annual meeting from numerous commercial severe intercurrent infection (temporary withdrawal); major sponsors including the manufacturers of the biological surgical procedures (temporary withdrawal in accordance with Ó 2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp486–497 496 Biological interventions for psoriasis, C.H. Smith et al.
22 Chan JJ, Gebauer K. Treatment of severe recalcitrant plaque psori- asis with single-dose intravenous tumour necrosis factor-alpha 1 Sampogna F, Sera F, Abeni D. Measures of clinical severity, quality antibody (infliximab). Australas J Dermatol 2003; 44:116–20.
of life, and psychological distress in patients with psoriasis: a clus- 23 Gach JE, Berth-Jones J. Successful treatment of recalcitrant psoriasis ter analysis. J Invest Dermatol 2004; 122:602–7.
with a combination of infliximab and hydroxyurea. J Dermatolog 2 Stern RS, Nijsten T, Feldman SR et al. Psoriasis is common, carries a substantial burden even when not extensive, and is associated 24 Ogilvie AL, Antoni C, Dechant C et al. Treatment of psoriatic arthri- with widespread treatment dissatisfaction. J Invest Dermatol Symp Proc tis with antitumour necrosis factor-alpha antibody clears skin lesions of psoriasis resistant to treatment with methotrexate. Br J 3 Kirby B, Richards HL, Woo P et al. Physical and psychologic meas- ures are necessary to assess overall psoriasis severity. J Am Acad Der- 25 Feletar M, Brockbank JE, Schentag CT et al. Treatment of refractory psoriatic arthritis with infliximab: a 12 month observational study 4 Choi J, Koo JY. Quality of life issues in psoriasis. J Am Acad Dermatol of 16 patients. Ann Rheum Dis 2004; 63:156–61.
26 Newland MR, Weinstein A, Kerdel F. Rapid response to infliximab 5 Rapp SR, Feldman SR, Exum ML et al. Psoriasis causes as much dis- in severe pustular psoriasis, von Zumbusch type. Int J Dermatol ability as other major medical diseases. J Am Acad Dermatol 1999; 27 Benoit S, Toksoy A, Brocker E-B et al. Treatment of recalcitrant pus- 6 Griffiths CEM, Clark CM, Chalmers RJG et al. A systematic review tular psoriasis with infliximab: effective reduction of chemokine of treatments for severe psoriasis. Health Technol Assess 2000; expression. Br J Dermatol 2004; 150:1009–12.
28 Schering-Plough. Infliximab (Remicade) Summary of Product Characteristics, 7 Ashcroft DM, Li Wan Po A, Williams HC, Griffiths CEM. Clinical measures of disease severity and outcome in psoriasis: a critical 29 Wyeth Pharmaceuticals. Enbrel. Summary of Product Characteristics, 2004.
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30 Zeltser R, Valle L, Tanck C et al. Clinical, histological, and immuno- 8 Finlay AY. Current severe psoriasis and the Rule of Tens. Br J Der- phenotypic characteristics of injection site reactions associated with etanercept: a recombinant tumor necrosis factor alpha receptor: Fc 9 Lewis V, Finlay AY. Ten years experience of the Dermatology Life fusion protein. Arch Dermatol 2001; 137:893–9.
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31 Chew A-L, Bennett A, Smith CH et al. Successful treatment of 10 Hongbo Y, Thomas CL, Harrison MA et al. Translating the science severe psoriasis and psoriatic arthritis with adalimumab. Br J Derma- of quality of life into practice: what do Dermatology Life Quality Index scores mean? J Invest Dermatol 2005 (in press).
32 Phillips K, Husni ME, Karlson EW et al. Experience with etanercept 11 Kyle S, Chandler D, Griffiths CEM et al. Guideline for anti-TNF- in an academic medical center: are infection rates increased? Arthri- alpha therapy in psoriatic arthritis. [errata appear in Rheumatology (Oxford) 2005; 44:569 and Rheumatology (Oxford) 2005; 44:701].
33 Keane J, Gershon S, Wise RP et al. Tuberculosis associated with inf- Rheumatology (Oxford) 2005; 44:390–7.
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14 Mease PJ, Goffe BS, Metz J et al. Etanercept in the treatment of pso- 35 Slifman NR, Gershon SK, Lee JH et al. Listeria monocytogenes infection riatic arthritis and psoriasis: a randomised trial. Lancet 2000; as a complication of treatment with tumor necrosis factor alpha- neutralizing agents. Arthritis Rheum 2003; 48:319–24.
15 Gottlieb AB, Matheson RT, Lowe N et al. A randomized trial of 36 Wallis R, Broder M, Wong Y et al. Granulomatous infectious dis- etanercept as monotherapy for psoriasis. Arch Dermatol 2003; eases associated with tumor necrosis factor antagonists. Clin Infect 16 Leonardi CL, Powers JL, Matheson RT et al. Etanercept as mono- 37 Wallis R, Broder M, Wong Y et al. Granulomatous infections due therapy in patients with psoriasis. N Engl J Med 2003; 349:2014–22.
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20 Gottlieb AB, Chaudhari U, Mulcahy LD et al. Infliximab monothera- 41 Ormerod LP. Tuberculosis and anti-TNF-a treatment. Thorax 2004; py provides rapid and sustained benefit for plaque-type psoriasis.
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42 Ormerod LP and Joint Tuberculosis Committee of the British Thor- 21 Rongioletti F, Borenstein M, Kirsner R et al. Erythrodermic, recalcit- acic Society. Recommendations for assessing risk and for managing rant psoriasis: clinical resolution with infliximab. J Dermatolog Treat M. tuberculosis infection and disease in adult patients due to start anti-TNF-alpha treatment. Thorax 2005; in press.
Ó 2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp486–497 Biological interventions for psoriasis, C.H. Smith et al. 497 43 Anker SD, Coats AJS. How to RECOVER from RENAISSANCE? The significance of the results of RECOVER, RENAISSANCE, RENEWALand ATTACH. Int J Cardiol 2002; 86:123–30.
44 Kwon HJ, Cote TR, Cuffe MS et al. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann Intern Med2003; 138:807–11.
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Well-conducted meta-analyses, systematic reviews 46 Calabrese LH, Zein N, Vassilopoulos D. Safety of antitumour necro- sis factor (anti-TNF) therapy in patients with chronic viral infec- Meta-analyses, systematic reviews of RCTs, or tions: hepatitis C, hepatitis B, and HIV infection. Ann Rheum Dis High-quality systematic reviews of case–control 47 Furst DE, Breedveld FC, Kalden JR et al. Updated consensus state- ment on biological agents, specifically tumour necrosis factor a High-quality case–control or cohort studies with (TNFa) blocking agents and interleukin-1 receptor antagonist (IL-1 ra), for the treatment of rheumatic diseases, 2004. Ann Rheum 48 De Franchis R, Hadengue A, Lau G et al. EASL, International Con- Well-conducted case–control or cohort studies with a sensus Conference on Hepatitis B, 13-14 September, 2002 Geneva, low risk of confounding, bias or chance and a moderate Switzerland. Consensus statement (long version). J Hepatol 2003; 39 probability that the relationship is causal Case–control or cohort studies with a high risk 49 Lebwohl M, Tyring SK, Hamilton TK et al. A novel targeted T-cell of confounding, bias or chance and a significant modulator, efalizumab, for plaque psoriasis. N Engl J Med 2003; risk that the relationship is not causala Nonanalytical studies (e.g. case reports, case series) 50 Gordon KB, Papp KA, Hamilton TK et al. Efalizumab for patients with moderate to severe plaque psoriasis: a randomized controlled RCT, randomized controlled trial. aStudies with a level of evidence trial. [erratum appears in JAMA 2004; 291:1070]. JAMA 2003; ‘–’ should not be used as a basis for making a recommendation.
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• At least one meta-analysis, systematic review, or 53 Gottlieb AB, Hamilton TK, Caro I et al. Long term continuous RCT rated as 1++ , and directly applicable to the efalizumab therapy maintains efficacy and safety in patients with moderate to severe chronic plaque psoriasis: updated results from • A systematic review of RCTs or a body of evidence consisting principally of studies rated as 54 Serono Ltd. Raptiva 100 mg ⁄ ml [Summary of Product Characteristics]. Elec- 1+ , directly applicable to the target population and tronic Medicines Compendium 2004 (emc.medicines.org.uk), demonstrating overall consistency of results • Evidence drawn from a NICE technology appraisal 55 Royal College of Nursing. Assessing, Managing and Monitoring Biologic • A body of evidence including studies rated as 2++, Therapies for Inflammatory Arthritis. Guidance for Rheumatology Practitioners.
directly applicable to the target population and London: Royal College of Nursing, 2003.
demonstrating overall consistency of results, or • Extrapolated evidence from studies rated as • A body of evidence including studies rated as 2+ , directly applicable to the target population Level of evidence and strength of recommendation. The pub- and demonstrating overall consistency of results, lished studies selected from the search were assessed for their methodological rigour against a number of criteria as currently • Extrapolated evidence from studies rated as 2++ recommended by the National Institute for Clinical Excellence (NICE) and the Scottish Intercollegiate Guidelines Network.
The overall assessment of each study was graded using a code: ‘+ +’, ‘+’ or ‘–’, based on the extent to which the potential • A good practice point (GPP) is a recommendation for best practice based on the experience of theguideline development group Ó 2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp486–497
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