GUIDELINES

BJD

British Journal of Dermatology

British Association of Dermatologists guidelines for biologic interventions for psoriasis 2009
C.H. Smith, A.V. Anstey,* J.N.W.N. Barker, A.D. Burden, R.J.G. Chalmers, D.A. Chandler, A.Y. Finlay, C.E.M. Grifths, K. Jackson, N.J. McHugh,** K.E. McKenna, N.J. Reynolds and A.D. Ormerod (Chair of Guideline Group)
St Johns Institute of Dermatology, Kings College London and Guys and St Thomas NHS Foundation Trust, London SE1 9RT U.K. *Department of Dermatology, Royal Gwent Hospital, Newport NP20 2UB, U.K. Department of Dermatology, Western Inrmary, Glasgow G11 6NT, U.K. The Dermatology Centre, Salford Royal Hospital, University of Manchester, Manchester Academic Health Science Centre, Manchester M6 8HD, U.K. Psoriasis and Psoriatic Arthritis Alliance, PO Box 111, St Albans AL2 3JQ, U.K. Department of Dermatology, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, U.K. **Royal National Hospital for Rheumatic Diseases, Bath BA1 1RL, U.K. Department of Dermatology, Belfast City Hospital, Belfast BT9 7AB, U.K. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, U.K. Department of Dermatology, Aberdeen Royal Inrmary, Foresterhill, Aberdeen AB9 2ZB, U.K.

Correspondence
Catherine H. Smith, E-mail: [email protected] or Anthony Ormerod, E-mail: [email protected]

1.0 Background
Psoriasis is a common, chronic inammatory skin disease which typically follows a relapsing and remitting course, and is associated with joint disease in approximately 25% of patients.1 The signicant reduction in quality of life and the psychosocial disability suffered by patients underline the need for prompt, effective treatment, and long-term disease control (reviewed2,3). Localized, limited disease can usually be managed satisfactorily with topical agents. Those with moderate to severe disease often require systemic treatment. Phototherapy and traditional standard systemic therapies, while often effective, can be associated with long-term toxicity; some are expensive, and some patients have treatmentresistant disease.4 Also, phototherapy is not available to many due to geographical, logistical or other constraints. Patients themselves demonstrate high levels of dissatisfaction with standard approaches to treatment.5,6 Biologic therapies for psoriasis utilize molecules designed to block specic molecular steps important in the pathogenesis of psoriasis and now comprise a number of well-established, licensed, treatment options for patients with severe disease. Since 2005, when the British Association of Dermatologists (BAD) rst published guidance on the use of biologic therapies in psoriasis,7 much has changed. There is a substantial body of new evidence pertinent to the clinical use of these treatments, the U.K. National Institute for Health and Clinical Excellence (NICE) has approved the use of a number of biologic therapies in severe chronic plaque psoriasis and the BAD Biologic Interventions Register (BADBIR) has been successfully launched. Despite these developments, use of biologic therapy in clinical practice remains limited in the U.K., with a shortfall in funding cited as a signicant obstacle to prescribing in approximately 40% of units recently surveyed.8

Accepted for publication

25 August 2009

Key words
adalimumab, biologics, efalizumab, etanercept, guideline, iniximab, psoriasis, ustekinumab

Conicts of interest
C.H.S., invited speaker and grant research support Abbott, Janssen-Cilag, Schering-Plough, Serono, Wyeth; A.V.A., grant research support Abbott, Janssen-Cilag, Schering Plough, Serono, Wyeth; J.N.W.N.B., advisory boards for Abbott, Janssen-Cilag, Novartis, Schering-Plough, Wyeth; grant research support Abbott, Janssen-Cilag, Schering-Plough, Serono, Wyeth; A.D.B., advisory boards and grant research support Janssen-Cilag, Schering-Plough, Serono, Wyeth; R.J.G.C., none; D.A.C., none; A.Y.F., consultant for Galderma, Novartis, Schering-Plough, Serono, Wyeth, Pzer; joint copyright owner of the DLQI; C.E.M.G., advisory boards and invited speaker for Abbott, Janssen-Cilag, Merck-Serono, Novartis, Schering-Plough, UCB Pharma, Wyeth; grant research support Amgen, Centocor, Merck-Serono, Wyeth; K.J., advisory boards for Abbott, Schering-Plough; educational support Merck-Serono; N.J.McH., advisory boards for Janssen-Cilag, Schering-Plough; grant research support Abbott; K.E.McK., advisory boards for Abbott, Janssen-Cilag; N.J.R., advisory boards (nonpersonal) for Abbott, Basilea Pharmaceutica, Janssen-Cilag, Merck-Serono, Schering-Plough, Succinct Healthcare; grant research support Stiefel Laboratories, AstraZeneca; A.D.O., advisory boards for Abbott, Merck-Serono, ScheringPlough; grant research support Abbott, Janssen-Cilag, Serono, Wyeth. This is an updated guideline prepared for the BAD Clinical Standards Unit, made up of the Therapy & Guidelines Subcommittee (T&G) and the Audit & Clinical Standards Subcommittee (A&CS). Members of the Clinical Standards Unit are: H.K. Bell (Chairman T&G), L.C. Fuller (Chairman A&CS), N.J. Levell, M.J. Tidman, P.D. Yesudian, J. Lear, J. Hughes, A.J. McDonagh, S. Punjabi, S. Wagle, S.E. Hulley and M.F. Mohd Mustapa (BAD Clinical Standards Administrator and Information Scientist). Guidelines produced in 2005 by the British Association of Dermatologists; reviewed and updated June 2009.

DOI 10.1111/j.1365-2133.2009.09505.x

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988 Biologic interventions for psoriasis, C.H. Smith et al.

2.0 Purpose and scope

These guidelines have been revised and updated in accordance with a predetermined scope. This is based on the original scope used in 2005, and extended to include additional areas of practice. Recommendations in this guideline supersede those in the 2005 guideline. The overall objective of these guidelines is to provide up-to-date, evidence-based recommendations on use of biologic therapies (iniximab, adalimumab, etanercept, ustekinumab) in adults and children with all types of psoriasis and, where relevant, psoriatic arthritis, for clinical staff involved in the care of patients treated with biologic therapies. Efalizumab remains in the scope of the guideline in relation to safety only, given that the European Medicines Agency has withdrawn the marketing authorization of this drug because of concerns over the development of progressive multifocal leukoencephalopathy (PML).

dence tables. Evidence on safety was extracted from literature on use of biologic agents for any indication in view of the relatively limited data specically relating to use in psoriasis. The methodological limitations of the safety analysis are detailed in section 15. The guideline was peer reviewed by the Clinical Standards Unit of the BAD (made up of the Therapy & Guidelines and Audit & Clinical Standards Subcommittees) prior to publication.

6.0 Limitations of the guideline

These guidelines have been prepared on behalf of the BAD and reect 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 specic 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.

3.0 Exclusions
This guidance does not cover agents licensed outside the U.K. (alefacept) or use of biologic therapies for indications other than psoriasis and psoriatic arthritis.

7.0 Plans for guideline revision

This eld of psoriasis biologic therapeutics is in a rapid phase of development, and revision of the scope and content of the guidelines will therefore occur on an annual basis. Where necessary, the guideline will be updated via the BAD website, and a fully revised version is planned for 2012.

4.0 Stakeholder involvement

The guideline working group represents all relevant stakeholders including dermatologists, nurses, rheumatologists and patients. Draft guidance was made available for consultation and review by patients, the BAD membership and the British Dermatological Nursing Group (BDNG). Advice relating to tuberculosis was reviewed and approved by the British Thoracic Society.

8.0 Which patients should be considered eligible for treatment?

Most patients with moderate to severe disease achieve satisfactory disease control (i.e. signicant or complete clearing of disease) in the short term with at least one of the systemic agents currently available.4 Long-term disease control frequently requires some form of continuous therapy and consequent, predictable risks of toxicity. At present, the risks and benets of biologic therapies relative to standard systemic therapy are largely unknown. Widespread use of these agents in uncomplicated moderate to severe psoriasis is inappropriate and is not supported by the licensed indications for these drugs. Eligibility criteria should encompass both objective measures of disease severity and the impact the disease has on quality of life. All existing disease severity assessment tools are imperfect1113 and most require some training to complete. The Psoriasis Area and Severity Index (PASI) is a measure of disease severity in chronic plaque psoriasis12 and has been chosen for the purposes of this guideline as it has been widely used in clinical trials including those investigating biologic therapies, and has also been adopted by NICE. A PASI score of 10 (range 072) 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,14 and reects the minimal level of disease severity required for patient inclusion
2009 The Authors

5.0 Methodology
The guideline has been developed using the BADs recommended methodology9 and with reference to the AGREE (Appraisal of Guidelines Research and Evaluation) instrument.10 Recommendations were developed for implementation in the National Health Service using a process of considered judgment based on the evidence and an awareness of the European product licence of the various treatments. Cochrane, EMBASE and Medline databases were searched between 1990 and June 2009 for clinical trials involving adalimumab, efalizumab, etanercept, iniximab and ustekinumab using an agreed protocol. Two reviewers screened all titles and abstracts independently, and full papers of relevant material were obtained. In relation to efcacy, only randomized controlled trials (RCTs) of high quality (1+ or more; see Appendix 1) were included for chronic plaque psoriasis, whereas in other clinical phenotypes, given the paucity of published data, all data were included. Data from each paper were extracted by two members of the guideline group using standardized literature evaluation forms in order to create evi-

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Biologic interventions for psoriasis, C.H. Smith et al. 989

in most of the clinical trials of biologic therapies to date. Where the PASI is not applicable (e.g. pustular psoriasis), body surface area (BSA) affected should be used, with severe disease dened as > 10% BSA affected.14 The Dermatology Life Quality Index (DLQI) is a validated tool for the measurement of quality of life across all skin diseases, including psoriasis, and has been used in both trial and clinical practice settings.13,15 A score of > 10 (range 030) has been shown to correlate with at least a very large effect on an individuals quality of life.12,14,16

(iv) have signicant, coexistent, unrelated comorbidity which precludes use of systemic agents such as ciclosporin or methotrexate (v) have severe, unstable, life-threatening disease Eligibility criteria for patients with skin and joint disease (i) patients with active psoriatic arthritis or skin disease that fulls dened British Society for Rheumatology (BSR)18 or BAD guideline criteria, respectively (ii) patients with severe skin psoriasis and psoriatic arthritis who have failed or cannot use methotrexate may need to be considered for biologic treatment given the potential benet of such treatment on both components of psoriatic disease Phototherapy may be inappropriate in patients (i) who have exceeded safe exposure limits (150200 treatments for PUVA, 350 treatments for narrowband UVB19,20), (ii) who are nonresponsive or relapse rapidly, (iii) who have a history of skin cancer or repeated episodes of severe sunburn, (iv) who are intolerant of UV exposure, especially if skin phototype I (sun-sensitive), or (v) for logistical reasons Standard systemic therapy includes ciclosporin (25 mg kg)1 daily; up to 5 mg kg)1 daily), and in men, and women not at risk of pregnancy, methotrexate [single dose (oral, subcutaneous, intramuscular) of 15 mg weekly; max 25 mg weekly] and acitretin (2550 mg daily)
b a

8.1 Exceptional circumstances

When using the PASI and DLQI to determine whether or not a patient should be considered for biologic therapy, clinicians should take into account the applicability of these measures to each individual patient. There are circumstances where the use of these tools fails to give a sufciently accurate assessment of the clinical situation. With respect to the PASI, this is especially pertinent in patients with localized disease that involves special high-impact sites (genitalia, hands, feet, head and neck) where highly signicant functional and or psychosocial morbidity may exist with a PASI < 10. The DLQI may be a poor indicator of emotional disabilities resulting from psoriasis and the validity of the DLQI (and of other quality of life measures) may also be undermined due to linguistic or other communication difculties.13

9.0 What is the denition of a disease response?

An adequate response to treatment is dened as either (i) a 50% or greater reduction in baseline PASI (PASI 50 response) (or % BSA where the PASI is not applicable) and a 5-point or greater improvement in DLQI4,2123 or (ii) a 75% reduction in PASI score compared with baseline (PASI 75 response). Initial response to therapy should be assessed at time points appropriate for the drug in question (Table 1). For patients on tumour necrosis factor (TNF) antagonist treatment with psoriasis and psoriatic arthritis, treatment may be continued if there has been a sufcient response in at least one of these components (see BSR guidelines18 for denition of disease response in psoriatic arthritis).

Recommendations: Eligibility criteria for biologic therapy Patients with psoriasis may be considered eligible to receive treatment with any of the licensed biologic interventions when they full the eligibility criteria set out below. However, the decision to proceed with treatment must be made in collaboration with the patient and include a careful assessment of the associated risks and benets17 Eligibility criteria To be considered eligible for treatment, patients must have severe disease as dened in (a) and full one of the clinical categories outlined in (b): (a) Severe disease dened as a PASI score of 10 or more (or a BSA of 10% or greater where PASI is not applicable) and a DLQI > 10. In exceptional circumstances (for example, disease affecting high-impact sites with associated signicant functional or psychological morbidity such as acral psoriasis), patients with severe disease may fall outside this denition but should be considered for treatment (Strength of recommendation D; level of evidence 3) AND (b) Full at least one of the following clinical categories (Strength of recommendation D; level of evidence 3, and formal consensus) (i) where phototherapya and alternative standard systemic therapyb are contraindicated or cannot be used due to the development of, or risk of developing, clinically important treatmentrelated toxicity. (ii) are intolerant to standard systemic therapy (iii) are unresponsive to standard systemic therapyb

10.0 The interventions 10.1 Tumour necrosis factor antagonists

TNF is a proinammatory cytokine produced by a wide variety of cell types including keratinocytes. It plays a central role in the pathogenesis of psoriasis, psoriatic arthritis and a number of other disease states. TNF is released from cells as a soluble cytokine (sTNF) following cleavage from its cell surface-bound precursor (transmembrane TNF, tmTNF). Both sTNF and tmTNF are biologically active, and bind to either of two distinct receptors: TNF receptor 1 (TNFR1, p55) and TNF receptor 2 (TNFR2, p75). This leads to NF-jB activation (which promotes inammation) and or cell apoptosis. In addition, tmTNF can

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Table 1 Summary of interventions and criteria for treatment

Intervention NICE criteria Severe psoriasis, i.e. PASI 10, DLQI > 10 and qualifying criteria BAD criteria Adults: 5 mg kg)1 at weeks 0, 2, 6 and then every 8 weeks (intravenous) Very severe plaque psoriasis, i.e. PASI 20, DLQI 18 and where CSA, MTX or PUVA has failed cannot be used Severe plaque psoriasis, i.e. PASI 10, DLQI > 10 and where CSA, MTX or PUVA has failed cannot be used Not applicable; proposed for Single Technology Assessment (2009)

Dosing schedule according to licencea

Decision to continue treatment 14 weeks (licence); 10 weeks (NICE)

Iniximabb (Remicade; Schering-Plough, Welwyn Garden City, U.K.)

990 Biologic interventions for psoriasis, C.H. Smith et al.

Etanerceptb (Enbrel; Wyeth, Maidenhead, U.K.)

Severe psoriasis, i.e. PASI 10, DLQI > 10 and qualifying criteria

12 weeks (NICE, licence)

Etanercept (Enbrel)

Severe psoriasis, i.e. PASI 10, DLQI > 10 and qualifying criteria Severe psoriasis, i.e. PASI 10, DLQI > 10 and qualifying criteria

12 weeks (licence)

Adalimumabb (Humira; Abbott, Maidenhead, U.K.)

Adults: 25 mg biweekly (50 mg once weekly up to 24 weeks); or 50 mg twice weekly up to 12 weeks reduced to once weekly thereafter (subcutaneous) Children > 8 years: 0.8 mg kg)1 up to max 50 mg weekly (subcutaneous) Adults: 80 mg week 0, 40 mg week 1, then every other week (subcutaneous) Adults: 45 mg at week 0, 4 and then every 12 weeks; adults > 100 kg: 90 mg week 0, 4 and then 90 mg every 12 weeks (subcutaneous) Severe plaque psoriasis, i.e. PASI 10, DLQI > 10 and where CSA, MTX or PUVA has failed cannot be used Severe plaque psoriasis, i.e. PASI 10, DLQI > 10 and where CSA, MTX or PUVA has failed cannot be used.

16 weeks (NICE, licence)

Ustekinumab (Stelara; Janssen-Cilag, High Wycombe, U.K.)

Severe psoriasis, i.e. PASI 10, DLQI > 10 and qualifying criteria

28 weeks (licence); 16 weeks (NICE)

NICE, National Institute for Health and Clinical Excellence; BAD, British Association of Dermatologists; PASI, Psoriasis Area and Severity Index; DLQI, Dermatology Life Quality Index; CSA, ciclosporin; MTX, methotrexate; PUVA, psoralen plus ultraviolet A. aLicensed indication for all therapies listed is treatment of patients with moderate to severe chronic plaque psoriasis who have failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapies including ciclosporin, methotrexate and PUVA. bAlso licensed for use in psoriatic arthritis; approved by NICE provided the person has arthritis with three or more tender joints and three or more swollen joints, and at least two other disease-modifying antirheumatic drugs, given on their own or together, have not worked.

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Biologic interventions for psoriasis, C.H. Smith et al. 991

itself act as a ligand (via a process of reverse signalling) to induce cell activation, cytokine suppression or apoptosis of the tmTNFbearing cell. Soluble forms of the TNF receptors also exist and, by binding and neutralizing sTNF, may act as natural TNF antagonists. There are currently two approved groups of biologic agents that target TNF: anti-TNF monoclonal antibodies (adalimumab and iniximab), and sTNF receptors (etanercept). Iniximab is a chimeric humanmurine monoclonal antibody (~ 25% mouse-derived protein) whereas adalimumab is fully human. Etanercept is a genetically engineered fusion protein composed of a dimer of the extracellular portions of human TNFR2 (p75) fused to the Fc domain of human IgG1. All three agents specically bind both soluble and transmembrane forms of TNF and act by (i) blocking TNFR-mediated mechanisms and (ii) inducing tmTNF (reverse-signalling) events. Etanercept also binds members of the lymphotoxin family [LTa3 (also known as TNF-b) and LTa2b1] although the biological signicance of this is unclear. Aside from the latter, there are important differences between the three agents with respect to pharmacokinetics, immunogenicity and structure-based mechanisms of action (only some of which are completely understood).24 It is likely that these differences, in the context of the highly complex biology of TNF, account for observed differences in the efcacy and adverse events prole of TNF antagonists.

monoclonal antibody which acts as an IL inhibitor by binding with high afnity and specicity to the p40 protein subunit. It thus prevents IL-12 and IL-23 from binding to their IL-12Rb1 receptor protein expressed on the surface of immune cells.

11.0 How effective is each intervention in chronic plaque psoriasis? 11.1 Etanercept
11.11 Etanercept in chronic plaque psoriasis Three large RCTs demonstrate that etanercept is effective in chronic plaque psoriasis.2931 Onset of action is slower than that seen with the monoclonal antibodies, with clinically signicant improvement in disease severity scores evident between 4 and 8 weeks after initiation of treatment.30 Response is dose related, with 34% (25 mg biweekly) and 48% (50 mg biweekly) of patients achieving PASI 75 by 12 weeks (Table 2). Continuing therapy up to 6 months improves response rates further (43% and 57% for 25 mg biweekly and 50 mg biweekly, respectively).29,30,32 While there are no RCT data establishing efcacy beyond 6 months, data from a 2-year, open-label etanercept 50 mg biweekly extension study32 (following the phase III study reported by Tyring et al.31) suggest that efcacy is maintained for up to 1 year, with approximately 75% of patients maintaining their PASI 75 response over the ensuing year. Overall, continuous therapy provides better disease control and higher levels of patient satisfaction compared with interrupted therapy. When treatment is stopped, disease relapses slowly: median time to disease relapse as dened by loss of PASI 50 in those who achieved PASI 75 after 24 weeks of continuous etanercept 25 or 50 mg biweekly, was 85 and 91 days, respectively, with no evidence of disease rebound. On re-treatment, mean PASI scores were similar, with the majority of patients achieving equivalent efcacy after 12 further weeks (i.e. 56% and 60% of PASI 75 responders achieved this level of efcacy on re-treatment).33,34 Aside from objective measures of disease improvement (PASI, physicians global assessments), studies also report associated clinically meaningful improvements in quality of life measures,3537 reduction in fatigue and depression,31 and increased proportions of patients in paid employment.38,39 Post hoc analysis of two of these RCTs demonstrated that response rates in those over 65 years were the same as those under 65 years, although numbers in the older age group were small (n = 77).40 The 25 mg twice weekly and 50 mg once weekly dosing regimens are probably interchangeable given that their pharmacokinetic proles are comparable,41 that the number of patients achieving PASI 75 at 12 weeks following etanercept 50 mg weekly (in an RCT setting compared with placebo)42 was comparable with that seen in other RCTs investigating etanercept 25 mg biweekly and that no signicant differences

10.2 Efalizumab (now withdrawn see section 15.3)

Lymphocyte function-associated antigen-1 (LFA-1) is a cell surface protein that binds to intracellular adhesion molecule (ICAM) 13 and plays a key role in T-lymphocyte recirculation, trafcking to sites of inammation, antigen presentation by dendritic cells and other activated cells including keratinocytes, and T-cell costimulation. Efalizumab is a recombinant humanized IgG1 monoclonal antibody that binds specically to the CD11a subunit of LFA-1, which by interfering with LFA-1 ICAM binding inhibits several key steps important in the pathogenesis of psoriasis including T-cell migration into the skin and T-cell activation. More recently, in vivo data have shown that efalizumab induces a state of reversible T-cell hyporesponsiveness including downregulation of a number of T-cell surface molecules unrelated to LFA-1 both in the circulation and in psoriatic plaques.25,26

10.3 Ustekinumab
Interleukin (IL)-12 and IL-23 are heterodimeric cytokines secreted by activated antigen-presenting cells, and share a common protein subunit, p40. Of relevance to psoriasis, IL-12 activates CD4 and natural killer cells to induce expression of type 1 cytokines (TNF and interferon-c) while IL-23 stimulates survival and proliferation of a subset of T cells that produce IL-17 (Th17 cells). Recent immunological27 and genetic studies indicate a central role for IL-23 in the pathogenesis of psoriasis.28 Ustekinumab is a fully human IgG1j
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992 Biologic interventions for psoriasis, C.H. Smith et al.

PASI, Psoriasis Area and Severity Index; PASI 75, 75% reduction in PASI score compared with baseline; PASI 90, 90% reduction in PASI score compared with baseline. aContinuous subgroup. For each of the outcomes the crude probability (not adjusted for the placebo response) of the biologic treatment achieving the specied endpoints is given followed by the 95% condence interval (CI). Longer-term data are not directly comparable between studies due to differences in accounting for study drop outs. Last observation carried forward (LOCF) may overestimate efcacy whereas nonresponder imputation gives a more conservative estimate of efcacy.

4860 weeks

053a53,54

06262,68

PASI 75

0632

were observed in mean PASI or DLQI in a cohort of patients receiving open-label etanercept 25 mg biweekly (at week 24) and etanercept 50 mg once weekly (at week 36).43 In the RCTs cited, the frequency of adverse events or serious adverse events in patients receiving etanercept was no greater than in the control patients, with the exception of injection site reactions. One small (n = 20 in each treatment arm) RCT has shown superior efcacy of etanercept 25 mg once weekly compared with acitretin 04 mg kg)1 daily at 24 weeks (see below).44 Given the role of TNF in adipocyte homeostasis, elevated levels of TNF in obese patients, and the xed (nonweight adjusted) dosing regimen used for etanercept, decreased response rates may occur in heavier patients, particularly with low-dose etanercept. This is supported, in part, by pharmacological modelling (using published RCT data)45 and data cited in the study by de Groot et al.46 11.12 Etanercept in chronic plaque psoriasis in combination with systemic therapies

LOCF LOCF; patients continued on unlicensed dose after 12 weeks LOCF

Nonresponder imputation Nonresponder imputation 054071 066072 065072

048057

052067

95% CI

037048 0520.6

069079

072077

95% CI

Nonresponder imputation

Comments

Methotrexate The combination of etanercept and methotrexate has been shown to be more effective in rheumatoid arthritis (RA) than either agent alone, with no signicant additional toxicity. Limited data suggest that the addition of methotrexate may also confer improved etanercept efcacy in psoriasis. A small RCT (n = 59) investigated the efcacy and safety of introducing etanercept (25 mg biweekly) in patients already established on methotrexate, and reported signicantly increased numbers of patients clear or nearly clear at 24 weeks on combination therapy, as compared with those in whom methotrexate was discontinued.47 A retrospective case series (n = 14) reported both improved efcacy with the introduction of methotrexate in patients on etanercept and loss of efcacy on withdrawal of methotrexate from patients on combination therapy.48 Acitretin Data from a small RCT (n = 60) reported that the combination of etanercept 25 mg once weekly with acitretin 04 mg kg)1 daily is as effective as etanercept 25 mg twice weekly, and that both these interventions are more effective that acitretin alone.44 These early data would suggest that in the short term at least, the combination may offer additional efcacy but, perhaps as importantly, there is no additional associated toxicity. 11.13 Quality of evidence The patient cohort in the cited RCTs may not be representative of patients likely to be treated in clinical practice as entry to the studies required patients only to be considered suitable for, or have previously had, PUVA or systemic therapy. How 2009 The Authors

06962,63,65,68 06871,72 040046 038046 0436265 04271,72 066079 063070 0696265 06771,72

04329,30 05729,30,32

26 weeks

Table 2 Summary of the pooled results for efcacy from all clinical trials evaluated in the systematic review

008015 017026

050060

01129,30 02129,30

05553,56

PASI 90

028038 044052

076082

1016 weeks

03429,30 0482931

0795256

PASI 75

Iniximab 5 mg kg)1 at 0, 2, 6 and every 8 weeks Adalimumab 40 mg every other week Ustekinumab 45 mg at 0, 4 and every 12 weeks Ustekinumab 90 mg at 0, 4 and every 12 weeks

Etanercept 25 mg biweekly Etanercept 50 mg biweekly

Journal Compilation 2009 British Association of Dermatologists British Journal of Dermatology 2009 161, pp9871019

07271,72

068075

95% CI

04571,72

042049

95% CI

07571,72

PASI 75

07453

Biologic interventions for psoriasis, C.H. Smith et al. 993

ever, objective disease severity criteria were the same as those currently recommended by the BAD and NICE, and mean PASI scores on entry to studies were signicantly higher (ranging from 16 to 18). Prospective case cohort studies of real life practice report comparable response rates in high-need patients who have previously failed multiple systemic therapies, all of which suggests that data from the RCTs can be extrapolated to clinical practice.46,49,50 There is a lack of longterm RCT data beyond 6 months, and only limited data on re-treatment (of the two published studies available,34,51 one is open label,34 and both report outcome following one repeat cycle of treatment only). Existing RCT data indicate that 50 mg biweekly is more effective than 25 mg biweekly, but there are no trial data indicating whether increasing the dose to 50 mg biweekly in patients who fail to achieve or maintain adequate responses on 25 mg biweekly results in improved disease control. This is especially pertinent given NICE guidance which currently limits treatment to the 25 mg biweekly dose (see below).

Methotrexate may be recommended comedication in certain clinical circumstances, e.g. where it is required for associated arthropathy, or to improve efcacy (Strength of recommendation B; level of evidence 1+)

11.2 Iniximab
11.21 Iniximab in chronic plaque psoriasis Three large RCTs5254 indicate that iniximab therapy is highly effective in chronic plaque psoriasis (Table 25256). Onset of action is rapid, with evidence of signicant improvement within the rst 2 weeks of treatment and maximum benet by week 10 when 79% of patients achieve PASI 75 (Table 2) (and mean drop in DLQI of 1054,57). This response is largely maintained over time with 74%53 and 53% achieving PASI 75 at 6 and 12 months, respectively (Table 2). Loss of efcacy correlates with development of antibodies to iniximab, which occurs in 19% of patients treated.53 One RCT54 (n = 835) investigated continuous vs. intermittent therapy (3 and 5 mg kg)1) following a standard induction course (at 0, 2 and 6 weeks); continuous therapy at 5 mg kg)1 every 8 weeks achieved optimal control. Time to relapse in the intermittent arm (dened by loss of PASI 75) was stated as being between week 14 and 22 in the majority of patients although data were not shown.54 An early (small) dose-nding study58 indicated that 50% (15 30) patients relapse (loss of PASI 75) by week 26. There are no published prospective trial data beyond 1 year. Nail disease One study prospectively assessed nail disease during therapy53 using the Nail Psoriasis Severity Index (NAPSI) to assess a target, worst affected, nail: a 268% improvement in NAPSI from baseline was observed at week 10 with a maximum of 572% improvement reported at week 24. This was maintained until week 50. Numbers of patients with complete clearance of nail disease (from the target nail) continued to improve between weeks 24 and 50 (262% and 447%, respectively). 11.22 Iniximab in chronic plaque psoriasis in combination with systemic therapies There are no RCT data on use of methotrexate in combination with iniximab in psoriasis. In both RA and psoriatic arthritis, cotherapy with methotrexate is a licensed recommendation, and response rates (with and without methotrexate) are at least comparable in these disease indications. Higher serum levels of iniximab have been reported with methotrexate coadministration which may in part explain reports of improved efcacy. Methotrexate (low dose, 75 mg weekly) also reduces the incidence of antibodies to iniximab.5961

11.14 Licensed indications and existing NICE guidance (Table 1) Etanercept is licensed for use in moderate to severe psoriasis at either 50 or 25 mg biweekly for the rst 3 months, and 25 mg biweekly thereafter, for up to 24 weeks. Continuous therapy beyond 24 weeks may be appropriate for some adult patients (SPC). NICE has approved use of etanercept in severe plaque psoriasis (subject to dened disease severity) at the 25 mg biweekly dose only, and did not nd the 50 mg twice weekly dose cost effective, with therapy to be continued only in those patients achieving disease response at 3 months (Table 1).

Recommendations: Etanercept Etanercept is recommended for the treatment of patients with severe psoriasis who full the stated disease severity criteria refer to section 8.0 (Strength of recommendation A; level of evidence 1++) Etanercept therapy may be initiated at either 50 or 25 mg twice weekly and disease response assessed at 34 months (Strength of recommendation A; level of evidence 1++) The choice of which dose to use will depend on clinical need, disease severity, body weight and, in the U.K., the dose that will be funded (Strength of recommendation B; level of evidence 1++) Patients established on etanercept 25 mg twice weekly may wish to consider switching to etanercept 50 mg once weekly as these two dosing regimens are equivalent in terms of efcacy (Strength of recommendation A; level of evidence 1+) In patients who respond, treatment may be continued according to clinical need, although long-term data on efcacy are limited to 2 years (Strength of recommendation C; level of evidence 2+) Treatment may be discontinued without risk of disease rebound, although there may be a lower response rate on restarting therapy (Strength of recommendation B; level of evidence 1+)

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11.23 Quality of evidence The patient cohort in the cited RCTs may not be representative of patients likely to be treated in clinical practice. The mean PASI at baseline was 10 in all the studies cited. However, failure of previous systemic therapy was not an entry criterion, in that most studies required patients to be candidates for systemic therapy and or failed topicals only. A subanalysis of patients in the study by Menter et al.54 (continuous vs. intermittent) did, however, indicate that baseline PASI (< 20 vs. > 20) and the nature of previous treatments (including two or more systemic therapies, or biologic therapy) had no effect on treatment response. The design of the study investigating continuous vs. intermittent iniximab therapy is problematic in that study visits occurred at monthly intervals: hence patients randomized to receive intermittent therapy could potentially receive iniximab at 4-weekly intervals (if PASI 75 was not maintained), and cumulative doses in both arms were reported as similar.

11.24 Licensed indications and existing NICE guidance (Table 1) Iniximab is licensed for use (5 mg kg)1 every 8 weeks) in moderate to severe plaque psoriasis. NICE has approved use of iniximab in patients with very severe disease (sic) (PASI 20, DLQI 18) with treatment beyond 10 weeks recommended only in those who achieve certain response criteria.

Recommendations: Iniximab

Iniximab is recommended for the treatment of patients with severe psoriasis who full the stated disease severity criteria refer to section 80 (Strength of recommendation A; level of evidence 1++) Iniximab therapy should be initiated at a dose of 5 mg kg)1 at weeks 0, 2 and 6 and disease response assessed at 3 months (Strength of recommendation A; level of evidence 1++) In patients who respond, subsequent infusions (5 mg kg)1) should be given at 8-week intervals to maintain disease control although long-term data are available only up to 1 year (Strength of recommendation A; level of evidence 1++) Interrupted therapy should be avoided given the associated increased risk of infusion reactions and poorer disease control (Strength of recommendation A; level of evidence 1+) Methotrexate may be recommended comedication in certain clinical circumstances, e.g. where it is required for associated arthropathy, to improve efcacy or to reduce the development of antibodies to iniximab (Strength of recommendation D; level of evidence 3)

Onset of action is rapid, with signicant improvements in disease severity evident within 2 weeks of treatment initiation62 and maximal disease response seen between weeks 12 and 16. Response is dose related with 69% of patients achieving PASI 75 at week 12 with adalimumab 40 mg every other week6265 (i.e. the licensed dose for psoriasis), and 80% achieving PASI 75 with adalimumab 40 mg weekly.62 Clinically relevant improvements in health-related quality of life indicators are also reported.66 In one study,62 a small subset of patients (n = 34) who had failed to achieve PASI 50 following at least 24 weeks of adalimumab every other week was escalated to the weekly dose for the remaining duration of the 60-week study (open-label); 40% of this cohort recorded PASI 50 responses, suggesting that dose escalation may further improve efcacy. Efcacy data are available up to 1 year, with no evidence of signicant loss of response over time in those patients who respond and are continued on treatment.63 Loss of response on stopping treatment was also investigated in the third phase of the study reported by Menter et al.;63 those who had maintained PASI 75 by week 33 were re-randomized to receive either placebo or a further 19 weeks of adalimumab (double blind). While mean time to relapse was not reported, 28% of patients receiving placebo relapsed (< PASI 50 response relative to baseline with a minimum of a 6-point increase in PASI score relative to week 33) compared with 5% relapse in those continuing on adalimumab by week 52. As part of this study, patients who lost adequate response after re-randomization to placebo could enrol into the openlabel extension phase of the trial (adalimumab 40 mg every other week). Re-treatment response rates in this group are stated (only) in the summary of product characteristics (SPC), where 38% (25 66) and 55% (36 66) regained PASI 75 response after 12 and 24 weeks, respectively. These response rates are lower than those reported following rst treatment, suggesting that interrupted therapy may result in loss of treatment response. Anti-adalimumab antibodies develop in 84% of patients and are associated with increased clearance and reduced efcacy of adalimumab (but not specic adverse events). 11.32 Adalimumab compared with standard systemic therapy in chronic plaque psoriasis One RCT comparing efcacy of adalimumab (40 mg every other week) vs. methotrexate (75 mg initial dose weekly, increasing to a maximum of 25 mg weekly as tolerated) showed adalimumab to be signicantly more effective than methotrexate by week 1, with 80% of patients achieving PASI 75 by week 16. This compared with surprisingly low methotrexate (36%) and high placebo (19%) response rates.64 The latter are considerably higher than seen in other comparable placebotreated cohorts where PASI 75 response rates are typically 5% or less. Improvements in DLQI and a number of other quality of life measures also indicated that adalimumab was the most effective intervention.67 Overall, the incidence of adverse
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11.3 Adalimumab
11.31 Adalimumab in chronic plaque psoriasis Three large RCTs demonstrate that adalimumab is a highly effective treatment for chronic plaque psoriasis (Table 2).6264

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events was similar in all three groups, with the exception of hepatic abnormalities which were signicantly higher in patients on methotrexate. 11.33 Adalimumab in chronic plaque psoriasis in combination with systemic therapies The addition of methotrexate to adalimumab in RA results in reduced immunogenicity (i.e. a lower rate of antiadalimumab antibody formation) and increased effectiveness (in part due to reduced clearance of adalimumab) with no increase in adverse events. No prospective studies have investigated the potential benet of adalimumab in combination with methotrexate in psoriasis. In the ADEPT study, a post hoc analysis comparing those patients who were on a stable dose of methotrexate at initiation of adalimumab, and those who were not, suggests that for both skin and joint disease the combination of adalimumab and methotrexate is more effective than adalimumab alone, although the differences were only signicant between the groups for the percentage achieving PASI 50.65,68 11.34 Quality of evidence The patient cohort in cited RCTs may not be representative of patients likely to be treated in clinical practice. With the exception of the rst (small) RCT62 where entry disease severity comprised BSA > 5%, and studies on psoriatic arthritis where skin disease severity criteria were not set (mean PASI on entry 7)65,68 all studies cited required PASI of at least 10 and or BSA 10%, and mean disease severity scores on entry to psoriasis studies63,64 tended to be signicantly higher than this. Previous use of systemic therapies was not an entry criterion for the RCTs cited, and of course, for the comparative study examining methotrexate vs. adalimumab, patients had to be treatment naive both to TNF antagonists and to methotrexate. One small (n = 30) open-label study evaluated the efcacy of adalimumab 40 mg once weekly in a cohort of patients with severe psoriasis who had failed both standard systemic therapy and other biologic therapies (including efalizumab, etanercept and iniximab).69 By week 12, 87% of patients had achieved PASI 75, which represents a response rate comparable with that reported in the RCT by Gordon et al.62 As adalimumab has only recently been licensed for use in psoriasis, few data exist on use outside clinical trials. The design of the study reported by Saurat et al.64 has been criticized as favouring adalimumab, given that the maximum efcacy of methotrexate may not have been apparent by 16 weeks. 11.35 Licensed indications and existing NICE guidance (Table 1) Adalimumab is licensed for use in moderate to severe psoriasis at 40 mg every other week (following 80 mg loading dose at
2009 The Authors

week 0), with continued therapy beyond 16 weeks to be carefully reconsidered in patients not responding within this time period; NICE has approved use of adalimumab (40 mg every other week) in severe plaque psoriasis (subject to dened disease severity) with continued therapy subject to adequate response at 16 weeks (Table 1).

Recommendations: Adalimumab

Adalimumab is recommended for the treatment of patients with severe psoriasis who full the stated disease severity criteria refer to section 8.0 (Strength of recommendation A; level of evidence 1++) Adalimumab therapy should be initiated according to the
licensed dosing regimen (i.e. 80 mg subcutaneously at week 0, 40 mg at week 1, and then every other week thereafter) and disease response assessed at 34 months (Strength of recommendation A; level of evidence 1++) Consideration may be given to increasing the dose of adalimumab to 40 mg weekly in certain clinical circumstances (e.g. in those with PASI > 10 despite achieving a responsea to adalimumab 40 mg every other week), although this is unlicensed and not approved by NICE (and in the U.K. may not be funded) (Strength of recommendation A; level of evidence 1+) In patients who respond, treatment may be continued according to clinical need although long-term efcacy data are available only up to 1 year (Strength of recommendation A; level of evidence 1++) If necessary, treatment may be discontinued without risk of disease rebound, although there may be a lower response rate on restarting therapy (Strength of recommendation A; level of evidence 1+) Methotrexate may be recommended comedication in certain clinical circumstances, e.g. where it is required for associated arthropathy, or to increase efcacy (Strength of recommendation B; level of evidence 3)
a

as dened in section 9.0 (PASI 50, DLQI 5)

11.4 Ustekinumab
11.41 Ustekinumab in chronic plaque psoriasis Three large RCTs7072 demonstrate that both doses of ustekinumab (i.e. 45 mg and 90 mg) are highly effective in psoriasis (Table 2); onset of action is evident within 2 weeks, with 67% and 72% of patients achieving PASI 75 by week 12 for the 45 mg and 90 mg doses, respectively, and maximal efcacy evident between week 20 and week 24. Disease responses are maintained with continued therapy for up to 15 years. On cessation of therapy, median time to relapse (i.e. loss of PASI 75) is 15 weeks, with no reports of rebound psoriasis. Similar response rates are achieved on re-treatment. While there is clearly a relationship between dose (serum drug levels) and response, this is not linear, as the 90 mg dose appears to be only slightly more effective than the 45 mg dose. Further, in partial responders, increasing the frequency of dosing to every 8 weeks (as compared with every 12 weeks), while increasing serum drug levels, signicantly improves response rates only in those on the 90 mg regimen

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[approximately 2 3 of partial responders (dened as > PASI 50, < PASI 75 at week 28) converted to responders (PASI 75) by week 52 with intensication of the 90 mg dose to 8-weekly]. Factors aside from the lower dose that are predictive of poorer response include higher body weight, previous poor response to at least one biologic therapy, longer duration of psoriasis and a history of psoriatic arthritis. While the inclusion criteria for these trials are comparable to those investigating other biologic therapies (PASI 12 and BSA 10% or greater), overall, the disease severity appears to be greater (mean PASI scores on entry around 20), with the majority of patients having received previous phototherapy and systemic therapy, and just over a third having received prior biologic therapy. A phase II study has evaluated the use of ustekinumab in the treatment of psoriatic arthritis (n = 146, active: control allocation 1:1, dose regimen 90 mg weekly for 4 weeks). At week 12, 42% of patients achieved a clinical response [dened as a 20% improvement from baseline in the American College of Rheumatology (ACR20) core set measures].73

12.0 How effective are biologic therapies in pustular psoriasis and palmoplantar pustulosis? 12.1 Localized disease
There are two disabling and difcult-to-treat conditions affecting the hands and feet in which localized pustules are associated with psoriasis elsewhere on the body. The more common of these, chronic palmoplantar pustulosis, has in the past been termed chronic palmoplantar pustular psoriasis. There is, however, evidence to suggest that, although it is associated with psoriasis in up to about 20% of cases, it is a distinct disease with a different clinical and genetic prole.75 This evidence is strengthened by the almost complete lack of reports of benet from TNF antagonists but, conversely, an increasing number of reports of newonset palmoplantar pustulosis in patients with conditions other than psoriasis treated with these agents.76,77 A recent small pilot study found no benet over placebo of etanercept 50 mg given twice weekly for 12 weeks.78 TNF antagonists should therefore be avoided in these patients. The second condition is acropustulosis (acrodermatitis continua) of Hallopeau. Although uncommon, acropustulosis can result in considerable morbidity from an intense pustular inammation centred around the terminal phalanges and often sufciently severe to destroy the nail plate. It is commonly associated with a destructive arthritis of adjacent joints. It is recognized that patients with acropustulosis are at risk of developing generalized pustular psoriasis. There are no controlled trials of interventions for acropustulosis. It is frequently unresponsive to conventional systemic antipsoriatic agents. There are now at least 10 case reports of signicant benet from TNF antagonists (etanercept, iniximab and adalimumab) for this rare but disabling condition. This contrasts with only two reports of failure to respond and, in one of those cases, the patient subsequently responded to a different TNF antagonist. If acropustulosis has a major impact on quality of life, it is therefore reasonable to recommend a trial of one of these agents.

11.42 Ustekinumab compared with etanercept in chronic plaque psoriasis A large (n = 903), phase III RCT indicates that ustekinumab is more effective than etanercept in the short term. The percentage of patients achieving PASI 75 by week 12 with ustekinumab 90 mg and 45 mg at week 0 and 4 was 74% and 68%, respectively, compared with 57% for patients randomized to etanercept 50 mg biweekly for 12 weeks.74

11.43 Licensed indications and existing NICE guidance (Table 1) Ustekinumab is licensed for use in patients with moderate to severe psoriasis at 45 mg (or 90 mg if >100 kg) at week 0, 4 and then 12 weekly thereafter with consideration given to discontinuing therapy in those who have not responded by week 28. NICE has approved the use of ustekinumab in patients with severe plaque psoriasis (subject to dened disease severity criteria) with treatment to be continued beyond 16 weeks only in those who respond (Table 1).

12.2 Generalized pustular psoriasis

Publications concerning biologic treatments for generalized pustular psoriasis are limited to case reports and small series, reecting the fact that these drugs are relatively new in the treatment of psoriasis, and that generalized pustular psoriasis is a very rare disorder. Iniximab has been used in the treatment of severe generalized pustular psoriasis with generally positive results. A 39-year-old man with severe generalized pustular psoriasis responded rapidly to iniximab with complete disease clearance which allowed withdrawal of all conventional systemic psoriasis treatments.79 A follow-up study of three patients with generalized pustular psoriasis included two who cleared completely with iniximab treatment, while
2009 The Authors

Recommendations: Ustekinumab

In light of limited patient exposure, ustekinumab should be reserved for use in patients with severe psoriasis who full the stated disease severity criteria AND where TNF antagonist therapy has failed or is contraindicated refer to section 8.0 (Strength of recommendation A; level of evidence 1+) For logistical and safety reasons, drug injections should be supervised by a health care professional (Strength of recommendation D (GPP); level of evidence 4)

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one was left with residual keratoderma.80 On stopping iniximab following a variable number of infusions, two of these three relapsed, while disease remission was maintained in one. Additional case reports and a small case series (n = 3) conrm efcacy for iniximab in the treatment of generalized pustular psoriasis.8184 Etanercept has also been shown to be of benet in generalized pustular psoriasis. One case series (n = 6) reports clinical efcacy of etanercept in generalized pustular psoriasis at 50 mg biweekly, but not at 25 mg biweekly, with maintenance of response for up to 48 weeks.85 One report conrms efcacy for etanercept in a single patient with generalized pustular psoriasis following withdrawal of ciclosporin,86 and a second, use of etanercept in generalized pustular psoriasis following induction of remission with iniximab.87 Reports of biologic therapies for generalized pustular psoriasis in childhood are limited to two cases: a 3-year-old child cleared rapidly with iniximab and was switched successfully to etanercept after 12 months of iniximab infusions.88 A 15-year-old girl with severe generalized pustular psoriasis treated with ciclosporin, methotrexate and adalimumab cleared completely by 2 months.89 Thus, for patients with generalized pustular psoriasis, experience of treatment with biologic agents is currently limited to iniximab, etanercept and adalimumab. These initial case reports and small case series are generally positive and justify formal clinical trials to assess safety and efcacy in more detail in this difcult patient group.

TNF antagonists may be considered for patients with severe, disabling acropustulosis (acrodermatitis continua) of Hallopeau which has failed to respond to standard systemic agents refer to section 8.1: exceptional circumstances (Strength of recommendation D; level of evidence 3) TNF antagonists may be considered for patients with generalized pustular psoriasis (Strength of recommendation D; level of evidence 3) TNF antagonists (iniximab and etanercept) may be considered for patients with erythrodermic psoriasis (Strength of recommendation D; level of evidence 3)

14.0 Use of biologic therapy in combination with phototherapy

The rationale for using these two contrasting forms of treatment together is that both have differing mechanisms of action which may be synergistic when used together. However, trial data are limited to a single arm, open-label study, evaluating etanercept 50 mg twice weekly combined with narrowband UVB phototherapy given three times weekly (n = 86).98 At week 12, 26% of patients achieved PASI 100, 581% achieved PASI 90, and 849% achieved PASI 75. It is unclear what effect each treatment had as this study failed to include a comparator group with either monotherapy or placebo. There is currently insufcient evidence to recommend the combination of narrowband UVB phototherapy with etanercept, and no data at all on combined use of iniximab or adalimumab with phototherapy. An RCT is needed to establish whether combining UVB phototherapy with biologic therapies offers more rapid clearance of disease which is sustained when monotherapy continues with the biologic agent.

13.0 How effective are biologic therapies in erythrodermic psoriasis?

TNF antagonists are reported to be of benet in this form of psoriasis, which given that many cases evolve from chronic plaque disease is perhaps not surprising. A case series of 10 patients with erythrodermic psoriasis responded well to etanercept 25 mg twice weekly. The mean PASI decreased from 391 to 51 at 24 weeks, when 60% had achieved PASI 75.90 Three of ve erythrodermic patients achieved PASI 75 with repeated infusions of iniximab 5 mg kg)1.80 There are also several case reports of successful treatment of erythrodermic psoriasis, including life-threatening disease, with iniximab therapy,9195 one clearing with a single infusion.96 Iniximab was also successful in three patients who experienced erythrodermic ares when transitioning from efalizumab to etanercept.97 No evidence was found concerning the efcacy of adalimumab in erythrodermic patients.

15.0 Adverse effects and toxicity

15.01 Methodological considerations When considering the relative risks (and benets) of biologic interventions, it is important to note that there are signicant methodological limitations to published safety data. Trials are powered to detect efcacy, not adverse events, and there is therefore a high chance that low-frequency, drug-related adverse events will not be identied.99 In addition, many of the data available in relation to psoriasis derive from clinical trials in which only the rst 3 months have a comparable placebo group. Long-term extensions of these trials look at patients who remain on therapy and those lost from the cohorts may be lost because of adverse reactions (leading to under-reporting). Long-term data are also poorly reported.100 Several high-quality meta-analyses of high-quality trials are limited by the sparsity of safety data within the original reports themselves. Information accrued on TNF antagonist therapies used in other indications may not necessarily be applicable to the

Recommendations: Use of biologic therapy for special types including pustular and erythrodermic psoriasis

Biologic therapies cannot at present be recommended for palmoplantar pustulosis

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population treated for psoriasis. This may be especially relevant in relation to assessment of skin cancer risk as patients with psoriasis may already have a higher risk of skin cancer due to prior phototherapy and immunosuppressive drugs. The demographics of different diseases are also likely to inuence the toxicity prole of any intervention. For example, the higher incidence of RA in women has resulted in a female bias to safety data reported to the BSR biologics register (BSRBR). This underlines the importance of ensuring that all patients are registered with the BADBIR which will assess safety issues in the relevant population. 15.02 Overview of adverse effects for all interventions A signicant body of data is now available on the adverse effects and toxicity associated with biologic therapies. Comprehensive, detailed information is available in the SPC for each drug and is regularly updated by pharmaceutical companies (and approved by the drug regulatory authorities). The U.K. versions can be accessed at http://emc.medicines. org.uk/. Schmitt et al.101 recently reviewed tolerability of biologic and nonbiologic therapies in a meta-analysis. Tolerability assessed by withdrawals showed monthly withdrawal rates of 13% (range 0516) for iniximab, 12% (0619) for efalizumab, 04% (0314) for etanercept and 03% for adalimumab. Additionally infusion reactions occurred in 21% of patients per month with iniximab. Serious adverse events occurred at a monthly rate of 11% with iniximab, 12% with efalizumab and 05% with adalimumab. Rates for etanercept could only be computed from the data for the 50 mg biweekly dose, and were 06%. Brimhall et al.102 conducted a meta-analysis of adverse events of biologic therapies based on pooled short-term trial data. They expressed a relative risk of adverse events and severe adverse events, compared with placebo. Risks for efalizumab were 115 (adverse events) and 143 (serious adverse events); for etanercept 105 (adverse events) and 117 (serious adverse events); and for iniximab 118 (adverse events) and 126 (serious adverse events). Of these, only the relative risk of adverse events with iniximab and serious adverse events with efalizumab reached an increased level of statistical signicance. Adalimumab was not included in the analysis.

they have included erysipelas, cellulitis, furunculosis, folliculitis, paronychia and wound infections. An increased risk of herpes zoster has also been reported in rheumatology patients on TNF monoclonal antibody therapy, but not etanercept, from the German rheumatology registry: crude incidence rate per 1000 patient-years 111 (95% CI 79151) for the monoclonal antibodies, 89 (95% CI 56133) for etanercept, and 56 (95% CI 3683) for conventional DMARDs.103 When rates were adjusted for age, RA severity and glucocorticoid use, a signicantly increased risk was still observed for treatment with the monoclonal antibodies (hazard ratio 182, 95% CI 105315), but not etanercept or TNF antagonist therapy as a class. These ndings are supported by cohort and case control studies using data from the U.K. general practice research database and a U.S. health plan claims database which showed increased risk of herpes zoster with biologic therapy (iniximab, etanercept and anakinra) compared with DMARDs in patients with RA.104 Serious infections, including opportunistic infections, have also been reported (see SPC and below for additional details). 15.12 Reactivation of tuberculosis This is a major concern with all TNF antagonist therapies, as TNF plays a key role in host defence against mycobacterial infection, particularly in granuloma formation (and hence containment of mycobacteria) and inhibition of bacterial dissemination.105,106 Early data (2003) from the BIOBADASER registry (Spanish Society of Rheumatology Database on Biologic Products) reported an estimated incidence of 1893 cases per 100 000 patient-years with iniximab107 compared with 21 in the general population. This led to careful selection pretreatment and monitoring and greatly reduced the incidence in those complying with pretreatment testing and prophylaxis, although adherence to guidelines was poor.108 The risk of tuberculosis may be greater with the monoclonal antibodies (iniximab and adalimumab) as compared with etanercept with incidences of tuberculosis in patients with RA reported to the BSRBR of 39 per 100 000 patient-years for etanercept, 103 per 100 000 patient-years for iniximab and 171 per 100 000 patient-years for adalimumab.109,110 Even when latent tuberculosis is identied and treated prior to TNF antagonist therapy, patients may develop clinical evidence of infection. Thus a high index of suspicion throughout treatment is required. The clinical presentation of infection is often atypical, with at least 50% of cases associated with iniximab111,112 and etanercept113 being extrapulmonary. Late diagnosis, development of disseminated disease and concomitant immunosuppressive therapy may all contribute to high rates of morbidity, and associated mortality.111,112 Onset of clinical infection varies according to the agent used, with median time between initiation of therapy and diagnosis of infection being 3 months,111,112 46 months106 and 115 months113 for iniximab, adalimumab and etanercept, respectively.
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15.1 Tumour necrosis factor antagonist therapies

15.11 Infections: bacterial, mycobacterial, viral Data from clinical trials indicate that infections are common, but overall rates of infection are no greater than with placebo. Rheumatology registry data do suggest an increased risk of skin and soft tissue infections [adjusted incidence rate ratio 428, 95% condence interval (CI) 1061717] compared with standard disease-modifying antirheumatic drugs (DMARDs)100 and although these are poorly characterized,

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The mode of action of ustekinumab predicts that it would also facilitate reactivation of tuberculosis. All the trials conducted with this agent excluded patients with latent tuberculosis. Although the levels of evidence and risk differ between agents the consensus of the guideline development group is to generalize the cautions and vigilance for latent or active tuberculosis to all biologic interventions.

15.13 Cardiovascular disease The risks of TNF antagonist therapy in the context of heart failure were rst highlighted when trials in severe congestive cardiac failure [New York Heart Association (NYHA) class III and IV, left ventricular ejection fraction < 35%; Table 3] were prematurely discontinued due to an excess mortality with high-dose iniximab; a similar trial of etanercept failed to show benet.114 Forty-seven spontaneous reports to the U.S. Food and Drug Administration (FDA) of new onset or worsening of pre-existing heart failure following either iniximab or etanercept have been reviewed in detail with the possibility of drug-induced pathology supported by an apparent temporal association between introduction of drug and onset of symptoms (median onset 3 months with iniximab, 85 months with etanercept).115 Pre-existing risk factors for heart disease were absent in 50% of cases, and complete resolution or substantial improvement of symptoms seen on withdrawal of drug in younger patients (< 50 years). Clinical trial data in psoriasis and other diseases116 show no excess risk of heart failure although selection bias (i.e. exclusion of those at risk) may account for this.117

Recommendations: Biologic therapy and infection risk

Patients on biologic interventions should be monitored for early signs and symptoms of infection throughout treatment (Strength of recommendation C; level of evidence 2+) Patients on biologic interventions should be warned against risk factors for Salmonella and Listeria and should not consume raw or partially cooked dairy, sh or meat produce or unpasteurized milk or milk produce. Salads should be washed (Strength of recommendation D (GPP); level of evidence 4) All patients should be fully assessed for both active and latent tuberculosis before starting biologic therapy with special attention paid to those groups at high risk (Strength of recommendation B; level of evidence 2+) Patients with active or latent tuberculosis should receive treatment prior to initiating biologic therapy (Strength of recommendation B; level of evidence 2+) A high index of suspicion for tuberculosis should be maintained during therapy and for 6 months after discontinuation, with special emphasis on extrapulmonary, atypical and disseminated forms of the infection, and in those patients on additional immunosuppressant agents (Strength of recommendation C; level of evidence 2+)
See section 18.5 for recommendations on screening and monitoring for tuberculosis

Recommendations: Cardiovascular disease and TNF antagonists

Table 3 New York Heart Association classication of heart failure symptoms Class Symptomsa I No limitations. Ordinary activity does not cause fatigue, breathlessness or palpitations (asymptomatic left ventricular dysfunction is included in this category) Slight limitation of physical activity. Such patients are comfortable at rest. Ordinary physical activity results in fatigue, breathlessness, palpitation or angina pectoris (symptomatically mild heart failure) Marked limitation of physical activity. Although patients are comfortable at rest, less than ordinary physical activity will lead to symptoms (symptomatically moderate heart failure) Inability to carry out physical activity without discomfort. Symptoms of congestive cardiac failure are present even at rest. With any physical activity increased discomfort is experienced (symptomatically severe heart failure)

TNF antagonist therapy should be avoided in patients with severe (NYHA class III and IV) cardiac failure (Strength of recommendation D; level of evidence 4) Patients with well-compensated (NYHA class I and II) cardiac failure should have a screening echocardiogram and those with an ejection fraction < 50% of normal should not be given TNF antagonist therapy (Strength of recommendation D; level of evidence 4) Treatment should be withdrawn at the onset of new symptoms or worsening of pre-existing heart failure (Strength of recommendation D; level of evidence 4)

15.14 Neurological disease TNF antagonist therapy has been associated with the development of, or worsening of demyelinating disease although evidence for causality is inconclusive. Lenercept, a soluble p55 receptor developed for the treatment of multiple sclerosis, was withdrawn from further development due to increasing severity and duration of symptoms in clinical trial subjects. Cases of demyelination have been reported with all three TNF blockers available for psoriasis (SPC and in reference118). A detailed review of cases reported to the FDA in 2001 identied 17 due to etanercept and two due to iniximab, partial or complete resolution of symptoms on discontinuation and with recurrence of symptoms in at least one case following rechallenge.118 Registry data in RA suggest that this risk is small.119,120 Guidelines recently issued from the American Academy of Dermatology recommend that TNF antagonist therapy be avoided in patients with a personal history of, or a rst-degree relative with a demyelinating disorder.121

II

III

IV

a Patients with heart failure may have a number of symptoms, the most common being breathlessness, fatigue, exercise intolerance and uid retention.

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1000 Biologic interventions for psoriasis, C.H. Smith et al.

Recommendations: Demyelination and TNF antagonists

TNF antagonists should be avoided in patients with history of demyelinating disease and used with caution in those with a rstdegree relative with such disease (Strength of recommendation D; level of evidence 3) If neurological symptoms suggestive of demyelination develop during TNF antagonist therapy, treatment should be withdrawn and specialist advice sought (Strength of recommendation D; level of evidence 4) 15.15 Paradoxical events Certain diseases, including psoriasis, that are commonly responsive to TNF antagonist therapy, have paradoxically been reported, rarely, to be triggered or exacerbated by TNF antagonist therapy. Various granulomatous reactions, particularly involving the lung and including some indistinguishable from sarcoid,122 small vessel vasculitis (predominantly in the skin)123 and uveitis124 have been described in patients on TNF antagonists for mainly rheumatological indications. These data derive largely from spontaneous reports or case series so it is currently unclear as to the size of any risk, and whether it is relevant to patients using TNF antagonist therapy for psoriasis. With respect to psoriasis, more than 120 sporadic cases of both new-onset and worsening psoriasis have been reported in patients using TNF antagonist therapy for a wide spectrum of predominantly rheumatological disorders although including some cases of psoriasis (reviewed76,77). This association is supported by data from the BSRBR indicating a signicantly increased incidence of new-onset psoriasis with TNF antagonist therapy as compared with standard DMARDs in patients with RA.125 15.16 Malignancy To date, there is no robust evidence of increased risk of malignancy with TNF antagonists in patients with psoriasis. Data from clinical trials are reassuring, and there is no indication from registry data in rheumatology populations of increased risk of solid tumours and lymphoma with TNF antagonist therapy as compared with standard DMARDs to date.126 However, uncertainty and conicting evidence remain around the possible increased risk of lymphoma, possibly because lymphomas are more common in patients with severe RA. Bongartz et al.127 carried out a meta-analysis of nine trials of patients with RA treated with iniximab or adalimumab. The data included 3493 patients who received TNF antagonist treatment and 1512 patients who received placebo and demonstrated a pooled odds ratio for malignancy of 33 (95% CI 1291). This paper raised a variety of methodological concerns128130 which included lack of adjustment for duration of exposure to TNF antagonist therapy, inclusion of open-label extension data for biologic therapy with no comparable placebo data, iniximab induction doses exceeding labelled dose in approximately 50% of patients and an unexpectedly low rate of malignancy in the control arms. In addition, both

iniximab and adalimumab have been rarely associated with hepatosplenic T-cell lymphoma.131 This rare, aggressive, and usually fatal tumour has occurred in adolescents and young adults with Crohns disease who were also receiving treatment with azathioprine or mercaptopurine.132136 There are also reports of cases of early onset of lymphoma after introduction of TNF antagonist therapy137,138 and regression of lymphoma following withdrawal of TNF antagonist therapy.137,139 With respect to skin cancer, data on TNF antagonists in RA are inconsistent. Pharmacovigilance data on 1440 patients with RA treated with etanercept from clinical trials (3530 personyears total exposure time) did not show any link between squamous cell carcinoma (SCC) development and etanercept.140 Lebwohl et al.141 carried out a retrospective analysis of 1442 patients with RA treated with etanercept for up to 5 years and similarly found no increased incidence of SCC (observed four SCCs, expected 59131). However, an increased risk of nonmelanoma skin cancer (NMSC) (odds ratio 15, 95% CI 1218) and a trend towards increased risk of melanoma (odds ratio 23, 95% CI 0954) has recently been reported in a large (> 13 000 patients) observational study comparing rates of malignancy in patients with RA on biologic therapies with population rates (drug-specic data from this analysis are given in the relevant section below).139 Leonardi et al.142 evaluated the incidence of malignancy in patients receiving efalizumab in 14 clinical trials (2980 patients). One case of malignant melanoma occurred in patients treated with efalizumab (incidence rate 004 per 100 patientyears, 95% CI 000022), compared with no cases in the placebo cohort and an incidence of 002 per 100 patient-years derived for the general population. For NMSC, 51 tumours [basal cell carcinomas (BCCs); 30 SCCs] were reported in efalizumab-treated patients (i.e. 12% of all efalizumab-treated patients), compared with four tumours (two BCCs, two SCCs in two patients) in placebo-treated patients, giving incidence rates of 138 per 100 patient-years (95% CI 096192) for efalizumab, 108 per 100 person-years (95% CI 013389) for placebo, and 039 per 100 patient-years in external psoriasis cohorts on oral therapy or phototherapy. This increased incidence of NMSC in both efalizumab and placebo groups was suggested to be possibly related to ascertainment bias. Long-term registry data collated from the pertinent population are essential to address properly the question of cancer risk in patients with severe psoriasis treated with biologic therapy.

Recommendations: Malignancy risk and biologic therapy

It is very strongly recommended that all patients being treated with biologic therapy should be entered into the BADBIR (subject to patient consent) in order to establish whether biologic therapy is associated with any increased risk of important side-effects such as malignancy, compared with standard systemic therapy (Strength of recommendation D (GPP); level of evidence 4) All patients should be fully assessed prior to, and during treatment with, biologic therapy with respect to their past or current history of malignancy and or any future risk of malignancy; the

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Biologic interventions for psoriasis, C.H. Smith et al. 1001

risks and benets of biologic therapy should be considered in this context (Strength of recommendation D; level of evidence 4) All patients should be encouraged to participate in national cancer screening programmes appropriate for their age and gender (Strength of recommendation D (GPP); level of evidence 4) Biologic therapy should be avoided in patients with a current or recent past history of malignancy unless the malignancy has been diagnosed and treated more than 5 years previously and or where the likelihood of cure is high (this includes adequately treated NMSC) (Strength of recommendation D; level of evidence 4) Regular, comprehensive dermatological assessment for skin cancer, including melanoma, is recommended before and at regular intervals during therapy, especially in those patients at increased risk of skin cancer at baseline (Strength of recommendation D; level of evidence 4) Biologic therapy is relatively contraindicated in patients who have had prior therapy with > 200 PUVA and or > 350 UVB treatments, especially when it has been followed by ciclosporin (Strength of recommendation D; level of evidence 4) See Table 4 for summarized recommendations on screening and monitoring

Lupus-like syndrome with positive antibodies is reported but is rare and affected patients have not experienced systemic features. Aplastic anaemias and pancytopenia have been reported rarely following etanercept and a neutropenia occurred in one of the long-term trials over 12 months.144 15.22 Iniximab The commonest side-effects are upper respiratory tract infection, headache, increased hepatic enzymes and infection. Acute infusion-related reactions with diverse symptoms occur in 322% of patients with psoriasis,149 including, rarely, anaphylactic shock and delayed hypersensitivity. Antibodies to iniximab can develop which can increase the risk of immunological reactions and reduce the efcacy of therapy. Detailed information on management of infusion reactions is available in a recent comprehensive review.149 Hepatoxicity in the form of elevation in liver transaminases is well recognized to occur with iniximab therapy.53 In general, these elevations are transient and asymptomatic but rare cases of severe hepatitis and acute liver failure resulting in transplantation or death have been reported. Infections. Soft tissue infections, sepsis, candidiasis, fungal infections, pharyngitis, sinusitis and rhinitis are uncommonly reported. Serious infections have included pneumonia, bronchitis, peritonitis, septicaemia, pyelonephritis, cellulitis, systemic fungal infection and herpes zoster. Aside from tuberculosis (discussed above), opportunistic infections are also of concern and include atypical mycobacteria, histoplasmosis, coccidioidomycosis, Pneumocystis pneumonia, candidosis and aspergillosis.145 Malignancy. There is no indication from registry data of increased malignancy risk with iniximab. In a clinical trial investigating efcacy of iniximab in chronic obstructive pulmonary disease, nine of 157 patients in the active arm developed a malignancy as compared with one of 77 with placebo,150 although this nding was not statistically signicant. An increased risk of skin cancer has been reported in patients treated with iniximab: NMSC 1.7 (95% CI 1322) and melanoma 26 (95% CI 1067).139 Other data in relation to malignancy are summarized in section 15.16. Other adverse effects. As with etanercept, there are reports of lupus-like reactions and demyelination, but these are rare. 15.23 Adalimumab The commonest adverse events reported are injection site reactions, viral, candidal and bacterial infections, dizziness, headaches, vertigo, gastrointestinal upset, musculoskeletal pain, rash, asthenia and malaise (SPC). Injection site reactions occur in 15% of patients treated (compared with 9% of patients receiving placebo or active control) but generally do not result in discontinuing therapy.

15.2 Drug-specic details

15.21 Etanercept The commonest adverse events reported are injection site reactions (14%),143 allergic reactions, headache and upper respiratory tract infection.102 Injection site reactions, while common, diminish with ongoing therapy and do not relate to antibody development. Infections constituted 21% of FDA reports of adverse effects in 2001.144 In a short-term evaluation of 1347 patients with psoriasis these included sinusitis, upper respiratory tract infections and inuenza, and were of similar rates to placebo. Skin infections occurred in 14% of patients.145 Serious infections were rare (04%) and comparable with placebo rates.143 Aside from tuberculosis (discussed above), opportunistic infections may occur including listeriosis,146,147 streptococcal pneumonia, aspergillosis, histoplasmosis,148 cryptococcosis, pneumocystis pneumonia, Legionella and Salmonella.144,147 Malignancy. A long-term 3-year open-label etanercept study of 1498 patients not treated with other disease-modifying drugs revealed no change in the rate of malignancy (or severe infections) over time and malignancies were fewer than expected in the normal population.119 An increased risk of NMSC of 12 (95% CI 1015) and melanoma 24 (95% CI 1058) has been reported in those patients treated with etanercept for RA.139 Combining the results of placebo- and active comparator-controlled clinical trials of etanercept, more cases of NMSC were observed in patients receiving etanercept compared with control patients, particularly in patients with psoriasis (SPC). Other data in relation to malignancy are summarized in section 15.16.

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1002 Biologic interventions for psoriasis, C.H. Smith et al. Table 4 Recommended pretreatment and monitoring investigations Grade of evidence; strength of recommendationb D; 4 disease response; thereafter disease response; thereafter A; 1+ A; 1+

Pretreatmenta BADBIR Disease severity assessment Skin: PASI (or BSA affected if PASI not applicable), DLQI Joints: follow recommended BSR guidelines for psoriatic arthritis Identication of contraindications to therapy and or development of therapy-induced toxicity Thorough history, symptom enquiry, clinical examination (including full skin check; assessment for lymphadenopathy, hepatosplenomegaly) Cardiovascular assessmentc Echocardiogram if well-compensated NYHA class I and II Neurological assessment Exclude demyelinationc Infection Consider risk factors for tuberculosis; sexual history; drug abuse; history of blood transfusions; any past or current chronic infection Malignancy Ensure concordant with national cancer screening programmes; gynaecological review of patients with history of cervical dysplasia; any past or current malignancy Assessment for latent tuberculosis See Figure 1 Blood tests Full blood count Creatinine, urea, electrolytes Liver function tests Hepatitis B Hepatitis C Human immunodeciency virus Autoantibodies (antinuclear antibodies, antinuclear double-stranded DNA antibodies Urine Urine analysis Urine pregnancy test Radiology Chest X-ray Yes Yes Yes

Monitoringa 6-monthly To establish 6-monthly To establish 6-monthly

Yes

At 3- to 6-monthly intervals

D (GPP)

Yes

Clinical assessment at 3- to 6-monthly intervals At 3- to 6-monthly intervals At 3- to 6-monthly intervals

D; 4

Yes Yes

D; 4 GPP

Yes

At 3- to 6-monthly intervals

GPP

Yes Yes Yes Yes Yes Yesa Yesd Yes

Annually (IGRA) At 3 months, then every 6 months At 3 months, then every 6 months At 3 months, then every 6 months Periodically in those at risk Periodic assessment of hepatitis C viral load if positive Periodically in those at risk Only if symptoms suggest development of autoimmune phenomena, e.g. abnormal liver function tests Not routinely Periodically in those at risk Only if clinically indicated

A; 2+ A; 1+ GPP A; 1+ D; 4 D; 4 D; 4 D; 4

Yes Yes Yes

BADBIR, British Association of Dermatologists Biologic Interventions Register; PASI, Psoriasis Area and Severity Index; BSA, body surface area; DLQI, Dermatology Life Quality Index; BSR, British Society for Rheumatology; NYHA, New York Heart Association; IGRA, interferon gamma release assay. aAdditional assessment and monitoring may be required in patients on concomitant therapy or in certain clinical circumstances. bSee Appendix 1. cApplies to tumour necrosis factor blockers only. dIn those with risk factors.

Infections. A composite of clinical trials involving 12 506 patient-years and postmarketing surveillance was reported for adalimumab in 2006.151 The rate of serious infection was 51 per 100 patient-years and was not increased above

those published in RA untreated with biologic therapy. Four cases of histoplasmosis occurred in endemic areas. Posttuberculin screening, the rate of tuberculosis was 330 per 100 000 patient-years in Europe and 80 per 100 000 in
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Biologic interventions for psoriasis, C.H. Smith et al. 1003

North America and 06% of patients receiving tuberculosis prophylaxis acquired tuberculosis. Postmarketing surveillance has revealed further cases of tuberculosis and opportunistic infections. Malignancy. In the same analysis outlined above,151 a standardized incidence ratio of 319 was reported for the rate of lymphomas but such increases are observed in severe RA without biologic interventions. A further analysis of an open-label study (REACT) with 6610 patients was published in 2007 and included patients with other concomitant disease-modifying drugs.152 Results were similar to those in the original report,151 with the exception of malignancy, where the standardized incidence ratio for malignancies (including lymphoma but excluding BCCs and carcinoma in situ) was 071 (95% CI 04910). The observed number of lymphoma cases was signicantly greater than the expected number only in the RA trials (standardized incidence rate 298; 95% CI 189447). Other data in relation to malignancy are summarized in section 1516. Other adverse effects associated with TNF antagonists have also been reported with adalimumab, with incidence rates of 008 per 100 patient-years for demyelinating disorders, 0.1 per 100 patient-years for lupus-like syndromes and 028 per 100 patient-years for congestive cardiac failure.151

15.3 Safety and efalizumab

Safety data for efalizumab are more limited compared with TNF antagonist therapy as therapy has largely been conned to patients with psoriasis, with approximately 47 000 patient-years exposed to date. Several studies have examined safety in clinical trials with extended open observation of patients for up to 3 years153157 and all give a similar incidence of adverse events. Very recently, three cases of conrmed PML have been reported in patients on efalizumab with consequent withdrawal of the European marketing licence by the European Medicines Agency. PML is a rare, progressive, demyelinating disorder of the central nervous system, associated with reactivation of John Cunningham virus (JCV) in immunosuppressed individuals. It leads to death or severe disability, and there are no known medical interventions that can reliably prevent or treat the disorder. All three of the reported cases occurred in patients on efalizumab monotherapy for 3 years or more. The occurrence of this usually fatal adverse event is of signicant concern particularly given that if PML is particularly associated with protracted use of efalizumab, estimates suggest that as many as 1500 patients have been exposed to treatment for as long as 3 years. It also highlights the risk of unexpected serious adverse events that follows the introduction of any new drugs into clinical practice. The commonest adverse events were headaches (36%), chills (11%), fever (9%), asthenia (6%) or inuenza-like symptoms (98%), back pain (6%), diarrhoea (6%) and myalgia (6%). These commonly occur during the rst few weeks of treatment but tend to resolve with continued therapy.155
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Thrombocytopenia occurs uncommonly (between one in 500 and one in 1000 patients), so platelet counts should be monitored. Lymphocytosis and leucocytosis (up to 35 upper limit of normal) is a regular nding with efalizumab therapy due to its effect of blocking their migration out of the bloodstream, and may be used to conrm patient concordance. A transient, acute, pruritic eruption occurs commonly in previously uninvolved sites (7%).156 The eruption may be sudden and resemble pustules joining into plaques. This eruption is self-limiting and should be treated with topical steroids and not be mistaken for a psoriasis are. Flares of psoriasis are uncommon (2%), and tend to occur in low or nonresponders.156 Arthralgia and exacerbation of psoriatic arthritis have been reported in association with efalizumab. A pooled review of RCT data reported no increased incidence of joint symptoms or development of psoriatic arthritis in those patients receiving efalizumab compared with placebo.154 However, in a 2-year follow-up study of 555 patients, the rate of arthralgia and arthritis increased over time from 16% to 56% at the end of the study with most of the affected patients having a prior history of psoriatic arthritis.158 In addition, a multicentre, retrospective case cohort review of all patients treated with efalizumab in France identied 16 patients with new-onset, severe psoriatic arthritis, with a median time to onset of 11 weeks, and evidence of improvement in symptoms on drug withdrawal.159 Infection rates. There is no direct evidence of increased rates of infection with efalizumab. We are not aware of reported cases of tuberculosis. Candida colitis and cytomegalovirus (CMV) have been reported. However, the SPC has special warnings for infection including tuberculosis, opportunistic infection, pyelonephritis, septic arthritis and septicaemia. Opportunistic infections are reported as uncommon in the SPC. Malignancy. There have not been increased reports of malignancy, with the overall incidence reported as 1.7 per 100 patient-years in a systematic review of safety data published in 2006.144 Leonardi et al.142 pooled data from clinical trials and reported no signicant increase in solid malignancies or lymphoproliferative disease. However, as summarized in section 15.16, an increase in NMSC was noted.142

15.4 Safety and ustekinumab

Safety of ustekinumab in psoriasis has been evaluated in two phase III trials.71,72 Five hundred and ten patients received up to 76 weeks of treatment in one study reported by Leonardi et al.71 and 1212 received treatment for up to 52 weeks in the study reported by Papp et al.72 Overall rates of adverse events were similar to placebo, and there was no consistent evidence for a relationship between dose or frequency of dosing, and the occurrence of adverse events. An RCT comparing ustekinumab and etanercept in psoriasis reported comparable rates of adverse events with both drugs through 12 weeks of

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1004 Biologic interventions for psoriasis, C.H. Smith et al.

therapy, with the exception of injection site reactions which were more common with etanercept.74 Further, limited data on adverse events are available in each of three phase II studies evaluating ustekinumab in psoriatic arthritis,73 Crohns disease160 and multiple sclerosis,161 respectively, where the pattern and rates of adverse events were similar in active and placebo groups. No exacerbation of demyelinating events was reported in the study evaluating ustekinumab in multiple sclerosis (n = 150 receiving active drug).161 Common adverse events in both studies included upper respiratory tract infection, nasopharyngitis, arthralgia, cough and headache. Injection site reactions were uncommon (15%), perhaps because of the infrequency of drug administration. Antibodies (neutralizing) develop in approximately 5% of patients and are associated with poorer responses to therapy, but do not correlate with injection site reactions. Infection. In the study by Leonardi et al.71 the incidence of serious infections was 0408% in the different subgroups and similar to the placebo phase. There were three incident cases of noncutaneous cancers and four cutaneous cancers. Laboratory abnormalities were low in rate and were similar between treated patients and the placebo group.71 In the study reported by Papp et al.,72 serious infection occurred in 0 05%, similar to placebo. There were seven cutaneous cancers and one other (noncutaneous) cancer on therapy, with similar rates in the placebo arm. No cases of tuberculosis, demyelination or lymphoma were identied. However, as discussed in section 15.1, the mode of action of ustekinumab would be expected to facilitate reactivation of tuberculosis.

Ustekinumab is more effective than etanercept in the short term (based on a large RCT directly comparing the two agents)74 and is probably of comparable efcacy to adalimumab and iniximab, but safety data are very limited. Ustekinumab should therefore be reserved for patients who have failed or cannot use TNF antagonists. There are only limited efcacy data on use of a second biologic therapy in patients with psoriasis where the rst has failed. Mechanisms underlying primary failure (i.e. inadequate response following initiation of treatment) or secondary failure (i.e. loss of response over time) are poorly understood,24 although in the case of TNF antagonists, development of antidrug antibodies with consequent reduction in circulating drug levels is well described with both iniximab and adalimumab.53,63 Further, while iniximab, adalimumab and etanercept all act to block TNF, they are pharmacologically distinct (see reference24 for a detailed review). Thus failure to respond to one TNF antagonist may not preclude response to a second. This is supported by ndings in a small open-label study69 and retrospective case cohort review162 which demonstrate efcacy of adalimumab following etanercept failure. Of note, approximately a third of patients entered into ustekinumab RCTs had been previously treated with biologic therapy (predominantly TNF antagonists), and this did not inuence therapeutic outcome.

Recommendations: How to determine the optimal choice and sequence of therapy

16.0 How to determine the optimal choice and sequence of therapy

Given the proven efcacy of TNF antagonists in psoriasis, the substantial body of available clinical safety data (albeit not conned to patients with psoriasis) and the high proportion of patients with associated psoriatic arthropathy, TNF antagonists should be considered the rst-line biologic intervention. Multiple factors will determine which of the three available TNF antagonists should be used rst in a particular patient. This includes those related to the drug itself and how they relate to the clinical circumstance, patient preferences (e.g. mode of administration) and access, the latter being determined largely by local funding arrangements. In the short term, the monoclonal antibodies (iniximab and adalimumab) have a quicker onset of action, and are more effective than etanercept, although by 1 year the proportion of patients maintaining a PASI 75 may be comparable (Table 2). With respect to safety, systematic review of RCT data from short-term studies suggests that the risk of adverse events may be slightly higher with iniximab compared with etanercept101,102 and adalimumab101 while registry data indicate that risks of reactivation of tuberculosis and herpes zoster may be greater with adalimumab and iniximab as compared with etanercept.103,109,110

TNF antagonists are recommended as rst-line intervention for patients fullling criteria for treatment with biologic therapy refer to section 8.0 (Strength of recommendation B; level of evidence 1+) The choice of which of the three TNF antagonists to use rst should be based on clinical need and requires a careful assessment of risks and benets of each agent in the context of the individual patient. With this proviso, the following additional recommendations are made: For patients with stable chronic plaque psoriasis, etanercept or adalimumab may be considered rst choice based on the favourable risk benet prole and ease of administration (Strength of recommendation D; level of evidence 4) For patients requiring rapid disease control, adalimumab or iniximab may be considered rst choice due to the early onset of action, and high chance of achieving PASI 75 by 3 months (Strength of recommendation A; level of evidence 1+) For patients with unstable or generalized pustular psoriasis, limited evidence indicates that iniximab is effective in these clinical situations, and may therefore be considered rst choice (Strength of recommendation D; level of evidence 3) For patients who do not respond to a TNF antagonist (either primary or secondary failure), a second TNF antagonist may be considered (Strength of recommendation D; level of evidence 3) Due to the lack of patient-years exposure and long-term safety data limited to 1 year, ustekinumab should be reserved for use as a second-line biologic agent where TNF therapy has failed or cannot be used (Strength of recommendation B; level of evidence 1+)

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17.0 How to use biologic therapy in special circumstances 17.1 Use of biologic therapy in children
One RCT163 indicates that etanercept is effective in chronic plaque psoriasis in children. Among 106 patients aged 417 years (median 14 years) who received etanercept 0.8 mg kg)1 (up to maximum dose of 50 mg) by weekly subcutaneous injection, 57% achieved a PASI 75 at 12 weeks as against 11% in the placebo arm. Subjects had psoriasis with a baseline PASI of 12 or more and had disease that was poorly controlled with topical therapy or had prior treatment with phototherapy or systemic therapy. Improvement was noted by 4 weeks of treatment and was maintained during an openlabel extension to week 36. There was no signicant difference in response when the results were analysed separately for those under the age of 12 years as compared with those over the age of 12 years. In the RCT the frequency of exposure-adjusted adverse events was low and similar to the placebo arm. Three serious infections were reported in the open-label phase in patients receiving etanercept. Longer-term safety data are needed in this patient group. 17.11 Quality of evidence The patient cohort in the cited RCTs may not be representative of patients likely to be treated in clinical practice, in that not all patients were required to have failed or be contraindicated to systemic therapy. 17.12 Licensed indications and existing NICE guidance (Table 1) Etanercept is licensed for treatment of chronic severe plaque psoriasis in children and adolescents from the age of 8 years who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies. NICE is currently considering a proposal for Single Technology Assessment. Etanercept is also licensed for treating juvenile idiopathic arthritis (JIA), a term which encompasses paediatric psoriatic arthritis. NICE has approved the use of etanercept in children aged 417 years with ve or more inamed joints who have failed to respond to methotrexate. The long-term safety of etanercept in JIA has been demonstrated up to 8 years.164
Recommendations: Use of biologic therapy in children Etanercept is recommended for the treatment of severe psoriasis in children from the age of 8 years who full the stated disease severity criteria refer to section 8.0 (Strength of recommendation A; level of evidence 1++) Etanercept therapy should be initiated at a dose of 08 mg kg)1 weekly and disease response assessed at 34 months (Strength of recommendation A; level of evidence 1++)

In patients who respond, treatment may be continued according to clinical need, although long-term data on efcacy are limited to 1 year (Strength of recommendation A; level of evidence 1+)

17.2 Use of biologic therapy in women planning pregnancy or who are pregnant
The overall question relates to the safety of biologic therapy in women who are pregnant. In practical terms this can be broken down to four main scenarios. Firstly, is it safe for women planning pregnancy or for women who are pregnant to continue with biologic therapy for psoriasis or should women established in biologic therapy come off biologic therapy prior to planning pregnancy? Secondly, is it safe for women who are pregnant and experience a are of psoriasis during pregnancy to be initiated on biologic therapy? Thirdly, what action should women who are established on biologic therapy for psoriasis take if they discover that they are pregnant? Fourthly, is it safe for women to initiate or continue biologic therapy while breast feeding? There are no prospective or retrospective studies that have addressed treatment of psoriasis during pregnancy with TNF antagonists. However, there are several publications concerning the outcome of pregnancy following exposure to TNF antagonists in a number of other diseases (principally Crohns disease and arthritis) although these patients, in contrast to patients with psoriasis, are more likely to have been exposed to combination therapy. 17.21 Surveys and retrospective series: tumour necrosis factor antagonists Mahadevan et al.165 describe the rst intentional use of iniximab during pregnancy in a retrospective review of 10 patients with Crohns disease. Eight patients received maintenance therapy during the whole of pregnancy, one received iniximab during the rst trimester and one during the third trimester. Concomitant medication included 6-mercaptopurine in ve women and systemic steroids in four women. Eight of the 10 women had caesarean sections. There were no fetal congenital abnormalities; three infants were premature and one had low birth weight but these were not thought to be secondary to iniximab therapy. Databases for monitoring safety set up by Centocor (pharmaceutical company that markets iniximab) include TREAT166 and the Iniximab Safety Database167 (which may in part overlap) and report 66 and 146 pregnancies,166,167 respectively, in which exposure to iniximab occurred. No fetal abnormalities were reported in the TREAT study and rates of miscarriage and neonatal complications were not increased compared with control groups in either study. One preterm death at 24 weeks and four infants born with complications are reported in the Iniximab Safety Database167 including one Fallots tetralogy and one neonatal sepsis.

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1006 Biologic interventions for psoriasis, C.H. Smith et al.

A report of the BSRBR includes information on 23 pregnancies in which exposure to TNF antagonists occurred at the time of conception resulting in 14 live births with no major fetal abnormalities.168,169 There were six rst-trimester spontaneous abortions and three elective rst-trimester abortions. In a retrospective study of 442 patients treated with TNF antagonists170 three women with RA became pregnant. One patient opted for elective abortion while two patients exposed to either adalimumab or etanercept proceeded to deliver healthy infants although one was premature. Perinatal complications included neonatal jaundice, neonatal urinary Escherichia coli infection and adrenal congenital hyperplasia of probable hereditary origin. Four further patients with severe arthritis were maintained on anti-TNF therapy (one etanercept, three iniximab) during pregnancy and all gave birth to healthy infants with no complications.171 As TNF has been hypothesized to be involved in the pathogenesis of spontaneous abortions, a recent study compared anticoagulants (group I), anticoagulants plus intravenous immunoglobulins (IVIG) (group II) or anticoagulants plus IVIG plus etanercept or adalimumab (group III; 17 patients) as treatment for women with recurrent spontaneous abortion.172 Anti-TNF agents were administered 30 days prior to a cycle of conception and continued until fetal cardiac activity was demonstrated by ultrasound. Signicant improvement in pregnancy outcome was observed in groups II and III compared with group I. No birth defects were observed in any of the babies in group III who had been exposed to anti-TNF agents. A recent publication describes the outcome of pregnancy of 15 women receiving anti-TNF therapy (iniximab, n = 3; adalimumab, n = 2; etanercept, n = 10) at the time of conception or during pregnancy reported by French rheumatologists, through a web-based structured questionnaire.173 The women had received anti-TNF therapy for a median of 8 months before pregnancy (range 148 months). Two miscarriages were reported and one woman who was also taking methotrexate opted for elective abortion. The median length of exposure to anti-TNF therapy during the 12 successful pregnancies was 6 weeks (range 338 weeks) with 12 of 12 women receiving anti-TNF therapy during the rst trimester compared with four of 12 women during the third trimester. No complications, prematurity, malformations or neonatal illnesses were described. In contrast to the reports above, congenital abnormalities have been associated with TNF antagonists in a recent review of the FDA database; a total of 61 congenital anomalies occurred in 41 children born to mothers taking a TNF antagonist (22 took etanercept, 19 took iniximab) in the period 19992005. In 24 of 41 cases, the mother was on no other medication. The most common reported congenital anomaly was some form of heart defect. Twenty-four of the 41 (59%) children had one or more congenital anomalies forming part of VACTERL (vertebral abnormalities, anal atresia, cardiac defect, tracheoesophageal, renal, and limb abnormalities). The

rate of specic anomalies was signicantly higher than historical controls implicating a causal role for TNF antagonists.174 A survey returned by 150 American rheumatologists indicated that they were more concerned about the risks of methotrexate in pregnancy than anti-TNF biologic agents.175 Three congenital abnormalities reported in the survey were all associated with methotrexate usage alone. 17.22 Case reports: tumour necrosis factor antagonists A patient with psoriasis and psoriatic arthritis who continued etanercept 50 mg subcutaneously twice weekly throughout her pregnancy gave birth to a child with fetal anomalies of the VATER association (including renal dysplasia, skeletal defects and tracheoesophageal stula).176 The successful use of etanercept (and IVIG) during pregnancy for are of systemic lupus erythematosus and RA has been reported and healthy babies with no complications ensued.177,178 There are limited data on outcomes of pregnancies following exposure to adalimumab. There are three case reports of women with Crohns disease who received adalimumab during pregnancy and gave birth to healthy babies with no complications.169,179,180 A patient with Takayasus arthritis continued adalimumab (and leunomide) during pregnancy and delivered a healthy baby with no complications.181 17.23 Iniximab crosses the placenta and has a long half-life but is not detected in breast milk High iniximab levels were detected in the serum of an infant born to a mother with refractory Crohns disease who continued to receive iniximab (10 mg kg)1) during her pregnancy.182 The last infusion was given 2 weeks prior to labour. Infant iniximab levels were high at 6 weeks (395 lg mL)1) and remained elevated up to 6 months of age. Iniximab was not detected in breast milk, suggesting that placental transfer results in neonatal exposure and that the half-life of iniximab is prolonged in infants. A recent case report describes a successful pregnancy with no infant abnormalities in a mother with refractory Crohns disease who continued to receive iniximab (10 mg kg)1) during her pregnancy and while breast feeding.183 Analysis of breast milk revealed no evidence of iniximab over 30 days. A recent report in abstract form of a prospective study of ve women receiving iniximab indicates that iniximab was detectable in infants up to 26 months of age depending on the date of the last infusion in relation to birth,184 suggesting further caution over the use of iniximab in the later stages of pregnancy. 17.24 Licensing guidance and summary Manufacturers of etanercept, iniximab and adalimumab advise avoidance during pregnancy. Although no toxicity or teratogenicity has been reported in animal studies of etanercept, caution

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should be exercised when considering the use of TNF antagonists during pregnancy. There are surveys and reports of successful and complication-free use of biologic therapy during pregnancy but these are limited and there are also some reports of perinatal complications including premature birth together with recent data associating VACTERL with TNF antagonists. Risk assessment is therefore difcult. Also, these drugs may be used in combination with methotrexate which is contraindicated in pregnancy because of welldocumented associations with spontaneous miscarriage, cleft palate and skeletal abnormalities.185187 17.25 Use of biologic therapy in men and conception There are very few publications that have addressed whether TNF or TNF antagonists may affect spermatogenesis, number or quality of sperm. It is therefore difcult to draw denitive conclusions. As TNF levels are elevated in infertile women with endometriosis, Eisermann et al.188 evaluated the effects of TNF on sperm mobility and found a dose-dependent decrease that was reversed by anti-TNF antibody. On the other hand, La Montagna et al.189 found reduced sperm mobility (although this was not quantied) in two of three patients evaluated with ankylosing spondylitis who were receiving iniximab. These data suggest that TNF TNF antagonists may have some biological effect on sperm motility but the clinical relevance of this is presently unclear.

17.3 Use of biologic therapy in the perioperative period for elective surgery
There are no prospective randomized trials comparing continuous vs. interrupted biologic therapy for patients on TNF antagonists undertaking surgery. Most published evidence comes from retrospective studies of orthopaedic procedures in RA190195 that have been the subject of detailed review.196 One study found an increase in serious postoperative infection rate associated with prior TNF antagonist use,192 whereas the other ve studies did not show signicant differences. However, in the largest of the latter studies195 there was a trend towards increased early and late surgical site infection in the group who continued TNF antagonist therapy perioperatively (87%) vs. those who had TNF antagonist therapy interrupted perioperatively, although this did not reach signicance. There was also a greater frequency of wound dehiscence in the group who continued TNF antagonist therapy (98%) vs. interrupted therapy (09%) compared with those who were TNF antagonist therapy naive (44%). In a retrospective study of patients with Crohns disease treated by intestinal resection, 40 patients on iniximab prior to surgery had no greater postoperative complication rate or prolonged hospital stay than a control group of 39 patients corrected for age, gender and type of surgery who were not exposed to iniximab.197 As a general rule it takes ve half-lives for a product to be completely eliminated from the body. Some studies have used four half-lives to determine the interval prior to surgery for interrupting therapy. There may be additional uncertainly about tissue bioavailability. The approximate half-lives of etanercept, adalimumab, iniximab, efalizumab and ustekinumab are 35 days, 1419 days, 89 days, 510 days and 21 days, respectively (in reference196 and SPCs). It is beyond the scope of these guidelines to address the risk of concomitant agents such as immunosuppressive drugs used with biologic therapy during surgery. However, in a welldesigned randomized prospective nonblinded study, perioperative use of methotrexate was not associated with an increased risk of adverse outcomes following joint replacement.198 17.31 Quality of evidence Most of the studies have been retrospective and underpowered to detect less than major risks of postoperative complications. It is also difcult to compare studies because of differences in source population, indications for surgery and underlying risk of infection due to the condition itself. From the studies available the two most robust reported192,195 would yield grade 2+ evidence. 17.32 Existing guidance The BSR guidelines for RA recommend that TNF antagonists (etanercept, adalimumab and iniximab) should be withheld

Recommendations: Use of biologic therapy in women planning pregnancy or who are pregnant

Pregnancy should be avoided in patients with psoriasis receiving biologic therapy and effective contraception is strongly recommended to prevent pregnancy in women of child-bearing potential (Strength of recommendation D; level of evidence 3) In patients who are planning a pregnancy, biologic agents should be avoided (and or stopped in advance) so the fetus is drug free during the critical developmental period of the rst 12 weeks (Strength of recommendation D; level of evidence 3) If patients who are established on biologic agents discover they are pregnant, they should be referred to a specialist fetal medicine unit for further assessment and consideration should be given to stopping biologic therapy (Strength of recommendation D; level of evidence 4) Notwithstanding recommendations above, patients should be assessed on a case-by-case basis and the risks to the mother of stopping biologic therapy should be balanced against any potential harm to the fetus infant (Strength of recommendation D; level of evidence 4) For those patients receiving iniximab during pregnancy, infusions should be avoided after 30 weeks if at all possible in view of its relatively long half-life and evidence that it crosses the placenta and may persist for several months in the fetal circulation (Strength of recommendation D; level of evidence 3) Breast feeding should be avoided in patients receiving biologic therapy although limited evidence indicates that iniximab is not excreted in breast milk (Strength of recommendation D; level of evidence 4)

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24 weeks prior to major surgical procedures and treatment restarted postoperatively if there is no evidence of infection and wound healing is satisfactory.199 Guidelines from the Dutch Society for Rheumatology (http://www.nvr.nl/) and the French Society for Rheumatology200 are similar and use four drug half-lives as the cut-off.

fatal) reactivation of occult hepatitis B infections have been reported (summarized201). 17.43 Human immunodeciency virus The safety of biologic therapy in the context of HIV infection is unknown but particular caution should be exercised in this group given the risks of infection. Paradoxically, perhaps, TNF has been implicated in HIV disease progression in HIV-associated tuberculosis, and therefore the benet of etanercept as adjunctive therapy for this indication has been investigated in a phase I study (25 mg twice weekly for 4 weeks, n = 16).207 There was a tendency towards improved outcome in the etanercept arm and, more importantly, no increased toxicity compared with standard antituberculous therapy (n = 47). There are several case reports of successful use of TNF antagonist therapy for rheumatological indications in patients who are HIV positive.201 17.44 Herpesviruses The risks of reactivation of latent herpesviruses in patients with psoriasis are unknown, although there are sporadic case reports of severe disseminated infections with both CMV and varicella-zoster201 in the context of TNF antagonists. Registry data also indicate an increased risk of herpes zoster with adalimumab and iniximab in patients with rheumatological disease (see section 15.1).103 In a short-term (14-week) evaluation of 60 consecutive patients with Crohns disease treated with iniximab, no evidence for reactivation of JCV, EpsteinBarr virus (EBV), human herpesvirus (HHV)-6, HHV-7, HHV-8 or CMV was identied in serum using polymerase chain reaction (PCR).208 A similar study prospectively measured viral DNA in plasma and peripheral blood mononuclear cells in patients with RA (n = 15) during the rst 6 weeks of iniximab treatment, and reported no evidence of reactivation of EBV, CMV or HHV-6. A further longer-term study evaluated EBV alone (measured in peripheral blood mononuclear cells using PCR) in patients with RA over a period of up to 5 years, and reported stable levels in patients using etanercept (n = 48) and iniximab (n = 68).209 Risks of herpes reactivation in the context of efalizumab and ustekinumab are unknown. However, with respect to efalizumab, recent reports of PML indicate that JCV reactivation can occur.

Recommendations: Use of biologic therapy in the perioperative period for elective surgery

Until there is more evidence available concerning the risk of perioperative use of biologic therapies in psoriasis and or psoriatic arthritis, BSR guideline recommendations on discontinuation of TNF antagonists in RA should be applied, i.e. TNF antagonists should be discontinued at least four half-lives prior to major surgery (2 weeks for etanercept, 68 weeks for adalimumab, 46 weeks for iniximab) Although there is no evidence for ustekinumab we would recommend ustekinumab is discontinued 12 weeks prior to major surgery (i.e. four half-lives prior to surgery) (Strength of recommendation D (GPP); level of evidence 4) Biologic therapy can be restarted postoperatively if there is no evidence of infection and wound healing is satisfactory (Strength of recommendation D; level of evidence 3)

17.4 Use of biologic therapy in patients with chronic viral infections (including hepatitis B and C and human immunodeciency virus)
Patients with potentially harmful chronic viral infections have been exposed to biologic therapy either coincident to treatment for psoriasis (or other inammatory indication) or as part of intentional adjuvant therapy, as is the case with TNF antagonist therapy in patients with hepatitis C and human immunodeciency virus (HIV) infections. The limited data available, mainly small case series and case reports, have been subject to a recent, comprehensive review, and guidelines on screening and monitoring provided.201 17.41 Hepatitis C TNF plays a role in hepatitis C-induced hepatocyte injury and treatment resistance to interferon alfa-2b. The role of TNF blockade has therefore been investigated in a phase II, randomized, placebo-controlled study, where etanercept (24 weeks, n = 19) was used as adjuvant therapy to ribavirin and interferon in treatment-naive patients.202 Etanercept improved viral clearance rates with no signicant increase in adverse events. Data from small case series and case reports203206 also report successful use of TNF antagonist therapy for rheumatological disease in hepatitis C virus-positive patients, with no increased rate of hepatotoxicity or viral replication. 17.42 Hepatitis B In contrast to hepatitis C, TNF may play a role in clearing and controlling hepatitis B virus. Cases of severe (and sometimes

Recommendations: Use of biologic therapy in patients with chronic viral infections

There is insufcient evidence to recommend treatment with biologic therapy in patients with known chronic, potentially harmful, viral infections and clinicians should seek specialist advice on a case-by-case basis (Strength of recommendation D; level of evidence 4) In patients who are hepatitis C carriers, there is limited evidence to support the use of etanercept provided they are appro-

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priately evaluated and monitored during therapy (Strength of recommendation D, level of evidence 4) TNF antagonist therapy should be avoided in chronic carriers of hepatitis B because of the risk of reactivation (Strength of recommendation D; level of evidence 4). See Table 4 for recommendations on screening for occult viral infections

17.5 Use of biologic therapy and vaccination

Live and live attenuated vaccinations can cause severe or fatal infections in immunosuppressed individuals due to the extensive replication of the vaccine strain and therefore are contraindicated in patients on biologic therapy.210 Current live vaccina rin tions available in the U.K. include bacille CalmetteGue (BCG), measles, mumps, rubella, yellow fever, oral polio and oral typhoid. There is no evidence available to provide recommendations on the safe time-frame from administration of a live vaccine to starting or recommencing a biologic therapy. Drug-specic advice is given only in the SPC for ustekinumab (i.e. withhold ustekinumab for 15 weeks before and 2 weeks after live vaccination). The UKs Department of Health210 gives comprehensive guidance on vaccination, and also indications for use of human normal immunoglobulin and human varicellazoster, for patients on immunosuppressive therapy [including cytokine inhibitors (sic)] and states that live vaccinations should not be administered until 6 months have elapsed from the withdrawal of immunosuppressive treatment.210 No data are available on risks for patients on biologic therapy who come into contact with individuals who have received a live vaccine (i.e. secondary transmission of infection by live vaccines) although current Department of Health guidance states that vaccination is not contraindicated in siblings close relatives of patients who are immunosuppressed.210 Inactivated vaccines are safe to give to patients receiving a biologic therapy.210 Several studies attempt to address the equally important question as to whether vaccination provides adequate protection from infection, using antibody response as a surrogate marker. Most of the evidence relates to TNF antagonists in rheumatological disease and ndings differ depending on the vaccine. With respect to pneumococcal vaccination, there is no evidence to indicate that monotherapy with iniximab, etanercept or adalimumab signicantly impairs humoral responses211215 although data on adalimumab are conned to measurement of vaccination responses following only 1 week of therapy.215 However, in a well-designed RCT in psoriatic arthritis, methotrexate led to a signicant reduction in humoral responses to pneumococcal vaccine when compared with etanercept or placebo control.213 Findings in this study are supported by further cohort studies where methotrexate alone, or in combination with any of the three TNF antagonists, was associated with reduced antibody formation, and appeared to be a strong predictor of poor response.211,212 Findings in relation to inuenza vaccination are slightly different, in that humoral responses were found to
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be reduced in patients on any of iniximab, etanercept or adalimumab216218 although antibody levels were still at levels predictive of clinical protection in most patients. Normal responses to inuenza have also been reported in a large RCT involving adalimumab (compared with placebo) although, as outlined above, this possibly reects the fact that vaccination occurred after only 1 week of treatment.215 There is little evidence available on what time period should elapse from drug discontinuation to administration of inactivated vaccines to yield an optimal immunological response.

Recommendations: Use of biologic therapy and vaccination

Vaccination requirements should be reviewed and brought up to date prior to initiation of biologic therapy with reference to Department of Health Guidance (Strength of recommendation D (GGP); level of evidence 4) Patients should not receive live or live attenuated vaccinations < 2 weeks before, during, and for 6 months after discontinuation of, biologic therapy (Strength of recommendation D; level of evidence 4) Inactivated vaccines are safe to administer concurrently with a biologic therapy (Strength of recommendation B; level of evidence 2++) Where possible, inactivated vaccines should be administered 2 weeks before starting therapy to ensure optimal immune responses (Strength of recommendation D (GGP); level of evidence 4) Clinicians should be aware that TNF antagonist monotherapy may lead to reduced antibody responses to inuenza vaccine and that TNF antagonists in combination with methotrexate (only) may lead to reduced antibody responses to pneumococcal vaccine (Strength of recommendation B; level of evidence 2++) Patients should be advised to receive the pneumococcal vaccine and annual inuenza vaccine while on biologic therapy (Strength of recommendation D; level of evidence 4)

18.0 How to prescribe therapy 18.1 Who should prescribe biologic therapy?
These treatments should be made available to all those patients fullling the currently recommended eligibility criteria. Treatment should be initiated and monitored by consultant dermatologists experienced in managing difcult 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 recommended for determining treatment eligibility and disease response. In the UK, supervising consultants are responsible for ensuring that all patients receiving biologic therapies are registered with the BADBIR throughout the treatment period.

18.2 Role of the specialist nurse

The specialist nurse is a key member of the multidisciplinary team delivering a biologic therapies service. With additional

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training a nurse may take responsibility for a number of the tasks outlined in the patient pathway including screening, disease assessments, treatment administration, patient education, prescription coordination, patient support, patient monitoring and data collection for the BADBIR. Competencies for nurses involved in the delivery of biologic therapies are in development by the British Dermatological Nursing Group, along the lines of those already developed by the Royal College of Nursing Rheumatology Forum.219

Recommendations: Prescribing biologic therapy

The specialist nurse is a key member of the multidisciplinary team delivering biologic therapy, and acts to facilitate all aspects of the patient pathway (Strength of recommendation D (GGP); level of evidence 4) In clearly dened clinical situations, suitably experienced and qualied nurse prescribers who have an expertise in the use of biologic therapies may prescribe biologic therapies under the direct supervision of a consultant dermatologist (Strength of recommendation D (GGP); level of evidence 4)

18.3 Patient information and consent

Patients should be fully informed of the risks and benets of biologic therapies through detailed, collaborative discussion with the supervising consultant and clinical nurse specialist.17 Written information should be provided (available on the BAD website) and patients given adequate time to consider their decision. Where therapies are being used outside their licensed indications, written consent should be obtained.

18.4 British Association of Dermatologists Biologic Interventions Registry

Short-term clinical trials in selected subjects do not adequately evaluate real world safety in long-term clinical usage of a drug. The potential for any new drug to result in delayed but important unexpected serious adverse effects is highlighted by recent experience with efalizumab. Voluntary reporting schemes lack the benets of prospective follow up of a known denominator of patients in whom safety data are specically collected. The BADBIR is now established, and collects vital long-term safety data throughout the U.K. with the intention that all patients on biologic interventions for psoriasis be registered and followed up for 5 years together with 4000 control subjects on conventional second-line drugs for psoriasis. Original NICE guidance on biologic therapies for psoriasis indicates registry participation as an important part of normal clinical care. The guideline development group very strongly recommends (above) that patients be registered in this way (see http://www.badbir.org/).

mendations above, and also based on the toxicity prole of the relevant drug. Recommended pretreatment and monitoring assessments (Table 4) are summarized. Assessment for risk of tuberculosis in patients considered for TNF antagonist therapy is outlined in Figure 1, and is based on the British Thoracic Society guideline which specically addresses this question.220 The British Thoracic Society guideline did not address the role of the now increasingly available in vitro interferon gamma release assay (IGRA) tests. The tests [QuantiFERONTB Gold (Cellestis Ltd, Carnegie, Vic., Australia) and T-SPOT.TB (Oxford Immunotec, Abingdon, U.K.)] are both in vitro tests, based on release of interferon gamma following stimulation by Mycobacterium tuberculosis-specic antigens (ESAT-6, CFP-10, TB7.7). QuantiFERON is cheaper to perform than the T-SPOT.TB and can be done in batches, but may be less sensitive. These tests have some advantages in being more specic in that there is no cross-reactivity with either BCG or most (but not all) clinically relevant atypical mycobacteria. They have proven utility in identifying latent tuberculosis but their place in screening low-risk individuals is still unclear. Repeated tuberculin skin testing may lead to a boosting of the in vitro interferon gamma release, and result in a false-positive result. The Health Protection Agency has issued an interim position statement (pending publication of the NICE Health Technology Assessment which is expected in 2010) and has provisionally approved the tests221 in certain clinical circumstances, while also discussing the lack of evidence on which to base recommendations. It recommends that the tests may be a suitable alternative to tuberculin skin testing for screening in BCG-vaccinated individuals and also for assessment of patients who are immunosuppressed in whom tuberculin skin testing is unreliable. However, the positive predictive value and negative predictive value in these situations are unknown. In the U.S.A., the Centers for Disease Control and Prevention advocate tuberculin skin testing in all patients irrespective of whether or not they are on immunosuppressant therapy and this is reected in the American Academy of Dermatology guidelines on tuberculosis screening for patients considered for TNF antagonist therapy.121 18.51 Monitoring Clinicians should maintain a high index of suspicion for tuberculosis throughout treatment, and for 6 months after discontinuation. Those at particular risk include recent immigrants from high-prevalence countries, injection drug users residents and employees of high-risk congregate settings (e.g. prisons, homeless shelters), mycobacteriology laboratory personnel, and persons with high-risk medical conditions (diabetes mellitus, chronic renal failure, some haematological conditions, conditions requiring prolonged high-dose corticosteroid or other immunosuppressive therapy, mastectomy jejunoileal bypass).222 Annual tuberculin skin testing has been recommended in the U.S.A. for both dermatology121 and rheumatology practice,223 although only 2137% of U.S. rheumatologists surveyed concord with this
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18.5 Pretreatment assessment and monitoring

All patients should undergo a full clinical history, physical examination and further investigations as indicated in recom-

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Group 1 Abnormal CXR suggestive of TB or previous history of TB treatment

Group 2 Normal CXR and no history of prior TB

On immunosuppressive therapy?

YES

NO

Refer to TB physician

Mantoux test invalid YES Perform IGRA**

Had BCG? NO

Mantoux test*

Mantoux test*

Mantoux 15 mm

Mantoux <15 mm

Mantoux <6 mm

Mantoux 6 mm

Positive

Negative

No further action

Fig 1. Algorithm for assessment and management of tuberculosis (TB) in patients scheduled for biologic therapy. Adapted from guidelines issued rin. *Interferon gamma release by the Joint Tuberculosis Committee of the British Thoracic Society.220 CXR, chest X-ray; BCG, bacille CalmetteGue assay (IGRA) may be used in place of Mantoux testing if available. **Seek advice if uncertain how to interpret the result.

advice, and the validity of skin testing in the context of biologic therapy is unproven. Where there is a low incidence of tuberculosis in the community annual testing is unnecessary but in patients with risk factors annual checks for conversion of IGRA may be useful.

Recommendations: Assessment and monitoring for tuberculosis (Fig. 1)

A pretreatment chest X-ray and Mantoux skin test currently remain the preferred screening tests in patients not on immunosuppression (Strength of recommendation D; level of evidence 4) Tuberculin testing is not valid in patients already established on immunosuppressive therapy (e.g. methotrexate). IGRA tests may have a role in this group and can be used if practicable, although the positive and negative predictive values are unknown. The T-SPOT.TB test may be more sensitive in patients on immunosuppressive drugs (Strength of recommendation D; level of evidence 4) Patients with signs to suggest tuberculosis or a history of previous treatment for tuberculosis should be referred to a tuberculosis physician (Strength of recommendation D; level of evidence 4) Patients with test(s) to support latent tuberculosis should be stratied for risk and considered for prophylactic antituberculous

therapy; further advice should be sought from a tuberculosis physician when necessary (Strength of recommendation D; level of evidence 4) When antituberculous therapy is indicated, patients should complete 2 months of treatment before commencing biologic therapy with either isoniazid (total treatment course 6 months) or rifampicin plus isoniazid (total treatment course 3 months) or rifampicin alone (total treatment course at least 4 months) (Strength of recommendation D; level of evidence 4) During treatment, and for 6 months following discontinuation, a high index of suspicion for tuberculosis should be maintained, especially in those at high risk (Strength of recommendation D; level of evidence 4) For patients on biologic therapies longer than 1 year who have negative screening tests for tuberculosis on initiation of therapy, annual assessment for tuberculosis may be considered in high-risk patients using whichever IGRA is locally available (Strength of recommendation D; level of evidence 4)

18.6 How should patients be transitioned from one therapy to another?

Patients may need to be transitioned from standard systemic therapy to biologic therapy, from one biologic therapy to another (either the same or different class) or from biologic

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therapy to standard systemic therapy. Ideally, there should be a washout period (the length of which is discussed below) between one drug and another so that pretreatment assessments occur off therapy (e.g. baseline disease severity, tuberculin skin tests) and so that the immunosuppressive burden is minimized. However, more commonly, the transition period involves either sequential use of therapy without a washout or a period of overlap between one drug and another, particularly where suddenly stopping therapy is associated with a risk of unstable disease (either treatment- or disease-related). All the RCTs cited required patients to discontinue standard systemic therapy for at least 4 weeks, and biologic therapy (for the ustekinumab trials) for 3 months, prior to initiating biologic therapies. Given that in the short term, overall, serious adverse events were no greater than placebo, this provides evidence to support ideal washout periods. In situations where a washout period is not feasible, it should be noted that safety data relating to TNF antagonists indicate additional risks of infection with concomitant use of immunosuppressive therapy. Also, even in the context of apparent treatment failure, loss of a drugs efcacy in psoriasis may not equate to loss of all pharmacological activity. This may be especially pertinent when switching from one biologic therapy to another, given that although these treatments are targeted, subsequent immunological events downstream are complex. Standard therapies should be rationalized wherever possible and stopped (or the dose reduced) once response to the biologic treatment is achieved. Methotrexate is not associated with increased toxicity when prescribed with TNF antagonists, and limited data on combined therapy with etanercept and acitretin show no excess toxicity. When switching from biologic therapy to biologic therapy, given the absence of data, overlap should be avoided. Traditionally, the time taken for a drug to be cleared from the body equates to four times a drugs terminal half-life and is therefore the recommended interval between therapies. Disease ares associated with discontinuation of efalizumab in low or nonresponders respond to standard systemic therapy.224226
Recommendations: Transitioning from one therapy to another

18.7 What are the indications for stopping therapy?

Therapy should be discontinued when patients fail to achieve an adequate response following treatment initiation or when treatment response is not maintained (see section 9.0 for denition of adequate treatment response). Withdrawal of therapy is also indicated due to the following events: (i) a serious adverse event. Serious adverse events which may justify the withdrawal of treatment include malignancy (excluding NMSC), severe drug-related toxicity, severe intercurrent infection (temporary withdrawal) (ii) pregnancy (temporary withdrawal) (iii) elective surgical procedures (see section 17.3)

19.0 Recommended audit points

Dermatology teams involved in prescribing biologic interventions should use audit as a tool to monitor their service against national guidelines of care. The aim should be to ensure that the service is high in quality, safe and cost-effective. Possible topics for audit might include one or more of the following: (i) Compliance with NICE guidance for patient selection criteria for prescribing of biologic therapies in psoriasis. (ii) Compliance with pretreatment assessment of patients referred for biologic therapies. (iii) Compliance with recommendation that all U.K. patients initiating biologic therapy should be registered with the BADBIR. (iv) Compliance with withdrawal recommendations for biologic therapies in patients who fail to respond adequately or develop signicant adverse events. (v) Patient satisfaction survey of biologic therapies care.

References
1 Zachariae H. Prevalence of joint disease in patients with psoriasis: implications for therapy. Am J Clin Dermatol 2003; 4:4417. 2 Smith CH, Barker JNWN. Psoriasis and its management. BMJ 2006; 333:3804. 3 Menter A, Grifths CE. Current and future management of psoriasis. Lancet 2007; 370:27284. 4 Grifths CEM, Clark CM, Chalmers RJG et al. A systematic review of treatments for severe psoriasis. Health Technol Assess 2000; 4:1 125. 5 Dubertret L, Mrowietz U, Ranki A et al. EUROPSO Patient Survey Group. European patient perspectives on the impact of psoriasis: the EUROPSO patient membership survey. Br J Dermatol 2006; 155:72936. 6 Nijsten T, Margolis D, Feldman SR et al. Traditional systemic treatments have not fully met the needs of psoriasis patients: results from a national survey. J Am Acad Dermatol 2005; 52:43444. 7 Smith CH, Anstey AV, Barker JNWN et al. British Association of Dermatologists guidelines for use of biological interventions in psoriasis 2005. Br J Dermatol 2005; 153:48697. 8 Eedy DJ, Grifths CEM, Chalmers RJ et al. Care of patients with psoriasis: an audit of U.K. services in secondary care. Br J Dermatol 2009; 160:55764. 2009 The Authors

Standard systemic therapy (with the exception of methotrexate) should be discontinued for 4 weeks prior to initiation of biologic therapy whenever possible to minimize risk of infection and establish baseline disease severity. When necessary, methotrexate cotherapy may be continued at the minimal required dose (Strength of recommendation B; level of evidence 1+) Where discontinuing standard systemic therapy is associated with risk of severe or unstable disease, use of concomitant systemic therapy should be rationalized during the transition period and stopped as soon as therapeutic efcacy of the biologic therapy is established (Strength of recommendation D; level of evidence 4) When switching from one biologic therapy to another biologic therapy, overlap should be avoided with the recommended interval being four times the drug half-life (Strength of recommendation D; level of evidence 4)

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Biologic interventions for psoriasis, C.H. Smith et al. 1013 9 Bell HK, Ormerod AD. Writing a British Association of Dermatologists clinical guideline: an update on the process and guidance for authors. Br J Dermatol 2009; 160:7258. 10 Appraisal of Guidelines Research and Evaluation. AGREE Instrument, 2004. Available at: http://www.agreecollaboration.org/instrument/ (last accessed 28 August 2009). 11 Garduno J, Bhosle MJ, Balkrishnan R et al. Measures used in specifying psoriasis lesion(s), global disease and quality of life: a systematic review. J Dermatolog Treat 2007; 18:22342. 12 Ashcroft DM, Li Wan Po A, Williams HC et al. Clinical measures of disease severity and outcome in psoriasis: a critical appraisal of their quality. Br J Dermatol 1999; 142:18591. 13 Both H, Essink-Bot M-L, Busschbach J et al. Critical review of generic and dermatology-specic health-related quality of life instruments. J Invest Dermatol 2007; 127:272639. 14 Finlay AY. Current severe psoriasis and the rule of tens. Br J Dermatol 2005; 152:8617. 15 Basra MK, Fenech R, Gatt RM et al. The Dermatology Life Quality Index 19942007: a comprehensive review of validation data and clinical results. Br J Dermatol 2008; 159:9971035. 16 Hongbo Y, Thomas CL, Harrison MA et al. Translating the science of quality of life into practice: what do Dermatology Life Quality Index scores mean? J Invest Dermatol 2005; 125:65964. 17 NICE. Medicines Adherence: Involving Patients in Decisions about Prescribed Medicines and Supporting Adherence. NICE Clinical Guidline 76, 2009. Available at: http://www.nice.org.uk/nicemedia/pdf/CG76NICE Guideline.pdf (last accessed 28 August 2009). 18 Kyle S, Chandler D, Grifths CE et al. Guideline for anti-TNF-alpha therapy in psoriatic arthritis [erratum appears in Rheumatology 2005; 44: 569]. Rheumatology 2005; 44:3907. 19 Ibbotson SH, Bilsland D, Cox NH et al. An update and guidance on narrowband ultraviolet B phototherapy: a British Photodermatology Group Workshop Report. Br J Dermatol 2004; 151:28397. 20 British Photodermatology Group guidelines for PUVA. Br J Dermatol 1994; 130:24655. 21 Shikiar R, Willian MK, Okun MM et al. The validity and responsiveness of three quality of life measures in the assessment of psoriasis patients: results of a phase II study. Health Qual Life Outcomes 2006; 4:71. 22 Melilli L. Minimum clinically important difference in Dermatology Life Quality Index in moderate to severe plaque psoriasis patients treated with adalimumab. J Am Acad Dermatol 2006; 54:2894. 23 Khilji FA, Gonzalez M, Finlay AY. Clinical meaning of change in Dermatology Life Quality Index scores. Br J Dermatol 2002; 147 (Suppl. 62):50. 24 Tracey D, Lareskog L, Sasso E et al. Tumour necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther 2008; 117:24479. 25 Guttman-Yassky E, Vugmeyster Y, Lowes MA et al. Blockade of CD11a by efalizumab in psoriasis patients induces a unique state of T-cell hyporesponsiveness. J Invest Dermatol 2008; 128:118291. 26 Joshi AB. An overview of the pharmacokinetics and pharmacodynamics of efalizumab: a monoclonal antibody approved for use in psoriasis. J Clin Pharmacol 2006; 46:1020. 27 Wilson NJ, Boniface K, Chan JR et al. Development, cytokine prole and function of human interleukin 17-producing helper T cells. Nat Immunol 2007; 8:9507. 28 Blauvelt A. T-helper 17 cells in psoriatic plaques and additional genetic links between IL-23 and psoriasis. J Invest Dermatol 2008; 128:10647. 29 Leonardi CL, Powers JL, Matheson RT et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med 2003; 349:201422. 30 Papp KA, Tyring S, Lahfa M et al. A global phase III randomized controlled trial of etanercept in psoriasis: safety, efcacy, and effect of dose reduction. Br J Dermatol 2005; 152:130412. 31 Tyring S, Gottlieb AB, Papp K et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet 2006; 367:29 35. 32 Tyring S, Gordon KB, Poulin Y et al. Long-term safety and efcacy of 50 mg of etanercept twice weekly in patients with psoriasis. Arch Dermatol 2007; 143:71926. 33 Gordon KB, Gottlieb AB, Leonardi CL et al. Clinical response in psoriasis patients discontinued from and then reinitiated on etanercept therapy [erratum appears in J Dermatolog Treat 2006; 17: 192]. J Dermatolog Treat 2006; 17:917. 34 Moore A, Gordon KB, Kang S et al. A randomized, open-label trial of continuous versus interrupted etanercept therapy in the treatment of psoriasis. J Am Acad Dermatol 2007; 56:598603. 35 Feldman SR, Kimball AB, Krueger GG et al. Etanercept improves the health-related quality of life of patients with psoriasis: results of a phase III randomized clinical trial. J Am Acad Dermatol 2005; 53:8879. 36 Krueger GG, Langley RG, Finlay AY et al. Patient-reported outcomes of psoriasis improvement with etanercept therapy: results of a randomized phase III trial. Br J Dermatol 2005; 153:1192 9. 37 Katugampola RP, Lewis VJ, Finlay AY et al. The Dermatology Life Quality Index: assessing the efcacy of biological therapies for psoriasis. Br J Dermatol 2007; 156:94550. 38 Gelfand JM, Kimball AB, Mostow EN et al. Patient-reported outcomes and health-care resource utilization in patients with psoriasis treated with etanercept: continuous versus interrupted treatment. Value Health 2008; 11:4007. 39 Krishnan R, Cella D, Leonardi C et al. Effects of etanercept therapy on fatigue and symptoms of depression in subjects treated for moderate to severe plaque psoriasis for up to 96 weeks. Br J Dermatol 2007; 157:12757. 40 Militello G, Xia A, Stevens SR et al. Etanercept for the treatment of psoriasis in the elderly. J Am Acad Dermatol 2006; 55:51719. 41 Zhou H. Clinical pharmacokinetics of etanercept: a fully humanized soluble recombinant tumor necrosis factor receptor fusion protein. J Clin Pharmacol 2005; 45:4907. 42 van de Kerkhof PCM, Segaert S, Lahfa M et al. Once weekly administration of etanercept 50 mg is efcacious and well tolerated in patients with moderate-to-severe plaque psoriasis: a randomized controlled trial with open-label extension. Br J Dermatol 2008; 159:117785. 43 Elewski B, Leonardi C, Gottlieb AB et al. Comparison of clinical and pharmacokinetic proles of etanercept 25 mg twice weekly and 50 mg once weekly in patients with psoriasis. Br J Dermatol 2007; 156:13842. 44 Gisondi P, Del Giglio M, Cotena C, Girolomoni G. Combining etanercept and acitretin in the therapy of chronic plaque psoriasis: a 24-week, randomized, controlled, investigator-blinded pilot trial. Br J Dermatol 2008; 158:13459. 45 Hutmacher MM, Nestorov I, Ludden T et al. Modeling the exposure-response relationship of etanercept in the treatment of patients with chronic moderate to severe plaque psoriasis. J Clin Pharmacol 2007; 47:23848. 46 de Groot M, Appelman M, Spuls PI et al. Initial experience with routine administration of etanercept in psoriasis. Br J Dermatol 2006; 155:80814. 47 Zachariae C, Mork NJ, Reunala T et al. The combination of etanercept and methotrexate increases the effectiveness of treatment in

2009 The Authors Journal Compilation 2009 British Association of Dermatologists British Journal of Dermatology 2009 161, pp9871019

1014 Biologic interventions for psoriasis, C.H. Smith et al. active psoriasis despite inadequate effect of methotrexate therapy. Acta Derm Venereol (Stockh) 2008; 88:495501. Driessen RJB, van de Kerkhof PCM, De Jong EMGJ. Etanercept combined with methotrexate for high-need psoriasis. Br J Dermatol 2008; 159:4603. Berends MA, Driessen RJ, Langewouters AM et al. Etanercept and efalizumab treatment for high-need psoriasis. Effects and side effects in a prospective cohort study in outpatient clinical practice. J Dermatolog Treat 2007; 18:7683. Ahmad K, Rogers S. Two years of experience with etanercept in recalcitrant psoriasis. Br J Dermatol 2007; 156:101014. Krueger GG, Elewski B, Papp K et al. Patients with psoriasis respond to continuous open-label etanercept treatment after initial incomplete response in a randomized, placebo-controlled trial. J Am Acad Dermatol 2006; 54:S11219. Gottlieb AB, Evans R, Li S et al. Iniximab induction therapy for patients with severe plaque-type psoriasis: a randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol 2004; 51:53442. Reich K, Nestle FO, Papp K et al. Iniximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial. Lancet 2005; 366:136774. Menter A, Feldman SR, Weinstein GD et al. A randomized comparison of continuous vs. intermittent iniximab maintenance regimens over 1 year in the treatment of moderate-to-severe plaque psoriasis. J Am Acad Dermatol 2007; 56:31. Chaudhari U, Romano P, Mulcahy LD et al. Efcacy and safety of iniximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet 2001; 357:18427. Antoni CE, Kavanaugh A, Kirkham B et al. Sustained benets of iniximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the Iniximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT) [erratum appears in Arthritis Rheum 2005; 52: 2951]. Arthritis Rheum 2005; 52:122736. Reich K, Nestle FO, Papp K et al. Improvement in quality of life with iniximab induction and maintenance therapy in patients with moderate-to-severe psoriasis: a randomized controlled trial. Br J Dermatol 2006; 154:11618. Gottlieb AB, Chaudhari U, Mulcahy LD et al. Iniximab monotherapy provides rapid and sustained benet for plaque-type psoriasis. J Am Acad Dermatol 2003; 48:82935. Maini RN, Breedveld FC, Kalden JR et al. Therapeutic efcacy of multiple intravenous infusions of anti-tumor necrosis factor monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998; 41:1552 63. Baert F, Noman M, Vermeire S et al. Inuence of immunogenicity on the long-term efcacy of iniximab in Crohns disease. N Engl J Med 2003; 348:6018. Kapetanovic MC, Larsson L, Truedsson L et al. Predictors of infusion reactions during iniximab treatment in patients with arthritis. Arthritis Res Ther 2006; 8:R131. Gordon KB, Langley RG, Leonardi C et al. Clinical response to adalimumab treatment in patients with moderate to severe psoriasis: double-blind, randomized controlled trial and open-label extension study. J Am Acad Dermatol 2006; 55:598606. Menter A, Tyring SK, Gordon K et al. Adalimumab therapy for moderate to severe psoriasis: a randomized, controlled phase III trial. J Am Acad Dermatol 2008; 58:10615. Saurat JH, Stingl G, Dubertret L et al. Efcacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br J Dermatol 2008; 158:55666. 65 Mease PJ, Gladman DD, Ritchlin CT et al. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2005; 52:327989. 66 Shikiar R, Heffernan M, Langley RG et al. Adalimumab treatment is associated with improvement in health-related quality of life in psoriasis: patient-reported outcomes from a phase II randomized controlled trial. J Dermatolog Treat 2007; 18:2531. 67 Revicki D, Willian MK, Saurat JH et al. Impact of adalimumab treatment on health-related quality of life and other patientreported outcomes: results from a 16-week randomized controlled trial in patients with moderate to severe plaque psoriasis. Br J Dermatol 2008; 158:54957. 68 Gladman DD, Mease PJ, Ritchlin CT et al. Adalimumab for longterm treatment of psoriatic arthritis: forty-eight week data from the adalimumab effectiveness in psoriatic arthritis trial. Arthritis Rheum 2007; 56:47688. 69 Papoutsaki M, Chimenti MS, Costanzo A et al. Adalimumab for severe psoriasis and psoriatic arthritis: an open-label study in 30 patients previously treated with other biologics. J Am Acad Dermatol 2007; 57:26975. 70 Krueger GG, Langley RG, Leonardi C et al. A human interleukin12 23 monoclonal antibody for the treatment of psoriasis. N Engl J Med 2007; 356:58092. 71 Leonardi CL, Kimball AB, Papp K et al. Efcacy and safety of ustekinumab, a human interleukin-12 23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 2008; 371:166574. 72 Papp K, Langley RG, Lebwohl M et al. Efcacy and safety of ustekinumab, a human interleukin-12 23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 2008; 371:167584. 73 Gottlieb A, Menter A, Mendelsohn A et al. Ustekinumab, a human interleukin 12 23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trial. Lancet 2009; 373:63340. 74 Grifths CEM, Strober BE, van de Kerkhof PC et al. Comparison of ustekinumab and etanercept for the treatment of moderate-to severe psoriasis. N Engl J Med (submitted). 75 Asumalahti K, Ameen N, Suomela S et al. Genetic analysis of PSORS1 distinguishes guttate psoriasis and palmoplantar pustulosis. J Invest Dermatol 2003; 120:62732. 76 Wollina U, Hansel G, Koch A et al. Tumor necrosis factor-alpha inhibitor-induced psoriasis or psoriasiform exanthemata: rst 120 cases from the literature including a series of six new patients. Am J Clin Dermatol 2008; 9:114. 77 Collamer AN, Guerro KT, Henning JS et al. Psoriatic skin lesions induced by tumor necrosis factor antagonist therapy: a literature review and potential mechanisms of action. Arthritis Care Res 2008; 59:9961001. 78 Bissonnette R, Poulin Y, Bolduc C et al. Etanercept in the treatment of palmoplantar pustulosis. J Drugs Dermatol 2008; 7:9406. 79 Elewski BE. Iniximab for the treatment of severe pustular psoriasis. J Am Acad Dermatol 2002; 47:7967. 80 Poulalhon N, Begon E, Lebbe C et al. A follow-up study in 28 patients treated with iniximab for severe recalcitrant psoriasis: evidence for efcacy and high incidence of biological autoimmunity. Br J Dermatol 2007; 156:32936. 81 Benoit S, Toksoy A, Brocker EB et al. Treatment of recalcitrant pustular psoriasis with iniximab: effective reduction of chemokine expression. Br J Dermatol 2004; 150:100912.

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2009 The Authors Journal Compilation 2009 British Association of Dermatologists British Journal of Dermatology 2009 161, pp9871019

Biologic interventions for psoriasis, C.H. Smith et al. 1015 82 Trent JT, Kerdel FA. Successful treatment of von Zumbusch pustular psoriasis with iniximab. J Cutan Med Surg 2004; 8: 2248. o V, Martins A, Lopes MJ. Iniximab in recalcitrant 83 Vieira Serra generalized pustular arthropatic psoriasis. Eur J Dermatol 2008; 18:713. 84 Routhouska SB, Sheth PB, Korman NJ. Long-term management of generalized pustular psoriasis with iniximab: case series. J Cutan Med Surg 2008; 12:1848. 85 Esposito M, Mazzotta A, Casciello C et al. Etanercept at different dosages in the treatment of generalized pustular psoriasis: a case series. Dermatology 2008; 216:35560. 86 Kamarashev J, Lor P, Forster A et al. Generalised pustular psoriasis induced by cyclosporin A withdrawal responding to the tumour necrosis factor alpha inhibitor etanercept. Dermatology 2002; 205:21316. 87 Weisenseel P, Prinz JC, Weisenseel P et al. Sequential use of iniximab and etanercept in generalized pustular psoriasis. Cutis 2006; 78:1979. 88 Pereira TM, Vieira AP, Fernandes JC et al. Anti-TNF-alpha therapy in childhood pustular psoriasis. Dermatology 2006; 213:3502. 89 Callen JP, Jackson JH. Adalimumab effectively controlled recalcitrant generalized pustular psoriasis in an adolescent. J Dermatolog Treat 2005; 16:3502. 90 Esposito M, Mazzotta A, de Felice C et al. Treatment of erythrodermic psoriasis with etanercept. Br J Dermatol 2006; 155:1569. 91 Fiehn C, Andrassy K. Case number 29: hitting three with one strike: rapid improvement of psoriatic arthritis, psoriatic erythroderma, and secondary renal amyloidosis by treatment with iniximab (Remicade). Ann Rheum Dis 2004; 63:232. 92 Lewis TG, Tuchinda C, Lim HW, Wong HK. Life-threatening pustular and erythrodermic psoriasis responding to iniximab. J Drugs Dermatol 2006; 5:5468. 93 Lisby S, Gniadecki R. Iniximab (Remicade) for acute, severe pustular and erythrodermic psoriasis. Acta Derm Venereol (Stockh) 2004; 84:2478. 94 Rongioletti F, Borenstein M, Kirsner R et al. Erythrodermic, recalcitrant psoriasis: clinical resolution with iniximab. J Dermatolog Treat 2003; 14:2225. 95 Takahashi MD, Castro LG, Romiti R. Iniximab, as sole or combined therapy, induces rapid clearing of erythrodermic psoriasis. Br J Dermatol 2007; 157:82831. 96 OQuinn RP, Miller JL. The effectiveness of tumor necrosis factor alpha antibody (iniximab) in treating recalcitrant psoriasis: a report of 2 cases. Arch Dermatol 2002; 138:6448. 97 Yip L, Harrison S, Foley P. From biologic to biologic to biologic: lessons to learn for erythrodermic and recalcitrant chronic plaque psoriasis. Australas J Dermatol 2008; 49:1525. 98 Kircik L, Bagel J, Korman N et al. Utilization of narrow-band ultraviolet light B therapy and etanercept for the treatment of psoriasis (UNITE): efcacy, safety, and patient-reported outcomes. J Drugs Dermatol 2008; 7:24553. 99 Yazici Y, Adler NM, Yazici H. Most tumour necrosis factor inhibitor trials in rheumatology are undeservedly called efcacy and safety trials: a survey of power considerations. Rheumatology 2008; 47:10547. 100 Woolacott NF, Khadjesari ZC, Bruce IN et al. Etanercept and iniximab for the treatment of psoriatic arthritis: a systematic review. Clin Exp Rheumatol 2006; 24:58793. 101 Schmitt J, Zhang Z, Wozel G et al. Efcacy and tolerability of biologic and nonbiologic systemic treatments for moderate-to-severe psoriasis: meta-analysis of randomized controlled trials. Br J Dermatol 2008; 159:51326. 102 Brimhall AK, King LN, Licciardone JC et al. Safety and efcacy of alefacept, efalizumab, etanercept and iniximab in treating moderate to severe plaque psoriasis: a meta-analysis of randomized controlled trials. Br J Dermatol 2008; 159:27485. 103 Strangfeld A, Listing J, Herzer P et al. Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents. JAMA 2009; 301:73744. 104 Allison LS, Hyon KC, Marc CH et al. The risk of herpes zoster in patients with rheumatoid arthritis in the United States and the United Kingdom. Arthritis Care Res 2007; 57:14318. 105 Gardam MA, Keystone E, Menzies R. Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis 2003; 3:14855. 106 Hernandez Cruz B, Cetner AS, Jordan JE et al. Tuberculosis in the age of biologic therapy. J Am Acad Dermatol 2008; 59:36380. 107 Gomez-Reino JJ, Carmona L, Valverde VR et al. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to signicant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum 2003; 48:21227. 108 Gomez-Reino JJ, Carmona L, Angel DM. Risk of tuberculosis in patients treated with tumor necrosis factor antagonists due to incomplete prevention of reactivation of latent infection. Arthritis Rheum 2007; 57:75661. 109 Dixon WG, Hyrich KL, Watson KD et al. Drug specic risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy; results from the BSR biologics register (BSRBR). Rheumatology 2008; 47:171. 110 Dharamsi JW, Bhosle M, Balkrishnan R et al. Using number needed to treat to help conceptualize the magnitude of benet and risk of tumour necrosis factor-alpha inhibitors for patients with severe psoriasis. Br J Dermatol 2009; 161:60516. 111 Lim WS, Powell RJ, Johnston ID. Tuberculosis and treatment with iniximab. N Engl J Med 2002; 346:6236. 112 Keane J, Gershon SK, Wise R. Tuberculosis associated with iniximab, a tumor necrosis factor a-neutralizing agent. N Engl J Med 2001; 345:1098104. 113 Mohan N, Cote TR, Block JA et al. Tuberculosis following the use of etanercept, a tumour necrosis factor inhibitor. Clin Infect Dis 2004; 39:2959. 114 Mann DL, McMurray JJ, Packer M. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 2004; 109:1594602. TR, Cuffe MS et al. Case reports of heart failure 115 Kwon HJ, Cote after therapy with a tumor necrosis factor antagonist. Ann Intern Med 2003; 138:80711. 116 Listing J, Strangfeld A, Kekow J. Does tumor necrosis factor alpha inhibition promote or prevent heart failure in patients with rheumatoid arthritis? Arthritis Rheum 2008; 58:66777. 117 Sarzi-Puttini P, Atzeni F, Shoenfeld Y et al. TNF-alpha, rheumatoid arthritis, and heart failure: a rheumatological dilemma. Autoimmun Rev 2005; 4:15361. 118 Mohan N, Edwards ET, Cupps TR et al. Demyelination occurring during anti-tumor necrosis factor alpha therapy for inammatory arthritides. Arthritis Rheum 2001; 44:28629. 119 Klareskog L, Gaubitz M, Rodriguez-Valverde V et al. A long-term, open-label trial of the safety and efcacy of etanercept (Enbrel) in patients with rheumatoid arthritis not treated with other disease-modifying antirheumatic drugs. Ann Rheum Dis 2006; 65:157884. 120 Konttinen L, Honkanen V, Uotila Y et al. Biological treatment in rheumatic diseases: results from a longitudinal surveillance: adverse events. Rheumatol Int 2006; 26:91622.

2009 The Authors Journal Compilation 2009 British Association of Dermatologists British Journal of Dermatology 2009 161, pp9871019

1016 Biologic interventions for psoriasis, C.H. Smith et al. 121 Menter A, Gottlieb A, Feldman SR et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol 2008; 58:82650. 122 Massara A, Cavazzini L, La Corte R, Trotta F. Sarcoidosis appearing during anti-tumor necrosis factor alpha therapy: a new class effect paradoxical phenomenon. Two case reports and literature review. Semin Arthritis Rheum (in press). n P, Mun oz S et al. Autoimmune dis123 Ramos-Casals M, Brito-Zero eases induced by TNF-targeted therapies: analysis of 233 cases. Medicine (Baltimore) 2007; 86:24251. 124 Lyndell LL, Frederick WF, James TR. Do tumor necrosis factor inhibitors cause uveitis? A registry-based study Arthritis Rheum 2007; 56:324852. 125 Harrison MJ, Dixon WG, Watson KD et al. Rates of new-onset psoriasis in patients with rheumatoid arthritis receiving antitumour necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis 2009; 68:20915. 126 Zink A, Askling J, Dixon WG et al. European biologicals registers methodology, selected results and perspectives. Ann Rheum Dis 2009; 68:12406. 127 Bongartz T, Sutton AJ, Sweeting MJ et al. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials [erratum appears in JAMA 2006; 295: 2482]. JAMA 2006; 295:227585. 128 Okada SK, Siegel JN. Risk of serious infections and malignancies with anti-TNF antibody therapy in rheumatoid arthritis. JAMA 2006; 296:22012. 129 Dixon WG, Silman AJ. Is there an association between anti-TNF monoclonal antibody therapy in rheumatoid arthritis and risk of malignancy and serious infection? Commentary on the meta-analysis by Bongartz et al. Arthritis Rheum 2006; 8:111. 130 Callegari PE, Schaible TF, Boscia JA. Risk of serious infections and malignancies with anti-TNF antibody therapy in rheumatoid arthritis. JAMA 2006; 296:2202. 131 Rosh JR, Gross T, Mamula P et al. Hepatosplenic T-cell lymphoma in adolescents and young adults with Crohns disease: a cautionary tale? Inamm Bowel Dis 2007; 13:102430. 132 Drini M, Prichard PJ, Brown GJ, Macrae FA. Hepatosplenic T-cell lymphoma following iniximab therapy for Crohns disease. Med J Aust 2008; 189:4645. 133 Mackey AC, Green L, Liang LC et al. Hepatosplenic T cell lymphoma associated with iniximab use in young patients treated for inammatory bowel disease. J Pediatr Gastroenterol Nutr 2007; 44:2657. 134 Navarro JT, Ribera JM, Mate JL et al. Hepatosplenic T-gammadelta lymphoma in a patient with Crohns disease treated with azathioprine. Leuk Lymphoma 2003; 44:5313. 135 Thayu M, Markowitz JE, Mamula P et al. Hepatosplenic T-cell lymphoma in an adolescent patient after immunomodulator and biologic therapy for Crohn disease. J Pediatr Gastroenterol Nutr 2005; 40:2202. 136 Zeidan A, Sham R, Shapiro J et al. Hepatosplenic T-cell lymphoma in a patient with Crohns disease who received iniximab therapy. Leuk Lymphoma 2007; 48:141013. 137 Brown SL, Greene MH, Gershon SK et al. Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum 2002; 46:31518. 138 Geborek P, Bladstrom A, Turesson C et al. Tumour necrosis factor blockers do not increase overall tumour risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas. Ann Rheum Dis 2005; 64:699703. Wolfe F, Michaud K. Biologic treatment of rheumatoid arthritis and the risk of malignancy: analyses from a large US observational study. Arthritis Rheum 2007; 56:288695. Burge D. Etanercept and squamous cell carcinoma. J Am Acad Dermatol 2003; 49:3589. Lebwohl M, Blum R, Berkowitz E et al. No evidence for increased risk of cutaneous squamous cell carcinoma in patients with rheumatoid arthritis receiving etanercept for up to 5 years. Arch Dermatol 2005; 141:8614. Leonardi CL, Toth D, Cather JC et al. A review of malignancies observed during efalizumab (Raptiva) clinical trials for plaque psoriasis. Dermatology 2006; 213:20414. Gottlieb AB, Leonardi CL, Goffe BS et al. Etanercept monotherapy in patients with psoriasis: a summary of safety, based on an integrated multistudy database. J Am Acad Dermatol 2006; 54:S92100. Woolacott N, Hawkins N, Mason A et al. Etanercept and efalizumab for the treatment of psoriasis: a systematic review. Health Technol Assess 2006; 10:1233, iiv. Woolacott N, Bravo Vergel Y, Hawkins N et al. Etanercept and infliximab for the treatment of psoriatic arthritis: a systematic review and economic evaluation. Health Technol Assess 2006; 10:iiixvi, 1 239 Slifman NR, Gershon SK, Lee JH et al. Listeria monocytogenes infection as a complication of treatment with tumor necrosis factor alphaneutralizing agents. Arthritis Rheum 2003; 48:31924. Symmons DP, Silman AJ. The world of biologics. Lupus 2006; 15:1226. Lee JH, Slifman NR, Gershon SK et al. Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists iniximab and etanercept. Arthritis Rheum 2002; 46:256570. Lecluse LL, Piskin G, Mekkes JR et al. Review and expert opinion on prevention and treatment of iniximab-related infusion reactions. Br J Dermatol 2008; 159:52736. Rennard SI, Fogarty C, Kelsen S et al. The safety and efcacy of iniximab in moderate to severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007; 175:92634. Schiff MH, Burmester GR, Kent JD et al. Safety analyses of adalimumab (Humira) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis. Ann Rheum Dis 2006; 65:88994. Burmester GR, Mariette X, Montecucco C et al. Adalimumab alone and in combination with disease-modifying antirheumatic drugs for the treatment of rheumatoid arthritis in clinical practice: the Research in Active Rheumatoid Arthritis (ReAct) trial. Ann Rheum Dis 2007; 66:7329. Pariser DM, Gordon KB, Papp KA et al. Clinical efcacy of efalizumab in patients with chronic plaque psoriasis: results from three randomized placebo-controlled phase III trials: part I. J Cutan Med Surg 2005; 9:30312. Menter A, Gordon K, Carey W et al. Efcacy and safety observed during 24 weeks of efalizumab therapy in patients with moderate to severe plaque psoriasis. Arch Dermatol 2005; 141:318. Gottlieb AB, Hamilton T, Caro I et al. Long-term continuous efalizumab therapy in patients with moderate to severe chronic plaque psoriasis: updated results from an ongoing trial. J Am Acad Dermatol 2006; 54:S15463. Costanzo A, Peris K, Talamonti M et al. Long-term treatment of plaque psoriasis with efalizumab: an Italian experience. Br J Dermatol 2007; 156 (Suppl. 2):1723.

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Biologic interventions for psoriasis, C.H. Smith et al. 1017 157 Selenko-Gebauer N, Karlhofer F, Stingl G et al. Efalizumab in routine use: a clinical experience. Br J Dermatol 2007; 156 (Suppl. 2):16. 158 Pincelli C, Henninger E, Casset-Semanaz F et al. The incidence of arthropathy adverse events in efalizumab-treated patients is low and similar to placebo and does not increase with long-term treatment: pooled analysis of data from phase III clinical trials of efalizumab. Arch Dermatol Res 2006; 298:32938. 159 Viguier M, Richette P, Aubin F et al. Onset of psoriatic arthritis in patients treated with efalizumab for moderate to severe psoriasis. Arthritis Rheum 2008; 58:1796802. 160 Sandborn WJ, Feagan BG, Fedorak RN et al. A randomized trial of ustekinumab, a human interleukin-12 23 monoclonal antibody, in patients with moderate-to-severe Crohns disease. Gastroenterology 2008; 135:113041. 161 Segal BM, Constantinescu CS, Raychaudari A et al. Repeated subcutaneous injections of IL12 23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, doseranging study. Lancet Neurol 2008; 7:796804. 162 Ryan C, Kirby B, Collins P, Rogers S. Adalimumab treatment for severe recalcitrant chronic plaque psoriasis. Clin Exp Dermatol 2009); 34:7848. 163 Paller AS, Siegfried EC, Langley RG et al. Etanercept treatment for children and adolescents with plaque psoriasis. N Engl J Med 2008; 358:24151. 164 Lovell DJ, Giannini EH, Reiff A et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. N Engl J Med 2000; 342:7639. 165 Mahadevan U, Kane S, Sandborn WJ et al. Intentional iniximab use during pregnancy for induction or maintenance of remission in Crohns disease. Aliment Pharmacol Ther 2005; 21:7338. 166 Lichtenstein GR, Cohen MD, Feasel A. Safety of iniximab in Crohns disease: data from the 5000-patient TREAT registry. Gastroenterology 2004; 126:A54. 167 Katz JA, Antoni C, Keenan GF et al. Outcome of pregnancy in women receiving iniximab for the treatment of Crohns disease and rheumatoid arthritis. Am J Gastroenterol 2004; 99: 238592. 168 Hyrich KL, Symmons DP, Watson KD et al. Pregnancy outcome in women who were exposed to anti-tumor necrosis factor agents: results from a national population register. Arthritis Rheum 2006; 54:27012. 169 Miskin DS, VanDenise W, Becker JM et al. Successful use of adalimumab for Crohns disease in pregnancy. Inamm Bowel Dis 2006; 12:8278. 170 Roux CH, Brocq O, Breuil V et al. Pregnancy in rheumatology patients exposed to anti-tumour necrosis factor (TNF)-alpha therapy. Rheumatology 2007; 46:6958. 171 Rosner I, Haddad A, Boulman N et al. Pregnancy in rheumatology patients exposed to anti-tumour necrosis factor (TNF)-alpha therapy. Rheumatology 2007; 46:15089. 172 Winger EE, Reed JL, Ashoush S et al. Treatment with adalimumab (Humira) and intravenous immunoglobulin improves pregnancy rates in women undergoing IVF. Am J Reprod Immunol 2009; 61:11320. 173 Berthelot JM, DeBandt M, Goupille P et al. Exposition to anti-TNF drugs during pregnancy: outcome of 15 cases and review of the literature. Joint Bone Spine 2009; 76:2834. 174 Carter JD, Ladhani A, Ricca LR et al. A safety assessment of tumor necrosis factor antagonists during pregnancy: a review of the Food and Drug Administration database. J Rheumatol 2009; 36:63541. 175 Chakravarty EF, Sanchez-Yamamoto D, Bush TM et al. The use of disease modifying antirheumatic drugs in women with rheumatoid arthritis of childbearing age: a survey of practice patterns and pregnancy outcomes. J Rheumatol 2003; 30:2416. 176 Carter JD, Valeriano J, Vasey FB et al. Tumor necrosis factor-alpha inhibition and VATER association: a causal relationship. J Rheumatol 2006; 33:101417. 177 Micheloud D, Nuno L, Rodriguez-Mahou M et al. Efcacy and safety of etanercept, high-dose intravenous gammaglobulin and plasmapheresis combined therapy for lupus diffuse proliferative nephritis complicating pregnancy. Lupus 2006; 15:8815. 178 Sinha A, Patient C. Rheumatoid arthritis in pregnancy: successful outcome with anti-TNF agent (etanercept). J Obstet Gynaecol 2006; 26:68991. 179 Vesga L, Terdiman JP, Mahadevan U. Adalimumab use in pregnancy. Gut 2005; 54:890. 180 Coburn LA, Wise PE, Schwartz DA. The successful use of adalimumab to treat active Crohns disease of an ileoanal pouch during pregnancy. Dig Dis Sci 2006; 51:20457. 181 Kraemer B, Abele H, Hahn M et al. A successful pregnancy in a patient with Takayasus arteritis. Hypertens Pregnancy 2008; 27:24752. 182 Vasiliauskas EA, Church JA, Silverman N et al. Case report: evidence for transplacental transfer of maternally administered iniximab to the newborn. Clin Gastroenterol Hepatol 2006; 4:12558. 183 Stengel JZ, Arnold HL. Is iniximab safe to use while breastfeeding? World J Gastroenterol 2008; 14:30857. 184 Mahadevan U, Terdiman JP, Church JA et al. Iniximab levels in infants born to women with inammatory bowel disease. Gastroenterology 2007; 132:A144 (Abstract). 185 Tauscher AEF, Fleischer AB Jr, Phelps KC, Feldman SR. Psoriasis and pregnancy. J Cutan Med Surg 2002; 6:56170. 186 Granzow JW, Thaller SR, Panthaki Z. Cleft palate and toe malformations in a child with fetal methotrexate exposure. J Craniofac Surg 2003; 14:7478. 187 Nguyen C, Duhl AJ, Escallon CS et al. Multiple anomalies in a fetus exposed to low-dose methotrexate in the rst trimester. Obstet Gynecol 2002; 99:599602. 188 Eisermann J, Register KB, Strickler RC et al. The effect of tumor necrosis factor on human sperm motility in vitro. J Androl 1989; 10:2704. 189 La Montagna G, Malesci D, Buono R, Valentini G. Asthenoazoospermia in patients receiving anti-tumour necrosis factor alpha agents. Ann Rheum Dis 2005; 64:1667. 190 Wendling D, Balblanc JC, Brousse A et al. Surgery in patients receiving anti-tumour necrosis factor alpha treatment in rheumatoid arthritis: an observational study on 50 surgical procedures. Ann Rheum Dis 2005; 64:13789. 191 Talwalar SC, Grennan DM, Gray J et al. Tumour necrosis factor alpha antagonists and early postoperative complications in patients with inammatory joint disease undergoing elective orthopaedic surgery. Ann Rheum Dis 2005; 64:6501. 192 Giles JT, Bartlett SJ, Gelber AC et al. Tumor necrosis factor inhibitor therapy and risk of serious postoperative orthopedic infection in rheumatoid arthritis. Arthritis Rheum 2006; 55:3337. 193 Bibbo C, Goldberg JW. Infectious and healing complications after elective orthopaedic foot and ankle surgery during tumor necrosis factor-alpha inhibition therapy. Foot Ankle Int 2009; 25:3315. 194 Ruyssen-Witrand A, Gossec L, Salliot C et al. Complication rates of 127 surgical procedures performed in rheumatic patients receiving tumor necrosis factor alpha blockers. Clin Exp Rheumatol 2007; 25:4306. 195 den Broeder AA, Creemers MC, Fransen J et al. Risk factors for surgical site infections and other complications in elective surgery

2009 The Authors Journal Compilation 2009 British Association of Dermatologists British Journal of Dermatology 2009 161, pp9871019

1018 Biologic interventions for psoriasis, C.H. Smith et al. in patients with rheumatoid arthritis with special attention for anti-tumor necrosis factor: a large retrospective study. J Rheumatol 2007; 34:68995. Pappas DA, Giles JT. Do antitumor necrosis factor agents increase the risk of postoperative orthopedic infections? Curr Opin Rheumatol 2008; 20:4506. Marchal L, DHaens G, van Assche G et al. The risk of post-operative complications associated with iniximab therapy for Crohns disease: a controlled cohort study. Aliment Pharmacol Ther 2004; 19:74954. Grennan DM, Gray J, Loudon J et al. Methotrexate and early postoperative complications in patients with rheumatoid arthritis undergoing elective orthopaedic surgery. Ann Rheum Dis 2001; 60:21417. Ledingham J, Deighton C. British Society for Rheumatology Standards, Guidelines and Audit Working Group. Update on the British Society for Rheumatology guidelines for prescribing TNFalpha blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology 2005; 44: 15763. Pham T, Claudespierre P, Deprez X et al. Anti-TNF alpha therapy and safety monitoring. Clinical tool guide elaborated by the Club Rhumatismes et Inammations (CRI), section of the French Soci te Franc ety of Rheumatology (Socie aise de Rhumatologie, SFR). Joint Bone Spine 2005; 72:S158. Domm S, Mrowietz U. The impact of treatment with tumour necrosis factor-alpha antagonists on the course of chronic viral infections: a review of the literature. Br J Dermatol 2008; 159:1217 28. Zein NN. Etanercept Study Group. Etanercept as an adjuvant to interferon and ribavirin in treatment-naive patients with chronic hepatitis C virus infection: a phase 2 randomized, double-blind, placebo-controlled study. J Hepatol 2005; 42:31522. Aslanidis S, Vassiliadis T, Pyrpasopoulou A et al. Inhibition of TNFalpha does not induce viral reactivation in patients with chronic hepatitis C infection: two cases. Clin Rheumatol 2007; 26:2614. Cecchi R, Bartoli L. Psoriasis and hepatitis C treated with anti-TNF alpha therapy (etanercept). Dermatol Online J 2006; 12:4. Marotte H, Fontanges E, Bailly F et al. Etanercept treatment for three months is safe in patients with rheumatological manifestations associated with hepatitis C virus. Rheumatology 2007; 46: 979. Peterson JR, Hsu FC, Simkin PA et al. Effect of tumour necrosis factor alpha antagonists on serum transaminases and viraemia in patients with rheumatoid arthritis and chronic hepatitis C infection. Ann Rheum Dis 2003; 62:107882. Wallis RS, Kyambadde P, Johnson JL et al. A study of the safety, immunology, virology, and microbiology of adjunctive etanercept in HIV-1-associated tuberculosis. AIDS 2004; 18:25764. Lavagna A, Bergallo M, Daperno M et al. Iniximab and the risk of latent viruses reactivation in active Crohns disease. Inamm Bowel Dis 2007; 13:896902. Balandraud N, Guis S, Meynard JB et al. Long-term treatment with methotrexate or tumor necrosis factor alpha inhibitors does not increase EpsteinBarr virus load in patients with rheumatoid arthritis. Arthritis Rheum 2007; 57:7627. Department of Health. The Green Book: Immunisation against Infectious Disease. 2009. Available at: http://www.dh.gov.uk/en/Publichealth/Healthprotection/Immunisation/Greenbook/DH_4097254 (last accessed 28 August 2009). Gelinck LB, van der Bijl AE, Visser LG et al. Synergistic immunosuppressive effect of anti-TNF combined with methotrexate on antibody responses to the 23 valent pneumococcal polysaccharide vaccine. Ann Rheum Dis 2006; 65:1914. Kapetanovic MC, Saxne T, Sjoholm A et al. Inuence of methotrexate, TNF blockers and prednisolone on antibody responses to pneumococcal polysaccharide vaccine in patients with rheumatoid arthritis. Rheumatology 2006; 45:10611. Mease P, Ritchlin C, Martin RW et al. Pneumococcal vaccine response in psoriatic arthritis patients during treatment with etanercept. J Rheumatol 2004; 7:135661. Visanathan S, Keenan GF, Baker D et al. Response to pneumococcal vaccine in patients with early rheumatoid arthritis receiving iniximab plus methotrexate or methotrexate alone. J Rheumatol 2007; 34:9527. Kaine JL, Kivitz AJ, Birbara C et al. Immune responses following administration of inuenza and pneumococcal vaccines to patients with rheumatoid arthritis receiving adalimumab. J Rheumatol 2007; 34:2729. Fomin I, Caspi D, Levy V et al. Vaccination against inuenza in rheumatoid arthritis: the effect of disease modifying drugs, including TNF alpha blockers. Ann Rheum Dis 2006; 65:1914. Gelinck LB, van der Bijl AE, Beyer WE et al. The effect of antitumour necrosis factor alpha treatment on the antibody response to inuenza vaccination. Ann Rheum Dis 2008; 67:71316. Kapetanovic MC, Saxne T, Nilsson JA et al. Inuenza vaccination as model for testing immune modulation induced by anti-TNF and methotrexate therapy in rheumatoid arthritis patients. Rheumatology 2007; 46:60811. Royal College of Nursing. Assessing, Managing and Monitoring Biologic Therapies for Inammatory Arthritis: Guidance for Rheumatology Practitioners. London: Royal College of Nursing, 2003. British Thoracic Society Standards of Care Committee. BTS recommendations for assessing risk and for managing Mycobacterium tuberculosis infection and disease in patients due to start anti-TNF-alpha treatment. Thorax 2005; 60:8005. Health Protection Agency. Position Statement on the Use of Interferon Gamma Release Assay (IGRA) Tests for Tuberculosis (TB). 2008. Available at: http://www.hpa.org.uk/web/HPAwebFile/HPAweb_C/ 1214808549127 (last accessed 28 August 2009). The National Collaborating Centre for Chronic Conditions. Tuberculosis. Clinical Diagnosis and Management of Tuberculosis, and Measures for its Prevention and Control. 2006. Available at: http://www.nice.org.uk/ nicemedia/pdf/CG033FullGuideline.pdf (last accessed 28 August 2009). Cush JJ. Biological drug use: US perspectives on indications and monitoring. Ann Rheum Dis 2005; 64(Suppl. 4):1823. Papp KA, Toth D, Rosoph L et al. Approaches to discontinuing efalizumab: an open-label study of therapies for managing inammatory recurrence. BMC Dermatol 2006; 6:9. Carey W, Glazer S, Gottlieb AB et al. Relapse, rebound, and psoriasis adverse events: an advisory group report. J Am Acad Dermatol 2006; 54:S17181. Menter A, Hamilton TK, Toth DP et al. Transitioning patients from efalizumab to alternative psoriasis therapies: ndings from an open-label, multicenter, phase IIIb study. Int J Dermatol 2007; 46:63748.

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Appendix 1 Level of evidence and strength of recommendation

The published studies selected from the search were assessed for their methodological rigour against a number of criteria as

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Biologic interventions for psoriasis, C.H. Smith et al. 1019

currently recommended by the Institute for Health and 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 biases have been minimized.
Level of evidence Level of evidence 1++ 1+ Type of evidence High-quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias Well-conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of biasa High-quality systematic reviews of casecontrol or cohort studies High-quality casecontrol or cohort studies with a very low risk of confounding, bias or chance and a high probability that the relationship is causal Well-conducted casecontrol or cohort studies with a low risk of confounding, bias or chance and a moderate probability that the relationship is causal Casecontrol or cohort studies with a high risk of confounding, bias or chance and a signi cant risk that the relationship is not causala Nonanalytical studies (e.g. case reports, case series) Expert opinion, formal consensus

Strength of recommendation Class A Evidence At least one meta-analysis, systematic review, or RCT rated as 1++, and directly applicable to the target population, or A systematic review of RCTs or a body of evidence consisting principally of studies rated as 1+, directly applicable to the target population and demonstrating overall consistency of results Evidence drawn from a NICE technology appraisal A body of evidence including studies rated as 2++, directly applicable to the target population and demonstrating overall consistency of results, or Extrapolated evidence from studies rated as 1++ or 1+ A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results, or Extrapolated evidence from studies rated as 2++ Evidence level 3 or 4, or Extrapolated evidence from studies rated as 2+, or Formal consensus A good practice point (GPP) is a recommendation for best practice based on the experience of the guideline development group

1) 2++

2+

2)

D (GPP)

3 4

RCT, randomized controlled trial.

RCT, randomized controlled trial. aStudies with a level of evidence ) should not be used as a basis for making a recommendation.

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