Nick Reynolds

British Association of Dermatologists’ guidelines for biologic interventions for psoriasis 2009

St John’s Institute of Dermatology, King’s College London and Guy’s 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 Infirmary, 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 Infirmary, Foresterhill, Aberdeen AB9 2ZB, U.K.

British Association of Dermatologists guidelines for use of biological interventions in psoriasis 2005

Psoriasis is a common, persistent, relapsing inflammatory skin disease that can be associated with significant morbidity. Quality of life studies in psoriasis reveal a negative impact on patients comparable with that seen in cancer, arthritis and heart disease.1–5 Patients with severe disease constitute approximately 20–30% of all patients with psoriasis, often require systemic treatment, and represent a major economic burden to the Health Service. All standard systemic therapies for severe disease are associated with the potential for major long-term toxicity, many are expensive, and a proportion of patients has treatmentresistant disease.6 Biological therapies or ‘biologics’ describe agents designed to block specific molecular steps important in the pathogenesis of psoriasis and have emerged over the last 3–5 years as potentially valuable alternative therapeutic options. Currently, biological therapies for psoriasis comprise two main groups: (i) agents targeting the cytokine tumour necrosis factor (TNF)-a (e.g. etanercept, infliximab, adalimumab) and (ii) agents targeting T cells or antigen-presenting cells (e.g. efalizumab, alefacept). Two of these, etanercept (Enbrel) and efalizumab (Raptiva) were licensed in 2004 in the U.K. for patients with moderate to severe psoriasis.

Azathioprine dosed by thiopurine methyltransferase activity for moderate-to-severe atopic eczema: a double-blind, randomised controlled trial

BACKGROUND Atopic eczema affects 1-2% of adults, and can cause considerable morbidity. We aimed to assess the safety and efficacy of azathioprine as systemic monotherapy for moderate-to-severe atopic eczema, and the therapeutic importance of the thiopurine methyltransferase (TPMT) polymorphism (a key determinant of azathioprine-induced myelotoxicity) by using TPMT enzyme activity to establish azathioprine dose. METHODS We did a parallel-group, double-blind, placebo-controlled trial in an outpatient setting. Minimisation was used to assign 63 patients with active disease despite optimum topical therapy to treatment with azathioprine (n=42) or placebo (n=21) for 12 weeks. As maintenance treatment, patients with heterozygous range TPMT activity received azathioprine 1.0 mg/kg daily, compared with 2.5 mg/kg daily in patients with normal TPMT activity. For the first 4 weeks, all participants received lower azathioprine doses (0.5 and 1.0 mg/kg daily, respectively) to reduce gastrointestinal side-effects. The primary measure of clinical response was disease activity assessed by the SASSAD (six area six sign atopic dermatitis) score. Analysis was by intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN58943280. FINDINGS 54 (86%) participants completed the study; two (3%) withdrew from the placebo group and seven (11%) from the azathioprine group. At week 12, there was a 37% (12.0 unit) improvement in mean disease activity with azathioprine compared with a 20% (6.6 unit) improvement with placebo (17% [5.4 unit] difference, 95% CI 4.3-29%). This finding was accompanied by significant improvements in patient-reported itch, area of involvement, global assessment, and quality of life. Between participants there was a wide variation in response to the drug. Generally, azathioprine was well tolerated, although two individuals developed drug hypersensitivity. Participants with heterozygous range TPMT activity responded to azathioprine in similar proportions to other participants, but none developed bone-marrow toxicity. TPMT-based dosing seemed to reduce predicted toxicity, and drug efficacy was maintained. INTERPRETATION Treatment with azathioprine as systemic monotherapy produces clinically relevant improvement in moderate-to-severe atopic eczema that remains active despite optimum therapy with topical corticosteriods. We believe the study of azathioprine as systemic monotherapy for atopic eczema has major advantages, which should allow clarification of the relation between azathioprine effectiveness and metabolite profiles in other inflammatory diseases.

Narrow-band ultraviolet B and broad-band ultraviolet A phototherapy in adult atopic eczema: a randomised controlled trial

BACKGROUND Narrow-band ultraviolet B (UVB) is an effective treatment for psoriasis, and open studies suggest that this phototherapy might improve atopic eczema. We did a randomised controlled trial to compare narrow-band UVB, UVA, and visible light phototherapy as second-line, adjunctive treatments in adult patients with moderate to severe atopic eczema. METHODS Phototherapy was administered twice a week for 12 weeks. 26 patients were randomly assigned narrow-band UVB, 24 were assigned UVA, and 23 visible fluorescent light. The primary endpoints were change in total disease activity (sum of scores at six body sites) and change in extent of disease after 24 treatments compared with baseline. Data were analysed by the method of summary measures. FINDINGS 13 patients withdrew or were excluded from analysis. Mean reductions in total disease activity over 24 treatments in patients who received narrow-band UVB and UVA, respectively, were 9.4 points (95% CI 3.6 to 15.2) and 4.4 points (-1.0 to 9.8) more than in patients who received visible light. Mean reductions in extent of disease after 24 treatments with narrow-band UVB and UVA were 6.7% (1.5 to 11.9) and -1.0% (-5.3 to 3.3) compared with visible light. A small proportion of patients developed erythema after phototherapy or had a flare in their eczema sufficient to withdraw from treatment. INTERPRETATION Narrow-band UVB is an effective adjunctive treatment for moderate to severe atopic eczema, and the treatment is well tolerated by most patients.

Differential Drug Survival of Biologic Therapies for the Treatment of Psoriasis: A Prospective Observational Cohort Study from the British Association of Dermatologists Biologic Interventions Register (BADBIR).

Drug survival reflects a drugs effectiveness, safety, and tolerability. We assessed the drug survival of biologics used to treat psoriasis in a prospective national pharmacovigilance cohort (British Association of Dermatologists Biologic Interventions Register (BADBIR)). The survival rates of the first course of biologics for 3,523 biologic-naive patients with chronic plaque psoriasis were compared using survival analysis techniques and predictors of discontinuation analyzed using a multivariate Cox proportional hazards model. Data for patients on adalimumab (n=1,879), etanercept (n=1,098), infliximab (n=96), and ustekinumab (n=450) were available. The overall survival rate in the first year was 77%, falling to 53% in the third year. Multivariate analysis showed that female gender (hazard ratio (HR) 1.22; 95% confidence interval (CI): 1.09-1.37), being a current smoker (HR 1.19; 95% CI: 1.03-1.38), and a higher baseline dermatology life quality index (HR 1.01; 95% CI: 1.00-1.02) were predictors of discontinuation. Presence of psoriatic arthritis (HR 0.82; 95% CI: 0.71-0.96) was a predictor for drug survival. As compared with adalimumab, patients on etanercept (HR 1.63; 95% CI: 1.45-1.84) or infliximab (HR 1.56; 95% CI: 1.16-2.09) were more likely to discontinue therapy, whereas patients on ustekinumab were more likely to persist (HR 0.48; 95% CI: 0.37-0.62). After accounting for relevant covariates, ustekinumab had the highest first-course drug survival. The results of this study will aid clinical decision making when choosing biologic therapy for psoriasis patients.

An open‐label, dose‐ranging study of methotrexate for moderate‐to‐severe adult atopic eczema

Background  Treatment options for moderate‐to‐severe atopic eczema are limited. Although methotrexate (MTX) is a widely used and effective treatment for psoriasis, there have been no previous prospective trials of its use in refractory atopic eczema, despite a few small, retrospective reports suggesting that it is a well‐tolerated and effective treatment.

Calcineurin inhibitors and sirolimus: mechanisms of action and applications in dermatology

Summary Controlled trials and clinical experience indicate that systemic cyclosporin A and tacrolimus are effective treatments for psoriasis, and that cyclosporin A also improves atopic eczema. A variety of other inflammatory and non‐inflammatory skin diseases are probably also responsive to these drugs. However, the widespread and longer‐term use of cyclosporin A and tacrolimus are limited by side effects. The molecular mechanisms of action of cyclosporin A, tacrolimus and a related drug, sirolimus, have been well defined in T cells and involve inhibition of critical signalling pathways that regulate T cell activation. For example cyclosporin and tacrolimus inhibit calcineurin phosphatase activity and thereby inhibit activation of the transcription factor NFAT. The therapeutic efficacy of topical calcineurin inhibitors in atopic eczema have restimulated interest in the mechanism of action of these drugs in skin disease. Recently the expression pattern of calcineurin and NFAT has been defined in non‐immune tissues including the akin. The relevance of this to the mechanism of action of systemic and topical calcineurin inhibitors and sirolimus in skin disorders is discussed.

Filaggrin null mutations and childhood atopic eczema: A population-based case-control study

BACKGROUND Null mutations within the filaggrin gene (FLG) are associated with moderate-to-severe atopic eczema; their role in mild-to-moderate eczema in the general population is unknown. OBJECTIVE We sought to investigate the significance of 5 common FLG null mutations in childhood atopic eczema in an unselected population cohort. METHODS Eight hundred eleven English children aged 7 to 9 years were screened for FLG mutations. Eczema cases were defined by using United Kingdom diagnostic criteria and skin examination. Asthma and seasonal rhinitis cases were defined by parental questionnaire. Association between phenotype and genotype was investigated using Fisher exact test and logistic regression analysis. RESULTS The 12-month period prevalence of atopic eczema was 24.2% (95% CI, 21.2% to 27.2%), with 96% (115/120) of cases having mild-to-moderate disease. The combined null genotype (carriage of > or = 1 FLG mutations) was significantly associated with atopic eczema (P = 1.2 x 10(-4)). The odds ratio (OR) for individuals carrying 2 null mutations was 26.9 (95% CI, 3.3-217.1), but heterozygote carriers showed no significant increase in risk (OR, 1.2; 95% CI, 0.7-1.9). Eight of 190 eczema cases (4.2%) carried 2 FLG null mutations and thus might be attributed to filaggrin deficiency. Asthma in the context of eczema showed significant association with the FLG null mutations (P = 7.1 x 10(-4)). There was no association of FLG with asthma independent of eczema (P = .15) and no association with seasonal rhinitis (P = .66). CONCLUSION FLG null mutations are significantly associated with mild-to-moderate atopic eczema in childhood, with a recessive pattern of inheritance.

Guidelines for prescribing azathioprine in dermatology

Azathioprine has been available as an immunosuppressive agent for over 40 years, and current routine usage in dermatology is not restricted to licensed indications. Advances in understanding the metabolic fate of azathioprine have led to significant changes in prescribing practice and toxicity monitoring by U.K. dermatologists. The current state of knowledge concerning the use of azathioprine in dermatology is summarized, with identification of strength of evidence. Clinical indications and contraindications for azathioprine usage in dermatology are identified. Evidence‐based recommendations are made for routine safety monitoring of patients treated with azathioprine, including pretreatment assessment of red blood cell thiopurine methyltransferase activity.

Comparison of three screening tools to detect psoriatic arthritis in patients with psoriasis (CONTEST study)

Background  Multiple questionnaires to screen for psoriatic arthritis (PsA) have been developed but the optimal screening questionnaire is unknown.