A.D. Burden

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.

Efficacy of biologics in the treatment of moderate to severe psoriasis: a network meta‐analysis of randomized controlled trials

Background  Ustekinumab, a novel monoclonal antibody for the treatment of moderate to severe plaque‐type psoriasis, has recently received regulatory approval in Europe, bringing the total number of biologic agents licensed in this indication to five. To assist treatment selection in daily practice it is essential to understand the benefit/risk profile of these agents and in the absence of a clinical trial comparing all available biologics a number of reviews have used statistical techniques to generate estimates of the comparative effectiveness of these therapies through the available network of randomized clinical trials. These estimates have previously been published for a limited range of psoriasis biologic treatments, although, to date no review has compared all the currently available agents in Europe.

Psoriasis is associated with pleiotropic susceptibility loci identified in type II diabetes and Crohn disease

Background: Psoriasis is an immune-mediated skin disorder that is inherited as a multifactorial trait. Linkage analyses have clearly mapped a primary disease susceptibility locus to the major histocompatibility complex (MHC) region on chromosome 6p21. More recently, whole-genome association studies have identified two non-MHC disease genes (IL12B and IL23R), both of which also confer susceptibility to Crohn disease (CD). Objective and methods: To ascertain the genetic overlap between these two inflammatory conditions further, we investigated 15 CD-associated loci in a psoriasis case–control dataset. Results: The analysis of 1256 patients and 2938 unrelated controls found significant associations for loci mapping to chromosomes 1q24 (rs12035082, p = 0.009), 6p22 (rs6908425, p = 0.00015) and 21q22 (rs2836754, p = 0.0003). Notably, the marker showing the strongest phenotypic effect (rs6908425) maps to CDKAL1, a gene also associated with type 2 diabetes. Conclusions: These results substantiate emerging evidence for a pleiotropic role for s genes that contribute to the pathogenesis of immune-mediated disorders.

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.

The British Association of Dermatologists’ Biologic Interventions Register (BADBIR): design, methodology and objectives

Background  The British Association of Dermatologists (BAD) established a web‐based pharmacovigilance register to assess the long‐term safety of biologics prescribed for patients with severe psoriasis in September 2007. The BAD Biologic Interventions Register (BADBIR) also participates in the network of European psoriasis biologics registers (Psonet).

Oral liarozole in the treatment of palmoplantar pustular psoriasis: A randomized, double-blind, placebo-controlled study

Background Palmoplantar pustular psoriasis (PPP) is a chronic, relapsing condition often recalcitrant to therapy. Synthetic retinoids have been found to be efficacious in the treatment of PPP, but their use is limited by side‐effects. Liarozole is an imidazole‐like compound that inhibits the retinoic acid (RA) 4‐hydroxylase‐mediated breakdown of all‐trans RA, causing elevation of plasma and cutaneous levels of RA. Thus liarozole acts as a retinoid‐mimetic drug. Liarozole has already been found to be effective in the treatment of retinoid‐responsive conditions such as chronic plaque psoriasis and ichthyoses.

Noninvasive monitoring for methotrexate hepatotoxicity.

The advent of targeted biological treatments for psoriasis has challenged the safety and efficacy of established systemic treatments. Methotrexate has been used for psoriasis since the late 1950s and is still the most widely prescribed drug for severe psoriasis worldwide. Its effectiveness in treating psoriasis was first detected by chance in a patient being treated for arthritis whose coincident psoriasis was observed to improve. This started a trend of serendipity in drug development for psoriasis, being subsequently followed by ciclosporin, vitamin D and infliximab. As methotrexate has been in use for almost 50 years it predates the development of randomized controlled trials, and high-quality data concerning its efficacy are sparse. Consequently there is considerable variability in the recommended weekly dose, the route of administration (oral, intramuscular, intravenous and subcutaneous) and the need for, and dosing of, concomitant folic acid. With improvements in our understanding of the immunopathogenesis of psoriasis, it has become apparent that the mechanism of action in psoriasis (originally attributed to the inhibition of the enzyme dihydrofolate reductase, disrupting DNA synthesis and interrupting epidermal cell division) is probably related to effects on T cells, rather than keratinocytes. Use of methotrexate is restricted by the risk of organ toxicity. Major concerns are myelosuppression, hepatotoxicity and pulmonary fibrosis, of which myelosuppression is the most important. Of the 164 fatalities associated with methotrexate therapy reported to the U.K. Committee on the Safety of Medicines (CSM) between 1969 and 2004, 67 were associated with myelosuppression. In contrast, 30 deaths occurred in association with pulmonary complications and only eight as a result of liver complications (CSM, personal communication, 2004). It is possible that there is under-reporting of cases to the CSM, as a survey in 1992 of 278 U.K. dermatologists treating approximately 10 000 patients with methotrexate over a mean period of 12 years reported 23 deaths as a result of liver failure and five as a result of liver biopsy. Prescribing error is a particular problem and this may increase in the U.K. with a shift in monitoring of methotrexate to primary care. The National Patient Safety Agency recorded 137 patient safety incidents in the U.K. over the last 10 years, including 25 deaths and 26 cases of serious harm to the patient as a consequence of methotrexate administration (http://www.npsa.nhs.uk, accessed 21 December 2004). Two-thirds of incidents were prescribing errors, 19% were due to a lack of, or poor monitoring, and 7% were due to misidentification of tablets by professionals or patients. Most incidents involved primary care clinicians. Among dermatologists, there is particular concern about the long-term hepatotoxic potential of methotrexate. Interestingly, this concern is not shared to the same extent by other specialities. It seems quite possible that the risk of hepatotoxicity varies in different diseases. For instance, patients with rheumatoid arthritis are more frequently treated with oral corticosteroids than are patients with psoriasis, and it is conceivable that this reduces hepatic inflammation. Psoriatic patients have a greater tendency to drink alcohol to excess, which may contribute. Among patients with psoriasis receiving methotrexate, rates of hepatic fibrosis as high as 25–50% have been published athough recent estimates are lower, at 0–4%. The cause of methotrexate-induced fibrosis is unknown. Methotrexate may also be an independent risk factor for nonalcoholic steatohepatitis (NASH), the most common cause of chronic liver disease in the developed world. Folate supplementation reduces the frequency of raised liver enzymes without altering efficacy, suggesting that this aspect of methotrexate toxicity may be divorced from its therapeutic efficacy. Understanding of liver fibrosis and cirrhosis has advanced significantly over recent years. Hepatic stellate cells (HSCs) are now known to be the final common pathway in the production of collagens. In hepatic fibrosis, HSCs are upregulated to become myofibroblast-like and produce collagen. Gliotoxin, which stimulates apoptosis of HSCs, promotes reversal of liver fibrosis in animal models. Research into the mechanisms of activation of HSCs by chemokines and cytokines may allow for therapeutic intervention in the future. Understanding of the role of metalloproteinases, which degrade collagen, may also provide a therapeutic target to reverse fibrosis. Ideally, individuals at particular risk of hepatotoxicity would be identified prior to treatment. Early pharmacogenetic studies have demonstrated an A1298C polymorphism in the methylenetetrahydrofolate reductase gene which may protect against methotrexate-related adverse effects, while a C667T polymorphism in the same gene correlates with methotrexate hepatotoxicity. These studies assessed tolerability of methotrexate and derangement of liver enzymes rather than progression to fibrosis, but hopefully this aspect will also be addressed. Environmental factors predisposing to methotrexate hepatotoxicity include exposure to other hepatotoxins such as alcohol, and also the various factors associated with NASH, such as obesity and diabetes. Many issues need to be considered in deciding a policy for screening for methotrexate hepatotoxicity, but it is important that the procedures used are not only accurate, but are also proportionate to the frequency and severity of this complication. It is widely accepted that elevations in liver enzymes are a poor guide to the development of liver fibrosis. However, although liver enzymes rise in the days following

Sequential use of biologics in the treatment of moderate-to-severe plaque psoriasis

A number of biologic agents, including the tumour necrosis factor (TNF) antagonists etanercept, adalimumab and infliximab, and the interleukin (IL)‐12/IL‐23 antagonist ustekinumab, are available for the treatment of moderate‐to‐severe plaque psoriasis in the U.K. Currently, the selection of the first biologic, and the choice of sequential biologics in the event of efficacy/tolerability concerns, is made using a limited evidence base. The efficacy of biologics, the potential mechanisms of primary and secondary failure and the evidence for sequencing therapy among TNF antagonists and between TNF antagonists and IL‐12/IL‐23 blockade are reviewed. As psoriasis biologics registers begin to produce long‐term safety and efficacy data, therapy decisions in plaque psoriasis may become more objective, and it may be possible to individualize treatment based on clinical or pharmacogenetic information.

British Association of Dermatologists guidelines for biologic therapy for psoriasis 2017

The overall aim of the guideline is to provide evidence-based recommendations on the use of biologic therapies (adalimumab, etanercept, infliximab, ixekizumab, secukinumab and ustekinumab) in adults, children and young people for the treatment of psoriasis; consideration is given to the specific needs of people with psoriasis and psoriatic arthritis. Biologic therapies have now been in use for over 10 years, and with accrued patient-years exposure and clinical experience, many areas that were covered in previous versions of the guideline are now part of the Summary of Product Characteristics (SPC) and/or routine care so that specific recommendations are redundant (see Toolkit A: Summary of licensed indications and posology for biologic therapy, in Supporting information 2). Therefore, in this update we focus on areas where there has been a major change in the evidence base or clinical practice, where practice is very varied and/or where clear consensus or guidelines are lacking (see section 3.1 in Supporting information 1).