Psoriasis and its management

Genetic factors

Scans of the human genome reveal at least nine different loci with susceptibility to psoriasis (PSORS1-9). PSORS-1, a region of the major histocompatibility complex on chromosome 6p2, is the major genetic determinant of psoriasis, and accounts for up to 50% of genetic susceptibility to the disease,1 ^w1 although the definitive gene has not yet been identified.

Several of the implicated loci are shared by other autoimmune and inflammatory diseases such as inflammatory bowel disease, type1 diabetes, multiple sclerosis, and atopic dermatitis, suggesting that similar mechanisms underlie many common genetically complex inflammatory diseases.

Immunological and environmental factors

Evidence is emerging that both innate (non-adaptive immunity that represents phylogenetically ancient, broad spectrum mechanisms that are not specific to antigens) and acquired (antigen specific) immune mechanisms are altered in clinically uninvolved skin.1 2 ^w2

In this environment key primary cytokines (for example, tumour necrosis factor α and interferon α) are released, perhaps as a result of environmental triggers, including infection, drugs, trauma, and stress.2 3 This hypothesis is supported by the profound efficacy of agents that block the actions of tumour necrosis factor α, such as infliximab,4 and the therapeutic potential of agents that interfere with pathways linking innate and acquired immunity.^w3

Psychosocial effect

As a result of the chronic, incurable nature of psoriasis, associated morbidity is significant. Patients in primary care5 and hospital settings have similar reductions in quality of life, comparable to those reported for major diseases such as cancer, heart disease, and diabetes.6^–8 Diminutions in quality of life encompass functional, psychological, and social dimensions. Symptoms specifically related to the skin (for example, chronic itch, bleeding, scaling, nail involvement), ^w4 problems related to treatments (mess, odour, inconvenience, time), arthritis, and the effect of living with a highly visible, disfiguring skin disease (difficulties with relationships, difficulties with securing employment, and poor self esteem) all contribute to morbidity.7 ^w5 Even those with minimal involvement (less than the equivalent of three palm areas) state that psoriasis has a major effect on their life.9 ^{w5 w6}

About one in four patients experience major psychological distress, and the extent to which they feel socially stigmatised and excluded is significant. Doctors, including dermatologists, often fail to appreciate the extent of this disability6 and even when it is correctly identified, fewer than a third of patients receive appropriate psychological interventions. Such factors may affect treatment outcome,6 but they are potentially amenable to intervention. In one study the addition of cognitive behavioural therapy to standard treatment led to significantly greater reductions in anxiety and depression, in self reported disability and stress, and in objective clinical severity of psoriasis.^w7

Associated comorbidity: cardiovascular disease and cancer

Patients with severe disease seem to have at least a twofold or threefold increase in mortality from cardiovascular disease.10 ^w8 Several potentially inter-related factors are likely to contribute to this risk (box 1). Several community and hospital based studies have shown an increased risk for a variety of malignancies,11^–13 ^w9 and in patients with severe disease the risk seems to be comparable to that of patients after organ transplantation, with significant increases documented for lymphoma and non-melanoma skin cancer. The relative influence of known confounders such as concomitant therapy with immunosuppressants and phototherapy,^{w9 w10} smoking, and alcohol14 is not yet clear.

Topical therapy

Adherence to topical therapy regimens is poor, and even when patients are told that drug use is monitored (in clinical trials through electronic bottle caps), treatment is adhered to just over half the time.^w13 Concordance in clinical practice is likely to be much lower but can be improved when attention is given to cosmetic acceptability, local side effect profiles, formulation, and practicalities of application. Nurses with dermatological training (particularly given the introduction of the extended nurse prescribing formulary in the United Kingdom) are ideally placed to fulfil this role, and some evidence supports this approach.^w14 Nurse led outpatient treatment centres are key sources of psychological support and advice for patients and also facilitate combining topical therapy with phototherapy.

Therapeutically active topical agents licensed for psoriasis include corticosteroids, vitamin D analogues, tar, dithranol, and tazarotene (a retinoid). A recent systematic review18 concluded that in the short term active treatment conferred significant benefit over vehicle (around a two point improvement on a 12 point total severity score after six to eight weeks), with no noticeable differences in magnitude of benefit between the different classes of drugs, with the exception of very potent corticosteroids (greatest effect). Comparison of agents in head to head studies indicated that vitamin D analogues were of similar efficacy to potent corticosteroids and more effective than dithranol (fewer reported adverse effects). Of the three vitamin D derivatives currently available, calcipotriol is marginally more effective than tacalcitol or calcitriol19 and, when combined with a potent or very potent steroid, more effective than calcipotriol alone.19

In practice topical corticosteroids (potent and, less commonly, very potent) are widely used since they are effective and onset of action is rapid. Mild strength corticosteroids or, provided it is for limited periods only, moderate strength corticosteroids can be used for facial and flexural disease. Intermittent use (twice weekly or at weekends)18 or use combined with non-steroidal agents (for example, calcipotriol)18 may maintain remission while minimising risks that can occur with continuous use, such as loss of efficacy, cutaneous atrophy, and rebound or pustular psoriasis.^w15 The vitamin D analogues are also widely used, but although efficacy is comparable to that of potent corticosteroids without the attendant risks, onset of action is slow and skin irritation common (about 20%-25% of users), hence the utility of combination therapy with corticosteroids that tends to abrogate both these problems. The calcineurin inhibitors tacrolimus (1%) and pimecrolimus are prescribed occasionally for difficult flexural or facial psoriasis,^{w16 w17} although no good evidence exists for size of benefit.

Phototherapy and systemic treatments

Firm, short term evidence on the efficacy of phototherapy—ultraviolet B light and photochemotherapy (psoralen plus ultraviolet A light, PUVA)—and most of the systemic treatments for psoriasis (see bmj.com) come from randomised controlled trials, but few comparative studies have examined the relative efficacy and safety of the different interventions.20 21 Those that do have failed to address clinically important questions such as duration of remission when treatment is stopped or whether efficacy is maintained with continuous or intermittent use. Strategies to reduce toxicity from long term treatment include rotational or sequential use of systemic therapy, drug holidays, and combination therapy. Tertiary centres with access to multidisciplinary teams with experience in multiple drug therapies provide specialist care for the minority of patients with severe, recalcitrant disease.

Phototherapy

In many centres conventional broad band ultraviolet B light (emission spectrum 270-350 nm) has been largely superseded by the newer, more effective, narrow band ultraviolet B light (311-313 nm) through the TL-01 lamp (Philips Lighting, Netherlands).^w18 The traditional hierarchy of treatment toxicity, when PUVA is perceived to be safer than systemic agents such as ciclosporin and methotrexate, may be changing also, especially when considering treatments in young people.

Also changing is the practice of proceeding to systemic treatments only when total cumulative dose exceeds recommended levels. This is because the inherent risks of skin cancer in association with PUVA^w19 are also substantially increased when ciclosporin is used.

Drug monitoring

Methotrexate is still considered the ideal therapy for moderate to severe psoriasis, especially if arthritis or nail involvement is present, since it is highly effective over protracted periods (50% reduction in disease severity in 75% of patients20 21). Clinicians and patients have been discouraged from using methotrexate, however, because of the need for routine liver biopsies to detect, albeit rare, clinically and biochemically silent liver fibrosis and cirrhosis. Recently, measurement of serum procollagen III (every three months during treatment) has been adopted as a surrogate marker of liver toxicity and means that most patients can avoid liver biopsies.22 23 ^w20

Systemic drugs for psoriasis pose a risk, but those specifically related to methotrexate were highlighted by the National Patient Safety Alert in 2004, including the need to closely monitor patients; make explicit where responsibility for this lies; and provide adequate, appropriate, and consistent information to all those involved in care (including the patient).^w21 Implementation of the recommendations required important changes in the detail and logistics of prescribing for methotrexate (including mandatory patient held records), but the process is of relevance and value to all drug prescribing.

Biological treatments

Biological treatments are agents that block molecular steps important in the pathogenesis of psoriasis. They have emerged over the past five years as valuable alternative therapeutic options for psoriasis. Currently they comprise two main groups: agents that target the cytokine tumour necrosis factor α (for example, etanercept, infliximab, adalimumab) and agents that target T cells or antigen presenting cells (for example, efalizumab). Despite the need for parenteral administration (intravenously every eight weeks for infliximab, self administered subcutaneous injections twice weekly, weekly, or every two weeks for the others), widespread dissatisfaction of patients with standard treatments9 has led to high demand. Their role in the context of existing standard systemic therapies is limited at the moment, given the relative lack of data on long term safety and efficacy,24 but undoubtedly for some patients with severe disease these treatments can be life saving. Risks of infection (especially tuberculosis with the antitumour necrosis factor agents) and possible future malignancy remain concerns. Availability of biological treatments in the United Kingdom is highly restricted at present, but this may change following recent approval (July 2006) by the National Institute for Health and Clinical Excellence for use of etanercept and efalizumab in severe psoriasis provided certain qualifying criteria are met.