Psoriasis is a systemic autoimmune inflammatory skin disease which affects 2-3% of the population¹ and is associated with serious comorbidities including cardiovascular disease, metabolic syndrome, arthritis and other autoimmune diseases. Those with early-onset severe psoriasis may have their life span reduced by up to 20 years. 

Disease pathogenesis is multifactorial including environmental influences (infection, excess alcohol intake)^2-4 and a possible role for at least 41 gene loci.⁵ Over half of all patients with moderate-to-severe psoriasis (body surface area [BSA] > 10%, Psoriasis Area and Severity Index [PASI] > 10%, Dermatology Life Quality Index [DLQI] > 10%) are receiving only topical treatment and therefore are under-treated,⁶ however, patients with more limited disease may be appropriately managed in primary care. 

A recent meta-analysis of topical treatments for psoriasis affecting the scalp, trunk and limbs indicates efficacy of twice-daily coal tar; twice-daily potent topical steroid; am/pm application of potent topical steroid/vitamin D analogue; or once-daily application of combination formulation of potent topical steroid/vitamin D.⁷

Unfortunately, there are minimal data on remission and potent topical steroid use carries risk for relapse, skin atrophy, adrenal suppression and life-threatening pustular disease flares. 

NICE guidelines advise that potent topical steroid could be used twice daily for up to four weeks or, alternatively, a potent topical steroid once daily with topical vitamin D or vitamin D analogue once daily for up to eight weeks, if < 10% BSA affected.⁸

Who is a candidate for biologic treatment?

The management of psoriasis has been revolutionised by the development of biologic therapies. These treatments are indicated for patients with moderate-to-severe psoriasis (PASI ≥ 10 or DLQI ≥ 10) that is resistant to, or where contraindications exist to, other treatment modalities including phototherapy and systemic agents such as methotrexate, acitretin, ciclosporin or fumaric acid esters.⁹ Therefore, in practice, an individual is likely to have failed/exhausted their lifetime dose of phototherapy and ≥ 2 systemic agents before being considered for biologic therapy. These agents are reserved for more recalcitrant disease because they are powerful immunosuppressant medications for which more limited practical experience exists, as well as having significant cost implications. 

Types of biologic agents available

Etanercept is a fusion protein of the human tumour necrosis factor (TNF)-alpha type II receptor and the Fc region of IgG1. It is self-administered as a subcutaneous injection at a dose of 50mg once or twice weekly (although 25mg formulation exists). 

Adalimumab is a human monoclonal TNF-alpha antibody, also given by subcutaneous injection. A loading dose of 80mg is usually followed by 40mg one week later and then maintained at 40mg fortnightly. This can be escalated to 40mg weekly if necessary. 

Infliximab is a chimeric, monoclonal, anti-TNF-alpha antibody given by intravenous infusion according to a standard protocol, usually repeated at two and six weeks after the first infusion and then at intervals of eight weeks. The dose varies according to weight and is usually commenced at 5mg/kg. 

Infusion reactions can occur with infliximab and pre-treatment with an antihistamine and/or hydrocortisone may be required.

Ustekinumab is a human monoclonal antibody to the p40 subunit that is shared by interleukin-12 (IL-12) and IL-23. Dosing is by weight-based subcutaneous injection: 45mg if < 100kg; 90mg if ≥ 100kg. The second dose is given at week four and then at 12-weekly intervals. Early clinical data suggest that patients weighing 90-100kg may be under-treated at the 45mg dose and, in such cases, 90mg might be considered.¹⁰

Factors influencing the choice of agent

Choice of biologic agent may be influenced by practical constraints, such as access to infusion facilities. Other considerations include mode of action, dosing schedules, need to treat concomitant psoriatic arthritis, obesity and prior biologic exposure. For example, if a patient loses response to one anti-TNF agent, they may still respond to a second agent in the same class, particularly if they initially achieved PASI-75 response on the first anti-TNF agent.¹¹

Loss of effect is attributed to development of anti-drug antibodies which are not known to cross-react between agents, thereby allowing freedom to switch within the same class of biologic, for example from etanercept to adalimumab or vice versa. 

Anti-drug antibody levels are not routinely available in clinical practice, although a rise in the titre of anti-nuclear and/or anti-dsDNA antibodies has been proposed as a surrogate marker for resistance to anti-TNF therapy.¹²

Genetic factors could also affect choice, with recent evidence showing that the presence of HLA-CW6 is associated with a better response to ustekinumab.¹³

This is an evolving story and, in time, we may be able to hand-pick the most appropriate targeted treatment for an individual, taking pharmacogenetics into consideration. 

Medium/long-term considerations

Increasing numbers of patients, many of whom are young, are receiving biologic agents; therefore practical questions arise about long-term safety. Soft-tissue infections are a common side-effect. 

The risk of opportunistic infections, including reactivation of latent tuberculosis, is increased on biologic treatment¹⁴ and patients are screened pre-treatment using chest radiograph and Mantoux test. Increased infections with listeria, salmonella, legionella, histoplasmosis and herpes zoster have been described during biologic therapy in rheumatology populations. 

Serious adverse events may only become apparent during long-term follow-up. Efalizumab was withdrawn following post-marketing surveillance reports of progressive multifocal leukoencephalopathy (PML) in four psoriasis patients receiving this treatment, demonstrating the importance of long-term vigilance.

Questions remain about the concept of a ‘drug holiday’. Once assigned to a particular treatment, is it possible or advisable to stop treatment for a while? The lack of a good biomarker for disease remission makes this decision a challenge. In addition, the natural history of psoriasis follows an undulating course, with relapse tending to occur following the interruption or discontinuation of treatment. 

While potential development of anti-drug antibodies is a concern, there is evidence that etanercept, adalimumab and ustekinumab can be safely withdrawn and reinitiated, with (almost complete) recapture of effect, in patients who initially respond well to treatment.¹⁵

Generally, for the majority of patients on biologic therapy, maintenance treatment is likely to be necessary for enduring remission. Lifestyle changes such as family planning may also impact on the decision to stop treatment. If a female patient wishes to conceive, it is generally advisable that biologic treatment be discontinued for at least three months prior to conception. 

Ciclosporin could be considered as an alternative, temporary measure in such cases. Despite this general advice, to date registries such as the British Association of Dermatologists Biologics Registry (BADBIR) have not highlighted any significant increased risk of malformations nor any consistent pattern of abnormalities in exposed versus non-exposed pregnancies. 

Switching between biologic agents is currently a contested topic. Some treatments appear to be less efficacious in heavier patients who may do better on weight-based dosing (eg. ustekinumab) versus fixed dosing (eg. adalimumab).¹⁶

If a patient fails to achieve a significant reduction in PASI with one anti-TNF medication, then he/she is less likely to achieve a response to a second agent from the same class but may respond to an agent from a different class, for example anti-IL-12/23 (ustekinumab).

New agents in development

The cytokine profile and molecular pathways in psoriasis have been the focus of much research in recent times and this has led to further advances in the development of targeted therapy. 

Knowledge of the central role of Th-17 cells in psoriasis is driving development of new anti-IL-17 agents which are performing extremely well in clinical trials.^17,18,19 These include the IL-17 inhibitors secukinumab and ixekizumab, and the anti-IL-17 receptor antibody brodalumab.

Conclusion

The armamentarium for psoriasis management has expanded substantially over the past two decades and continues to evolve. Long-term safety and efficacy data are still being generated by registries such as the British Association of Dermatologists Biologic Interventions Register (BADBIR). 

There is some early evidence that the combination of methotrexate and biological therapy is protective for cardiovascular risk.²⁰

It remains to be elucidated whether or not extended periods of treatment with biologics will significantly modify the cardiovascular morbidity and mortality associated with this inflammatory skin disease.  

References

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4. Fortune DG, Richards HL, Main CJ et al. What patients with psoriasis believe about their condition. J Am Acad Dermatol 1998; 39: 196–201
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