More than skin-deep

Although not life-threatening, psoriasis has serious effects on sufferers' quality of life. Sarah Houlton looks at the latest therapeutic developments

Skin conditions such as psoriasis are not life-threatening, yet they affect large numbers of people, causing distress and discomfort to sufferers.'The public sees them as contagious, believes them to be caused by poor hygiene, and often does not consider them to be a proper disease,' says Peter Lapsley, chief executive of the UK's Skin Care Campaign pressure group. 'Studies show that skin diseases can be as damaging to the quality of people's lives as angina, asthma, diabetes and hypertension - and often more so.'

While the conditions themselves rarely endanger lives directly, in severe cases they can lead to depression and even suicide. Treatment is largely based on topical drugs, and great strides have been made recently in vastly improved medicines, notably for psoriasis. The potential of the numerous biological products currently undergoing clinical trials is particularly exciting.

Psoriasis is a common chronic condition, in which thick, scaly pink or red patches are formed on the skin, particularly the scalp, trunk, elbows and knees, and the skin becomes inflamed. The skin lesions that form in patients with plaque psoriasis usually have a well defined edge, and the raised red patches are covered with silvery scales. The disease frequently runs in families, but the precise cause remains unclear. As many as 2% of the population of Europe and the US are affected. In susceptible people triggers can include stress, injuries or operation scars, sore throats and medicines. Currently available drug treatments provide symptomatic relief but they do not cure the condition.

skin lesions

There are several forms of the disease. The most common is plaque psoriasis, but there are several others. Erythrodermic psoriasis is a serious condition where the entire skin is inflamed. In flexural psoriasis, skin lesions are smooth, often with a glazed appearance, and tend to appear under the arms, and in the groin, the buttock cleft and the folds of the breasts. Guttate psoriasis lesions appear suddenly on the trunk and/or the limbs. Most frequently seen in young adults, it often develops after a streptococcal throat infection. Sufferers from palmoplantar psoriasis develop sterile pustules on the palms of the hands or the soles of the feet. And patients with scalp psoriasis have a dry or flaky scalp, which becomes red and inflamed in severe cases. Around half of sufferers have lesions on their scalps, and temporary hair loss is common.

rapid cell division

When skin lesions develop, cells in the basal layer of the skin are dividing as much as 20 times faster than normal. The cells are pushed upwards through the epidermis too quickly for them to form into normal keratinocytes. The dermal papillae become elongated and small blood vessels proliferate, and all of this extra tissue builds up into the raised, thickened patches of the lesions. Clusters of immune and inflammatory cells are also present, which can penetrate the horny layer and form small abscesses, with others contributing to the inflammatory process. Even when apparently healthy, the skin of psoriasis sufferers is abnormal.

Other complications include arthritis in the joints of the fingers and toes, which affects around 5% of psoriasis sufferers. The disease bears many hallmarks of autoimmune conditions, where the body's immune system attacks its own tissues. The lymphocytes that accumulate in the dermis are characteristic of this.

The simplest preparations to ease the symptoms of psoriasis are emollient creams, ointments, lotions and gels that soften the skin, moisturising it to help prevent cracking. Tar impregnated bandages and dressings can also help, and appear to work by preventing the synthesis of DNA in cells, halting cell division. Dithranol has been used for many years, and also appears to stop cells dividing. However, it irritates normal skin and stains everything it touches a dark purple-brown colour, making the treatment regime unpleasant and difficult to follow, as careful application is essential.

Corticosteroids are an important weapon in the arsenal of treatments for the symptoms of psoriasis, and are often the first line of attack. Numerous different topical steroid preparations are available, some of which are formulated in combination with antibacterial agents to combat infections. Low concentrations of steroid drugs can even be injected directly into well-defined, isolated lesions.

However, the steroids can sometimes make the symptoms worse, particularly if they are overused or when treatment ceases. In emergencies, they are occasionally used systemically, often in combination with methotrexate, but care must be taken to avoid withdrawal symptoms when treatment is stopped.

Vitamin A derivatives, such as Roche's isotretinoin, can be administered either topically or orally. While they often have good results, side-effects such as depression and psychotic problems can result, and the drugs are potential teratogens, so effective contraception in women of child bearing age is essential during treatment.

Ligand Pharmaceuticals is carrying out Phase II trials on bexarotene, a derivative of vitamin A that has oral activity against moderate to severe psoriasis. Skin biopsies have confirmed its effectiveness, although the side-effects that dog the class may again limit its usefulness as a medicine.

immunosuppressive drugs

Several drugs that block cell division can also help, including methotrexate, cyclosporin, azathioprine and hydroxy-urea. Other immune suppressive drugs are also being investigated. Isotechnika, for example, is carrying out Phase II trials on the novel cyclosporin analogue ISA 247 in conjunction with Roche. Another immunosuppressant from Roche, mycophenylate mofetil, is also being investigated in psoriasis sufferers, largely those who had been experiencing nephrotoxic side-effects with cyclosporin. In Phase I studies, it allowed a reduction in the dose of cyclosporin in about a third of those treated, and so it may be useful for seriously ill patients.

antisense compound

Other potential blockers of cell division are being developed. For example, Vertex's VX0148 is in Phase II trials. It inhibits an enzyme that is involved in the production of one of the nucleotides needed to make DNA, and hence prevents cell division. BCX-1777 from Biocryst is a PNP inhibitor that also blocks T-cell proliferation, and is still undergoing preclinical work.

ISIS Pharma's ISIS 104838 is an antisense compound that binds to DNA, preventing genes from being switched on. It is specific for TNF-a mRNA, inhibiting the synthesis of TNF-a itself, and is the first potential drug based on ISIS's proprietary 2'-O-methoxyethyl derivatisation chemistry to enter clinical trials. It showed activity in some psoriasis models, and is now being investigated in cream formulation for the treatment of severe cases.

Boehringer Ingelheim's BIBR-796 has shown promise in Phase II trials: it blocks an enzyme involved in the internal pathways that lead to the production of TNF-a and some of the interleukins.

An alternative small molecule target is the inhibition of angiogenesis. Because small blood cells proliferate in psoriatic skin, blocking this process may have a positive effect on psoriasis. Angiogenesis is caused by growth factors that stimulate the formation of blood vessels, and so inhibiting one or more of these growth factors could have the desired effect.

Aeterna's AE-941 has been shown to block angiogenesis by two separate routes in model studies, and clinical trials have now begun. In one Phase I study, half of the patients given AE-941 orally saw an improvement in their symptoms.

Anticancer agent paclitaxel also blocks angiogenesis, and is in common clinical use against advanced tumours. Angiotech has created a form of the drug where the active is trapped inside micelles, and early clinical trials are under way. And, following positive results in a trial on nearly 3,000 patients in Venezuela, Astralis is planning a large trial on the natural product psoraxine in the US. Its mechanism of action is, as yet, unknown.

Two further areas have been generating a lot of interest from pharma companies in recent years: vitamin D analogues and biologicals. Vitamin D is converted to its active form in the body, and its actions include key roles in regulating the maturation and growth of keratinocytes, and stimulating the immune system.

However, because the vitamin also causes the accumulation of calcium in the body, it is of limited use as a treatment because of the potentially serious side-effects of the elevated calcium levels. As a result, in excess of 1,500 vitamin D analogues have been created in an attempt to find a compound with the antipsoriasis effects of the vitamin, but without its ability to cause calcium accumulation.

vitamin analogues

Three such analogues are already available for topical administration. Calcipotriol (Leo Pharmaceuticals) is formulated both on its own and in combination with a steroid to treat stable plaque psoriasis. Tacalcitol from Crookes Healthcare is another. And the most recent to reach the market is Galderma's calcitriol, which is indicated for mild to moderate plaque psoriasis. The crystal structure of the vitamin D receptor has recently been established, and this is being used by Leo Pharma as an aid to creating better analogues of the vitamin to treat psoriasis.

Perhaps the greatest potential lies with the raft of new biological medicines that are being developed. Biogen IDEC's alefacept is a fusion product of two human proteins, and was approved in the US at the beginning of 2003 for treating patients with moderate to severe plaque psoriasis who are suitable for systemic therapy or phototherapy. It is thought to have two effects in the body that improve the symptoms of psoriasis. It blocks CD2 receptors on overactive T cells, which rebalances T cell numbers away from those that are messengers of the disease process. It also induces the apoptosis of immature keratinocytes.

Another fusion product, Wyeth's etanercept, was approved in 2002 for the treatment of psoriatic arthritis, and also in the US for treating moderate to severe plaque psoriasis. It works by a completely different mechanism to alefacept: it is a soluble tumour necrosis factor α (TNF-α) receptor that binds to excess TNF-α, neutralising its activity. TNF-α is a cytokine that has a protective effect against tumours and infections, but no adverse effects due to this suppression of action in patients treated with etanercept have been seen thus far.

close supervision

ONTAK from Ligand Pharmaceuticals is a fusion protein of part of the interleukin-2 molecule and part of the diphtheria toxin. Phase II trials indicated that nearly half of the seriously ill subjects given the protein had a positive response. However, there is a drawback: the effective dose is very close to the toxic dose, so vigilant supervision of treatment is essential.

TNF-α is the target of several developmental treatments, notably monoclonal antibodies. Schering-Plough's infliximab is a humanised MAb, and is now in Phase II trials for psoriasis. And adalimumab, discovered by Cambridge Antibody Technology and being developed in collaboration with Abbott Laboratories, is already available to treat severe rheumatoid arthritis. Like etanercept, it binds to and neutralises TNF-α, and it is now in Phase III trials for both psoriasis and psoriatic arthritis.

A number of other targets are also being addressed with MAbs. Efalizumab is a humanised MAb being developed by Xoma, Genentech and Serono, and is now licensed in the US for adults with moderate to severe plaque psoriasis. As well as regulating T cells, it also blocks the CD11a receptor, stopping the T cells from binding to several targets in the skin, and thus preventing inflammation. It can reduce the thickness, redness and scaling of psoriatic plaques.

neutralising interleukins

Various interleukins are also implicated in psoriasis. Abgenix has developed a fully human MAb that neutralises interleukin 8, ABX-IL8. As much as 150 times the normal level of the cytokine can be present in psoriatic skin, so reducing this could well have a positive effect on the disease.

Another interleukin, IL-15, is neutralised by HuMax-IL15, being developed by Genmab and Amgen. Both of these are now in Phase II trials. Still in Phase I is Protein Design Laboratories' fontolisumab, which targets interferon-g, another chemical messenger thought to be implicated in psoriasis.

Cell receptors are targets, too. GenMab's HuMax-CD4 is a human MAb that acts at the CD-4 receptor. A promising Phase II trial has been carried out, in which nearly a third of subjects had their disease area and severity reduced by a quarter, and over half had a sustained benefit from the treatment 12 weeks after treatment had finished. Siplizumab from MedImmune is another humanised MAb, and binds to the CD-2 receptor, and has completed Phase I/II trials.

skin damage

Completely different is eculizumab, a MAb being developed by Alexion. Rather than acting at TNF-a or a cell receptor, it is designed to stop the blood proteins in the complement cascade. Activated complement has been found in inflamed tissue and affected skin in psoriasis sufferers, and can cause both inflammation and skin damage. Eculizumab inhibits the step in which complement C5 is converted into the inflammatory fragments C5-a and C5-b9. Although the MAb is still in Phase I trials, it is hoped that it will slow down active psoriasis.

While psoriasis remains incurable, recent developments in symptomatic treatments have made the condition easier to live with. And if the new biologicals that are in trials, in particular, succeed, then the lives of sufferers will be revolutionised.