Dr Dmitri Wall and Prof Sarah Rogers look at the different clinical types of psoriasis and examine the many treatment options, including topical treatments, phototherapy, systemic therapy and biologic agents
Psoriasis is a chronic dermatosis characterised by red scaly patches which classically occur on extensor aspects of the limbs. Psoriasis is most prevalent in the northern hemisphere, where it affects 1-3 per cent of the population, with males and females affected equally. It can begin at any age group from infancy to old age.
The basic lesion is an inflammatory papule, which becomes scaly, and so the disease is referred to as a papulosquamous eruption. Although it is described as a non-itchy dermatosis, many patients will say otherwise.
It is a T-cell mediated disease in which the epidermis renews itself up to six times faster than normal, resulting in thickened, abnormal keratin called parakeratosis. The rash may appear in healing wounds — the so-called Koebner phenomenon, and small bleeding points appear when scale is removed (the Auspitz sign).
The nails are affected in 60 per cent of cases. Psoriatic arthritis (PsA) occurs in up to 20 per cent of patients with psoriasis.
Pathogenesis
As 50 per cent of patients give a family history of psoriasis at presentation, it has long been recognised as an inherited disorder. The major genes for psoriasis are located on chromosome 6p, in particular, Cw62. In those predisposed, psoriasis may be triggered by a number of factors including hormonal, infective, drugs, alcohol and stress.
These are believed to activate a cascade of inflammatory mediators culminating in the influx of T cells into the epidermis, and resulting in the chronic inflammation and excessive proliferation of keratinocytes that give rise to the characteristic plaques seen in psoriasis.
That hormonal factors are important is evidenced by the peak onset of psoriasis in teenage and young adult life with a smaller peak at the menopause; psoriasis usually clears in pregnancy. The most common precipitating infection is streptococcal, as a sore throat. Many teenagers with guttate psoriasis have enlarged tonsils. Acute viral infections may also exacerbate psoriasis.
Of the drugs that precipitate or aggravate psoriasis, lithium has the most dramatic effect. Beta-blockers and antimalarials may exacerbate the disease.
High alcohol intake, in particular, may trigger psoriasis. Stress has long been held to aggravate psoriasis. This has now been backed up in recent work.
Comorbidities
With the exception of its link to PsA, psoriasis had been considered a standalone disease. It was first observed that patients with psoriasis had an increased risk of cardiovascular disease in the 1970s and increased rates of peripheral artery disease and stroke have since been recognised. Psoriatics have a higher incidence of hypertension, dyslipidaemia, central obesity and type 2 diabetes. This is referred to as the metabolic syndrome.
Psoriatics with severe disease and an increased body mass index are prone to fatty liver disease. Excess alcohol consumption in psoriatics not only increases cardiovascular morbidity, but also is associated with greater than threefold increase in fatty liver disease and cirrhosis.
Clinical types
Chronic plaque psoriasis (psoriasis vulgaris) is characterised by red scaly plaques on the extensor aspect of the limbs (fig. 1). It may be localised or generalised. Psoriasis frequently presents in the scalp (fig. 2) where it may be misdiagnosed as seborrhoeic dermatitis or tinea capitis (ringworm).
Guttate psoriasis is eruptive and may cover all areas of the body within the space of a week (fig. 3). It may be mistaken for an exanthem in its early stages and is associated with young age and with streptococcal infection. Its natural history is for spontaneous clearance within eight weeks although it may develop into chronic plaque psoriasis.
Flexural psoriasis (psoriasis inversus) occurs in crease areas of the body, e.g. groin, inframammary region and perineum. Because these areas are warm and can be moist, the rash, while red, will not be scaly and so may be mistaken for intertrigo.
Erythrodermic psoriasis is characterised by generalised redness, exfoliative scaling, swinging temperatures, hypervolaemia and low urinary output (fig. 4).
It constitutes a medical emergency. It may be precipitated by overuse of both oral and potent topical steroids. The patient is admitted for intensive nursing care, temperature control and fluid balance. Though the disease itself is associated with hyperpyrexia, this may be due to septicaemia due to broken areas of skin. Patients with erythrodermic psoriasis are likely to require systemic treatment.
Generalised pustular psoriasis (von Zumbusch) is characterised by widespread, sterile pustules ranging from 2mm up to 1cm in diameter. It may be triggered, as with erythrodermic psoriasis, by withdrawal of steroids, by pregnancy or infection.
The patient is ill with a fever and will require admission for intensive nursing care. This form of psoriasis is also likely to require systemic treatment.
Palmoplantar pustulosis (PPPs) is characterised by flat lakes of pustules on palms and soles that dry up to form a brown papule (fig. 5). It may occur in association with plaque psoriasis or in isolation. It is frequently mistaken for tinea pedis.
In nails, pitting and onycholysis, or distal separation of the nail, are the most common changes. Separation in the centre of the nail gives an oil-drop appearance. The nails may be thickened and discoloured.
Topical treatment
The treatment of psoriasis depends on a number of factors including the type of rash and the site involved. For mild-to-moderate chronic plaque psoriasis topical treatment will suffice.
The majority of patients have mild disease and manage their psoriasis with over-the-counter medication or by consultation with their GP.
Topical treatment is used in all types of psoriasis either alone, or as an adjunct to phototherapy and systemic treatment. It includes dithranol, coal tar, vitamin D analogues, topical steroids, salicylic acid and, of course, emollients.
l Dithranol and coal tar are traditional in-patient treatments. The mechanism of action of both treatments is not fully understood, but both have an anti-inflammatory and anti-proliferative effects. Dithranol was the mainstay of in-patient treatment in Ireland and the UK in days when there were dermatology beds, whereas coal tar was favoured in the USA.
Compounds of dithranol and coal tar suitable for home use contain low concentrations of the active ingredient and are more likely to help than clear. Because dithranol can burn the skin it should be prescribed with caution, particularly in those not experienced in its use.
It may be applied for home use in the short-contact method as Dithrocream, building up the concentration from 0.1 per cent to 2.0 per cent. Crude coal tar ointment and pastes, though effective, are too messy for home use. Tar pomade BP and tar creams contain an aqueous solution of coal tar and are easy to use but tend to help rather than clear.
l Calcipotriol (Dovonex) is a vitamin D analogue that inhibits keratinocyte proliferation and blocks numerous inflammatory mediators. It is now only available in a cream base, which is less effective than the ointment preparation, but more cosmetically acceptable. Dovonex may cause irritation. It is applied BD and may take to to three weeks to become effective. It is also available as a scalp lotion.
l Potent topical steroids (Der-movate, Elocon, Betnovate, Diprosone) are powerful anti-inflammatory and anti-proliferative agents that should not be used in widespread plaque psoriasis. If they are prescribed, it should be for a very limited period only. This is because systemic absorption — which can be significant from inflamed skin — can lead to adrenal suppression, and because psoriasis flares on their withdrawal, becoming unstable (rebound flare). These preparations are suitable for palms and soles where the keratin layer is thick, in an ointment base, and on the scalp as a lotion. One per cent hydrocortisone cream or ointment is suitable for the face. Care should be taken not to overuse around the eye because of the risk of raised intraocular pressure. For flexural involvement, anti-yeast agents are traditionally combined with 1 per cent hydrocortisone, e.g. Daktacort.
l Salicylic acid may be used as a compound in combination with dithranol or tar or on its own as a keratolytic in an ointment base at varying concentrations from 0.5 – 20 per cent. It is used in scalp preparations, often with tar, and alone for thick scaling on palms and soles.
Phototherapy
When psoriasis is widespread, topical treatment becomes impractical and phototherapy is the treatment of choice. The beneficial effect of natural sunlight in psoriasis was known for many years and artificial sources of ultraviolet radiation (UVR) have been used by dermatologists for decades.
Phototherapy is carried out in a hospital unit that is run by nurses, regulated by medical physicists and supervised by consultant dermatologists. Psoralen-UVA (PUVA) requires two visits a week and TLO1 three.
The average number of treatments required to clear psoriasis is 25 and remission, which occurs in greater than 80 per cent, can be expected to last for up to six months.
l Broadband UVB (BB-UVB) formed part of Goerkerman’s coal tar and Ingram’s dithranol regimens, but as a monotherapy it causes significant burning in fair skin and is rarely used as such.
l UVA, by contrast, causes little burning but tans. To enhance its effect, UVA is combined with a psoralen, a photosensitising compound. The combination is called photochemotherapy or PUVA.
l PUVA has been in use since the 1970s but its use is restricted because high cumulative doses lead to the development of squamous cell carcinoma (SCC).
l Narrowband 311nm UVB (NB-UVB/TLO1) has a wavelength close to UVA and causes little burning. It is as effective as PUVA but is considered to be less carcinogenic. It is now the standard form of phototherapy for psoriasis. In order to reduce the development of SCC, no more than 200 exposures of either form of phototherapy are given in a lifetime.
Systemic therapy
Systemic therapy is indicated in psoriasis when phototherapy fails, or when the lifetime number of exposures has been reached. It is also given for erythrodermic psoriasis, general pustular psoriasis, unstable psoriasis and in severe localised disease such as palmoplantar psoriasis when day-to-day function is restricted.
Systemic treatment includes:
l methotrexate (MTX); hydro-xyurea;
l fumaric acid esters (FAE, Fumaderm);
l acitretin (Neotigason);
l ciclosporin (CSA; Neoral);
l biologic therapy.
Because of the close association between psoriasis and comorbidities, the patient’s general health status is assessed prior to systemic treatment. This includes weight, blood pressure, liver function tests (LFT) and glucose as well as their routine bloods and nutritional status.
l Methotrexate (MTX) was first used as an anti-cancer drug and has been used for psoriasis since the 1960s. Although its mechanism of action in psoriasis is not fully known, it is believed to act by reducing the proliferation of T lymphocytes and also by inhibiting their migration once activated.
MTX is hepatotoxic and so should not be prescribed unless the patient undertakes to abstain from alcohol. It is combined with 5mg a day of folic acid to reduce morbidity from the drug. MTX is effective for PsA.
Dose: A test dose to rule out idiosyncratic hypersensitivity is followed by a starting dose of 10mg, increased to a maximum of 30mg a week depending on response. The average maintenance dose is between 7.5 and 15mg weekly.
Side effects: Nausea, hepatotoxicity, bone marrow suppression and teratogenicity. Women of childbearing age must take effective contraception while taking MTX and men should not father children because it interferes with DNA synthesis.
Monitoring: Baseline full blood count (FBC), urea and electrolytes (U&E) and LFT should be carried out. Tests are repeated fortnightly for a month and then three-monthly. Type III procollagen peptide (PIIINP), a marker of hepatic fibrosis, is checked three-monthly.
lHydroxyurea is another anticancer drug used for many years for psoriasis that prevents DNA synthesis and repair by inhibiting ribonucleotide reductase.
It is used less frequently than MTX as it is less effective, but it works well in a small cohort of patients. Hydroxyurea is not effective for PsA.
Dose: Ranges from 500mg daily to TID.
Side effects: The main side effects are marrow suppression and teratogenicity and so it is contraindicated in females of childbearing age. The mean corpuscular volume is high (>100).
Monitoring: Baseline FBC, U&E and LFT. Repeated after weeks one, two and four and three-monthly thereafter. U&E and LFT are monitored less frequently as renal and hepatic side effects are rare.
l Fumaric acid esters (FAE; Fumaderm) have been used in Germany for over 30 years but were only recently introduced here. It is thought that FAE interfere with the cellular metabolic pathways that regulate inflammation and alter the ratio of T cell subtypes in the epidermis. FAE are not effective in PsA.
Dose: FAE are given according to the manufacturers protocol starting with 30mg (Fumaderm Initial), and increased to a maximum dose of 240mg TID (Fumaderm). The reason for the slow build up is to minimise side effects.
Side effects: Flushing, abdominal cramps and diarrhoea; tolerance usually develops with time. Lymphopenia occurs in most patients; the drug is discontinued if it falls below 0.5 ×109/L. Nephrotoxicity is rare and reversible.
Monitoring: Baseline FBC, U&E and LFT. Repeated at weeks two and four and at three-monthly intervals thereafter. Dipstick urinalysis for proteinurea at each visit should be carried out.
l Acitretin (Neotigason) is a vitamin A derivative (retinoid), modulates immune response and increases epidermal cell proliferation. It is infrequently used as a monotherapy because of its unpleasant side effects.
More commonly, it is combined with PUVA (retinoid PUVA; Re-PUVA) as it decreases both the length of treatment and dose of UVA. Acitretin is not effective for PsA.
Dose: Between 0.25 and 1mg/kg daily with the maintenance dose between 10mg and 50mg daily.
Side effects: Cheilitis, pruritus, skin fragility and hair fall. It is not given to women of childbearing age as it is teratogenic and is held in body fat for up to three years. Hypertriglyeridaemia (in 50 per cent) and hepatotoxicity may occur. Calcification of ligaments and diffuse idiopathic skeletal hyperostosis (DISH) may occur.
Monitoring: Baseline FBC, U&E, LFT and fasting lipids. Repeated after weeks one, two and four and at three-monthly intervals thereafter. Twice-yearly X-ray of the thoracic spine or ankle should be carried out.
l Ciclosporin (CSA) inhibits Il-2 and reduces the number of cytotoxic T cells in the epidermis. It is highly effective for psoriasis but its use is restricted because of nephrotoxicity which may be permanent.
Because of nephrotoxicity, CSA is now most often used as a rescue treatment in order to bring severe psoriasis under control quickly. Once the patient’s psoriasis has been stabilised, CSA is replaced with another systemic agent. It is safe in pregnancy. CSA is not effective in PsA.
Dose: Starting at 2.5mg/kg in a BD dose and increased to a maximum of 5mg/kg. The average maintenance dose is 3mg/kg taken as a BD dose.
Side effects: Hypertrichosis, tremor, gum hypertrophy and headache are some common side effects. Nephrotoxicity, hypertension, which increases with dose and time, hyperlipidaemia and hypomagnesaemia.
Monitoring: Baseline BP reading, FBC, U&E, LFT, magnesium and lipids. Repeated after weeks one, two and four and then at each visit. Fasting lipids every six months. If serum creatinine rises by 30 per cent, glomerular filtration rate is measured.
Biologic agents
These powerful new immunosuppressive drugs are used to treat severe psoriasis recalcitrant to other treatments as well as Crohn’s disease and psoriatic arthritis. They are either fusion proteins or monoclonal antibodies that block TNF-α or other cytokines.
By blocking T-cell activation and migration and, subsequently, the inflammatory cascade that leads to keratinocyte proliferation, biologics inhibit plaque formation.
Infliximab is the fastest working and most effective of the biologic agents. It is given by IV infusion. The other biologics are given by sub-cutaneous injection at varying intervals from twice weekly to three monthly.
The real concern with biologics is the unmasking of latent TB, and so patients must be screened before treatment5. If latent TB is suspected, the patient is given a nine-month course of isoniazid and pyrazinamide, with at least two months of treatment prior to commencing biologic treatment.
With active TB, triple therapy with Rifater (containing isoniazid, pyrazinamide and rifampicin) is given for six to nine months. Patient well being, night sweats and weight loss are enquired about at each clinic visit.
Infliximab, etanercept and adalimumab are licensed for both while, at present, ustekinumab is licensed for use in psoriasis but not as yet for PsA.
Side effects: Injection site reactions occur with subcutaneous agents and anaphylaxis may occur with infliximab. They lead to an increased rate of infections such as respiratory tract infections including TB as mentioned above.
Lupus may be precipitated by biologic agents and they are contraindicated in demyelinating diseases and congestive heart failure.
Monitoring: Baseline FBC, U&E, LFT, hepatitis screen and ANA repeated at clinics.
References on request.
l Dr Dmitri Wall
and Professor Sarah Rogers, Department of Dermatology, St Vincent’s University Hospital, Elm Park,
Dublin 4.
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