Systemic therapy for psoriasis

Learning objectives
Introduction
Methotrexate
Acitretin
Ciclosporin
Other immunosuppressive agents
New biologics
Activity

Learning objectives

• Describe use of systemic therapies for psoriasis

Introduction

Patients are considered to have severe psoriasis if they have extensive plaques, psoriasis on exposed sites or resulting in functional impairment (e.g. on hands preventing work, or feet preventing walking). ‘Severity’ may depend on the patient’s age, cultural background and occupation. Systemic therapy should be considered for those more than 10% to 20% body surface involvement, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis and more localized, recalcitrant psoriasis. This is true for children as well as adults, but systemic treatment is rarely necessary in children or adolescents.

PASI score
The PASI (Psoriasis Area and Severity Index) was set up as an attempt to assess the severity of psoriasis for clinical trials. The percentage of patients achieving a 50% or 75% reduction in PASI is used to evaluate the efficacy of new drugs. The PASI combines assessments of the percentage of body area affected, erythema, desquamation, and induration to produce a score ranging from 0 (no psoriasis) to 72 (the most severe case of psoriasis).

Methotrexate

Methotrexate, a synthetic analogue of folic acid, is the most widely used systemic agent in the treatment of psoriasis and psoriatic arthritis. It is probably effective because of its immunosuppressive effects. It is also used to treat various malignancies because it has antimetabolite activity.

Methotrexate has the following actions:

• Competitive inhibitor of the enzyme dihydrofolate reductase
• Inhibits DNA synthesis and cell division
• Inhibits replication and function of T and B cells
• Suppresses the secretion of cytokines such as interleukin 1, interferon-g, and tumour necrosis factor.
• Suppresses epidermal cell division in psoriasis

Pharmaceutical schedule funding in New Zealand is restricted to specialists or requires their approval. Methotrexate is administered either as a single weekly dose, usually orally, or as an intermittent oral schedule of three divided doses up to about 25mg over a 36-hour period once a week. Folic acid 1-5mg daily may help reduce adverse effects such as nausea and macrocytic anemia. Safety should be monitored by regular blood count, renal and liver function tests.

The aminoterminal peptide of type 3 procollagen (P3NP) can be measured in the serum and is a marker of active liver fibrosis. should be obtained prior to starting treatment and repeated every 3 to 6 months. Some patients require liver biopsy; current evidence indicates liver biopsy is not necessary if the P3NP collagen level remains consistently below the upper limit of normal, <4.2 µg/L.

Adverse reactions include:

• Gastrointestinal complaints
• Malaise, headaches
• Mouth ulceration
• Pulmonary fibrosis
• Bone marrow suppression & macrocytic anaemia
• Liver damage including fibrosis and cirrhosis
• Important drug interactions (refer to standard texts).

Acitretin

Acitretin is an oral retinoid (vitamin A derivative) used to treat psoriasis and other disorders of keratinisation. It appears to thin down thick psoriatic plaques and reduce inflammation. Acitretin is especially useful for pustular psoriasis, erythrodermic psoriasis and palmoplantar keratoderma.

The usual dose is 10-50mg daily, and should be prescribed by a dermatologist. Since March 2009, acitretin has required Special Authority application for funding in New Zealand; restrictions apply. It can be combined with other topical or systemic therapy and is especially useful with phototherapy. Monitoring requires pregnancy testing in females, complete blood count, lipids and liver function tests.

Adverse effects often limit tolerability and include:

• Teratogenicity (causes major human fetal abnormalities): acitretin must not be used by females who are pregnant or who intend to become pregnant during therapy or at any time for at least two years following the discontinuation of therapy
• Mucocutaneous adverse effects: dry fragile lips, skin, nose and eyes, peeling palms and soles, hair loss, thinned fragile nails, delayed wound healing
• Arthralgias, myalgias, raised intracranial pressure (oral retinoids must not be taken with tetracycline or tetracycline derivatives), decreased night vision
• Hepatotoxicity (rare) and hypertriglyceridaemia (more common).

Ciclosporin

Ciclosporin is an effective immunosuppressive agent used to prevent allograft rejection. It is very effective in the treatment of all forms of psoriasis.

Ciclosporin is a calcinerin inhibitor, which inhibits T cell activation and so reduces the production of cytokines especially IL-2 and interferon-g.

In New Zealand, it is funded for severe psoriasis on Special Authority application using doses of 2.5 to 5mg/kg/day. Renal function and blood pressure must be carefully monitored and may require dose reductions or treatment interruptions.

Adverse effects include:

• Nephrotoxicity
• Hypertension (may be treated using calcium channel blockers)
• Gastrointestinal symptoms
• Headache, myalgias, arthralgias, paresthesias and fatigue
• Hypertrichosis and gingival hypertrophy
• Induction of skin cancer, especially squamous cell carcinoma
• Risk of lymphoma
• Numerous drug interactions.

Other immunosuppressive agents

Although less effective that methotrexate and ciclosporin, the following immunosuppressive medications are sometimes used to treat psoriasis:

• Hydroxyurea
• Azathioprine
• 6-Thioguanine
• Mycophenolic mofetil
• Tacrolimus

Biological response mediators

Several newer strategies specifically aimed at reducing or eliminating the pathogenic effects of T cells are currently under investigation. Treatment with several drugs appears effective in many patients and relatively safe. The expense of treatment limits their use at present.

Alefacept
Alefacept binds to CD2 on activated memory T cells. One-third of those treated once weekly with IM or IV alefacept achieve 75% reduction in PASI, and two-thirds achieve 50% reduction. Treatment may not be required again for some months. It appears to have few adverse effects.

Efalizumab
Efalizumab (anti-CD11a) is a humanized monoclonal antibody. One-quarter of those treated once weekly with IV efalizumab achieve 75% reduction in PASI, and half achieve 50% reduction.

Infliximab
Infliximab is an anti-TNFa humanized monoclonal antibody, currently registered for treating Crohn’s disease and severe rheumatoid arthritis. It is quickly very effective in controlling psoriasis (up to 80% achieve 75% reduction in PASI) and may result in prolonged remissions. It is delivered IV three times over six weeks. Concurrent treatment with methotrexate is recommended to prevent formation of anti-infliximab antibodies. Untreated tuberculosis must be eliminated prior to treatment.

Etanercept
Etanercept is a fusion protein, which acts as a competitive inhibitor of TNF-a. Subcutaneous etanercept is currently approved for psoriatic arthritis, rheumatoid arthritis and moderate to severe psoraisis. Pharmaceutical schedule funding is only available for patients with severe juvenile arthritis (August 2005). Thirty percent of those treated twice weekly achieve 75% reduction in PASI. It may be associated with activation of tuberculosis but otherwise appears to have an excellent safety profile.

Activity

Describe monitoring necessary when ciclosporin is prescribed for psoriasis

 

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