PSORIASIS

Treatment strategy using Rotational, Sequential and Combination therapy

In treating psoriasis, many factors must be taken into account, including the extent of involvement, areas of involvement, the patient’s lifestyle, and other health problems and concomitant medications.

In sunny climates, sun exposure can be added to the therapeutic regimen.

It is essential to identify alternative treatment methods for patients receiving medications such as lithium, which are known to exacerbate psoriasis

In patients who have had multiple skin cancers, PUVA and cyclosporine should be avoided. These treatments increase the tendency to develop skin cancers

The possibility of using acitretin, which suppresses the development of skin cancers, should be considered for these patients.

One particularly important factor when selecting patient’s treatment is the affected body surface area. In individuals with less than 5% body surface area involvement, initially topical therapy is usually applied, unless the patient has previously failed topical therapy or the psoriasis is debilitating because of the site of involvement.

In patients with mild localized plaques, mild, mid-potency or potent topical corticosteroids can be prescribed, or other topical agents such calcipotriene, calcitriol or tazarotene can be tried. Anthralin preparations have fallen into disfavour because of the difficulty associated with their use, but they still offer an effective alternative to corticosteroids. Anthralin preparations are used in some day-care centers.

It is quite often observed that patients use a topical medication that is inadequate as monotherapy, and in such cases combination therapy is warranted.

The combined use of a superpotent corticosteroid and calcipotriol or tazarotene is often effective when monotherapy with either of the agents does not work, and new formulations that combine betamethasone dipropionate with calcipotriol are available.

For certain areas, despite the fact that psoriasis is limited in extent, alternative treatments are required.

For example, in cases of involvement of the palms and soles treatment may be quite demanding, as these areas are notoriously difficult to treat.

Another example is that pustular psoriasis of the palms and soles, only occasionally responds to topical therapy.

Although the palms and soles involve only a small percentage of the body surface area, treatment with oral medications or injected medications or phototherapy may be warranted. The combination of acitretin 25mg daily with ‘bath-PUVA’ – applied by soaking the hands in a water-filled basin to which methoxsalen has been added, followed by UVA irradiation – has been used successfully.

Similarly effective is the use of the 308nm Excimer Laser for palm and sole psoriasis, as can oral methotrexate, acitretin and cyclosporine.

Although no longer available due to reports of progressive multifocal leukoencephalopathy in patients in efalizumab, double-blind placebo-controlled trials have demonstrated the efficacy of efalizumab for palm and sole psoriasis, and it is likely that other biologics also work for this difficult form of the disease.

Involvement of the scalp is common and for its treatment gels, solutions, or foams are used, which are not as messy as ointments and creams.

Shampoos containing tars, salicylic acid, or corticosteroids are useful adjunctive therapies for the scalp.

The face and intertriginous sites are highly responsive to topical medications, but are particularly sensitive to the side effects of many topical agents.

Topical corticosteroids cause cutaneous atrophy, telangiectasia, and striae.

Therefore, only milder, safer corticosteroids should be used on the face and intertriginous sites, and alternating with non-corticosteroids may be optimal if psoriasis recurs.

Topical immunomodulators tacrolimus 0.1% ointment and pimecrolimus 1% cream are effective and safe for facial and intertriginous psoriasis, but not as effective on thick plaques on the rest of the body.

Calcipotriol (50μg/g) can be irritating on facial or intertriginous psoriasis, but alternative vitamin D analogues such as calcitriol and tacalcitol are less irritating and therefore particularly suited for facial or flexural psoriasis.

Tazarotene may be too irritating to use on genital skin, but it can be used on the face. The irritation of tazarotene can also be minimized by using it in a regimen with topical corticosteroids.

With 5–10% body surface involvement, topical therapy is usually prescribed, but may require the addition of phototherapy using the 308nm Excimer LASER or oral medications.

In patients with more than 10% body surface involvement, topical therapy may be impractical for all lesions but may provide a useful adjunct to phototherapy or systemic therapy.

Phototherapy with UVB has been in use since the 1920s and has a proven record of safety and efficacy. It is particularly useful in patients who have responded well to sun exposure.

Patients who have failed UVB or have not done well with sun exposure often respond to narrowband UVB (nb-UVB), Excimer Laser in particular.

PUVA is one of the most effective treatments for psoriasis and offers long remissions for many patients. Because of its increased risk of cutaneous malignancy, PUVA is usually reserved for those who do not achieve adequate remissions with UVB.

In patients who have not achieved satisfactory clinical outcome with these treatments, low-dose oral retinoids can be added.

Acitretin in doses of 10–25mg daily dramatically improves the response to UVB and to PUVA. By keeping the dose at 25mg or less, the side effects of acitretin can be minimized.

For patients who are not candidates for UVB phototherapy or PUVA, oral methotrexate is highly effective in combination with other treatments or as monotherapy. However in some patients it is associated with hepatic fibrosis and regular monitoring of liver function tests in addition to blood counts is necessary.

Current guidelines in the USA call for periodic liver biopsies in selected patients treated with methotrexate. In parts of Europe, the serum level of the aminoterminal pro-peptide of type III pro-collagen has been used as a marker for hepatic fibrosis as an alternative to routine use of liver biopsy.

Ciclosporin is also dramatically effective as monotherapy for psoriasis, but is associated with nephrotoxicity as well as hypertension and a theoretical risk of malignancy with long-term use.

Therefore, according to the current guidelines the use of cyclosporine should be limited to 1 or 2 years.

Recently, the ability to develop new drugs that target specific parts of the immune system has led to the development of biologic agents for psoriasis.

These drugs are not associated with the nephrotoxicity of cyclosporine or the hepatotoxicity and bone marrow toxicity of methotrexate. Nevertheless, the long-term side effects of biologics are not known, and their cost is often prohibitive.

The opinions among experts in psoriasis are divided on the point at which biologics should be considered. Some consider them first-line therapy when the disease is too extensive for topical therapy. Because of their expense, biologics are used by others only after phototherapy or other systemic therapies have been tried.

There are at least eight approved biologic agents or have been used in completed large clinical trials for psoriasis.

Agents that block tumour necrosis factor-α (TNF-α), including etanercept, infliximab, adalimumab, and certolizumab, are ideal for patients with psoriatic arthritis.

TNF-blocking agents have unique side effects, including the reactivation of latent tuberculosis, exacerbation of multiple sclerosis, and the development of antinuclear antibodies.

Agents that block T-cell activation include efalizumab and alefacept. The latter achieves 75% improvement in the psoriasis area and severity index (PASI 75) in less than 25% of patients, but many patients who achieve remission remain clear for many months. In contrast to alefacept, doses of efalizumab, like those of infliximab, are adjusted according to body weight.

The latter two drugs are therefore appropriate for patients who are obese and hence less likely to respond to fixed-dose therapies. Following the development of progressive multifocal leukoencephalopathy in at least 3 efalizumab-treated patients, this drug was withdrawn from the market in 2009.

Recently two other drugs that block the p40 component of IL-12 and IL-23 have been introduced and they are highly effective for psoriasis. Ustekinumab has been studied in 45mg and 90mg doses; dose elevation can be beneficial in overweight patients.

The drug can be administered as infrequently as every 3 months. ABT-874 works by the same mechanism and is also likely to gain approval for psoriasis.

As the therapy for psoriasis has toxicities, several approaches have evolved for controlling the disease while minimizing side effects.

For example, rotational therapy, involves treating psoriasis with a medication such as methotrexate for varying periods, followed by switching to PUVA, retinoids, or cyclosporine for limited periods. The different treatments used in rotation are determined by patient response.

Because biologic therapies have not been associated with major organ toxicity, they are often used long term without the need for rotation.

Another option is combination therapy, which involves the mixing of two or more treatments. Topical therapies are often used in combination with phototherapy and systemic therapy.

Phototherapy with Excimer Light, nb-UVB is often combined with oral retinoids or methotrexate, thereby minimizing the number of treatments and the toxicity of each of the therapies.

Furthermore, phototherapy has been used with many of the biologic agents for psoriasis, resulting in improved response rates. Low doses of methotrexate and cyclosporine can be used in combination to minimize the nephrotoxicity of cyclosporine and the hepatotoxicity of methotrexate. The latter combination can be effective in patients who have failed monotherapy with either agent.

Biologics have been used in combination with methotrexate, cyclosporine, and acitretin. Because acitretin is not immunosuppressive, it is an ideal agent for combination therapy with the new drugs that target the immune system. Many advocate combining infliximab with methotrexate, not only to achieve better results, but to reduce the development of human antichimeric antibodies which are associated with increased infusion reactions and reduced efficacy of infliximab.

Sequential therapy refers to the concept of treatment in which potent agents are used to clear the disease, and safer but less effective agents are used to maintain remission.

For example, cyclosporine can be used to clear psoriasis and patients can then be switched to oral retinoids in combination with UVB or 308nm Excimer Light for maintenance or to a biologic agent.

Similarly, sequential therapy can be applied to topical medications. For instance, calcipotriol or tazarotene can be used in combination with superpotent corticosteroids to clear psoriasis and to reduce irritation induced by calcipotriol or tazarotene monotherapy. The corticosteroid can then be tapered to a regimen where it is used only 2 days per week or eliminated altogether, while the non-corticosteroid agent can be continued.

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