Review of Conventional Systemic Therapies for Severe Psoriasis

D. Richard Thomas, MD, FRCPC

Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

Introduction

Psoriasis is a chronic inflammatory cutaneous disorder that can significantly affect patient quality of life (QoL). Although the exact pathogenesis remains to be elucidated, immunologic abnormalities with an increase in immune mediators are likely primary contributing factors. Most patients have mild disease that can be adequately managed by topical therapy. However, a subset of the psoriatic population with severe disease requires phototherapy and/or systemic treatment. Due to its chronic and recalcitrant course, a combinational approach (including topical, systemic, and nondrug interventions) is often necessary for successful long-term management.

Of the conventional systemic agents, acitretin, cyclosporine, and methotrexate are the most commonly used. In the new era of biologics, these agents remain as valuable therapeutic options for severe psoriasis. Recent studies have also provided insights into enhanced efficacy and safety when these drugs are used in combination with the biologics. A review of these conventional systemic antipsoriatic agents will be discussed.

As family physicians frequently serve on the frontlines of patient care and are instrumental in managing comorbidities associated with psoriasis, it may be helpful to be aware of more aggressive approaches. However, because systemic treatment carries a higher risk for adverse effects, moderate to severe cases are best co-managed with dermatologists, who are more familiar with the use of these agents.

Disease Overview

• Psoriasis is a common multisystem disease that affects the skin and may involve the joints.
• Immune dysregulation of T cells results in overactivation, triggering an inflammatory response that leads to the accelerated production of epidermal cells.
• Build-up of the epidermis produces red, scaly, and well demarcated plaques of variable size.
• Psoriasis can affect any part of the body, including the scalp, elbows, knees, lower back, and nails, but the face is usually unaffected.
• Chronic lesions, particularly of the hands and feet, can result in persistent dryness, hyperkeratosis (thickening of the other layer of the skin), itching, fissuring, and infection.

Prevalence

• Genetic factors increase disease susceptibility.
• It affects about 2-3% of the general population.1
• Up to 35% of people with psoriasis have moderate to severe disease.²
• It may eventually progress to the joints (arthritis). Up to 30% of Canadians with psoriasis develop psoriatic arthritis.³

Types of Psoriasis⁴

• Plaque – chronic plaque psoriasis is the most common variant, affecting more than 80% of the psoriatic patient population.⁵
• Guttate – multiple small (5-15 mm) red lesions are round or oval, and drop-like in shape. Lesions appear suddenly and will typically cover the trunk, arms, legs, face, and scalp. It is often associated with streptococcal infection.
• Inverse – also known as flexural psoriasis occurs in the creases and folds of the skin, such as the armpits, groin, and under the breasts. The lesions are characterized by smooth, well defined red patches, but scaling is generally minimal or absent.
• Pustular – a rare form that can be localized to the palms and soles or become generalized. Although pustules are seen, they do not indicate an infection.
• Erythrodermic – a very rare form; most of the skin’s surface is affected by inflammation, redness, and scaling. It can be fatal due to associated complications.

Severity Assessment

• Psoriasis Area Severity Index (PASI) is widely used in clincial trials.
• One common method for measuring psoriasis severity is based on the percentage of affected body surface. For example, one palm-sized lesion represents 1% of body surface area (BSA).⁴
  • Mild psoriasis affects <3% of BSA.
  • Moderate psoriasis affects 3%-10% of BSA.
  • Severe psoriasis affects >10% of BSA.
• The measure of social, emotional, and fuctional impairment resulting from psoriasis is critical.
• The Dermatology Life Quality Index (DLQI) questionnaire is a commonly used tool to assess patient reported outcomes.
• In a questionnaire study, investigators assessed the extent of psychosocial comorbidity and functional impairment in 43 psoriasis patients.⁶
  • About 48% of psoriasis patients reported adverse impacts on social functioning, leading to decreased work efficiency in 51% and to workplace distress in 63%.⁶
  • Stress in the home environment and interpersonal relationships were reported by 70%.⁶

Comorbidities

• Psoriasis can significantly impact a patient’s QoL, e.g., loss of productivity, depression, and an increased incidence of malignancy.⁷
• Associated comorbidities include cardiovascular disease and metabolic syndrome, which may be linked to the underlying chronic inflammation.
• Psoriasis patients have demonstrated an increased prevalence of obesity, dyslipidemia, and insulin resistance.

Treatment Rationale

Formulation of an effective treatment strategy will depend on several factors, including findings from diagnostic investigations, extent and severity of psoriasis, treatment history, age, and patient preferences. Aside from achieving tangible improvements, the adopted therapeutic approach must also minimize QoL impairment, such as discomfort, disability, and heighten self-consciousness, which can lead to social avoidance behaviours. Consequently, early diagnosis and ongoing medical and adjunctive care are crucial for controlling chronicity and disease severity.

Biologics represent the newest class of antipsoriatic agents, although their advent has revolutionized the treatment of moderate to severe psoriasis, long-term safety remains to be established and their high cost can be prohibitive. The common traditional systemic agents (i.e., acitretin, cyclosporine, and methotrexate) continue to have a place in the management of severe psoriasis and novel combined uses have emerged.

Acitretin

Acitretin is a second generation aromatic retinoid (a vitamin A
derivative). Acitretin is prescribed mainly for men and also for post-menopausal women. Due to its teratogenic potential, premenopausal women are generally excluded as treatment candidates. Acitretin’s mechanism of action includes inhibiting cell replication by controlling cellular differentiation within the epidermis. It reduces inflammation and influences the growth rate of skin cells.

Advantages and Benefits

• Convenient once daily oral dosing.
• Very helpful as an adjunct to phototherapy.
• Acitretin may be the safest oral systemic agent for psoriasis, apart from its teratogenic risk that persists 2-3 years following treatment discontinuation.⁸
• Highly effective for treating pustular (including palmoplantar psoriasis) or erythrodermic forms of psoriasis; less effective as monotherapy for plaque psoriasis.
• Acitretin usually does not cause organ damage, which is a side-effect with other medicines (such as methotrexate and cyclosporine), therefore, it can be used for long-term maintenance therapy.
• Unlike other systemic therapies for psoriasis, it does not suppress the immune system.
• Relatively safe for long-term treatment.
• For psoriasis patients with a history of melanoma, acitretin should be considered as a therapeutic option.

Risks and Side-Effects

• Onset of response is usually 2-4 months.
• Combination treatment with phototherapy or biologic agents is superior to monotherapy.
• Side-effects include dryness and irritation of the skin, lips, eyes, nose, and mucous membrane surfaces. Frequent use of a moisturizer is essential to help reduce the irritation.
• Other adverse side-effects include elevation of cholesterol and triglyceride levels, liver toxicity, bone changes, and alopecia.
• As birth defects can occur with retinoids, acceptable method(s) of birth control must be practiced by and discussed with the patient. Because of its relatively long bioelimination, even following treatment cessation, female patients must continue to avoid pregnancy for the next 2-3 years.
• The main issue with compliance is to minimize side-effects through inclusion of topical agents and phototherapy.
• Due to the medication’s drying effects, starting with a lower dose may ease the intensity.

Cyclosporine

Cyclosporine is an immunosuppressant that is also frequently used in organ transplantation. Although it is a very effective antipsoriatic agent, cyclosporine is generally reserved for patients with severe, disabling, or recalcitrant psoriasis (also referred to as a crisis drug), owing to its cost and potentially serious side-effect profile (e.g., renal impairment). Cyclosporine offers rapid disease control in severe cases by suppressing the body’s immune system and slowing the rapid production of skin cells.

Advantages and Benefits

• Treatment is administered orally 1-2 times daily.
• Onset of effect is rapid (4-8 weeks); improvement is often seen within the first 4 weeks.
• Highly effective for severe psoriasis, especially helpful for treating acute flare-ups.
• It can be used intermittently in short-term courses or combined with other topical and systemic therapies.
• Multiple short courses are prescribed to reduce the potential for toxicity.

Risks and Side-Effects

• Long-term use leads to kidney damage, although the damage is often reversible with treatment cessation.
• Total duration of therapy should not exceed 1-2 years to avoid severe adverse systemic effects.
• Regular assessments through blood and urine tests, and blood pressure monitoring are required throughout treatment.
• Rebounds are common if the dosage is tapered or when the medication is stopped.
• Side-effects include flu-like symptoms, nausea, diarrhea, hair growth, high blood pressure, numbness and tingling, and kidney damage.
• Because cyclosporine suppresses the body’s immune system, there is an increased risk of infections and certain cancers, such as skin cancer and lymphomas, but reported incidences usually involve use in organ transplantation where the medication is administered long-term and at higher doses.
• Cyclosprine cannot be used at the same time with psoralen + UVA (PUVA) or UVB phototherapy, methotrexate or other immunosuppressive agents, coal tar, or radiation therapy.
• As a potent immunosuppressive agent, increasing the risk of skin cancer, patients being treated with cyclosporine should be advised to take sun-protective measures, i.e., as applying a broad-spectrum sunscreen daily and wearing long-sleeved clothing and hats.

Methotrexate

Methotrexate (MTX) is an antimetabolite drug that has been in use since the 1950s. It continues to be one of the most widely prescribed drugs for treating severe psoriasis. MTX is effective against diseases that are affected by abnormally rapid cell growth (e.g., psoriasis, rheumatoid arthritis, and cancer). It helps to control psoriasis by reducing immune responses and slowing joint destruction. MTX is usually given after other medications have been tried unsuccessfully.

• The mechanism of action is the interference with DNA synthesis repair and cellular reproduction.
• Antifolate agents, such as MTX, impair the function of folic acid (a B vitamin) that is essential for cellular activity.
• MTX is usually administered orally once weekly at doses ranging from 2.5-25 mg or occasionally by injection.
• It can be administered either as a single dose or in a split dose 12 hours apart for 3 doses.

Advantages and Benefits

• Reasonably effective, convenient dosing, and relatively inexpensive
• Improvements are noticeable following 6-8 weeks of therapy.
• MTX can be used for longer periods of time in comparison with other agents (such as cyclosporine), but patients must be regularly monitored for potentially serious side-effects.
• MTX can also enhance the effect of UVB phototherapy.

Risks and Side-Effects

• Side-effects include headache, skin irritation (itch and rash), hair loss, mouth sores, upset stomach, nausea, low white blood cell count, and fatigue.
• Long-term MTX use can cause serious liver damage. Routine blood tests assessing hepatic function may not detect the damage, hence, a liver biopsy may be necessary every 1.5-2 years while undergoing treatment.
• Long-term risks include birth defects, kidney damage, bone marrow toxicity, and bone marrow suppression (rare, but potentially life-threatening).
• There are many drugs (e.g., non-steroidal anti-inflammatory drugs) that can adversely interact with MTX.
• MTX can cause birth defects and miscarriages, resultantly, women with child-bearing potential taking the drug must use a reliable method of contraception.
• To mitigate the risk of liver damage, patients must be advised not to consume alcohol while on therapy.

Phototherapy

• For generalized psoriasis, UVB phototherapy offers an effective option that allows both rapid disease control and long-term maintenance.8
• Narrowband UVB may be more effective than broadband.
• Use of low doses of acitretin enhances both therapeutic benefits of UVB and PUVA.
• MTX may also improve the effect of UVB.
• Phototherapy in combination with acitretin not only improves efficacy, but may also reduce long-term side-effects and the number of required treatments.
• For patients unresponsive to phototherapy or who find the treatment schedule too demanding, MTX can be an effective alternative.

Conclusion

Effective ongoing management of patients with severe psoriasis requires knowledge of available therapies, including mechanism of action, potential toxicity, and appropriate monitoring. Combinational, rotational, and sequential therapeutic methods that aim to improve overall efficacy while reducing the toxicity of the chosen medications are the goals of treatment. Optimal patient care also requires continued education and support, as well as addressing quality of life concerns. It is important to encourage patients to be involved in therapeutic decision-making and to report any side-effects that they are experiencing, in order that symptoms can be mitigated with dose adjustments, the addition of other treatments, or even temporary discontinuation of therapy.

References

1. Griffiths CE, et al. Lancet 370(9583):263-71 (2007 Jul 21).
2. Thomas VD, et al.J Am Acad Dermatol 53(2):346-51 (2005 Aug).
3. The Arthritis Society. Psoriatic Arthritis.
4. National Psoriasis Foundation. Facts about psoriasis.
5. Pathirana D, et al. J Eur Acad Dermatol Venereol 23(Suppl 2):1-70 (2009 Oct).
6. Gaikwad R, et al. Indian J Dermatol Venereol Leprol 72(1):37-40 (2006 Jan-Feb).
7. Gottlieb AB, et al. J Dermatolog Treat 19(1):5-21 (2008).
8. Feldman S. Dermatol Online J 6(1):4 (2000 Sep).