A Comprehensive Guide to Treating Moderate to Severe Psoriasis

Introduction: Psoriasis is a chronic multisystem autoimmune disease with cutaneous involvement. It is characterised by the rapid growth of skin cells, leading to the formation of thick, red, and scaly plaques, although other presentations can occur.

Approximately 73,000 people have psoriasis in Ireland. Individuals with moderate to severe psoriasis often experience significant physical and psychological co-morbidities. Most patients with psoriasis can be treated in primary care or in the outpatient setting. However, life-threatening presentations such as erythrodermic psoriasis or pustular psoriasis can require intensive inpatient management. While severe psoriasis should be managed by consultant dermatologists with access to advanced therapeutics, this article explores the various treatment options available for moderate to severe psoriasis, highlighting the importance of personalised and multimodal approaches.

Understanding Moderate-Severe Psoriasis

Psoriasis is driven by immune dysfunction that mistakenly targets healthy skin cells, triggering rapid cell turnover. This abnormal cell proliferation leads to the formation of plaques, commonly found on the elbows, knees, scalp, and lower back. Other patterns of psoriasis include guttate, flexural, pustular, and erythrodermic.

Moderate to severe psoriasis is usually defined by the extent of skin involvement, with more than 10% of the body surface affected, or a psoriasis area and severity index (PASI) over 10. Special sites that may warrant intensive treatment for localised disease include the face, palms and soles, and genitals. Additionally, individuals with severe psoriasis may be more likely suffer from arthritis, uveitis, inflammatory bowel disease, and cardiometabolic complications, highlighting the importance of a systemic approach to treatment. Systemic or biologic therapy should be considered for extensive disease, but topical treatments are often required for localised resistant areas, in tandem with these advanced therapies.

Referral to Dermatology

Referral to a dermatologist should be considered in the following settings:

• The diagnosis is unclear
• The response to topical treatment is inadequate
• There is significant impact on quality of life
• The patient has widespread severe disease (over 10% body surface area)
• The patient has persistent involvement of ‘special sites’ –face, palms/soles, genitals
• In cases of co-morbidities, psoriatic arthritis, referral and/ or collaboration with other specialties (eg rheumatology in the case of arthritis)

Treatment Modalities

Treatment for psoriasis can be prescribed in a step-wise ladder, with topical treatments for mild disease and phototherapy, systemic agents, or biologic agents for more severe disease (Figure 1). There are theoretically more potential side effects with immunomodulatory systemic or biologic medications given that they are administered systemically, although they are usually well tolerated when prescribed under the conscientious care of a dermatologist.

Topical Treatments

Emollients

Hydration and emollients are valuable and inexpensive adjuncts to psoriasis treatment. Keeping psoriatic skin soft and moist minimizes the symptoms of itching and tenderness. Additionally, maintaining proper skin hydration can help prevent irritation and thus the potential for subsequent Koebnerisation (development of new psoriatic lesions at sites of trauma). There is no secret emollient of choice for psoriasis, and patients should be led by which emollient they find most helpful.

Corticosteroids

Topical corticosteroids exert antiinflammatory, antiproliferative, and immunosuppressive actions. However topical corticosteroids have more limited ability to modify disease when used as monotherapy, so they are often combined with other topical preparations such as vitamin D analogues eg betamethasone/ calcipotriol foam. Less potent topical steroids such as hydrocortisone 1% or Eumovate should be used for facial and genital psoriasis due to greater propensity for skin thinning. There is no benefit to application more frequently than once daily, and adherence to greater than once daily topical corticosteroid therapy is very low. Topical corticosteroids generally can be continued as long as the patient has thick active lesions. Skin atrophy from topical corticosteroids is rarely a problem unless the medication is continuously applied after the skin has returned to normal thickness or if areas without psoriasis are exposed. Once clinical improvement occurs, the frequency of application should be reduced. For patients in whom lesions recur quickly, topical corticosteroids can be applied intermittently (e.g. on weekends only) to maintain improvement. The addition of noncorticosteroid topical treatments to the treatment regimen can also facilitate reduced dependence on long-term daily topical corticosteroids. The risks of cutaneous and systemic side effects associated with chronic topical corticosteroid use are greater with high-potency formulations compared with lowerpotency formulations. Oral steroids should never be used to treat psoriasis due to the significant risk of potentially serious rebound flares once they are stopped.

Vitamin D analogues

Calcipotriene and calcipotriol are synthetic forms of vitamin D that regulate skin cell growth and are used alone or used in combination with corticosteroids for enhanced efficacy.

Tar

Tar is a time-honoured modality for treating psoriasis, although newer (and less messy) treatment options have reduced its popularity. The precise mechanism of action of tar is not known but may involve aryl hydrocarbon receptors, producing anti-inflammatory and antiproliferative effects. Tar can be helpful as an adjunct to topical corticosteroids, or be combined in the form of LPC e.g. with betamethasone. Patients should be warned that tar products have the potential to stain hair, skin, and clothing. It may help to use them at night and wear inexpensive night clothes (e.g. old pyjamas) as tar products tend to be messy. Patients may also find the odour of tar products unpleasant.

Calcineurin inhibitors

Topical tacrolimus 0.1% is effective in the treatment of psoriasis in sensitive areas such as the face and intertriginous areas, although likely less effective than topical steroids. However, they are very safe and well-tolerated, so can be used as a prophylactic agent to reduce the frequency of topical steroid use. Topical tacrolimus 0.1% is licensed from 16 years of age, while the 0.03% formulation is licensed from 2 years. However, due to the superior efficacy and lack of increased risk with the stronger version, the 0.1% option should be preferentially prescribed for children.

Topical retinoids and salicylic acid

Salicylic acid has keratolyic activity and is combined with topical steroids eg betamethasone/ salicylic acid. Derived from vitamin A, topical retinoids eg tazarotene help normalise skin cell growth and are especially useful in areas with thick scales, such as the palms and soles. However they are used less commonly in Ireland.

Phototherapy

Ultraviolet (UV) irradiation has long been recognized as beneficial for the control of psoriatic skin lesions. UV radiation may act via antiproliferative effects (slowing keratinisation) and anti-inflammatory effects (inducing apoptosis of pathogenic T cells in psoriatic plaques). Therapeutic doses of UV light can be administered as narrowband ultraviolet B (UVB) phototherapy, or oral or bath psoralen plus ultraviolet A (PUVA) photochemotherapy. Narrowband UVB involves the delivery of 311 nm of UVB radiation. In particular, this is extremely effective for treating guttate psoriasis. Photochemotherapy (PUVA) involves treatment with a photosensitizer (either oral or bath psoralen) followed by ultraviolet A (UVA) radiation (320 to 400 nm). There are concerns about increased risk of skin cancer with very longterm use of PUVA. While individual treatment sessions are very short, a course of phototherapy can last several months, with multiple visits per week. Selection among modalities of phototherapy is based upon consideration of efficacy, safety, availability, and ease of therapy. Narrowband UVB is generally preferred over PUVA photochemotherapy based upon greater ease of administration (administration of psoralens not required) and a less severe side effect profile. Commercial tanning beds should not be used to treat psoriasis as there is significant variability in the UV output of tanning beds and they are associated with dramatically increased risks of skin cancer.

Systemic Medications

There are multiple international guidelines on treatment decisions for systemic and biologic medications. Systemic or biologic medications usually have immunomodulatory effects but some such as acitretin reduce keratinocyte proliferation (Figure 2). Patients require a workup to ensure there are no underlying conditions or infections that may become problematic during treatment. Typically patients should have testing before starting treatment for full blood count, renal function, liver function, hepatitis B and C serology, HIV serology, varicella immunity, and tuberculosis infection (usually with interferon-gamma release assays).

Methotrexate

Methotrexate is a folic acid antagonist which has antiinflammatory effects and has been used for psoriasis for over 50 years. It is also effective for the treatment of psoriatic arthritis and psoriatic nail disease. Methotrexate has multiple contraindications including pregnancy, alcoholic liver disease or other chronic liver disease, immunodeficiency syndromes, bone marrow hypoplasia, cytopaenias, or hypersensitivity to methotrexate. Relative contraindications include liver and renal function abnormalities and active infection. In addition, concomitant treatment with certain drugs (eg, nonsteroidal anti-inflammatory drugs, certain antibiotics) can increase risk for methotrexate toxicity. Regular monitoring is essential due to potential liver and bone marrow side effects. Methotrexate is usually administered in an intermittent low-dose regimen such as once weekly, orally or subcutaneously. The usual dose range is between 5 and 25 mg per week. Subcutaneous methotrexate can be used and may be helpful when doses higher than 15 mg/week are needed, as hepatic metabolism may limit the bioavailability of higher methotrexate doses. Unlike ciclosporin, which is generally used for only a limited duration of treatment because of cumulative renal toxicity, methotrexate can be used for long-term therapy.

Folic acid is co-prescribed to protect against some of the common side effects seen with low-dose methotrexate such as stomatitis. Concurrent use of other medications that interfere with folic acid metabolism, such as sulfa antibiotics, can increase the toxicity of methotrexate.

Ciclosporin

Ciclosporin suppresses T cell activity, reducing inflammation. Usual doses are 3-5mg/ kg/day divided twice daily. Contraindications to ciclosporin therapy include abnormal renal function, uncontrolled hypertension, malignancy, and hypersensitivity to cyclosporine. Caution is indicated in the setting of major infections or poorly controlled diabetes. Cyclosporine also has multiple drug interactions. Ciclosporin is reserved for shortterm use due to potential kidney damage with prolonged use.

Acitretin

Acitretin is a retinoid (vitamin D derivative) taken orally, which regulates skin cell growth. Acitretin is particularly useful for patients with pustular psoriasis or in patients with a history of immunodeficiency or neoplasia. Acitretin can be combined with UVB or PUVA. The usual dose range is 10-25mg daily and the onset of action is relatively slow. Monitoring for hypertriglyceridemia and hepatotoxicity are required with retinoid therapy. Common side effects include cheilitis and alopecia. Acitretin is teratogenic; it is only indicated in men and in women of nonreproductive potential. Pregnancy is contraindicated for three years after discontinuing the drug.

Apremilast

Apremilast, a phosphodiesterase 4 inhibitor, is another oral agent for the treatment of plaque psoriasis. PDE4 inhibition reduces production of multiple cytokines involved in the pathogenesis of psoriasis. Apremilast is costly, priced closer to biologics than to methotrexate. The drug can also be effective for psoriatic arthritis.

Apremilast is associated with a short-term risk of diarrhoea, especially when treatment is started, occurring in roughly 15 to 20 percent of patients. Tolerability of apremilast is improved by slowly ramping up the dose when treatment is initiated. In adult patients with severe renal impairment, the recommended final dose is 30 mg once daily. At the start of therapy, only the morning dose of the above titration schedule is given. Examples of other reported side effects of apremilast include nausea, upper respiratory infection, headache, drug interactions, and weight loss. Periodic monitoring of weight is recommended. Advising patients, their caregivers, and families to be alert for worsening depression, suicidal thoughts, or other mood changes during treatment also is suggested based upon the possibility of a slight increase in risk for depression.

Fumaric acid esters

Fumaric acid esters (fumarates) are frequently used to treat psoriasis in Germany. Lymphopenia is an occasional side effect of treatment with fumaric acid esters. In 2013, two cases of progressive multifocal leukoencephalopathy (PML) were reported in patients who continued to receive long-term fumaric acid ester therapy despite the development of severe lymphopenia. These patients did not have other known causes of immunodeficiency. PML in the setting of fumaric acid therapy for psoriasis has also been reported in patients without severe lymphocytopenia.

Biologics

Biologics are different from conventional systemic drugs that impact the immune system more globally. Biologics target highly specific parts of the immune system. The biologics used to treat psoriatic disease block the action of specific types of proteins in the immune system, such as tumor necrosis factor-alpha (TNF-alpha), interleukin 17-A, or interleukins 12 and 23 (Figure 3). These cells and proteins all play a major role in developing psoriasis and psoriatic arthritis.

TNF-alpha Inhibitors

Tumour necrosis factor alpha (TNF-alpha) inhibitors, such as etanercept and adalimumab, target specific immune system proteins involved in psoriasis. Other examples include certolizumab which is pegylated (and therefore does not cross the placenta) and infliximab (which is administered intravenously). Biosimilars are now available for etanercept, adalimumab, and infliximab, which have dramatically reduced their cost. TNF inhibitors are effective for both skin lesions and joint symptoms in psoriatic arthritis, and can be used to treat inflammatory bowel disease in patients who have comorbid disease.

IL-12/23 inhibitor

Ustekinumab is a human monoclonal antibody that targets IL-12 and IL-23. Ustekinumab is indicated for the treatment of adults and children with moderate to severe psoriasis who are candidates for phototherapy or systemic therapy. Dosing of ustekinumab is weight based. Standard dosing for ustekinumab for adults ≤100 kg is 45 mg given at weeks 0, 4, and every 12 weeks thereafter. A 90 mg dose given in the same regimen is recommended for adults who weigh more than 100 kg. Ustekinumab can also improve psoriatic arthritis.

IL-17 Inhibitors

Drugs like secukinumab and ixekizumab target interleukin-17, a protein implicated in psoriasis.

These agents are effective for individuals who do not respond well to other treatments, and are typically used as secondline agents after TNF inhibitors or ustekinumab. IL-17 inhibitors can rarely be associated with candidiasis and new-onset inflammatory bowel disease.

IL-23 Inhibitors

Guselkumab risankizumab, and tildrakizumab are examples of medications that target interleukin-23 by binding to the p19 subunit.

Novel/Emerging agents

Newer agents for psoriasis include other biologic targets and janus kinase inhibitors

The management of moderate to severe psoriasis requires a personalized approach, taking into account the patient’s overall health, lifestyle, and preferences.

Lifestyle Modifications

Encouraging patients to adopt a healthy lifestyle can complement medical treatments. Smoking cessation, weight management, and stress reduction are important aspects of managing psoriasis.

Regular Monitoring

Patients undergoing systemic treatments require regular monitoring of liver function, blood cell counts, and other relevant parameters. Close communication between healthcare providers and patients is essential to address any emerging concerns promptly.

Assessing Comorbidities

Psoriasis is associated with an increased risk of cardiovascular diseases, diabetes, and other systemic conditions. Dermatologists often collaborate with rheumatologists when joint involvement is present, ensuring a comprehensive strategy for addressing both skin and joint symptoms.

Combination Therapies

Dermatologists may opt for combination therapies, such as using a biologic alongside a topical treatment for enhanced efficacy. This approach aims to achieve better control of psoriasis while minimizing potential side effects.

Patient Education and Support

Educating individuals with psoriasis about their condition is crucial for empowering them to actively participate in their treatment. Patient support groups, online forums, and educational resources can provide valuable information and a sense of community for those navigating the challenges of moderate to severe psoriasis.

Managing Emotional Well-being

The visible nature of psoriasis lesions can significantly impact an individual’s self-esteem and mental health. Mental health support, counseling, and resources can help patients cope with the emotional aspects of the condition.

Adherence to Treatment

Ensuring patient adherence to prescribed treatments is vital for achieving optimal outcomes. Understanding the importance of consistent treatment and addressing any concerns or barriers to adherence is essential.

Conclusion

The treatment landscape for moderate to severe psoriasis has evolved significantly, offering a range of options tailored to individual needs. From traditional therapies like topical treatments and phototherapy to advanced biologics targeting specific immune pathways, dermatologists have a diverse toolkit to address this challenging condition. A holistic approach that considers the patient’s overall health, lifestyle, and emotional well-being is essential for comprehensive psoriasis management. With ongoing research and advancements in treatment.

Written by Dr Cathal O’Connor, RCPI dermatology specialist registrar in dermatology dual training in general paediatrics, ICAT paediatric dermatology fellow

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