A review of current and novel treatment strategies for chronic plaque psoriasis
Psoriasis is a chronic, immune-mediated inflammatory dermatosis with many comorbidities, particularly psoriatic arthritis, metabolic syndrome, and depression. Psoriasis has a significant impact on quality of life, especially for those with severe disease. It is therefore important for the physician to evaluate patient preferences and choices when considering an optimal treatment approach and therapeutic regimen for the individual patient. Currently, the physician can select from multiple treatment options. Lifestyle modifications should be considered for all patients to minimise triggering factors. Topical therapy, particularly corticosteroids and vitamin D creams, are first-line for most patients with chronic plaque psoriasis. Other conventional therapies for psoriasis include phototherapy and systemic agents. Over the past decade, advances in the understanding of psoriasis pathogenesis have allowed the emergence of newer biologic agents that have significantly improved disease outcomes for patients with moderate-to-severe psoriasis. These include tumour necrosis factor alpha (TNFα) inhibitors, such as infliximab, adalimumab, and etanercept; an interleukin-12/interleukin-23 (IL-12/IL-23) inhibitor, namely ustekinumab; and the latest class of biologics, IL-17 inhibitors, such as secukinumab. New oral molecule inhibitors, such as phosphodiesterase-4 inhibitors and Janus kinase (JAK) inhibitors are currently being trialled in severe psoriasis.
Psoriasis is a chronic, recurrent, immune-mediated inflammatory dermatosis with wide-ranging systemic effects. It affects approximately 2-3% of the population worldwide, with an estimated prevalence of 2.3-6.6% in Australia, where it is reported to be almost twice as prevalent in men as in women.  Psoriasis is currently understood as a multifactorial disorder with immune dysregulation, genetic susceptibility, and internal and environmental factors contributing to the disease onset. [1,2] The most common form of psoriasis is chronic plaque psoriasis, where salmon-pink plaques with silvery scales develop over the scalp, extensor surfaces, elbows, and knees, (due to the Koebner phenomenon). Sometimes it develops over the entire body surface and patients can become erythrodermic. Other subtypes of psoriasis are well described, such as guttate, flexural, pustular, and erythrodermic psoriasis.
Psoriasis is associated with several comorbidities, including psoriatic arthritis (PsA), cardiovascular disease, metabolic syndrome, hypertension, diabetes mellitus, dyslipidaemia, malignancies (skin cancers and lymphomas), inflammatory bowel disease, and psychiatric illness, including depression and anxiety. [1,3,4] It can have a significant impact on the patient’s quality of life (QOL) and cause considerable psychosocial distress and disability.
The management of psoriasis, therefore, necessitates that the physician develop a holistic approach towards the patient. It is important for the patient to develop an understanding of the disease to allow discussion of therapeutic strategies with the physician and for the patient to express his/her treatment preferences. Common goals of therapy in psoriasis include complete remission of skin disease, optimising QOL, preserving functional status, and minimising or controlling comorbidities, particularly diseases of the joints.
Over the past decade, increasing understanding of the molecular and immunological mechanisms of psoriasis pathogenesis and the advent of newer monoclonal antibodies that demonstrate immense efficacy in treating psoriasis have dramatically expanded the treatment strategies that the physician can employ to treat an individual patient’s condition. This paper will review and examine the various treatment modalities that are currently available to treat psoriasis, as well as highlight several upcoming novel agents for psoriasis treatment. It will focus on the Australian patient context, which will be relevant and practical to the Australian medical student.
A computerised search strategy was performed using MEDLINE and EMBASE up to November 2015. The search was limited to human studies of adults published in the English language and included reference lists of papers published.
Severity and impact of disease
Severity of disease can be measured using the Psoriasis Area and Severity Index (PASI) or body surface area (BSA) affected by psoriatic lesions. Mild disease is considered with lesions covering <10% of BSA or PASI ≤ 10.  PASI is one of the most commonly used measures of a clinically meaningful improvement. Clinical trials often use PASI 75 as a primary outcome, where the percentage of patients having at least 75% reduction in baseline PASI is evaluated.  Dermatology Life Quality Index (DLQI) is a quantitative measure examining the patient’s perspective of the disease impact on his/her life. 
The impact of psoriasis on the patient’s QOL cannot be underestimated. Various studies have assessed and evaluated DLQI and the clinical severity of psoriasis. QOL of psoriasis patients, in general, is strongly reduced and there is a linear, positive correlation between DLQI and BSA.  Patients suffer in many aspects of their lives, most frequently in social and emotional areas.  With the use of biologics, patients report satisfaction with their treatment, and DLQI and PASI decline and remain low for prolonged periods, with improvement in QOL. [10,11] It is important for the physician to evaluate patient preferences, choices regarding dosing frequency, and satisfaction with prior treatments in order to determine appropriate treatment regimens for the individual patient.
Considerations to treatment approach
Currently, the physician can select from a range of treatment strategies for psoriasis, from topical therapy and phototherapy to systemic oral agents and novel biologics,. However, there are currently no consensus guidelines that provide a specific treatment algorithm.  Treatment regimens should hence be considered and individualised to each patient.
There are several factors that have to be considered by the physician in selecting an appropriate treatment regimen. The physician has to consider the patient’s ability to apply and comply with topical therapy, which can be influenced by factors, such as the patient’s age (young or elderly patients), presence of lesions over inaccessible areas, and the ease of application of topical therapy. [13,14] Extensive psoriasis-afflicted areas, such as in moderate or severe disease affecting large body surface areas, may be better treated with UV therapy, systemic therapy, or biologics, as compared to topical therapy, which may be a less practical treatment option.  The presence of PsA may suggest use of systemic therapies or biologics, which can be efficacious against both skin and joint diseases. 
Obesity has a strong known association with psoriasis severity.  Lifestyle weight loss intervention, by dieting or exercise, has been shown to reduce severity of psoriasis by a PASI score of 2.5, compared to a non-intervention group.  It is postulated that weight loss and the consequent decrease in adipose tissue decreases inflammatory cytokines, contributing to the improvement in severity of psoriasis.  Other modifiable lifestyle factors, such as stress, smoking, and trauma (in cases of the Koebner phenomenon) are also well-documented triggers of psoriasis.  Active steps can be taken by the patient, supported by their physician, to modify such factors to help decrease psoriasis flares and disease severity.
Topical therapies are the first-line treatment for most patients with psoriasis, as most patients tend to have mild or limited disease. [13,14] It is common practice for patients to be on combination therapies, such as multiple topical agents, or topical therapies with a systemic or biologic therapy. 
Topical corticosteroids, such as hydrocortisone, mometasone and clobetasol, are the most frequently used treatments for psoriasis and remain the mainstay of therapy, having anti-inflammatory and anti-proliferative activity. [14,15] Topical steroids are classified based on potency and the selection of the steroid class depends on the location and sensitivity of the lesion to topical steroids.  High potency preparations are required for scalp and palmoplantar lesions and low potency preparations are used for facial and genital lesions. Ointments are considered the most efficient delivery systems, being more occlusive than creams or lotions.  Side effects of topical steroids include skin atrophy, telangiectasia, and easy bruising. 
Topical vitamin D3 analogues, calcipotriol and calcipotriene, have anti-proliferative properties and provide significant improvement after a three-month course of therapy.  Calcipotriene is one of the most commonly used non-corticosteroid treatments for psoriasis.  Topical vitamin D3 analogues can cause perilesional skin erythema and irritation.  Recent studies have demonstrated that a combination of topical steroids and calcipotriene is more effective and safer than either agent alone. 
Other topical therapies may be used with corticosteroids or vitamin D analogues. Tar is sometimes used as an adjunct therapy, having some anti-inflammatory and anti-pruritic properties.  It is, however, messy to use and can cause skin irritation and folliculitis, especially in higher concentrations.  Dithranol, an anthracene derivative, is postulated to work by inhibiting keratinocyte proliferation and has been shown to produce prolonged, sustained remission of psoriasis. [14,17] It can cause skin irritation and staining.  Topical retinoids, such as tazarotene, may also be used in localised psoriasis. Compounded creams with salicyclic acid have been used for thickened scales, as salicyclic acid has anti-inflammatory and desquamative effects and increases corticosteroid penetration. 
Phototherapy is a second-line treatment modality that is often used in eczema and other pruritic dermatoses, and has been shown to be safe and effective.  Narrow-band ultraviolet B radiation (NB-UVB) and psoralen and ultraviolet A radiation (PUVA) are the current phototherapy treatments used in psoriasis. UVB radiation primarily acts on epidermal and epidermodermal junction components, while UVA radiation affects epidermal and dermal components.  Phototherapy has both immediate and delayed effects on the skin. Immediate effects include formation of DNA photoproducts and damage, which cause apoptosis of resident skin cells and inflammatory cells, while delayed effects include local and systemic immune suppression, leading to suppression of disease activity.  As a monotherapy, PUVA has been demonstrated to be more effective than NB-UVB, with respect to achieving PASI 75.  Although short-term adverse effects are shown to be mild with a low withdrawal rate, use of PUVA has been consistently shown to be associated with increased risk of skin cancer. [19,20] Phototherapy with NB-UVB, now more commonly used in Australia instead of PUVA, can be an appropriate treatment for moderate-to-severe psoriasis and may be combined with other systemic therapies, such as methotrexate, that, overall, may be more efficacious than monotherapy. 
Various systemic immunosuppressants have been used for decades in the treatment of psoriasis. Used in other diseases, such as rheumatological diseases and inflammatory bowel disease, their long-term safety and side effect profiles are well documented and understood. Approximately 20-30% of patients suffer from moderate-to-severe disease and often require systemic therapies, in addition to conventional therapies.  Data of head-to-head studies on these systemic therapies, however, are lacking and insufficient. 
Methotrexate is a systemic drug that has been proven to have great efficacy as a monotherapeutic option in the treatment of psoriasis, though it can be considered with other agents or phototherapy to maximise its effectiveness.  It has long-term potential in causing hepatotoxicity, bone marrow suppression, and lung fibrosis.
Cyclosporine, a calcineurin inhibitor, is similarly very efficacious in the treatment of moderate-to-severe psoriasis as monotherapy by inducing immunosuppression.  It can sometimes be used in combination with methotrexate or tumour necrosis factor (TNF) inhibitors.  Cyclosporine is associated with hypertension and impaired renal function.
Acitretin is a vitamin A derivative that is often used for palmoplantar, pustular, and erythrodermic psoriasis, but has lower efficacy in chronic plaque psoriasis.  Unlike methotrexate and cyclosporine, acitretin is not immunosuppressive.  Acitretin can cause hyperlipidaemia, hepatitis, and alopecia.
The traditional systemic therapies, such as methotrexate, have been the mainstay of therapy, particularly in moderate-to-severe psoriasis. However, some patients suffer loss of efficacy, adverse effects, cumulative organ-specific toxicity and inadequacy or inability to clear resistant lesions with the use of these conventional therapies.  With rapid advances in the understanding of psoriasis pathogenesis, newer biologic agents, such as monoclonal antibodies targeting TNFα and interleukin-12/interleukin-23 (IL-12/IL-23), have emerged over the past decade. These agents have broadened treatment options for patients with moderate-to-severe psoriasis and have demonstrated high efficacy and favourable safety profiles, improving disease outcomes.
TNFα inhibitors represent the first wave of biologics in the therapeutic strategy for treatment of psoriasis. TNFα inhibitors that are US Food and Drug Administration (FDA)-approved and Australian Pharmaceutical Benefits Scheme (PBS)-approved for use in psoriasis include etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade). All three agents have been shown in various trials to produce significant benefits to psoriasis outcomes in terms of PASI and DLQI. [23-26] Etanercept has been shown to produce 59% PASI 75, versus taking placebo, at week 12, with improvement in DLQI.  A twice-weekly regimen has been demonstrated to be more beneficial than a once-weekly regimen, producing a more rapid and greater response in the PRISTINE trial.  Infliximab produced 81% PASI 75 and 88% clearance at week 10.  Infliximab has been shown to be superior to etanercept, in terms of efficacy, at 24 weeks.  Adalimumab has demonstrated improvement in self-reported work productivity, total productivity impairment, and total activity impairment. 
There are currently limited direct, long-term, head-to-head trials comparing the efficacy of the three TNFα inhibitors in treating psoriasis.  Use of these TNFα inhibitors, in particular infliximab and adalimumab, has been associated with a higher risk of serious infections, compared to non-methotrexate and non-biologic therapies. 
Molecular studies in recent years have shed light on the immuno-pathogenesis of psoriasis. IL-12 is a cytokine involved in stimulating naïve T cells to differentiate into CD4 cells and natural killer cells (NK cells) and upregulating production of interferon-γ (IFNγ).  IL-23 is a heterodimeric cytokine consisting of IL-23p19 and IL-12/23p40 subunits.  Recent evidence suggests that IL-12 antagonism inhibits T helper cell type 1 (Th1) development or responsiveness, while IL-23 antagonism impairs survival, expansion, or function of IL-17-producing T cells (Th17).  IL-23 has been proven to be a necessary upstream mediator to the Th17 pathway, as it activates Th17 cells to produce IL-17.  IL-23 is thought to be significantly important in psoriatic inflammation and specific inhibition of IL-23 is speculated to have profound therapeutic value.
This is clearly seen in the use and subsequent FDA-approval of ustekinumab (Stelara) in 2009 for use in psoriasis and PsA, where it demonstrated 81% achievement of PASI 75, versus 2% by placebo, at week 12.  It was found to be superior to etanercept.  More than 80% of patients were able to maintain PASI 75 for more than 3 years, without evidence of cumulative damage, in the POENIX 1 trial. 
Along with IL-12 and IL-23, molecular studies have brought attention to a central pathogenic pathway in psoriasis, where interleukin-17A (IL-17A) is regarded as the most critical T-cell-derived cytokine in altering growth and differentiation of skin cells. [3,6] IL-17A acts on endothelial cells, fibroblasts, chondrocytes, osteoblasts, monocytes, synovial cells, and keratinocytes.  The main physiological function of IL-17A is protection from infections by recruiting inflammatory cells to local sites of infection.  However, in psoriasis, there is hyperproliferation of keratinocytes driven by these cytokines from T cells. The psoriatic plaque typically shows infiltration of activated T cells, especially Th1 and Th17 cells that produce large amounts of IL-17, interferon-α (IFNα), and TNFα.  Hence, IL-17A is considered as a potential therapeutic target that may reduce the inflammation seen in psoriasis.
The results of phase II trials using IL-17 inhibitors support the hypothesis that IL-17 is indeed an essential target in treatment of chronic plaque psoriasis.  Targeting the IL-17 pathway may result in additional systemic benefits, particularly to arthritis and cardiovascular risk.  These novel agents acting on the IL-17 pathway have shown promising results in the therapeutic management of psoriasis.
Secukinumab (Cosentyx) was the first IL-17 inhibitor and was approved by the FDA in January 2015 for use in psoriasis treatment. It is also approved for PBS-subsidised treatment for chronic plaque psoriasis. Secukinumab neutralises IL-17A and had achieved 63% PASI 50 at week 12 in phase I trials.  Subsequent phase II and III clinical trials showed more than 80% of patients achieve PASI 75 at week 12.  Phase III trials have demonstrated that patients taking secukinumab are less likely to experience loss of response and showed superior PASI outcomes, compared to placebo, etanercept, and ustekinumab groups. [36-38]
Two other IL-17 inhibitors, brodalumab and ixekizumab, are in the last stages of development before they are approved for use. Ixekizumab is similar to secukinumab, as it inhibits IL-17. Phase II trials have shown significant scores of PASI 75 in 76.7%, 82.8% and 82.1% of patients receiving 25mg, 75mg, and 150mg, respectively, of ixekizumab at week 12, with significant and sustained reduction in DLQI scores.  Interestingly, use of ixekizumab has resulted in a reduction in inflammatory infiltrate, with modulation and normalisation of psoriasis disease-related genes.  Brodalumab inhibits the receptor subunit IL-17RA. Phase II trials have showed improvements, with a PASI scores of 85.9% and 86.3% using 210mg and 140mg, respectively, at 12 weeks, with significantly lower DLQI.  Both ixukizumab and brodalumab are currently in phase III trials to investigate their safety and efficacy.
Adverse effects of the three IL-17 inhibitors are reported in their respective trials. They are generally well-tolerated, but may show various drug reactions, such as nasopharyngitis, arthralgia, injection-site erythema, headache, and pruritus.  There are theoretical concerns that suppressing IL-17, which is a pro-inflammatory cytokine that activates innate immune responses against extracellular organisms, will increase the risk of neutropaenia with the decreased attraction of neutrophils. [3,6,34] However, these trials have not found that bacterial or fungal infections pose a significant problem.  It should be noted that most of these trials are short in duration and long-term efficacy, safety, and tolerability are not yet fully established.  Further longitudinal studies will be required to follow these trial patients.
Novel molecule inhibitors
New oral molecule inhibitors that are awaiting PBS approval include apremilast and tofacitinib. Apremilast, a phosphodiesterase-4 inhibitor, is a new oral agent approved in 2014, which has been shown to be effective against moderate-to-severe plaque psoriasis.  An oral inhibitor of the JAK/STAT signalling pathway, tofacitinib, is being trialled and will soon receive PBS-approval for subsidy. [42,43]
Biologic therapies for patient use in Australia
Given their hefty cost, these biologic agents are heavily subsidised under the PBS and strict qualifying criteria are applied to prescribe them in Australia. To qualify for the five currently approved biologic agents (adalimumab, etanercept, infliximab, secukinumab, and ustekinumab), patients must have failed to achieve an adequate response to at least three of the four treatments of: phototherapy, methotrexate, cyclosporine, or acitretin.  The biologic agent must be used as systemic monotherapy and the patient must subsequently be assessed to have demonstrated an adequate response to this current treatment by having a PASI score of greater than 15 in order to be eligible for continuing treatment. 
We need to further explore and deepen our understanding of the pathogenic pathways in psoriasis to uncover components that can be potential therapeutic targets. Further understanding of the impact of psoriasis on other systemic co-morbidities is required, such as evaluating and quantifying the risk of cardiovascular disease. We will need to have more long-term, head-to-head trials to allow comparison of efficacy and safety of these novel biologics. We need further evaluations of combination regimens using traditional and biologic therapies to increase efficacy of treatment, decrease cumulative dose, and minimise side effects. This ultimately allows us to establish combined, multi-modal therapies for the individual patient to produce complete remission of skin disease and optimal QOL and functional status. Our healthcare system should explore various strategies aimed to reduce the cost of biologics and improve their accessibility to patients.
Advances that have been made into understanding psoriasis have led to emerging, promising, and effective treatments. As we witness an ever-expanding treatment armamentarium with novel agents, further work is still required to examine their efficacies and evaluate their use in combination regimens. Future understanding of disease pathogenesis, stratification of disease, outcome measures, and novel therapeutics will allow physicians to optimise disease and functional outcomes for patients.
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