Overview of the drug therapy for Psoriasis
ZHENG, Sin-Man Michelle
Drugs & Therapeutics
HKPharm J Volume 30 (1), Jan-Apr-2023 (2023-10-01): P.16
ABSTRACT
Psoriasis is a chronic inflammatory skin disease that is characterised by the appearance of well-delineated red and silvery scaly plaques that varies in extent from a few patches to generalised involvement. Research has shown that psoriasis is caused by both genetic and environmental factors. It is a chronic relapsing disease which requires long term therapy. The choice of therapy for psoriasis depends on the disease severity, relevant comorbidities, patient’s preferences and evaluation of patient’s response. Mild to moderate psoriasis can be managed by topical agents including corticosteroids and vitamin D analogues, while moderate to severe psoriasis will require phototherapy or systemic treatment. This article provides an overview of the background and treatment therapies of psoriasis, from the conventional topical and oral medications to the promising new therapy of biologics.
INTRODUCTION
Psoriasis is a complex immune-mediated inflammatory disease affecting about 2% of the population worldwide.(1) It occurs in genetically susceptible individuals and presents with the development of inflammatory plaques on the skin. Although genetics plays a role in the disease, patients may not have positive family history. Other factors that may trigger psoriasis include: smoking, alcohol, obesity, skin injury and some common medications. The disease can have a significant effect on the quality of life of patients.
Patients with psoriasis are at increased risks of comorbidities, including, but not limited to, psoriatic arthritis, cardiovascular disease, diabetes mellitus, obesity, inflammatory bowel disease and non-alcoholic fatty liver disease compared with the general population. The epidemiological studies of psoriasis allow us to understand the pathogenesis contribution, so as to reveal predisposing genetic and autoimmune traits in the process of the disease. The ideal goal of treatment with psoriasis is to optimise the controls of symptoms, improve quality of life, prevent psychological comorbidity, as well as structural damage and disability. This review will give an overview of the background of psoriasis and its management.
PATHOPHYSIOLOGY
Recent studies have provided better insight into the immune system’s role in the pathogenesis of psoriasis. Inciting events that propagate psoriasis begin with the stimulation of plasmacytoid dendritic cells through complexes consisting of host DNA with keratinocyte produced cathelicidins, leading to the subsequent release of interleukin (IL)-12 and IL-23. (2) The signalling pathway for the production of IL-23 is mediated intracellularly by the Janus Kinase (JAK) pathway. Production of these cytokines stimulates differentiation of naïve T cells to T-helper (Th) 1 and Th17 cells. This ultimately leads to the production of tumour necrosis factor (TNF)-alpha, IL-22, and IL-17, causing hyperproliferation of keratinocytes and vascular endothelial growth factor-induced angiogenesis. (3) (Figure 1) Stimulation of keratinocytes leads to additional release of immune-mediating complexes and chemoattractants, resulting in a self-perpetuating cycle. (4) The inflammatory cascade in patients with psoriasis is not contained solely to the skin. Systemic inflammation is associated with a high risk of comorbid illnesses. Hence, novel therapies for psoriasis are directed at interrupting this immune-mediated cycle.
Figure 1: Pathophysiology of Psoriasis.
CLINICAL MANIFESTATIONS
Psoriasis occurs in a variety of clinical forms and may exhibit different features depending on the body area that it affects. The most common subtype of psoriasis is plaque psoriasis, representing 90% of all manifestations of psoriasis. (5) The three other less frequently observed subtypes are guttate psoriasis, erythrodermic psoriasis, and pustular psoriasis. Although one subtype typically predominates in one patient, different subtypes may also coexists in an individual patient at one time.
Classical clinical manifestations in plaque psoriasis are sharply demarcated raised lesions covered in silvery scales. The elbows, knees and scalp are the most common sites for involvement, and the extent of involvement can range from localised area to involvement of the majority of the body surface area. The plaques may be asymptomatic, but pruritus is common. Painful fissures can also occur in the involvement of the palm or sole of patients.
Guttate psoriasis is a particular form of psoriasis with the appearance of multiple small, psoriatic salmon-pink papules and plaques, which are usually 1-10 mm in diameter and predominantly appears on the trunk. A strong association between group A streptococcal infection and guttate psoriasis has been identified. Also, about one third of guttate psoriasis would progress to chronic plaque psoriasis. (6)
Erythrodermic psoriasis is an uncommon form of psoriasis that is treated as a dermatological emergency as it can be associated with electrolyte imbalance and sepsis. (7, 8) It is characterised by the development of erythema, scales and exfoliation of the skin involving over 75% of the body surface area. The affected skin is often painful and itchy. Systemic symptoms such as fever, chills, tachycardia and malaise may also occur in patients with erythrodermic psoriasis. (9)
Another rare subtype of psoriasis is pustular psoriasis with life-threatening complications including skeletal and joint disease, as well as renal and hepatic abnormalities. It presents with the acute onset of widespread painful erythema, scaling and areas of superficial pustules. (10, 11)
CHOICE OF THERAPY
Selecting an appropriate treatment modality for psoriasis should be matched to the severity of the disease while considering the presence of any comorbidities. For most patients with mild plaque psoriasis, topical therapies are recommended initially, which are usually sufficient to achieve the recommended goals. For patients with moderate to severe disease, systemic therapies alone or in combination with topical agents are typically required. (Figure 2)3 shows an algorithm for the general approach to treatment that incorporates both classification systems - mild vs. moderate to severe, and topical vs. systemic therapy. Moderate to severe psoriasis is typically referred to as involving more than 5 to 10 percent of the body surface area or the involvement of face, palm or sole, or disease that is otherwise disabling. As the application of topical therapy to a large body surface area is not practical, those patients with more than 5 percent of body surface area affected are generally candidates for phototherapy or systemic therapy. At all times, the risk and benefit of treatments should be discussed with patients, and a shared decision-making process should be applied to the selection of an appropriate therapy that will achieve the target goals and meet the patient’s expectation. Although medication safety plays an important role in treatment selection, this must be balanced by the risks of undertreatment of psoriasis, leading to inadequate clinical improvement and patient dissatisfaction.
Figure 2: Overall Treatment Approach for Plaque Psoriasis.
TOPICAL THERAPIES
Topical medications are the most common agents used to treat patients with mild to moderate psoriasis. They are also frequently used as adjunctive therapies for patients on phototherapy, systemic or biologic therapy. Patient adherence is the largest factor to successful treatment with topical therapies. (12) One of the most valuable and inexpensive topical adjunct is emollient. Maintaining psoriatic skin soft and moisturised is important as it can help with itching and irritation. Other agents include topical corticosteroids, topical vitamin D analogues (calcitriol and calcipotriol), topical keratolytics (tazarotene, salicylic acid, urea), topical calcineurin inhibitors (pimecrolimus and tacrolimus), and tar.
Topical Corticosteroids
Topical corticosteroids are the cornerstone of psoriasis despite the developments of newer therapies. They are often effective and well tolerated, especially in patients with mild psoriasis. They help with inflammation and proliferation of psoriatic skins, as well as exert their locally vasoconstrictive effect through a down regulation of genes coding proinflammatory cytokines. (13) Hence, making it a useful therapy for this immune-mediated disease. To minimise the adverse effects and maximise adherence, the choice of topical corticosteroids is very important. Topical corticosteroids are available in a wide range of preparations including cream, gel, ointment, foam, lotion, and spray. Studies show that the vehicle can directly affect a preparation’s therapeutic and adverse effects by changing the pharmacokinetics of the topical corticoid molecule. (14, 15) In addition, different potency of corticosteroids will have different efficacy and may be chosen for different parts of the body to treat psoriatic skin. Lower potency corticosteroids are particularly recommended to apply on the face, groin, axillary areas, and in infants and children, while mild and high potency corticosteroids are mainly used for initial therapy and all other parts of the body. Super potent corticosteroids are reserved for stubborn, cutaneous plaques or lesions on the palms, soles, and scalp. (16) In clinical practice, to achieve a faster improvement of lesions, a high potency or super potent corticosteroids are often chosen as an initial therapy. However, they should not be used for more than 2 weeks and if longer treatment durations are required, the patient should be under close clinical supervision. (17-18)
Although the adverse effects of corticosteroids tend to be more severe with systemic rather than topical treatment, risk of systemic side effects associated with chronic topical corticosteroid use increases with high potency formulations. With frequent and prolonged use of high potency topical corticosteroids on skin or intertriginous areas, the adverse effects may include skin atrophy, telangiectasia, and striae. Regular examinations by physicians are recommended. Other systemic adverse effects such as suppression of the hypothalamus pituitary and adrenal gland axis is rare and can be minimised by limiting long-term use of high potency topical corticosteroids on large body surface areas, especially limiting such use in children. (19, 20) Special attention should also be paid when applying topical corticosteroids in the presence of an infection, as there is a risk of exacerbation. Topical corticosteroids can inhibit the skin's ability to fight against bacterial or fungal infections. (21) Hence, balancing between the adverse reactions of corticosteroids and maintaining its efficacy at the same time has been a great challenge to researchers and physicians.
Topical Vitamin D analogues
Topical vitamin D analogues for the treatment of psoriasis includes calcitriol and calcipotriol. The mechanism of action of topical vitamin D analogues involves the drug’s ability to inhibit keratinocyte proliferation and boost keratinocyte differentiation. (22) In addition, vitamin D analogues bind to vitamin D receptors on T cells and inhibit T cell proliferation and other inflammatory mediators. (23) The efficacy of topical vitamin D analogues are modest when used alone and in the same preparation, calcitriol and calcipotriol are equally effective. (24, 25) However, on the sensitive and intertriginous areas of the skin, calcitriol appears to be less irritating than calcipotriol. Perilesional erythema, perilesional oedema, and stinging or burning sensations were less common in the areas treated with calcitriol than calcipotriol. In another systemic review of randomised controlled trials, calcipotriol exerts the same effectiveness as potent topical corticosteroids and calcitriol. (26) Combined use of calcipotriol and potent corticosteroids also increases clinical response and tolerability in clinical trials compared with either agent used alone. (27, 28) Hence, topical calcipotriol may serve as an alternative or adjunct to topical corticosteroid therapy. The most common adverse effects of topical vitamin D analogues include skin irritation, burning sensation, pruritus, and oedema. Systemic absorption generally does not result in adverse outcomes unless patient has severe renal failure. (29, 30)
Topical keratolytics
Topical keratolytic agents include topical tazarotene, salicylic acid and urea. Topical tazarotene is a retinoid that inhibits proliferation of keratinocytes and helps to break down the thick scales on the plaque. In two randomised controlled trials, it was shown that it was safe and effective, with up to one-third of patients experienced at least 50% improvement of psoriasis after 12 weeks. (31) Adverse effects may include irritation and burning sensation on the skin. Salicylic acid is the most commonly used keratolytic compound. It exerts an increasingly potent, rapid, and deep keratolytic effect on the stratum corneum which leads to descaling in psoriatic skins. (32) Topical urea is useful in treating plaque psoriasis upon its keratolytic, hydrating, hygroscopic, penetration-enhancing, epidermis-thinning, and anti-pruritic effects. The moisturizing action of urea in dry and scaly psoriatic skin has been widely studied and is well accepted. (33, 34) They are usually well tolerated with only non-systemic side effects reported, with mild irritation being the most common.
Topical calcineurin inhibitors
Topical tacrolimus 0.3% and 0.1%, and pimecrolimus 1% are effective in the treatment of psoriasis in sensitive areas such as the face, axillary, and groin regions. They work by blocking T cell activation through inhibiting the synthesis of IL-2 and interferon gamma (IFN-γ), hence exerting its immunomodulatory effect. (35) In a randomised, double-blind, vehicle-controlled study, up to 71% of patients experienced clear or almost clear psoriasis after eight weeks treatment with topical pimecrolimus 1% compared with placebo. (36) Tacrolimus 0.1% ointment has also shown its effect in clearing psoriatic lesions in another eight-week, randomised, double-blind, vehicle controlled trial with 167 patients ages 16 and older, using twice-daily treatment on intertriginous and facial lesions with tacrolimus 0.1% ointment. 65% of patients achieved excellent improvements compared with placebo in the study. (37) Common adverse effects with topical use of calcineurin inhibitors include skin irritation, especially in highly inflamed lesions. This can be reduced by treating first with topical corticosteroids before transitioning to topical calcineurin inhibitors.
Tar
Topical tar preparations include shampoo, cream, lotion, ointment and oil. Its exact mechanism of actions are not yet fully discovered but it may involve aryl hydrocarbon receptors to exert its anti-inflammatory and anti-proliferative effect. (38, 39) Choosing tar as treatment option has become less popular with newer and less messy alternatives, but it still serves as a useful adjunct to topical corticosteroids therapy.
PHOTOTHERAPY
Phototherapy consists of exposure to specific wavelength of light. It has been used for years to treat patients with plaque psoriasis and has long been recognised as beneficial for the control of psoriatic skin lesions. Unlike sunlight, phototherapy delivers specific wavelengths that are therapeutic for psoriasis, and it minimizes emission of wavelength responsible for carcinogenesis.
A targeted phototherapy such as excimer laser can be used to treat localised mild plaque psoriasis. It emits high intensity ultraviolet B (UVB) of 308 nm and a considerably higher dose can be administered to psoriatic plaques at each treatment session when compared to traditional phototherapy.(40) It is also particularly useful for treating psoriasis plaques that are located in difficult areas such as scalp, palms, knees, elbows and soles. In some uncontrolled trials, it is suggested that laser therapy has more efficient responses than conventional phototherapy. Patients achieved the outcome of better percentage of clearing of plaques than those typically required phototherapy.(41, 42) Excimer laser therapy has very low carcinogenic potential and the main adverse effects are a burning sensation and blistering.
A full-body-surround phototherapy is used to treat more extensive psoriasis. However, since the emerging of new biologics treatment, the use of phototherapy for moderate to severe psoriasis has drastically decreased. The main types of phototherapy for moderate to severe psoriasis includes narrowband UVB, broadband UVB, and psoralen plus ultraviolet A (PUVA). Narrowband UVB involves in delivering 311 nm of radiation while broadband UVB aims to deliver 290 to 320 nm of radiation. PUVA involves treatment with a photosensitiser (either oral or bath psoralen) followed by ultraviolet A (UVA) radiation of 320 to 400 nm. The theory behind UVB phototherapy is that it decreases DNA synthesis, leading to keratinocyte apoptosis and decreased production of proinflammatory cytokines by T cells. (43, 44) Compared with broadband UVB, narrowband UVB are more commonly used due to greater efficacy, longer duration of remission, lower photocarcinogenic potential and less erythema upon the use of same physical dose.(45) As for PUVA, psoralens are used to intercalate into DNA to supress DNA synthesis. (46) Hence, exerting its therapeutic effect through its immunomodulatory properties. Although treatment with PUVA is more efficient than UVB, it is no longer preferred due to the development of skin cancer with long term use. Long term studies have shown a dose-related increase in the incidence of nonmelanoma skin cancers among patients exposed to high cumulative doses of oral PUVA. (47-49) Patients who have received prolonged courses of PUVA are required to have ongoing monitoring. Adverse events of PUVA include gastrointestinal upset, burning, pruritus, hypertrichosis, and photoaging. In general, phototherapy is contraindicated in patients with a history of melanoma or extensive non-melanoma skin cancer.
SYSTEMIC THERAPY
Small molecules
Traditional systemic treatment options for psoriasis include methotrexate, cyclosporin A and retinoids. All of them are oral drugs with the exception of methotrexate, which is also available for subcutaneous administration.
Methotrexate
Methotrexate is a folate antagonist that inhibits dihydrofolate reductase, thereby inhibiting DNA synthesis by blocking thymidine and purine biosynthesis. The mechanism of action involved in psoriasis includes the antiproliferative effects of methotrexate on DNA synthesis in epidermal cells, and also its immunosuppressive effects on activated T cells that control psoriasis. (50) When compared to biologics, methotrexate seems to be less effective than some of them. In a randomised controlled comparative study of methotrexate, adalimumab and placebo, 271 patients with moderate to severe plaque psoriasis were randomized to receive oral methotrexate 7.5 mg to 25 mg per week, adalimumab 40 mg every other week, or placebo. After 16 weeks, the proportion of patients achieving over 75% improvement in Psoriasis Area and Severity Index (PASI 75) with methotrexate was more than placebo but less than adalimumab. (51) Similar results were shown in another study using subcutaneous methotrexate in patients with moderate to severe plaque psoriasis. (52) The most common side effects of methotrexate include nausea, leukopenia and liver transaminase elevation, as well as increased risk of hepatic, pulmonary, hematologic and renal toxicity. Folic acid may protect patients against some of the common side effects seen with low dose methotrexate. Despite the potential side effects and its hepatotoxicity, it remains a frequently used cost-effective first-line drug. Close monitoring of liver and renal function, and regular full blood counts allows the long term administration of methotrexate feasible.
Cyclosporin
Cyclosporin is a T cell inhibiting immunosuppressant and is effective in patients with severe psoriasis. It belongs to the group of calcineurin inhibitors and exerts it anti-psoriatic effects by reducing production of IL-2. The use of cyclosporine in psoriasis was based on studies supporting its status as a highly and rapidly effective treatment in achieving up to 80% clear of psoriasis. (53) In addition, a meta-analysis of 3 major studies on the use of cyclosporin in 597 patients with severe plaque psoriasis revealed that cyclosporin given at a dosage of 2.5 and 5 mg/kg/day was significantly superior to etretinate, a synthetic retinoid indicated to treat severe psoriasis. In addition, cyclosporine 1.25 mg/kg/day was proved to be significantly more effective than placebo. (54) Hypertension, renal toxicity and non-melanoma skin cancer are significant potential side effects. Hence, close monitoring is required and often limit the long term use of cyclosporin in patients with psoriasis. (55)
Acitretin
Acitretin is a retinoid, belonging to derivatives of vitamin A, used in the treatment of moderate to severe psoriasis, including pustular and erythrodermic forms. The mechanism of action of acitretin in psoriasis involves normalising of keratinocyte proliferation and differentiation, as well as affecting the transcriptional processes by acting through nuclear receptors. (56, 57) The efficacy of acitretin was shown in a multi-centred, randomised study which reported 22.2% and 44.4% of patients reaching PASI 75 and PASI 50 at 24 weeks. (58) Dry lips, hair loss, skin peeling, pruritus and nail disorders were the most frequently reported side effects of acitretin. Monitoring for hypertriglyceridemia and hepatotoxicity are also required with acitretin treatment. It is worth noting that acitretin is teratogenic and it is only indicated in men and in women of non-reproductive potential. Pregnancy is contraindicated for three years after discontinuing the drug. (59)
Biologic agents
Development of biologic therapies that specifically target immune mediators involved in the pathogenesis of psoriasis has significantly improved the likelihood that patients can achieve clear or almost clear skin. Emerging evidence also suggests that the ability of these agents to supress the underlying systemic inflammation has long-term benefits on the various comorbidities associated with psoriasis. Currently, 11 biologic agents are marketed in the United States with evidence in managing plaque psoriasis.
- Tumour necrosis factor-alpha (TNF-α) inhibitors: Adalimumab, Certolizumab, Etanercept, Infliximab
- IL-12/IL-23 inhibitors: Ustekinumab
- IL-17 inhibitors: Brodalumab, Ixekizumab, Secukinumab
- IL-23 inhibitors: Guselkumab, Risankizumab, Tildrakizumab
All biologics used to treat psoriasis are administered subcutaneously except infliximab, which is administered intravenously. Overall, side effects that occur at slightly higher rates than placebo are common to all biologics including injection site reactions, nasopharyngitis, and upper respiratory tract infections.
TNF-α inhibitors
TNF-α inhibitors are the oldest class of currently approved biologics for the treatment of psoriasis. By inhibiting TNF-α, these biologics decrease the downstream inflammatory cascade taking part in the psoriasis pathogenesis.
Etanercept was the first TNF-α inhibitor approved by the United States Food and Drug Administration (FDA) for psoriasis. It is different from others in the biologic category in that it is not a monoclonal antibody, but rather a recombinant human fusion protein between a TNF-α receptor protein and the crystallisable fragment portion of IgG1. It competitively inhibits the interaction of TNF with cell surface receptors, preventing TNF-mediated cellular responses and modulating the activity of other proinflammatory cytokines that are regulated by TNF in psoriasis. (60) Etanercept’s safety and efficacy was illustrated in a global phase III randomised controlled trial. It was shown that etanercept provided clinically meaningful benefit to patients with chronic plaque psoriasis when compared to placebo group, with no apparent decrease in efficacy after dose reduction. (61) Standard adult dosing for etanercept is subcutaneous injection of 50 mg twice weekly for the initial three months of therapy, followed by a 50 mg injection once weekly for maintenance therapy.
Infliximab was first approved for the treatment of plaque psoriasis by the FDA in 2006. It is a chimeric IgG1 monoclonal antibody that binds to soluble and transmembrane forms of TNF-α, thereby interfering with endogenous TNF-α activity. (62) Its safety and efficacy was established in a phase III, multicentre, double-blind trial. In this trial, 378 patients with moderate to severe plaque psoriasis were allocated in a 4:1 ratio to receive infusions of either infliximab 5 mg/kg or placebo at weeks 0, 2, and 6, then every 8 weeks to week 46. It was shown that infliximab is effective in both an induction and maintenance regimen for the treatment of moderate to severe psoriasis, with a high percentage of patients achieving sustained PASI 75 and PASI 90 improvement through 1 year. (63) Standard dosing for infliximab for adults is intravenous infusion of 5 mg/kg at weeks 0, 2, and 6, followed by every eight weeks thereafter.
Adalimumab, a human monoclonal antibody against TNF-α was originally used for patients with rheumatoid arthritis, and then later on approved by the FDA for treatment of adult patients with moderate to severe chronic plaque psoriasis in 2008. The mechanism of action is based on both the neutralisation of TNF-α bioactivity and the induction of apoptosis of TNF-expressing mononuclear cells. (64) Adalimumab has illustrated its efficacy and safety in several clinical studies. A controlled phase III trial of 1212 patients randomised to receive adalimumab 40 mg or placebo every other week for the first 15 weeks shown that 71% of adalimumab and 7% of placebo-treated patients achieved PASI 75 at week 16. In addition, continuing adalimumab resulted in a higher percentage of patients maintaining their response at week 52. (65) Standard dosing for adalimumab for adults is an initial subcutaneous injection of 80 mg, followed by 40 mg given every other week, beginning one week after the initial dose.
Certolizumab is a pegylated humanized antibody fragment with specificity for TNF-α. It binds to human TNF-α and neutralises the pathological inflammation caused by the cytokine. In 2018, the FDA approved the drug for the treatment of adults with moderate to severe psoriasis. Support for the use of certolizumab comes from two phase III randomised trials CIMPASI-1 and CIMPASI-2. Patients with moderate to severe chronic plaque psoriasis were randomised in a ratio of 2:2:1 to certolizumab 400 mg, certolizumab 200 mg, or placebo every 2 weeks. At week 16, certolizumab-treated patients achieving a PASI 50 continued treatment through week 48. It was concluded that treatment with either certolizumab 400 mg or 200 mg every 2 weeks was associated with significant and clinically meaningful improvements in moderate to severe psoriasis. The 400 mg dose could provide additional clinical benefit and safety profile was consistent with the therapeutic class. (66) A point worth noting is that unlike other anti-TNF-α agents, certolizumab has no fragment crystallizable region, and is thus not actively transported across the placenta. Hence, it is approved for use during pregnancy and breastfeeding. (67) Standard dosing for certolizumab is 400 mg every other week. An optional regimen for patients who weigh ≤90 kg is 400 mg at weeks 0, 2, and 4, followed by 200 mg every other week.
IL-12/IL-23 inhibitors
Ustekinumab is a human monoclonal antibody that targets both IL-12 and IL-23, with it being the only biologic that inhibits both IL-12 and IL-23 through inhibition of their shared p40 subunit. The FDA approved its use to treat psoriasis in 2009, and is now indicated for the treatment of adults and children 12 years and older with moderate to severe psoriasis. The therapeutic effect of ustekinumab is primarily mediated through its inhibition of IL-23. Two phase III trials, PHOENIX-1 and PHOENIX-2, has demonstrated the efficacy and safety for ustekinumab. In PHOENIX-1, 766 patients with moderate to severe psoriasis were randomly assigned to receive ustekinumab 45 mg (n=255) or 90 mg (n=256) at weeks 0 and 4 and then every 12 weeks, or placebo (n=255) at weeks 0 and 4, with subsequent crossover to ustekinumab at week 12. 67% patients receiving ustekinumab 45 mg, 66% receiving ustekinumab 90 mg, compared to 3% receiving placebo achieved PASI 75 at week 12. Responders who were kept on therapy generally maintained improvements in psoriasis out to at least week 76. PHEONIX-2 showed similar results, indicating that ustekinumab is an effective treatment for moderate to severe psoriasis, and dosing every 12 weeks maintains efficacy for at least a year in most patients. (68, 69) 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.
IL-17 inhibitors
To date, there are three human monoclonal antibodies targeting IL-17 available for the treatment of psoriasis. Secukinumab and ixekizumab block IL-17A, whereas brodalumab is directed against the IL-17 receptor A. IL-17A is a naturally occurring cytokine that functions in innate and adaptive immune responses, and specifically mediates effects in antibacterial and fungal immunity and tissue repair. (70) IL-17A acts by activating several cell types, including keratinocytes, fibroblast-like, endothelial cells, chondrocytes, and osteoblasts, and resulting in a release of pro-inflammatory cytokines. Thus, apart from promoting inflammation, hyperproliferation, matrix destruction, vessel activation, bone erosion, and cartilage damage could result. (71) It was found that the level of IL-17A is elevated in psoriatic plaques.
Secukinumab was the first IL-17 inhibitor approved by the FDA for plaque psoriasis in 2015. It selectively binds to IL-17A and inhibits its interaction with several cell types as mentioned above. As a result, it inhibits the downstream inflammatory pathways that drive psoriasis pathogenesis. (72) Two phase III, multi-centred, doubled-blind trials, ERASURE and FIXTURE, had investigated the efficacy and safety of secukinumab in moderate to severe plaque psoriasis versus placebo. In both studies, secukinumab was shown to be superior to placebo in terms of clinical efficacy. In both trials, secukinumab was given as a 300 mg or 150 mg dose once weekly for five weeks, then once every four weeks. In the ERASURE trial, at week 12, 82% and 72% of patients in the 300 mg and 150mg secukinumab group respectively, achieved a PASI 75, while only 5% of patients in the placebo group achieved the same results. Similar results were found in the FIXTURE trials, where superior efficacy of secukinumab over placebo were demonstrated for PASI 75. (73) Standard dosing for plaque psoriasis is 300 mg given subcutaneously once weekly at weeks 0, 1, 2, 3, and 4 followed by 300 mg every four weeks. Doses of 150 mg are also sufficient for some patients.
Ixekizumab, as a humanised IgG4 monoclonal antibody, selectively binds to IL-17A and prevents IL-17A from binding to the IL-17A receptor. Thus, this attenuates an inflammatory response mediated by IL-17A and disrupts the pathogenic inflammatory cascade of psoriasis. (74) It was approved by the FDA for the treatment for plaque psoriasis in 2016. Ixekizumab’s safety and efficacy in plaque psoriasis in adults were established in three phase III clinical trials, UNCOVER-1, UNCOVER-2 and UNCOVER-3, with a total of 3,866 participants with moderate to severe plaque psoriasis. 1296 patients were randomly assigned in the UNCOVER-1 trial, 1224 patients in the UNCOVER-2 trial, and 1346 patients in the UNCOVER-3 trial to receive subcutaneous injections of placebo, 80 mg of ixekizumab every 2 weeks after a starting dose of 160 mg (2-week dosing group), or 80 mg of ixekizumab every 4 weeks after a starting dose of 160 mg (4-week dosing group). At week 12 in the UNCOVER-3 trial, the patients entered a long-term extension period during which they received 80 mg of ixekizumab every 4 weeks through week 60. At week 12 in the UNCOVER-1 and UNCOVER-2 trials, the patients who had a response to ixekizumab were randomly reassigned to receive placebo, 80 mg of ixekizumab every 4 weeks, or 80 mg of ixekizumab every 12 weeks through week 60. In all three trails, ixekizumab was effective and achieved greater clinical response than placebo. Treatment with ixekizumab in the long term has also demonstrated a sustained efficacy in patients with plaque psoriasis. (75) Standard dosing for ixekizumab is 160 mg at week 0, followed by 80 mg at weeks 2, 4, 6, 8, 10, and 12. Subsequently, 80 mg are given every four weeks.
Brodalumab is an anti-IL-17A monoclonal antibody which has high efficacy for psoriasis. In February 2017, the FDA approved brodalumab for the treatment of moderate to severe plaque psoriasis in adult patients. Efficacy and safety of brodalumab has been supported by the data from phase III randomised trials (AMAGINE-2 and AMAGINE-3). 3721 patients were assigned in a 2:2:1:1 ratio to receive brodalumab 210 mg every two weeks, brodalumab 140 mg every two weeks, standard dosing of ustekinumab on day 1, week 4, and then every 12 weeks, or placebo. At week 12, more patients receiving 210 mg of brodalumab (86%) or 140 mg of brodalumab (67%) achieved PASI 75 compared with 8% of patients in the placebo group in AMAGINE-2, and 85%, 69%, and 6% of patients respectively in AMAGINE-3. In addition, the rate of complete clearance of skin disease (PASI 100) at week 12 was higher among patients given 210 mg of brodalumab compared with patients receiving ustekinumab. 44% vs. 22%, respectively in AMAGINE-2, and 37% vs. 19%, respectively in AMAGINE-3. The PASI 100 response rates with 140 mg of brodalumab were 26% in AMAGINE-2 and 27% in AMAGINE-3. It was concluded that brodalumab treatment resulted in significant clinical improvements in patients with moderate-to-severe psoriasis. (76, 77) Recommended dosing of brodalumab is 210 mg given at weeks 0, 1, and 2 and then every two weeks.
IL-23 inhibitors
In recent years, inhibitors of IL-23 have emerged as safe and effective options for the treatment of moderate to severe plaque psoriasis. Selective IL-23 inhibitors also require less frequent dosing than IL-17 inhibitors. To date, guselkumab, tildrakizumab, and risankizumab have been approved in the last 4 years with targeting of the p19 subunit of IL-23.
Guselkumab is a fully human, IgG1 monoclonal antibody that binds to the p19 subunit of IL-23 and inhibits its signalling. It was approved by the FDA for the treatment of moderate to severe plaque psoriasis in 2017. VOYAGE-1 and VOYAGE-2 were the first phase III trials to evaluated the efficacy and safety of guselkumab in psoriasis treatment. In VOYAGE-1, 837 patients were randomised at a 2:1:2 ratio to receive guselkumab 100 mg at weeks 0, 4, then every 8 weeks, placebo given at weeks 0, 4, and 12 followed by guselkumab 100 mg at weeks 16 and 20 then every 8 weeks, or adalimumab 80 mg at week 0, 40 mg at week 1, then 40 mg every 2 weeks. In VOYAGE-2, 992 patients with moderate to severe plaque psoriasis in a 2:1:1 ratio was randomised to receive guselkumab, placebo followed by guselkumab or adalimumab groups, with dosing regimens similar to those in VOYAGE-1. The primary endpoint was compared to placebo and evaluated by an Investigator Global Assessment (IGA) score 0 or 1 (on a scale of 0 to 5, with higher scores indicating more severe disease) at week 16 achieved by 84-85%. PASI 90 was coprimary endpoints and achieved by 70-73%. Guselkumab was also superior to adalimumab at these endpoints. It was concluded that guselkumab shows durable efficacy and a consistent safety profile in patients with moderate to severe psoriasis treated for up to 3 years. (78, 79) Upper respiratory tract infections, tinea and herpes simplex virus infections, arthralgia, diarrhoea, and gastroenteritis are the most common adverse effects of guselkumab. Recommended dosing for guselkumab is 100 mg at weeks 0, 4, and then every 8 weeks.
Tildrakizumab was approved by the FDA for the treatment of moderate to severe plaque psoriasis in 2018. Phase III trials reSURFACE-1 and reSURFACE-2 supports the superiority of tildrakizumab compared with placebo and etanercept. In reSURFACE-1, 772 adults with moderate to severe plaque psoriasis were randomly assigned to receive tildrakizumab 200 mg, tildrakizumab 100 mg, or placebo at weeks 0 and 4 and then every 12 weeks. After 12 weeks, 62%, 64% and 6% of patients in the 200 mg, 100 mg, and placebo groups, respectively, achieved PASI 75. The reSURFACE-2 trial randomly assigned 1090 patients to similar groups plus an etanercept group. After 12 weeks, 66%, 61%, 6% and 48% of patients in the tildrakizumab 200 mg, tildrakizumab 100 mg, placebo, and etanercept groups, respectively, achieved PASI 75. It was concluded that tildrakizumab 200 mg and 100 mg were efficacious compared with placebo and etanercept and were well tolerated in the treatment of patients with moderate to severe chronic plaque psoriasis. (80) Tildrakizumab had a similar safety profile to guselkumab with nasopharyngitis, headache, and injection-site reaction being the most common adverse effects. Recommended dosing of tildrakizumab is 100 mg given subcutaneously at weeks 0 and 4 and then every 12 weeks.
Risankizumab was approved in the following year 2019 by the FDA as the third IL-23 inhibitor for the treatment of moderate to severe plaque psoriasis in adults. Risankizumab has shown greater efficacy than placebo and ustekinumab in two phase III trials UltIMMa-1 and UltIMMa-2. In the 16-week blinded phase of the 52-week trails, 506 patients in UltIMMA-1 and 491 patients in UltIMMa-2 with moderate to severe plaque psoriasis were randomly assigned to receive risankizumab 150 mg, ustekinumab 45 or 90 mg based upon weight, or placebo in a 3:1:1 ratio. In UltIMMa-1, 75% 42% and 5% of patients, respectively, achieved PASI 90 at 16 weeks. In UltIMMa-2, 75% 48% and 2% achieved this endpoint, respectively. (81) It was concluded that risankizumab was superior to both placebo and ustekinumab in the treatment of moderate to severe plaque psoriasis. Treatment emergent adverse event profiles were similar across treatment groups and there were no unexpected safety findings. The most common adverse events seen in those treating with risankizumab were nasopharyngitis, headache, gastroenteritis and back pain. Recommended dosing for risankizumab is 150 mg at week 0 and week 4, then every 12 weeks.
CONCLUSION
Psoriasis is an inflammatory skin disease that is associated with multiple comorbidities and substantially diminishes patients’ quality of life. Although psoriasis cannot currently be cured, management should aim to minimise physical and psychological harm by treating patients early in the disease process, as well as identifying and preventing associated comorbidity, instilling lifestyle modifications, and employing a personalised approach to treatment. With the wealth of research and the developments of newer treatment options, both allows the potential to give patients with psoriasis an improved quality of life and control of key aspects of psoriasis.
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Questions for Pharmacy Central Continuing Education Committee Program
Overview of the drug therapy for Psoriasis(2CE Units)
- What plays a major role in Psoriasis?
- The nervous system
- The digestive system
- The circulatory system
- The immune system
- The most prevalent form of psoriasis is plaque psoriasis, and it is characterized by –
- Pimples all over the face
- White blisters of pus localized on the hands and feet
- Sharply demarcated raised lesions covered in silvery scales on their elbows, knees, scalp or the back
- White to yellowish flaky scales on the scalp or back of the ear
- Which of the following about Psoriasis is/are true?
- Psoriasis cannot be cured
- Stress can trigger psoriasis
- Psoriasis is contagious
- Psoriasis can be associated with arthritis
- (i) and (ii) only
- (i), (ii) and (iii) only
- (i), (ii) and (iv) only
- (ii), (iii) and (iv) only
- Which of the following types of psoriasis is characterized by small salmon-pink papules (1-10 mm in diameter) predominantly on the trunk?
- Erythrodermic psoriasis
- Plaque psoriasis
- Pustular psoriasis
- Guttate psoriasis
- Which of the following about phototherapy is INCORRECT?
- Excimer laser is particularly useful for treating psoriasis plaques that are located in difficult areas such as scalp, palms, knees, elbows and soles
- Narrowband UVB are more commonly used than broadband UVB due to greater efficacy, longer duration of remission, lower photocarcinogenic potential and less erythema
- PUVA is the most efficient phototherapy and hence most commonly used to treat moderate to severe psoriasis
- In general, phototherapy is contraindicated in patients with a history of melanoma or extensive non-melanoma skin cancer
- Which of the following statement regarding the treatment of psoriasis is TRUE?
- There is a risk of exacerbation of infection when topical corticosteroids is applied to infected psoriatic skin
- Combined use of calcipotriol and potent corticosteroids is not recommended to treat psoriasis
- Super potent corticosteroids are used to treat psoriasis on the face and groin areas
- Tazarotene is a topical calcineurin inhibitor used to treat psoriasis
- Which of the following statement regarding systemic treatment for psoriasis is INCORRECT?
- Cyclosporin exerts it immunosuppressive effect through inhibiting the production of IL-2
- Acitretin belongs to the derivatives of vitamin A
- Methotrexate is a folic acid antagonist that is available in both oral and subcutaneous form of administration
- Methotrexate should not be used long term due to its potential adverse effects
- Which of the following statement regarding biologics treatment for psoriasis is TRUE?
- Etanercept was the first TNF-α inhibitor approved by the FDA for psoriasis
- Ustekinumab is the only biologic that inhibits both IL-12 and IL-23 through inhibition of their shared p40 subunit
- Ixekizumab attenuates an inflammatory response mediated by IL-17A and disrupts the pathogenic inflammatory cascade of psoriasis
- Risankizumab is one of the newest IL-23 inhibitor to date approved by the FDA for the treatment of moderate to severe psoriasis
- (i) and (ii) only
- (ii) and (iii) only
- (i), (ii) and (iv) only
- All of the above
- Which of the following biologics is approved for use during pregnancy and breastfeeding?
- Etanercept
- Certolizumab
- Secukinumab
- Guselkumab
- Which of the following statement is INCORRECT?
- Secukinumab has established its efficacy and safety through ERASURE and FIXTURE trials
- Ustekinumab has established its efficacy and safety through PHOENIX-1 and PHOENIX-2 trials
- Brodalumab has established its efficacy and safety through AMAGINE-2 and AMAGINE-3 trials
- Tildrakizumab has established its efficacy and safety through VOYAGE-1 and VOYAGE-2 trials
(Answers will be released in the next issue of HKPJ)
Author’s background
ZHENG, Sin-Man Michelle was graduated from the University of Bath, United Kingdom. She is currently a pharmacist working in Queen Mary Hospital.
Address: Department of Pharmacy, Queen Mary Hospital, 102 Pokfulam Road, Pokfulam, Hong Kong SAR, China
Email: zsm797@ha.org.hk