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Plaque psoriasis
Psoriasis Treatment

Psoriasis Treatment

Read time: 90 mins
Last updated:7th Aug 2023
Published:7th Aug 2023

Treatment goals for psoriasis

How important is maintenance of response to patients with psoriasis?

 

Psoriasis is a chronic systemic inflammatory condition, with long-term systemic maintenance therapy  recognised as the preferred method of clinical management. Greater understanding of the inflammatory and immunological pathways involved in psoriasis has led to the development of many targeted psoriasis treatments1–8.

Many people with psoriasis express frustration and dissatisfaction with their treatment because of a failure to achieve their treatment goals and long-term control9

This is especially true for people with moderate-to-severe psoriasis who experience a high adverse impact on quality of life, have long absences from work, and require frequent inpatient care9.

In cases of high disease activity, continual treatment is the preferred option over switching of therapies9. Data from long-term clinical studies could therefore be a valuable guide for determining treatment goals.

Clinically meaningful goals for psoriasis

Several factors should be taken into account when establishing treatment goals for systemic therapy in people with moderate-to-severe psoriasis, including disease severity, the coexistence of psoriatic arthritis (PsA) or other comorbidities, physical impact, psychological and social well-being, and the risk–benefit ratio of continuous systemic treatment1–8.

A person-centred approach to care requires therapeutic decisions to align with patients’ needs and goals for treatment. In people with moderate-to-severe psoriasis, the desired treatment goals can be wide-ranging and go beyond merely achieving skin clearance10.

An analysis of the German Psoriasis Registry (PsoBest), which aimed to establish important treatment goals for patients receiving systemic treatment, found that in addition to symptom reduction, patients desired a normal everyday life and treatment that did not constitute an additional burden (n = 3,066)10.

Greater clearance also translates to greater patient satisfaction; however, effective treatment of psoriasis may lead to a lower level of disease that can be tolerated11. As a consequence, discontinuation of treatment following an initial success can also lead to a worsening of quality of life11.

How important is maintenance of response to people with psoriasis?

Learn about the importance of maintaining treatment response for improving the social, environmental, and occupational quality of life of patients.

Even small recurrences of psoriasis can have a disproportionately large impact on quality of life in patients with psoriasis12. This may also be true of drug dose reduction following initial treatment success13.

This highlights the importance of avoiding unnecessary switching and recognising patient expectations for long-term control and improved quality of life in order to develop and reach achievable clinical goals. Failure to do so could also be a contributing factor to the lower adherence to treatment in psoriasis compared to other chronic conditions11.

Notably, a cross-sectional observational study reported treatment goal misalignment in 67.9% of patient-physician pairs14

Misalignment was mainly seen as ‘patient predominant’ (60.9%), suggesting that patients had higher goals for their psoriasis than their physicians, especially patients with more severe illness (P<0.0001), who are younger (P=0.008) or have an occupation (P=0.043)14.

Impact on wellbeing in people with psoriasis

The negative impact of psoriasis on patient wellbeing may be considered comparable to that reported in studies of patients with diseases such as type 2 diabetes mellitus (T2DM) or breast cancer, when results from the 5-item WHO Well-being Index (WHO-5) are indirectly compared across studies15–18. The WHO-5 is a short, self-administered measure of wellbeing, in which lower scores indicate worse wellbeing19. While a mean WHO-5 score of approximately 64–65 has been reported for the general European population18, the mean baseline WHO-5 score in a cohort of patients with psoriasis was approximately 5417, compared to approximately 50–52 across patients with T2DM and high diabetes-related distress, or those with stage 0–III breast cancer (post-treatment)15,16.

A study that pooled data from three phase III trials investigating the impact of total psoriasis skin clearance on quality of life found that patients with total skin clearance (Psoriasis Area Severity Index [PASI] 100 and Physician’s Global Assessment [PGA] of 0) showed minimal or no impact on quality of life20. The study also revealed that even small areas of residual disease can have a negative impact on the quality of life of the patient.

The long-term clearance of psoriasis symptoms is a clinically meaningful treatment goal for people with moderate-to-severe psoriasis20

The impact of moderate-to-severe psoriasis also extends beyond the patient to family members, partners, and carers. In a qualitative study, the quality of life of partners and relatives of people with psoriasis was shown to be significantly impacted21. Common burdens faced (Figure 1) included psychological pressures, disruption of social, holiday, and sports activities, and disturbance in daily activities21.

Almirall_PA_MarUpdate_Fig1.png

Figure 1. The percentage of subjects reporting different aspects of quality of life affected (Adapted21).

Patients may, however, be unaware of the possibility of eliminating most of their burdensome symptoms or achieving 100% clearance in the short or long-term22. Long-term control of symptoms, individualised treatment and improved quality-of-life for patients and their carers are therefore important goals in psoriasis treatment plans. With the current broad spectrum of available psoriasis therapies and long-term data becoming available, sustained and consistent clearance of psoriasis is possible20.

Inflammatory pathways in psoriasis

Psoriasis is more than a dermatological disorder – it is a chronic, immune-mediated disease, in which genetically susceptible individuals develop cutaneous inflammation and keratinocyte hyperproliferation23,24

Psoriasis is associated with epidermal thickening and keratinocyte hyperproliferation. As a result, the skin becomes inflamed and develops raised plaques with silvery scales, which can cover large areas of the body23,24,25.

Clinical course of psoriasis

The clinical course of psoriasis can be divided into two stages: an initiation phase and a maintenance phase that perpetuates the inflammatory state26. This separation may be helpful when considering treatments that act in the trigger phase and those that block the self-perpetuating cycle of inflammation27

The histological features of psoriasis include epidermal (keratinocyte) hyperplasia, leukocyte infiltration and an increased number of leaky vessels in the dermis of the skin; lymphoid-like tissues have been identified in psoriatic plaques27

The pathophysiology of psoriasis is summarised in Figure 2.

Almirall_PA_Fig3

Figure 2. Psoriasis pathophysiology (Adapted25).

Initiation phase of psoriasis

An interplay between environmental and genetic factors facilitates disease-initiating events, and the initiation of the complex and dynamic psoriatic cascade within skin and immune cells23

Find out more about the basics of psoriasis pathophysiology in this brief, yet highly informative introductory video from Professor Stefano Piaserico (Dermatology Unit, Department of Medicine, University of Padova, Italy).

Introduction to Psoriasis Pathophysiology – Professor Stefano Piaserico

 

The histological features of cutaneous psoriasis are due to interactions between T cells, dendritic cells (DCs) and keratinocytes, giving rise to sustained inflammation in the skin (Figure 3)27,28. It is now well accepted that T cells, particularly T helper (Th) 17 lymphocytes, play an important role as effector cells in the pathogenesis of psoriasis26,29.

Almirall_PA_Fig4

Figure 3. Initiation of psoriasis (Adapted28). CCL20, chemokine ligand 20; CCR6, chemokine receptor 6; CLA, cutaneous lymphocyte antigen; CXCL, chemokine (C-X-C motif) ligand; IFN-γ, interferon-gamma; IL, interleukin; ILC, innate lymphoid cells; PRRs, pattern recognition receptors; RORγt, retinoid-related orphan receptor γt; TH, T helper cell; TNF-α, tumour necrosis factor-alpha.

Maintenance phase of psoriasis

Key processes during disease maintenance involve ‘cross talk’ between epithelial and immune cells, and the transition from innate to adaptive immunity23, as shown in Figure 4.

Almirall_PA_Fig5

Figure 4. Maintaining psoriasis – transition from adaptive to innate immunity (Adapted23). CCL, chemokine ligand; CXCL, chemokine (C-X-C motif) ligand; IFN-α, interferon-alpha; IFN-γ, interferon-gamma; IL, interleukin; TH, T helper cell; TNF-α, tumour necrosis factor-alpha.

Targeting inflammatory pathways in psoriasis has been a common strategy in therapeutic approachs for psoriasis. The cells and cytokines involved in the perpetuation/maintenance of psoriasis represent key therapeutic targets23,24,27,30–32:

  • Secretion of IL-23 and IL-12 by DCs within the lymph nodes induces naive T cells to differentiate into Th17 or Th1 cells, respectively
  • T cells migrate to skin and produce further cytokines (IFNγ, IL-17 and IL-22), which drive epidermal cell proliferation

These cytokines lead to over-activity of keratinocytes and this leads to the release of cytokines and chemokines that continue to recruit and activate inflammatory cells. The balance between regulatory and effector functions is lost, and regulatory T cells (Tregs) are unable to control ongoing inflammation.

Cytokines in psoriasis

Cytokines are a large group of secreted small polypeptides (8–80 kDa) that can regulate immune and inflammatory reactions. They are produced in response to non-infectious stimuli, microorganisms and antigens33. The main functions of cytokines are inducing inflammation, promoting the growth and differentiation of immune cells, activating the effector functions of lymphocytes and phagocytes, and stimulating directed movement of immune cells from blood into and within tissues34.

Levels of many inflammatory cytokines are elevated in psoriasis; for a subset of these cytokines, serum concentrations correlate with disease severity35

The combined effects of the cytokines found in psoriasis lesions may explain key clinical features of psoriasis35, including:

  • Keratinocyte hyperproliferation 
  • Increased neovascularisation 
  • Skin inflammation 

An understanding of which cytokines play a pivotal role in psoriasis has revealed potential therapeutic targets, and several cytokines have been successfully targeted as approved treatments in psoriasis35.

TNF-α in psoriasis

Tumour necrosis factor alpha (TNF-α) is an important Th1 pro-inflammatory cytokine that is upregulated in psoriasis33,36. It is often described as a ‘primary cytokine’, as it can independently initiate a number of mechanisms capable of triggering inflammation. Expression of TNF-α is increased expression skin lesions/serum/synovial fluid of psoriasis patients33.

Studies suggest TNF-α is involved in33,36:

  • Endothelial activation
  • Immunocyte recruitment
  • Immunocyte-keratinocyte recruitment
  • Amplification of inflammation
  • Keratinocyte hyperproliferation
What causes the reduction in inflammation during anti-TNF-α therapy? 

The decrease in tissue inflammation during anti-TNFα therapy is not due to immediate killing of TNF-α-producing cells, but results from a rapid downregulation of the pathogenic interleukin (IL)-12/IL-23-driven immune response37.

IL-17 cytokines in psoriasis

IL-17 sustains inflammation in psoriatic plaques by stimulating production of antimicrobial peptides, leading to the recruitment of inflammatory cells, enhanced proliferation of keratinocytes and inhibition of keratinocyte differentiation27,36,38. The IL-17 family of cytokines (Figure 5) consists of six members (IL-17A–IL-17F), which exist as a combination of homo- and heterodimers.

Almirall_PA_FigC

Figure 5. The IL-17 cytokine and receptor family (Adapted39). IL, interleukin.

IL-17A as a therapeutic target in psoriasis

Studies have shown the expression of IL-17A (as well as IL-17F) is elevated in the skin of patients with psoriasis40,41 , and strongly contributes to tissue inflammation41. IL-17 (as well as IL-17E and IL-17F) contributes to neutrophil accumulation and formation of epidermal microabcesses in psoriatic lesions41. Along with other Th17 cytokines, IL-17 upregulates production of various chemokines that have been implicated in psoriasis pathogenesis41. IL-17A is a target for the IL-17 inhibitors secukinumab and ixekizumab, as shown in Figure 640

Almirall_PA_Fig6

Figure 6. IL-17A as a target for brodalumab, secukinumab, and ixekizumab in psoriasis(Adapted40). IFN-γ, interferon-gamma; NK, natural killer; Tc, cytotoxic T cell; TGF-β, transforming growth factor-beta; Th, T helper cell; TNF-α, tumour necrosis factor-alpha.

IL-17 receptor as a therapeutic target in psoriasis

Brodalumab disrupts IL-17 signalling by targeting the IL-17 receptor itself, rather than binding the IL-17 cytokine. This means brodalumab blocks signalling not just of IL-17A, but also IL-17F, the IL-17A/F heterodimer, IL-17C and IL-17E (also called IL-25). To date, brodalumab is the only anti-IL-17 treatment that affects IL-17C, as it blocks the shared IL-17 receptor42.

IL-12/23 cytokines in psoriasis

IL-23 is a heterodimeric cytokine composed of a p40 subunit also found in IL-12, and a p19 subunit exclusive to IL-23 that is highly expressed in psoriatic skin lesions. It has emerged as a pro-inflammatory cytokine, influencing autoimmunity and the development of IL-17A-producing Th17 cells43,44.

In the ‘IL-23/Th17 axis’ model of psoriasis (Figure 7), Th17 cells interact with skin-resident cells and contributes to the psoriatic disease phenotype.

813_PsoriasisAcademyUpdate2023_Tab4_Fig7_LO.png

Figure 7. The ‘IL-23/Th17 axis’ model of psoriasis (Adapted44). IL, interleukin. IL-23 secreted by dermal dendritic cells (DCs) induces Th17 cell activation, with production of pro-inflammatory cytokines such as IL-17A and IL-22. These cytokines act on keratinocytes, inducing epidermal hyperplasia and keratinocyte activation. Activated keratinocytes produce proinflammatory mediators, and keratinocytes mediate crosstalk with Th17 cells, in cooperation with IL-23, to sustain and amplify skin inflammation44.

The IL-12/23 inhibitor ustekinumab and IL-23 inhibitors guselkumab and tildrakizumab have demonstrated efficacy in psoriasis45–49. Agents that specifically inhibit IL-23p19 have demonstrated high efficacy in the treatment of moderate-to-severe plaque psoriasis, with a tolerable safety profile44.

IL-1 cytokine in psoriasis

IL-1 is a proinflammatory cytokine principally expressed by keratinocytes and involved in homeostasis of the skin. IL-1 signalling is regulated by various activating, promoting and inhibitory agents, which all function together to prevent excessive inflammatory responses50.

Dysregulation of IL-1 has been associated with the development of a variety of chronic, autoinflammatory skin diseases, including psoriasis. Data suggest that IL-1β-IL-1R signalling may contribute to autoinflammatory skin diseases via regulation of IL-17-producing cells within the skin and stimulation of keratinocytes, resulting in amplification of the inflammatory cascade51

In psoriasis, IL-1 receptor (IL-1R) signalling appears to correlate with disease progression and treatment response51

IL-36 cytokines in psoriasis

Within the IL-1 superfamily, the IL-36 cytokine subfamily has emerged as a key driver of skin inflammation52. The IL-36 cytokine subfamily consists of three pro-inflammatory agonists (IL-36α, IL-36β, IL-36γ) that bind to and activate the IL-36 receptor, and one antagonist (IL-36Ra)53.

IL-36 plays a central role in signalling between epithelial, dendritic and neutrophil cells53. In psoriasis, IL-36 is secreted by keratinocytes and activates neutrophils and dendritic cells in the dermis53. Signalling through the IL-36 receptor results in expression of antimicrobial peptides, alongside pro-inflammatory cytokines and chemokines by keratinocytes and immune cells52.

IL-36 cytokines are consistently upregulated in lesions of psoriasis vulgaris, the IL-36Ra is also upregulated to a lesser extent in psoriatic skin52. Results of a small study (n = 15) indicated up to 93% of patients with psoriasis had an elevated IL-36 agonist/antagonist ratio, suggesting that the balance of IL-36 receptor activation and inhibition may be tipped towards IL-36 pathway hyperactivation in psoriasis52,54.

IL-22 cytokine in psoriasis

IL-22 is produced by Th17 and Th22 cells, and has been implicated in several inflammatory diseases, including systemic lupus erythematosus, rheumatoid arthritis and psoriasis55,56

Expression of the IL-22 receptor is increased in psoriatic lesional skin and IL-22 signalling in psoriasis has been linked to enhanced keratinocyte migration, increased epidermal thickness, reduced keratinocyte differentiation and higher expression levels of various molecules such as chemokines and chemoattractants, although not as strongly as IL-1756. IL-22 may collaborate with other soluble factors and cells together forming inflammatory circuits that become pathologically amplified in psoriasis. Targeting IL-22 may be a promising potential therapeutic for plaque psoriasis57.

Chemokines in psoriasis

CXC chemokine ligand 1 (CXCL1) and CXCL8 are neutrophil chemoattractants that are produced by keratinocytes in response to IL-17 and IL-22 signalling. The cytokine-mediated upregulation of chemokines, including CXCL1 and CXCL8, has been shown to promote the recruitment of neutrophils to psoriatic lesions58

The presence of neutrophils may be an important driver in the induction phase of psoriasis through 59:

  • their secretion of proinflammatory cytokines, including IL-17
  • the formation of neutrophil extracellular traps, which contain high-levels of self-DNA/nucleic acids

Systemic treatments for psoriasis

Professor Peter van de Kerkhof (Radboud University Nijmegen Medical Centre, Netherlands) discusses treatment options for localised psoriasis and highlights the importance of contraindications and risk factors when considering systemic treatments for psoriasis.

What should you consider in managing patients with moderately severe disease?
 
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For people with milder disease, first-line psoriasis treatment often involves topical therapies including corticosteroids, vitamin D3 analogues and combination products6. However, people with moderate-to-severe and refractory symptoms may be candidates for systemic therapy4,5,60.

In a survey conducted in the United States, Canada, France, Germany, Italy, Spain and the United Kingdom, dermatologists reported that among people with moderate-to-severe psoriasis, approximately 75% of patients were receiving topical therapy, 20% of patients were receiving conventional oral therapy and 20% of patients were receiving biologics61 

Non-biologic systemic treatments for psoriasis

Options for systemic therapy in psoriasis include immunosuppressive and immunomodulatory drugs such as methotrexate, ciclosporin, acitretin, fumaric acid esters, apremilast and biologic agents4,5,62.

Systemic treatments for psoriasis are usually reserved for people with:

  • moderate-to-severe forms of the disease (as defined in different countries)4
  • milder forms with manifestations that can significant impair quality of life, and cannot be adequately controlled by topical treatment63

Current treatment guidelines recommend a conventional oral drug as first-line systemic treatment for moderate-to-severe psoriasis, whereas a biologic is applied as second-line treatment in case of treatment failure, intolerance or contraindication to an oral therapy4,5,62.

While the trend is for biologics to be prescribed earlier, other systemic options, such as dimethyl fumarate and apremilast offer an alternative in the moderate-to-severe psoriasis population in the goal of achieving long-term control4,5,64,65.

There are many current systemic treatments available that differ in terms of efficacy and safety, and the two must be balanced when making therapeutic decisions. Treatment with systemic treatments can provide long-term benefit for some patients with psoriasis. Patient quality of life should also be considered in the decision to move to systemic treatment. 

Key facts on non-biologic systemic treatments for psoriasis

The mechanisms of action of non-biologic systemic treatments for psoriasis, and their European therapeutic indications, are summarised in Table 1.

Table 1. Summary of key facts on non-biologic systemic treatments for psoriasis66–73. DMARD, disease-modifying antirheumatic drug; FAE, fumaric acid ester; PDE4, phosphodiesterase 4; PUVA, psoralen and ultraviolet A radiation. *Indications also include psoriatic arthritis in adults, or †juvenile idiopathic arthritis.

Systemic agent for psoriasis Mechanism of action Therapeutic indication (Europe)
Ciclosporin A cyclic polypeptide and potent immunosuppressive agent

Induces immunosuppression by inhibiting the first phase of T cell activation

Binds to cyclophilin and inhibits phosphatase activity, leading to reduced cytokine production
Patients with severe psoriasis in whom conventional therapy is inappropriate or ineffective
Methotrexate*† DMARD

Competitively inhibits dihydrofolate reductase, leading to antiproliferative and immunomodulatory effects
Severe, treatment-refractory/recalcitrant, disabling psoriasis which has not adequately responded to other forms of treatment such as phototherapy, PUVA therapy and retinoids
Dimethyl fumarate Fumaric acid ester with anti-inflammatory and immunomodulatory activity

Inhibits production of pro-inflammatory cytokines, induces apoptosis
Moderate-to-severe plaque psoriasis in adults in need of systemic medicinal therapy
Acitretin Systemic retinoid

Exact mechanism of action unknown, thought to modulate proliferation, differentiation, and have immunomodulatory and anti-inflammatory activity
Severe extensive psoriasis which is resistant to other forms of therapy

Palmo-plantar pustular psoriasis
Apremilast* Small-molecule inhibitor of PDE4

Down-regulation of inflammatory response by modulation of inflammatory cytokines (e.g. TNF-α, IL-23, IL-17, IL-10)
Moderate-to-severe chronic plaque psoriasis in adult patients who failed to respond to or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, methotrexate or PUVA

Efficacy and tolerability of non-biologic systemic agents for psoriasis

Ciclosporin

Efficacy

Clinical improvements are typically observed after four weeks with a maximal response at 8–16 weeks64. A review of 15 clinical studies of ciclosporin in psoriasis found that after 12–16 weeks of treatment, approximately 50% of patients achieved a PASI 75 response64.

Tolerability

Ciclosporin is considered suitable only as a short-term induction therapy4. Considering possible adverse drug reactions with long-term use, and the range of other treatment options, long-term ciclosporin treatment  for more than 2 years is usually avoided4.

Methotrexate

Efficacy

Methotrexate is the most frequently prescribed traditional systemic treatment worldwide, and may be used for induction and long-term treatment of psoriasis74.

Although the limited number of studies investigating the efficacy of methotrexate were performed during the 1960s and 1970s, and may not have complied with today’s methodological standards, significant clinical experience exists relating to the use of methotrexate in psoriasis. A clinically significant response is expected in 4–12 weeks of treatment4,5,64.

Tolerability

The most important serious adverse events associated with methotrexate are myelosuppression and hepatotoxicity, both of which require dose reduction or discontinuation of treatment4,5,64

Patients receiving methotrexate also appear to be at a greater risk of infection, compared with the biologic systemic treatments apremilast (hazard ratio [HR] 0.50; 95% CI, 0.26–0.94), etanercept (HR 0.75; 95% CI, 0.61–0.93) and ustekinumab (HR 0.65; 95% CI, 0.47–0.89)76.

Key side effects reported with methotrexate are shown in Figure 8.

Almirall_PA_Fig7

Figure 8. Overview of important side effects reported with methotrexate4,5,64.

Dimethyl fumarate

Efficacy

Fumaric acid esters (FAEs) are the most frequently used systemic treatment in Germany with more than 220,000 patient‐years experience77. A clinically meaningful improvement can be observed after 6–8 weeks of therapy in people with psoriasis; this improvement continues during prolonged treatment4,5,64.

Tolerability

FAEs have a well‐characterised side effect profile; most adverse effects are mild and do not lead to discontinuation of treatment65,78. The most common adverse effects are gastrointestinal symptoms, flushing and white blood cell count abnormalities78.

Patients may be advised to take tablets with milk and/or after a meal to help reduce gastrointestinal effects. Dose adjustment can reduce symptoms, and dosing can be adapted to the individual patient’s clinical needs. However, effective communication regarding potential side effects is necessary prior to starting treatment as it helps manage patient expectations and prevents unnecessary anxiety, should these side effects occur.

Dimethyl fumarate is sometimes seen as advantageous when compared with alternative therapies, as it modulates the immune system rather than suppressing it, there is no evidence of cumulative toxicity and it is suitable for co-medicating. However, patients should be closely monitored, especially for leucocyte and lymphocyte counts, and given realistic expectations of the typical side effects. Side effects have been reported to often occur exclusively during initiation and up-titration, and lessen as patients become established on the treatment78,79

Gastrointestinal and flush side effects 

Gastrointestinal complaints and flush symptoms are the most frequent adverse effects during treatment with fumarates4,5,64,78. Gastrointestinal side effects include diarrhoea, abdominal distension, abdominal pain, nausea, vomiting, dyspepsia, constipation and flatulence, and occur in up to 60% of patients on FAE treatment78,79.  The general consensus is that such effects often cause issues in weeks 3–6, but stabilise or improve by weeks 8–94,5,64,78.

Gastrointestinal tolerance may be improved by taking the tablets after eating and/or swallowing them with dairy products4,5,64,78. On the other hand, the administration of acetylsalicylic acid (aspirin) can help to decrease flush symptoms4,5,64,78. Key side effects reported with dimethyl fumarate are shown in Figure 9.

Almirall_PA_Fig8

Figure 9. Overview of important side effects reported with dimethyl fumarate4,5,64,78.

Acitretin

Efficacy

A clinically significant response is expected to be observed in 4–6 weeks; however, the efficacy of acitretin in clinical studies varies greatly64.

Tolerability

Acitretin is a derivative of vitamin A. Hence, vitamin A toxicity (presenting as cheilitis and xerosis, conjunctival inflammation, hair loss, photosensitivity and hyperlipidaemia) is a frequently reported, but reversible, side effect that responds to dose reduction4,5,62,64. Skeletal toxicity, specifically hyperostosis, is thought to be the main cumulative adverse effect of acitretin therapy, with some early retrospective studies reporting an increased risk of skeletal hyperostosis following long-term treatment80.

Monitoring for hypertriglyceridemia and hepatotoxicity is required and, in order to prevent elevation of serum lipids and liver enzymes, alcohol abstinence and a low-fat and low-carbohydrate diet are advised4,5,62,64. All side effects are reversible except for hyperostosis4,5,62,64.

Key side effects reported with retinoids are shown in Figure 10.

Almirall_PA_Fig9

Figure 10. Overview of important side effects reported with retinoids4,5,62,64.

The safety profile and potential adverse effects of acitretin should be considered when prescribing this agent for psoriasis, ensuring patients understand them and the importance of avoiding alcohol81. The FDA has issued several boxed warnings about the risk of hepatitis when combining with alcohol or methotrexate81. Acitretin is absolutely contraindicated in pregnancy and breastfeeding because of teratogenicity67,81.  

Apremilast

Efficacy

The most significant improvement was observed within the first 24 weeks of treatment, and discontinuation should be considered if no evidence of therapeutic benefit is observed after 24 weeks82

Two phase III trials (ESTEEM-1 and ESTEEM-2) evaluated the safety and efficacy of apremilast. At Week 16, around 30% achieved PASI 75, and 56% of patients achieved PASI 50 in the apremilast group versus placebo83,84.

 Post-hoc analyses of the ESTEEM clinical trials have demonstrated that at Week 16:

  • Significantly more apremilast patients achieved a Palmoplantar Psoriasis Physician Global Assessment (PPPGA) score 0 (clear), or 1 (almost clear), vs. placebo (P=0.021)85 
  • A significantly greater reduction in Nail Psoriasis Severity Index (NPSI) score was observed with apremilast vs. placebo (P<0.0001)86
  • Apremilast improves all health-related quality of life (HRQoL) patient-reported outcomes (PROs) in moderate-to-severe psoriasis vs. placebo87

Despite the encouraging results from the ESTEEM trials, a comparison of the relative efficacy of apremilast and methotrexate in moderate-to-severe psoriasis revealed no statistically significant difference in PASI 75 between apremilast and methotrexate, with apremilast treatment associated with substantially increased costs88

A later study indicated that patients treated only with apremilast are less likely to get infections compared to those treated with methotrexate76

Tolerability

Apremilast is associated with a short-term risk of diarrhoea, especially when treatment is started, occurring in roughly 15%–20% of patients. Tolerability of apremilast is improved by slowly ramping up the dose when treatment is initiated89.

Long-term clinical trials of apremilast with up to 3 years’ follow-up have shown that the most common adverse events (AEs) include gastrointestinal (GI) AEs (nausea, diarrhoea); infections (upper respiratory tract infection, nasopharyngitis); and headache89.

Apremilast demonstrates an acceptable long-term safety profile, and has been shown to be generally well tolerated for ≥156 weeks. The oral route of administration, lack of laboratory monitoring requirements during treatment, and lack of cumulative, specific organ toxicity, may be attractive treatment benefits for patients with psoriasis requiring long-term systemic therapy89.

Biologic and small molecule inhibitor treatments for psoriasis

Biologic agents have become well-established as second-line treatments for psoriasis, and a number of biologics are also recommended for first-line treatment in specific circumstances7. The efficacy and relative safety of these agents has greatly improved the treatment of psoriasis and allowed for long-term maintenance therapy, with the ultimate goal of achieving clearance of skin symptoms in moderate-to-severe psoriasis patients3,7,24,76.

While the long-term use of many conventional systemic treatments is limited mostly by poor tolerability and cumulative toxicity, the long-term use of biologics may be preferred as a result of their safety profiles7,90.

Summary of biologic and small molecule inhibitor treatments for psoriasis

The mechanisms of action of biologic treatments for psoriasis, and their European therapeutic indications in adults and children, are summarised in Table 2.

Table 2. Summary of psoriasis and related indications for biologic treatments in Europe92–106. EMA, European Medicines Agency; PUVA, psoralen and ultraviolet A radiation; TNF-α, tumour necrosis factor alpha. *Indications also include juvenile psoriatic arthritis or juvenile idiopathic arthritis or psoriatic arthritis in adults. Information is intended as a summary, and is current as of 3 July 2023; however, regulatory-approved indications for each treatment should be verified in your region to confirm the most recent information.

Biologic treatment for psoriasis Therapeutic indication (EMA, Europe)
  Adults Children
TNF-α inhibitors
Adalimumab†‡
(biosimilars available)
Moderate-to-severe chronic plaque psoriasis in adult patients who are candidates for systemic therapy Severe chronic plaque psoriasis in children and adolescents from 4 years of age who have had an inadequate response to or are inappropriate candidates for topical therapy and phototherapies
Certolizumab pegol Moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy
Etanercept†‡

(biosimilars available)
Moderate-to-severe plaque psoriasis who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapy, including ciclosporin, methotrexate or PUVA Chronic severe plaque psoriasis in children and adolescents from the age of 6 years who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies
Infliximab

(biosimilars available)
Moderate-to-severe plaque psoriasis in adult patients who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapy including ciclosporin, methotrexate or PUVA
IL-12/23 inhibitors
Ustekinumab Moderate-to-severe plaque psoriasis in adults who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapies including ciclosporin, methotrexate and PUVA Moderate-to-severe plaque psoriasis in children and adolescent patients from the age of 6 years and older, who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies
IL-23 inhibitors
Guselkumab
Risankizumab
Tildrakizumab
Moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy
IL-17 inhibitors
Bimekizumab Moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy
Brodalumab Moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy
Secukinumab*† Moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy Moderate-to-severe plaque psoriasis in children and adolescents from the age of 6 years who are candidates for systemic therapy
Ixekizumab Moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy Moderate-to-severe plaque psoriasis in children from the age of 6 years and with a body weight ≥25 kg and adolescents who are candidates for systemic therapy
IL-36 inhibitor
Spesolimab Treatment of flares in adult patients with generalised pustular psoriasis as monotherapy
Tyrosine kinase 2 inhibitor
Deucravacitinib Moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy

Efficacy and tolerability of biologic treatments for psoriasis

TNF-α inhibitors

TNF-α represents a key therapeutic target within the psoriasis inflammatory cascade. This cytokine has multiple effects on the development and maintenance of psoriasis, including increased keratinocyte proliferation and increased recruitment of T cells to the skin7,106

Four agents selectively block the role of TNF-α and have demonstrated efficacy in psoriasis clinical trials:

Adalimumab           

Efficacy

Adalimumab is one of the most commonly used biologics for psoriasis. In clinical trials, adalimumab demonstrated superior efficacy in the reduction of psoriasis signs and symptoms, as measured by a reduction in the PASI from baseline, when compared with placebo. Adalimumab showed improvements in HRQOL on the basis of the DLQI, the short form 36 health survey, and patient’s global assessment (PtGA) of psoriasis107

A post-hoc analysis of REVEAL and CHAMPION demonstrated that adalimumab was effective regardless of prior exposure to systemic therapies; PASI 75 response rates in the overall population were similar to those who did not respond to methotrexate, cyclosporin or PUVA108.

Safety

In the 7 and 10-year results of the ESPRIT registry, no new or unexpected safety signals were observed with adalimumab treatment, and the safety was consistent with the known safety profile of adalimumab109,110. In the 10-year results120:

  • Incidence rates of serious infections, cardiovascular events, and malignancy remained stable, with more than 9 years of overall adalimumab exposure
  • The number of treatment-emergent deaths was below the expected rate compared with the general population
  • As-observed adalimumab effectiveness and DLQI 0 or 1 achievement were maintained through 120 months

 

Adalimumab biosimilars

Adalimumab has been the highest grossing drug in the world for several years, and is a prime candidate for biosimilar development. Several biosimilars are under development, and numerous adalimumab biosimilars have already been approved in Europe111.

Certolizumab pegol

Efficacy

Phase III development of certolizumab pegol involved three studies that enrolled approximately 1,000 patients, including patients with and without prior treatment experience with biologic products112,113.

Certolizumab is efficacious in both psoriasis and psoriatic arthritis, including in patients who are biologic failures114. Results from the CIMPASI-1 and CIMPASI-2 studies have demonstrated the high efficacy of certolizumab in the treatment of psoriasis at both Week 16 and 48115. Of 180 patients treated with CZP 400 mg Q2W that achieved PASI 75 at Week 16, 98.0% had maintained that response at Week 48116.

Safety

No new or unexpected safety signals emerged in a published long-term cross-indication pooled safety analysis of certolizumab pegol across 49 clinical trials117.

In a 2021 pooled analysis over 3 years of CIMPASI-1, CIMPASI-2, and CIMPACT, incidence rates of treatment-emergent adverse events (TEAE) was 144.9 for all study patients, 134.1 for certolizumab 200 mg, and 158.3 for certolizumab 400 mg. For serious TEAEs, incidence rates were 6.7 and 8.7 for certolizumab 200 mg and 400 mg, respectively118.

Two studies focusing on pregnant and postpartum women have shown evidence of no to minimal placental transfer of certolizumab pegol from mothers to infants and minimal transfer into breast milk. These two studies provide safety evidence for treatment with certolizumab pegol during breastfeeding and during pregnancy if clinically necessary119,120.

Etanercept

Efficacy

Etanercept is one of the most commonly used biologics for psoriasis107

In clinical trials, etanercept, has demonstrated efficacy in managing psoriasis as measured by improvements in PASI scores, Physician’s Global Assessment (PGA) and quality of life121.  

A non-interventional, open-label, multicentre, observational study to evaluate the long-term, real-world outcomes of etanercept treatment demonstrated that the mean duration of drug-free intervals was relatively short (12.9 weeks [±12.8]), and most patients experienced improvements in disease activity and HRQoL within 12 weeks of either continuous or intermittent etanercept treatment122.

Safety

Etanercept was well-tolerated in two Phase III studies123,124. In addition, the 5-year observational registry OBSERVE-5, which enrolled 2,510 patients with plaque psoriasis who received etanercept, found that Kaplan-Meier cumulative incidences of serious adverse events, serious infectious events, and serious infectious events requiring hospitalisation were low. Incremental yearly incidences decreased during the 5 years of the registry125

Infliximab

Efficacy

Infliximab has been used to treat psoriasis for many years7. It is highly efficacious in the treatment of moderate-to-severe psoriasis, with better skin clearance and faster onset of action than topical medications such as methotrexate, narrow-band ultraviolet B, and calcipotriol7. Infliximab also significantly improves patients’ HRQoL. However, loss of response is a problem in some patients receiving long-term infliximab therapy and has been a major reason for the discontinuation of the drug in clinical trials7,126.

Time to onset of action for infliximab is shorter (approximately 3.5 weeks) than for other biologics such as adalimumab, ustekinumab and etanercept7,126. Infliximab as continuous infusion has demonstrated improved efficacy when compared to as-needed infusion7,127

Data shows that infliximab maintenance at a dose of 5 mg/kg every eight weeks produces an effective, safe and sustainable response for up to two years7,128

Safety

Although infliximab is generally well tolerated, there are some adverse effects associated with its use, that represent a key reason for discontinuation of therapy among some patients7,126. One Canadian multicentre retrospective study showed that 15% of patients withdrew from infliximab therapy owing to adverse effects129

IL-12/23 inhibitor

IL-23 has been shown to play an important role in the pathophysiology of psoriasis24. The first interleukin inhibitor to be approved was ustekinumab, an IL-12/23 inhibitor whose clinical efficacy is associated with indirect inhibition of Th17 cell expansion and function due to antagonism of its regulator cytokine, IL-2330.

Ustekinumab

Efficacy

Comparable efficacy of ustekinumab (standard dose) has been demonstrated in both adults and psoriasis patients aged 12–17 with no unexpected adverse events130. A substantial proportion of patients respond to ustekinumab and continuous treatment effectively maintains long‐term control46.

Efficacy and safety of ustekinumab and other psoriasis treatments in a real-world setting was assessed using the PSOLAR registry data131,132. Analyses concluded that ustekinumab in patients with psoriasis:

  • Is more effective than infliximab, etanercept and adalimumab, with no increased risk of malignancy, major adverse cardiovascular events (MACE), serious infection, or mortality131,132
  • Presents a lower risk of infections compared to methotrexate treatment (HR 0.65; 95% CI, 0.47–0.89)76
  • Offers superior drug survival compared with infliximab, adalimumab and etanercept133,134
  • In addition to its clinical efficacy, ustekinumab has demonstrated improvements in QoL135

The PSOLAR efficacy findings were confirmed by data from the prospective BioCAPTURE registry comparing one- and five-year efficacy of adalimumab, etanercept and ustekinumab in psoriasis patients in daily clinical practice. BioCAPTURE suggested that after one year, PASI 75 is more often achieved with adalimumab and ustekinumab than etanercept and that after five years, ustekinumab has the highest efficacy (P=0.019)136.

In the double-blind Phase IIIb trial CLARITY, at Week 52, secukinumab was superior to ustekinumab in the proportion of patients who achieved ≥90% improvement in PASI (73.2% vs. 59.8%; odds ratio [OR] 1.84; 95% CI, 1.41–2.41; P<0.0001), Investigator’s Global Assessment modified 2011 responses of clear (0) or almost clear (1) skin (76.0% vs. 60.2%; OR 2.12; 95% CI, 1.61–2.79; P<0.0001) and DLQI response of no effect (0/1) (69.9% vs. 61.2%; P=0.0028)137.

At Week 16 in the randomised, Phase III BE VIVID trial, 273 (85%) of 321 patients in the bimekizumab group had PASI90 compared to 81 (50%) of 163 in the ustekinumab group (risk difference 35 [95% CI, 27–43]; P<0.0001) and four (5%) of 83 in the placebo group (risk difference 80 [95% CI, 74–86]; P<0.0001). At week 16, 270 (84%) patients in the bimekizumab group had an IGA response versus 87 (53%) in the ustekinumab group (risk difference 30 [95% CI, 22–39]; P<0.0001) and four (5%) in the placebo group (risk difference 79 [95% CI, 73–85]; P<0.0001)138.

Safety

The 5‐year follow‐up clinical experience from across the PHOENIX trials confirms that ustekinumab maintains efficacy against psoriasis over time and is well-tolerated for long‐term treatment46

In CLARITY, proportions of patients with any adverse events were comparable between secukinumab and ustekinumab137.

In BE VIVID, over 52 weeks, serious treatment-emergent adverse events were reported in 24 (6%) of 395 patients in the bimekizumab group, and 13 (8%) of 163 in the ustekinumab group138.

IL-23 inhibitors

The IL-23/IL-17 axis has been identified as the primary signalling pathway that leads to the characteristic changes observed in psoriatic skin139,140

While ustekinumab targets IL-12/IL-23 through the common p19 subunit, three approved therapies selectively block IL-23 only141–145.

Guselkumab

Efficacy

Selective IL-23 inhibitors such as guselkumab have demonstrated a very effective, durable, and safe profile. Several clinical trials have demonstrated potential benefits of guselkumab over other already approved immunomodulators in terms of safety and efficacy146

Safety

Guselkumab was generally well-tolerated in pivotal trials. Guselkumab also offers a less frequent dosing regimen in comparison to secukinumab, an IL-17 inhibitor (guselkumab: initially at Weeks 0 and 4, but then every 8 weeks versus secukinumab: administered weekly for 4 weeks followed by every 4 weeks as a maintenance dosing)146

Guselkumab’s efficacy and safety profiles were reinforced by studies such as ECLIPSE, demonstrating great potential for long-term treatment of psoriasis146

Tildrakizumab

Efficacy

Tildrakizumab, an inhibitor of IL-23p19, significantly improves both cutaneous manifestations and quality of life in people with moderate-to-severe psoriasis versus placebo. Tildrakizumab offers the additional advantages of every 12-week maintenance dosing and long period of action147.

The results of a 3-year follow-up of a pooled analysis of individuals enrolled in key trials reSURFACE1 and reSURFACE2 who had achieved PASI 75 at Week 20, have been published148. PASI 75 or greater was maintained in 91% of individuals who continued the 100-mg dosing and in 92% of those continuing the 200-mg dosing148.

ReSURFACE 2 showed that tildrakizumab 200 mg was associated with significantly higher proportions of patients achieving PASI 75 and PGA responses at week 12 than etanercept49.

The first report of 5-year data for tildrakizumab showed sustained disease control in a large proportion of tildrakizumab responders, and etanercept partial and non-responders switched to tildrakizumab at week 28149.

In a real-world prospective cohort study, a high rate of previous systemic (87.3%) and biologic (31.8%) therapy and comorbidity was found in people with moderate-to-severe plaque psoriasis treated with tildrakizumab (n = 150; included in the Kiel Tildra Cohort [KTC]), compared to the Phase III clinical trials analysed in the study. Baseline PASI was lower in the KTC, but DLQI was similar in both patients treated with tildrakizumab and the Phase III trials. There was improvement in PASI, BSA, DLQI, and itch, from baseline until week 76, in patients treated with tildrakizumab150.

In conditions close to clinical practice, the efficacy of tildrakizumab and impact on health-related quality of life (HRQoL) was assessed in the open-label Phase 4 TRIBUTE study, which included 177 patients with moderate-to-severe psoriasis151. In this multicentre study, HRQoL was assessed using PASI and DLQI as co-primary endpoints, while secondary endpoints included assessments across variety of patient-reported outcomes including pruritus, skin pain, scaling, sleep and work and activity151. After 24 weeks of treatment, results of this study indicated improvements to physical signs of psoriasis and clinically-relevant benefits to HRQoL151. Patients reported significant improvements in sleep outcomes and work productivity, and high treatment satisfaction151. The safety profile of tildrakizumab was consistent with that reported in Phase III trials151.

Safety

Tildrakizumab is well-tolerated. Most adverse events are mild, and do not require treatment cessation. No dose-related increase in adverse events has been observed147,148,152

In the reSURFACE trials, inflammatory bowel disease, which has been reported to worsen with therapeutic inhibition of IL-17, was not observed in tildrakizumab-treated patients over 28 weeks. Additionally, the 3-year safety profile of tildrakizumab is comparable with placebo, particularly with regards to the rates of serious infection and major cardiovascular events147.

From the 5-year data for tildrakizumab, low rates of AEs of special interest were reported over a 244-week period, and comparable between patients treated with tildrakizumab 100 and 200 mg149. No new or unexpected AEs were reported with tildrakizumab, and rates of discontinuations due to AEs were very low149.

Risankizumab

Efficacy

Risankizumab demonstrates significant efficacy in the treatment of psoriasis, exceeding the effectiveness of ustekinumab, which may be a result of its stronger molecular activity153

Risankizumab shows higher PASI 75, PASI 90, and PASI 100 rates compared to ustekinumab, along with a convenient every 12-week maintenance dosing regimen154

An integrated analysis of 797 patients included in the two Phase III trials evaluated the efficacy of risankizumab as the proportion of patients achieving PASI 90 by baseline patient demographics, disease characteristics and prior biologic exposure compared to ustekinumab. The data revealed consistent and superior efficacy compared with ustekinumab regardless of patient demographics, disease characteristics or prior biologic exposure155

In LIMMitless, an ongoing, Phase III open-label extension study evaluating the long-term efficacy and safety of risankizumab in adults with moderate-to-severe plaque psoriasis, following 172 weeks of continuous risankizumab treatment, 85.5% of patients achieved PASI 90, 54.4% achieved PASI 100, 85.2% achieved static PGA 0/1, and 78.4% achieved DLQI 0/1 using modified nonresponder imputation156.

Safety

Overall, risankizumab is well-tolerated155. The most common adverse event was upper respiratory tract infection155. An additional integrated analysis has also confirmed that risankizumab offered a comparable safety profile to placebo in people with moderate-to-severe psoriasis157

In LIMMitless, rates of adverse rates leading to discontinuation, and adverse events of safety interest were low with long-term treatment, and comparable with those identified in the base studies156.

IL-17 inhibitors

Due to the central role of IL-17A in the psoriatic inflammatory process, development of antibodies to IL-17A has led to targeted treatments for psoriasis158. Three monoclonal antibodies targeting IL-17A are approved for use in psoriasis (brodalumab, secukinumab, ixekizumab), and an additional one that targets both IL-17A and IL-17F (bimekizumab).

Bimekizumab

The efficacy and safety of bimekizumab has been assessed across four key Phase III randomised trials in patients with moderate-to-severe plaque psoriasis, with comparators including placebo, ustekinumab, secukinumab or adalimumab159–163.

Efficacy

Primary efficacy results from these key Phase III trials indicated significantly more participants treated with bimekizumab achieved PASI90 and IGA success, compared with those who received placebo (BE READY), ustekinumab (BE VIVID) or adalimumab (BE SURE), and PASI100 versus secukinumab (BE RADIANT) after 16 weeks 159–163.

Safety

Bimekizumab is considered a relatively tolerable treatment option for moderate-to-severe psoriasis159. While adverse events were reported more frequently in participants who received bimekizumab than those who received placebo up to week 16 (61% versus 41%)162, head-to-head trials reported similar rates of adverse events for bimekizumab and secukinumab up to 48 weeks (86.1% versus 81.4%)160, adalimumab up to 24 weeks (70.9-72% versus 69.8%)161, and ustekinumab up to 16 weeks (56% vs 51%)163.

Brodalumab

Efficacy

Brodalumab was the third to market in this class of agents targeting IL-17164. Brodalumab rapidly improves psoriatic lesions in people with moderate-to-severe psoriasis. These benefits are also evident in patients who have responded poorly to other biologics165.

Brodalumab exhibits a broader mechanism of action than other IL-17 inhibitors, in that it blocks the IL-17 receptor. This could confer an advantage over treatments blocking IL-17A, as it blocks additional members of the IL-17 cytokine family, including IL-17C and IL-17F. However, it has also been suggested that withdrawal of therapy could lead to a rebound effect via rapid stimulation of effector Th17 cells164

Brodalumab is a highly efficacious therapy for psoriasis and has clinical trial evidence documenting robust efficacy for >2 years164,166.

Safety

Brodalumab’s development programme was initially halted in May 2015 due to the emergence of a suicide signal. Brodalumab is likely to be avoided in those with known inflammatory bowel disease, and where there is a history of depression or suicidal ideation164. Despite these initial concerns, brodalumab is well-tolerated; safety through 120 weeks was comparable to that of the blinded study periods166

Secukinumab

Efficacy

In the SCULPTURE extension study, secukinumab delivered high and sustained levels of skin clearance and improved quality of life through to 5 years in people with moderate‐to‐severe psoriasis167.

Results from a secukinumab Phase II study suggest that in moderate-to-severe psoriasis, patients receiving early treatment with secukinumab demonstrate QoL improvements, with significantly higher Dermatology Life Quality Index responses vs. placebo (40.8% vs. 1.6%; P<0.001)135.

A further pooled analysis of results from four Phase III clinical trials (ERASURE, FIXTURE, FEATURE and JUNCTURE) reported positive results, showing improvements in patient QoL with secukinumab168.

Safety

Favourable safety established in the secukinumab Phase II/III programme was maintained through to 5 years167.

A pooled analysis of safety data from a large cohort (3,430 patients) across ten Phase III studies demonstrated that secukinumab is well-tolerated, with a safety profile consistent with previous reports171

Ixekizumab

Efficacy

In clinical trials, ixekizumab has demonstrated a significant improvement in psoriasis following 12 and 60 weeks of treatment, as well as a rapid and visible improvement in plaque psoriasis in as early as one week of treatment172.

In terms of quality of life, the UNCOVER trials showed significantly greater improvement in DLQI scores with ixekizumab compared to both placebo and etanercept-treated groups following 12 weeks of treatment. Improvement in DLQI scores correlated positively with PASI improvement173.

Safety

Ixekizumab is well-tolerated by patients, with the most common adverse events being injection site reaction, and infections such as nasopharyngitis and upper respiratory tract infections173.

Safety data from ixekizumab-treated patients in seven Phase III clinical trials (n = 4,209) showed that the overall incidence of treatment-emergent adverse events of special interest (serious infections, malignancies and major adverse cardiovascular events) were comparable for ixekizumab and etanercept174.

As shown in an integrated analysis of eleven clinical trials, the safety profile of long-term ixekizumab treatment with up to 3 years of continuous use remains consistent with previous reports, with no new safety signals175.

IL-36 receptor inhibitor: Spesolimab

As the first anti-IL36 agent available for treatment of psoriasis176, spesolimab received conditional EMA approval (pending further evidence) in 2022 for treatment of flares in adults with generalised pustular psoriasis98,177.

Efficacy

Conditional approval of spesolimab was based on the efficacy and safety results of the randomised, double-blind, placebo-controlled Phase II Effisayil 1 clinical trial in 53 adult patients with flares of generalised pustular psoriasis98. At 1 week after a single intravenously administered dose, a statistically significant difference in the proportion of patients achiving a Generalised Pustular Psoriasis Physician Global Assessment (GPPGA) subscore of 0 (indicating no visible pustules) was reported in the spesolimab versus placebo group (54.3% versus 5.6%, respectively; P<0.001). The treatment effect was observed irrespective of IL36RN mutation status98,178.

Safety

Based on results of this study, spesolimab treatment may be associated with infections and systemic drug reactions178. In the first week after treatment, infections were reported in 17% of participants in the spesolimab group versus 6% in placebo, and in 47% of participants at week 12178. Drug reactions with eosinophilia and systemic symptoms (DRESS) were reported in 2 patients treated with spesolimab, one of which occurred at the same time as a drug-induced hepatic injury178.

As these results are based on a single study, further data from longer term and larger clinical trials are required to evaluate the benefits and risks of spesolimab in patients with pustular psoriasis178.

TYK2 inhibitor: Deucravacitinib

The 2023 EMA approval of deucravacitinib for the treatment of moderate-to-severe plaque psoriasis97,179 was based on the efficacy and safety results of two multicentre, randomised, double-blind trials: POETYK PSO-1 and POETYK PSO-2 97,180–182.

In both trials97,180,181:

  • patients with moderate-to-severe plaque psoriasis were randomised to deucravacitinib 6 mg once daily, apremilast 30 mg twice daily, or placebo
  • the co-primary endpoints were the proportions of patients who achieved: (1) ≥75% improvement in PASI scores (PASI 75) from baseline, and (2) a static Physician’s Global Assessment (PGA) score of clear or almost clear (0 or 1) versus placebo, at week 16.

Efficacy

The results of these trials showed significantly higher response rates for deucravacitinib versus apremilast or placebo for PASI75 and sPGA 0/1. Efficacy was maintained for up to 52 weeks in the majority of patients (≥80%) who continued deucravacitinib treatment97,180,181.

Safety

Deucravacitinib was considered well tolerated180, with similar rates of adverse events reported across all 3 treatment groups180,181. However, a higher incidence of serious infections and herpes zoster infections was noted with deucravacitinib, compared with apremilast or placebo, at up to 52 weeks in both studies180,181.

Investigational biologic and small molecule inhibitor treatments for psoriasis

Developments in understanding the immunological pathways involved in psoriasis pathogenesis have provided insights into potential new targets and have led to the development of novel biologic and non-biologic treatments. Investigational treatments in clinical development for psoriasis are summarised in Table 3.

Table 3. Investigational treatments in clinical development for psoriasis184–188. GM-CSF, granulocyte-macrophage colony stimulating factor; IL, interleukin; JAK, Janus kinase; TYK2, tyrosine kinase 2. Trial status last verified on 11 July 2023.

Investigational treatment Target/mechanism of action Phase of development
Interleukin inhibitors
Imsidolimab (ANB019) Anti-IL-36 receptor antibody Phase III (recruiting)

JNJ-77242113 IL-23 antagonist Phase II (completed)
Phase II long-term extension study (active, not recruiting)
Moderate-to-severe plaque psoriasis
Netakimab IL-17A antagonist Phase III (completed)
Sonelokimab Anti-IL-17A/F nanobody that neutralises IL-17A and IL-17F Phase II (completed)
Moderate-to-severe psoriasis
JAK inhibitors
Baricitinib Inhibits JAK1, JAK2, JAK3, TYK2 Phase IIb (completed)
Moderate-to-severe plaque psoriasis
Tofacitinib (CP-690,550) Inhibits JAK1, JAK2, JAK3, TYK2 Phase III (completed)
Moderate-to-severe plaque psoriasis
Small molecule inhibitors
Orismilast Phosphodiesterase 4 inhibitor Phase II (completed)
Moderate-to-severe plaque-type psoriasis
Piclidenoson (CF101) Small molecule A3 adenosine receptor agonist Phase III (completed)
Moderate-to-severe plaque psoriasis
TYK2 inhibitors
Brepocitinib (PF-06700841) Orthosteric TYK2 inhibitor Phase II (completed)
Moderate-to-severe plaque psoriasis
ESK-001 Allosteric TYK2 inhibitor Phase II (enrolling by invitation)
Plaque psoriasis
NDI-034858 Allosteric TYK2 inhibitor Phase II (completed)
Moderate-to-severe plaque psoriasis
Ropsacitinib (PF06826647) Orthosteric inhibitor of TYK2 Phase II (completed)
Moderate-to-severe plaque psoriasis
VTX958  Allosteric inhibitor of TYK2 Phase II (recruiting)
Moderate-to-severe psoriasis
Other
Neihulizumab (AbGn-168H) Anti-CD162 antibody (CD162 is expressed on activated T cells) Phase II (completed)
Moderate-to-severe chronic plaque psoriasis
Namilumab GM-CSF inhibitor Phase II (completed)
Plaque psoriasis

Effective treatment selection in psoriasis

Recommended approach to psoriasis treatment

For people with psoriasis, treatment selection should take into account the severity of psoriasis, treatment efficacy and safety, time until onset of treatment response, comorbidities, and individual patient factors4,5,188,189.

For people with moderate-to-severe psoriasis, systemic treatment is usually recommended4,189.

  • European guidelines generally recommend initiating a conventional systemic agent4,189
  • If the response to conventional systemic agents is inadequate, or if they are contraindicated or not tolerated, it is recommended to initiate a biologic 4,189

In cases of psoriasis where conventional treatments are not expected to lead to a sufficient response, European guidelines suggest initiating a biologic agent that has a ‘first-line label’ based on their EMA-approved therapeutic indications 4,189. This may include patients with 4,189:

  • particularly severe disease (e.g., PASI ≥ 20) or rapid worsening of disease
  • severe involvement of the nails, the genital area or the scalp; or
  • a particularly strong impact on quality of life (e.g., DLQI ≥ 15)

Apremilast may be used where an oral treatment is preferred, and conventional systemic agents produce an inadequate response or are contraindicated or not tolerated 4,189.

Treatment selection for specific populations with psoriasis

Treatment options for specific groups of people with psoriasis are summarised in Table 4.

Table 4. Considerations for treatment selection in specific groups of patients with psoriasis5,188,190. IL, interleukin; TNF-α, tumour necrosis factor alpha. *Note age restrictions that may apply per the approved indications (e.g. for adalimumab, etanercept, ustekinumab).

Population Treatment options
Children (<12 years) Options include:
• Biologics: adalimumab*, etanercept*
• Conventional systemic drugs: methotrexate and cyclosporin (short‐term use only)
Adolescents (12–18 years) Options include:
• Biologics: adalimumab, etanercept, infliximab and ustekinumab*
• Conventional drugs acitretin, cyclosporine (for short‐term use only), fumarates, methotrexate
• Note acitretin not recommended for adolescent girls (due to risk of teratogenicity and need for contraception post-treatment)
Pregnant or planning conception Biologics:
• Certolizumab pegol is the first-line choice when starting biologic therapy in women planning conception (when a biologic is considered essential to use in pregnancy) and  when it is necessary to start a systemic therapy during the second or third trimester. It is the only biologic that is not actively transferred across the placenta.
• Guidelines suggest stopping biologic therapy in the second and third trimester (except certolizumab pegol) to minimise fetal exposure and limit potential infection risk to the neonate

Non-biologics:
• Ciclosporin should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the fetus
• Methotrexate, acitretin, fumarates and apremilast are contraindicated in women planning conception
Elderly (≥65 years) Options include:
• TNF-α inhibitors (adalimumab, certolizumab pegol, etanercept and infliximab)
• Anti-IL17: brodalumab, ixekizumab and secukinumab
• Anti-IL12/23: ustekinumab
• Anti-IL23: guselkumab, risankizumab, tildrakizumab
• Apremilast
• Conventional drugs including methotrexate, cyclosporine, and fumarates and acitretin

Treatment selection for psoriasis with comorbidities

Treatment options for people with psoriasis who have comorbidities and/or concurrent health conditions are summarised in table 5, including those with psoriatic arthritis, inflammatory bowel disease, cancer, depression, cardiovascular disease, or kidney disease.

Table 5. Considerations for treatment selection in patients with psoriasis according to specific comorbidities and/or concurrent health conditions5,189. eGFR, estimated glomerular filtration rate; IBD, inflammatory bowel disease; IL, interleukin; TNF-α, tumour necrosis factor alpha; UC, ulcerative colitis; UVB, ultraviolet B. *Except patients with a recent and/or high risk of cutaneous malignancy. If other patient characteristics do not preclude its use. Refer to specific guideline recommendations in cases of concomitant congestive heart failure, §or concomitant ischaemic heart failure. Intended as a summary based on most recent European psoriasis guidelines. For full and up-to-date information on approved therapeutic indications, contraindications, precautions and warnings, refer to the relevant summary of product characteristics for each medicine.

Population Treatment options
Psoriatic arthritis • Methotrexate (If peripheral active joint involvement;
not recommended for treatment of axial involvement or enthesitis)

If non-response to methotrexate:
• TNF-α inhibitors (etanercept, infliximab, adalimumab, certolizumab)
• Anti-IL12/23: Ustekinumab
• Anti-IL17: Secukinumab, ixekizumab
Chronic inflammatory bowel disease
General guidance • Acitretin is an option as adjunct therapy with other treatments (especially in cases with mild paradoxical psoriasis)
• Guidelines suggest against the use of anti-IL-17 antibodies in patients with IBD (e.g. secukinumab, ixekizumab, brodalumab)
Crohn’s disease First choice:
• TNF-α inhibitors (infliximab, adalimumab, certolizumab)
• Anti-IL-12/23: ustekinumab
Second choice:
• If TNF-α inhibitor not suitable: anti-IL-23 (risankizumab or guselkumab preferred; tildrakizumab also possible)
• If oral option preferred: methotrexate
Ulcerative colitis First choice:
• TNF-α inhibitors (infliximab, adalimumab)
• Anti-IL-12/23: Ustekinumab
Second choice:
• If first-choice treatment cannot be used: anti-IL-23 (risankizumab or guselkumab preferred; tildrakizumab also possible)
• If oral options preferred in active UC: ciclosprin is preferred, apremilast also possible
Recent history of cancer • Topical therapies, phototherapy (narrow band UVB)* and/or acitretin
     o If inadequate response: methotrexate can be used,
     apremilast also an option
• To consider on a case-by-case basis:
     o TNF-α inhibitors
     o Ustekinumab
     o Anti-IL-17 or anti-IL-23
Guidelines suggested against use of ciclosporin
History of depression and/or suicidal ideation Guidelines suggest using alternatives to brodalumab and apremilast
Diabetes mellitus/metabolic syndrome Guidelines suggest against using:
• Ciclosporin or methotrexate as a first-line treatment in patients with diabetes and/or features of the metabolic syndrome
• Using acitretin or ciclosporin as a first-line treatment in patients with dyslipidemia
Ischaemic heart disease/atherosclerosis In patients with psoriasis and ischaemic heart disease
• Preferred first-line therapy: methotrexate†‡
• Preferred targeted therapies: TNF-α inhibitors, ustekinumab, and IL-17 inhibitors
Heart failure In patients with psoriasis and advanced congestive heart failure§:
• Methotrexate, acitretin and apremilast can be considered
• Guidelines suggest that ustekinumab, inhibitors of IL-17 and of IL-23 can be considered
• Guidelines recommend against use of ciclosporin or TNF-α inhibitors
Kidney disease Guidelines suggest:
• For patients with psoriasis and mild-to-moderate renal impairment (eGFR ≥30 mL/min/1.73 m²): acitretin, apremilast, fumarates, methotrexate may be used (noting careful dosing/dose adjustment may be needed; and for apremilast if eGFR <30 mL/ min/1.73 m²)
• Biologics in patients with chronic kidney disease and all stages of renal impairment

Guidelines recommend against using ciclosporin, fumarates or methotrexate in psoriasis patients with chronic kidney disease and severe renal impairment (eGFR <30 mL/ min/1.73 m²).
Multiple sclerosis Guidelines suggest:
• Using fumarates in psoriasis patients with multiple sclerosis
Against use of TNF-α inhibitors in psoriasis patients with a first-degree relative with multiple sclerosis or other demyelinating disease, if other suitable treatment options are available

Guidelines recommend against using TNF-α inhibitors in psoriasis patients with a diagnosis of multiple sclerosis or other demyelinating disease.

In most cases, it is recommended to collaborate with an appropriate specialist (e.g. rhueumatologist, gastroenterologist, cardiologist, obstetrician) when selecting the appropriate treatment option for an individual patient5,188.

Learn more about current guidelines on psoriasis management in Europe

Achieving long-term control in moderate-to-severe psoriasis

Listen to expert insights on treatment considerations for long-term control of moderate-to-severe psoriasis.

Are there new insights on the long-term efficacy of biologics for psoriasis?
Relative medication durability and medication choice for people with moderate-to-severe psoriasis
How important is maintenance of response from the perspective of people with psoriasis?
How might recent long-term safety and efficacy data on IL-23 inhibitors impact psoriasis clinical practice?
Has our understanding of the long-term safety of IL-23 inhibitors improved since 2021?
How does the long-term safety and efficacy of IL-23 inhibitors compare to older biologic agents for psoriasis?
Long-term IL-23 inhibitor safety and efficacy data in vulnerable psoriasis patient groups
COVID-19’s impact: on psoriasis clinical practice, and on biologics with reduced dosing schedules
2

Put your knowledge to the test

Do you know all the latest updates on the long-term efficacy data for biologics? Do your patients want a greater durability of response in their treatment? Find out now, by seeing if you can beat our quiz!

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