Psoriasis Treatment

Treatment goals for psoriasis

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.

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 psoriasis^26,29.

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.

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 targets^{23,24,27,30–32}:

• 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 psoriasis^33,36. 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 in^33,36:

• 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 differentiation^27,36,38. 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.

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 psoriasis^40,41 , 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. 

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 cells^43,44.

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.

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 psoriasis^45–49. 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 psoriasis^52,54.

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 psoriasis^55,56. 

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

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 psoriasis^66–73. 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.

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 treatment^4,5,64.

Tolerability

The most important serious adverse events associated with methotrexate are myelosuppression and hepatotoxicity, both of which require dose reduction or discontinuation of treatment^4,5,64. 

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.

Figure 8. Overview of important side effects reported with methotrexate^4,5,64.

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 treatment^4,5,64.

Tolerability

FAEs have a well‐characterised side effect profile; most adverse effects are mild and do not lead to discontinuation of treatment^65,78. 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 treatment^78,79. 

Gastrointestinal and flush side effects 

Gastrointestinal complaints and flush symptoms are the most frequent adverse effects during treatment with fumarates^4,5,64,78. 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 treatment^78,79.  The general consensus is that such effects often cause issues in weeks 3–6, but stabilise or improve by weeks 8–9^4,5,64,78.

Gastrointestinal tolerance may be improved by taking the tablets after eating and/or swallowing them with dairy products^4,5,64,78. On the other hand, the administration of acetylsalicylic acid (aspirin) can help to decrease flush symptoms^4,5,64,78. Key side effects reported with dimethyl fumarate are shown in Figure 9.

Figure 9. Overview of important side effects reported with dimethyl fumarate^4,5,64,78.

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 reduction^4,5,62,64. 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 advised^4,5,62,64. All side effects are reversible except for hyperostosis^4,5,62,64.

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

Figure 10. Overview of important side effects reported with retinoids^4,5,62,64.

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 teratogenicity^67,81.  

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 placebo^83,84.

 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 patients^3,7,24,76.

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 profiles^7,90.

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 Europe^92–106. 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.

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 skin^7,106. 

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 adalimumab^109,110. 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 products^112,113.

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 necessary^119,120.

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 studies^123,124. 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 trials^7,126.

Time to onset of action for infliximab is shorter (approximately 3.5 weeks) than for other biologics such as adalimumab, ustekinumab and etanercept^7,126. Infliximab as continuous infusion has demonstrated improved efficacy when compared to as-needed infusion^7,127. 

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 years^7,128. 

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 patients^7,126. 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 data^131,132. 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 mortality^131,132
• 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 etanercept^133,134
• 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 skin^139,140. 

While ustekinumab targets IL-12/IL-23 through the common p19 subunit, three approved therapies selectively block IL-23 only^141–145.

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 observed^147,148,152. 

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 adalimumab^159–163.

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 years^164,166.

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 psoriasis^98,177.

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 status^98,178.

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 psoriasis^97,179 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 trials^97,180,181:

• 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 treatment^97,180,181.

Safety

Deucravacitinib was considered well tolerated¹⁸⁰, with similar rates of adverse events reported across all 3 treatment groups^180,181. 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 studies^180,181.

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 psoriasis^184–188. GM-CSF, granulocyte-macrophage colony stimulating factor; IL, interleukin; JAK, Janus kinase; TYK2, tyrosine kinase 2. Trial status last verified on 11 July 2023.

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