Psoriasis Treatment

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 hyperproliferation^23,24

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 body^23,24,25.

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.

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

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.

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.

Effective treatment selection in psoriasis

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.

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!

References

1. Nograles KE, Davidovici B, Krueger JG. New Insights in the Immunologic Basis of Psoriasis. Semin Cutan Med Surg. 2010;29(1):3–9.
2. Nast A, Boehncke WH, Mrowietz U, Ockenfels HM, Philipp S, Reich K, et al. S3 - Guidelines on the treatment of psoriasis vulgaris (English version). Update. JDDG - Journal of the German Society of Dermatology. 2012;10(SUPPL.2):S1-s95.
3. Boehncke WH, Boehncke S. More than skin-deep: The many dimensions of the psoriatic disease. Swiss Medical Weekly. 2014;144. doi:10.4414/smw.2014.13968.
4. Nast A, Smith C, Spuls PI, Avila Valle G, Bata-Csörgö Z, Boonen H, et al. EuroGuiDerm Guideline on the systemic treatment of Psoriasis vulgaris – Part 1: treatment and monitoring recommendations. Journal of the European Academy of Dermatology and Venereology. 2020;34(11):2461–2498.
5. Nast A, Smith C, Spuls PI, Avila Valle G, Bata-Csörgö Z, Boonen H, et al. EuroGuiDerm Guideline on the systemic treatment of Psoriasis vulgaris – Part 2: specific clinical and comorbid situations. Journal of the European Academy of Dermatology and Venereology. 2021;35(2):281–317.
6. Elmets CA, Korman NJ, Prater EF, Wong EB, Rupani RN, Kivelevitch D, et al. Joint AAD–NPF Guidelines of care for the management and treatment of psoriasis with topical therapy and alternative medicine modalities for psoriasis severity measures. J Am Acad Dermatol. 2021;84(2):432–470.
7. Menter A, Strober BE, Kaplan DH, Kivelevitch D, Prater EF, Stoff B, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics. J Am Acad Dermatol. 2019;80(4):1029–1072.
8. Menter A, Gelfand JM, Connor C, Armstrong AW, Cordoro KM, Davis DMR, et al. Joint American Academy of Dermatology–National Psoriasis Foundation guidelines of care for the management of psoriasis with systemic nonbiologic therapies. J Am Acad Dermatol. 2020;82(6):1445–1486.
9. Reich K, Mrowietz U. Therapieziele bei der behandlung der psoriasis. JDDG - Journal of the German Society of Dermatology. 2007;5(7):566–574.
10. Blome C, Gosau R, Radtke MA, Reich K, Rustenbach SJ, Spehr C, et al. Patient-relevant treatment goals in psoriasis. Arch Dermatol Res. 2016;308(2):69–78.
11. Strober BE, van der Walt JM, Armstrong AW, Bourcier M, Carvalho AVE, Chouela E, et al. Clinical Goals and Barriers to Effective Psoriasis Care. Dermatol Ther (Heidelb). 2019;9(1):5–18.
12. Papp K, Menter A, Poulin Y, Gu Y, Sasso EH. Long-term outcomes of interruption and retreatment vs. continuous therapy with adalimumab for psoriasis: Subanalysis of REVEAL and the open-label extension study. Journal of the European Academy of Dermatology and Venereology. 2013;27(5):634–642.
13. Poulin Y, Sheth P, Gu Y. Psoriasis patients required to discontinue adalimumab therapy have worsening in their quality of life out of proportion to worsening in the objective signs of disease: Subanalysis of REVEAL. J Am Acad Dermatol. 2012;66(4):AB201.
14. Okubo Y, Tsuruta D, Tang AC, Inoue S, Torisu-Itakura H, Hanada T, et al. Analysis of treatment goal alignment between Japanese psoriasis patients and their paired treating physicians. Journal of the European Academy of Dermatology and Venereology. 2018;32(4):606–614.
15. Pintaudi B, Lucisano G, Gentile S, Bulotta A, Skovlund SE, Vespasiani G, et al. Correlates of diabetes-related distress in type 2 diabetes: Findings from the benchmarking network for clinical and humanistic outcomes in diabetes (BENCH-D) study. J Psychosom Res. 2015;79(5):348–354.
16. Topp CW, Østergaard SD, Søndergaard S, Bech P. The WHO-5 Well-Being Index: A Systematic Review of the Literature. Psychother Psychosom. 2015;84(3):167–176.
17. Mrowietz U, Sommer R, Reguiai Z, Gerdes S, Dauden E, Weger W, et al. Patient-reported well-being in value-based care using tildrakizumab in a real-world setting: 28-week interim data of the phase IV POSTIVE study. In: Poster presentation at the 25th World Congress of Dermatology 2023, July 3–8. 2023.
18. Eurofound. European Quality of Life Survey - Data visualisation: WHO-5 mental well-being scale. European Quality of Life Survey 2016. 2016.
    External link access here. Accessed 4 July 2023.
19. Omani-Samani R, Maroufizadeh S, Almasi-Hashiani A, Sepidarkish M, Amini P. The WHO-5 Well-Being Index: A Validation Study in People with Infertility. Iran J Public Health. 2019;48(11):2058–2064.
20. Strober B, Papp KA, Lebwohl M, Reich K, Paul C, Blauvelt A, et al. Clinical meaningfulness of complete skin clearance in psoriasis. J Am Acad Dermatol. 2016;75(1):77-82.e7.
21. Eghlileb AM, Davies EEG, Finlay AY. Psoriasis has a major secondary impact on the lives of family members and partners. British Journal of Dermatology. 2007;156(6):1245–1250.
22. Armstrong A, Jarvis S, Boehncke WH, Rajagopalan M, Fernández-Peñas P, Romiti R, et al. Patient perceptions of clear/almost clear skin in moderate-to-severe plaque psoriasis: results of the Clear About Psoriasis worldwide survey. Journal of the European Academy of Dermatology and Venereology. 2018;32(12):2200–2207.
23. Nestle FO, Kaplan DH, Barker J. Mechanisms of disease: Psoriasis. N Engl J Med. 2009;361(5):496–509.
24. Boehncke WH, Schön MP. Psoriasis. The Lancet. 2015;386(9997):983–994.
25. Palfreeman AC, McNamee KE, McCann FE. New developments in the management of psoriasis and psoriatic arthritis: A focus on apremilast. Drug Des Devel Ther. 2013;7:201–210.
26. Sabat R, Philipp S, Höflich C, Kreutzer S, Wallace E, Asadullah K, et al. Immunopathogenesis of psoriasis. Exp Dermatol. 2007;16(10):779–798.
27. Diani M, Altomare G, Reali E. T cell responses in psoriasis and psoriatic arthritis. Autoimmunity Reviews. 2015;14(4):286–292.
28. Becher B, Pantelyushin S. Interleukin-17-producing γδ T cells go under the skin? Nat Med. 2012;18(12):1748–1750.
29. Büchau AS, Gallo RL. Innate immunity and antimicrobial defense systems in psoriasis. Clinics in Dermatology. 2007;25(6):616–624.
30. Chandrakumar SF, Yeung J. Interleukin-17 antagonists in the treatment of psoriasis. J Cutan Med Surg. 2015;19(2):109–114.
31. Sugiyama H, Gyulai R, Toichi E, Garaczi E, Shimada S, Stevens SR, et al. Dysfunctional Blood and Target Tissue CD4 + CD25 high Regulatory T Cells in Psoriasis: Mechanism Underlying Unrestrained Pathogenic Effector T Cell Proliferation . The Journal of Immunology. 2005;174(1):164–173.
32. Goodman WA, Levine AD, Massari J V., Sugiyama H, McCormick TS, Cooper KD. IL-6 Signaling in Psoriasis Prevents Immune Suppression by Regulatory T Cells. The Journal of Immunology. 2009;183(5):3170–3176.
33. Brotas AM, Cunha JMT, Lago EHJ, Machado CCN, Carneiro SC da S. Fator de necrose tumoral-alfa e a rede de citocinas na psoriase. An Bras Dermatol. 2012;87(5):673–683.
34. Ferreira VL, Borba, HL, de F. Bonetti, AF, Leonart, LP, Pontarolo R. Cytokines and Interferons: Types and Functions. In: Autoantibodies and Cytokines. 2019. IntechOpen: 65–87.
35. Baliwag J, Barnes DH, Johnston A. Cytokines in psoriasis. 2015. Academic Press.
36. Lowes MA, Suárez-Fariñas M, Krueger JG. Immunology of psoriasis. Annu Rev Immunol. 2014;32:227–255.
37. Brunner PM, Koszik F, Reininger B, Kalb ML, Bauer W, Stingl G. Infliximab induces downregulation of the IL-12/IL-23 axis in 6-sulfo-LacNac (slan)+ dendritic cells and macrophages. Journal of Allergy and Clinical Immunology. 2013;132(5):1184–93.
38. Soler DC, McCormick TS. The dark side of regulatory T cells in psoriasis. Journal of Investigative Dermatology. 2011;131(9):1785–1786.
39. Amatya N, Garg A V., Gaffen SL. IL-17 Signaling: The Yin and the Yang. Trends Immunol. 2017;38(5):310–322.
40. Lønnberg AS, Zachariae C, Skov L. Targeting of interleukin-17 in the treatment of psoriasis. Clin Cosmet Investig Dermatol. 2014;7:251–259.
41. von Stebut E, Boehncke W-H, Ghoreschi K, Gori T, Kaya Z, Thaci D, et al. IL-17A in Psoriasis and Beyond: Cardiovascular and Metabolic Implications. Front Immunol. 2020;10. https://www.frontiersin.org/articles/10.3389/fimmu.2019.03096.
42. Galluzzo M, D’Adamio S, Massaro A, Piccolo A, Bianchi L, Talamonti M. Spotlight on brodalumab in the treatment of plaque psoriasis: The evidence to date. Clin Cosmet Investig Dermatol. 2019;12:311–321.
43. Di Meglio P, Nestle FO. The role of IL-23 in the immunopathogenesis of psoriasis. F1000 Biol Rep. 2010;2(1):40.
44. Girolomoni G, Strohal R, Puig L, Bachelez H, Barker J, Boehncke WH, et al. The role of IL-23 and the IL-23/TH17 immune axis in the pathogenesis and treatment of psoriasis. Journal of the European Academy of Dermatology and Venereology. 2017;31(10):1616–1626.
45. Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). The Lancet. 2008;371(9625):1665–1674.
46. Langley RG, Lebwohl M, Krueger GG, Szapary PO, Wasfi Y, Chan D, et al. Long-term efficacy and safety of ustekinumab, with and without dosing adjustment, in patients with moderate-to-severe psoriasis: Results from the PHOENIX 2 study through 5 years of follow-up. British Journal of Dermatology. 2015;172(5):1371–1383.
47. Gordon KB, Duffin KC, Bissonnette R, Prinz JC, Wasfi Y, Li S, et al. A Phase 2 Trial of Guselkumab versus Adalimumab for Plaque Psoriasis. New England Journal of Medicine. 2015;373(2):136–144.
48. Blauvelt A, Papp KA, Griffiths CEM, Randazzo B, Wasfi Y, Shen YK, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: Results from the phase III, double-blinded, placebo- and active comparator–. J Am Acad Dermatol. 2017;76(3):405–417.
49. Reich K, Papp KA, Blauvelt A, Tyring SK, Sinclair R, Thaçi D, et al. Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials. The Lancet. 2017;390(10091):276–288.
50. Gómez-García F, Ruano J, Gay-Mimbrera J, Aguilar-Luque M, Sanz-Cabanillas JL, Hernández Romero JL, et al. A Scoping Review Protocol to Explore the Use of Interleukin-1-Targeting Drugs for the Treatment of Dermatological Diseases: Indications, Mechanism of Action, Efficacy, and Safety. Dermatol Ther (Heidelb). 2018;8(2):195–202.
51. Cai Y, Xue F, Quan C, Qu M, Liu N, Zhang Y, et al. A Critical Role of the IL-1β–IL-1R Signaling Pathway in Skin Inflammation and Psoriasis Pathogenesis. Journal of Investigative Dermatology. 2019;139(1):146–156.
52. Sachen KL, Arnold Greving CN, Towne JE. Role of IL-36 cytokines in psoriasis and other inflammatory skin conditions. Cytokine. 2022;156:155897.
53. Sugiura K. Role of Interleukin 36 in Generalised Pustular Psoriasis and Beyond. Dermatol Ther (Heidelb). 2022;12(2):315–328.
54. Boutet M-A, Bart G, Penhoat M, Amiaud J, Brulin B, Charrier C, et al. Distinct expression of interleukin (IL)-36α, β and γ, their antagonist IL-36Ra and IL-38 in psoriasis, rheumatoid arthritis and Crohn’s disease. Clin Exp Immunol. 2016;184(2):159–173.
55. Hao JQ. Targeting interleukin-22 in psoriasis. Inflammation. 2014;37(1):94–99.
56. Chiricozzi A, Romanelli P, Volpe E, Borsellino G, Romanelli M. Scanning the immunopathogenesis of psoriasis. International Journal of Molecular Sciences. 2018;19(1):179.
57. Wawrzycki B, Pietrzak A, Grywalska E, Krasowska D, Chodorowska G, Roliński J. Interleukin-22 and Its Correlation with Disease Activity in Plaque Psoriasis. Arch Immunol Ther Exp (Warsz). 2019;67(2):103–108.
58. Reich K, Armstrong AW, Foley P, Song M, Wasfi Y, Randazzo B, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: Results from the phase III, double-blind, p. J Am Acad Dermatol. 2017;76(3):418–431.
59. Steffen S, Abraham S, Herbig M, Schmidt F, Blau K, Meisterfeld S, et al. Toll-Like Receptor-Mediated Upregulation of CXCL16 in Psoriasis Orchestrates Neutrophil Activation. Journal of Investigative Dermatology. 2018;138(2):344–354.
60. Kim WB, Jerome D, Yeung J. Diagnosis and management of psoriasis. Canadian Family Physician. 2017;63(4):278.
61. Feldman SR, Goffe B, Rice G, Mitchell M, Kaur M, Robertson D, et al. The challenge of managing psoriasis: Unmet medical needs and stakeholder perspectives. Am Health Drug Benefits. 2016;9(9):504–512.
62. Nast A, Gisondi P, Ormerod AD, Saiag P, Smith C, Spuls PI, et al. European S3-Guidelines on the systemic treatment of psoriasis vulgaris - Update 2015 - Short version - EDF in cooperation with EADV and IPC. Journal of the European Academy of Dermatology and Venereology. 2015;29(12):2277–2294.
63. Mrowietz U, Kragballe K, Reich K, Spuls P, Griffiths CEM, Nast A, et al. Definition of treatment goals for moderate to severe psoriasis: A European consensus. Arch Dermatol Res. 2011;303(1):1–10.
64. Pathirana D, Ormerod AD, Saiag P, Smith C, Spuls PI, Nast A, et al. European S3-guidelines on the systemic treatment of psoriasis vulgaris. Journal of the European Academy of Dermatology and Venereology. 2009;23(SUPPL. 2):1–70.
65. Mrowietz U, Barker J, Boehncke WH, Iversen L, Kirby B, Naldi L, et al. Clinical use of dimethyl fumarate in moderate-to-severe plaque-type psoriasis: a European expert consensus. Journal of the European Academy of Dermatology and Venereology. 2018;32:3–14.
66. Otezla (apremilast). Summary of product characteristics. 2015. Last updated 2022. https://www.ema.europa.eu/documents/product-information/otezla-epar-product-information_en.pdf. Accessed 5 May 2023.
67. Electronic Medicines Compendium. Acitretin (Neotigason). Summary of product characteristics. 2023. https://www.medicines.org.uk/emc/product/10248/smpc. Accessed 5 May 2023.
68. Skilarence (dimethyl fumarate). Summary of product characteristics. 2017. Last updated 2022. https://www.ema.europa.eu/documents/product-information/skilarence-epar-product-information_en.pdf. Accessed 5 May 2023.
69. Nordimet (methotrexate). Summary of product characteristics. 2016. Last updated 2023. https://www.ema.europa.eu/documents/product-information/nordimet-epar-product-information_en.pdf. Accessed 5 May 2023.
70. Jylamvo (methotrexate). Summary of product characteristics. 2017. Last updated 2023. https://www.ema.europa.eu/documents/product-information/jylamvo-epar-product-information_en.pdf. Accessed 5 May 2023.
71. Benjamin O, Goyal A, Lappin S. Disease Modifying Anti-Rheumatic Drugs (DMARD). 2022. Treasure Island (FL). StatPearls Publishing.
72. Yamauchi PS, Rizk D, Kormeili T, Patnaik R, Lowe NJ. Current systemic therapies for psoriasis: where are we now? J Am Acad Dermatol. 2003;49(2):66–77.
73. Electronic Medicines Compendium. Capimune. Summary of Product Characteristics. 2021. https://www.medicines.org.uk/emc/product/695/smpc. Accessed 4 May 2023.
74. Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies. J Am Acad Dermatol. 2009;60(4):643–659.
75. Rivera R, Vilarrasa E, Ribera M, Roe E, Kueder-Pajares T, Zayas AI, et al. Unmet needs in patients with moderate-to-severe plaque psoriasis treated with methotrexate in real world practice: FirST study. Journal of Dermatological Treatment. 2020. doi:10.1080/09546634.2020.1801977.
76. Dommasch ED, Kim SC, Lee MP, Gagne JJ. Risk of Serious Infection in Patients Receiving Systemic Medications for the Treatment of Psoriasis. JAMA Dermatol. 2019;155(10):1142–1152.
77. Reich K, Mrowietz U, Radtke MA, Thaci D, Rustenbach SJ, Spehr C, et al. Drug safety of systemic treatments for psoriasis: results from The German Psoriasis Registry PsoBest. Arch Dermatol Res. 2015;307(10):875–883.
78. Reszke R, Szepietowski JC. A safety evaluation of dimethyl fumarate in moderate-to-severe psoriasis. Expert Opin Drug Saf. 2020;19(4):373–380.
79. Mrowietz U, Szepietowski JC, Loewe R, van de Kerkhof P, Lamarca R, Ocker WG, et al. Efficacy and safety of LAS41008 (dimethyl fumarate) in adults with moderate-to-severe chronic plaque psoriasis: a randomized, double-blind, Fumaderm®- and placebo-controlled trial (BRIDGE). British Journal of Dermatology. 2017;176(3):615–623.
80. Naldi L, Griffiths CEM. Traditional therapies in the management of moderate to severe chronic plaque psoriasis: An assessment of the benefits and risks. British Journal of Dermatology. 2005;152(4):597–615.
81. Zito P, Mazzoni T. Acitretin. 2023. Treasure Island (FL). StatPearls Publishing https://www.ncbi.nlm.nih.gov/books/NBK519571. Accessed 5 May 2023.
82. European Medicines Agency. Otezla. Summary of Product Characteristics. 2021. https://www.ema.europa.eu/en/documents/product-information/otezla-epar-product-information_en.pdf. Accessed 17 February 2021.
83. Papp K, Reich K, Leonardi CL, Kircik L, Chimenti S, Langley RGB, et al. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J Am Acad Dermatol. 2015;73(1):37–49.
84. Paul C, Cather J, Gooderham M, Poulin Y, Mrowietz U, Ferrandiz C, et al. Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: A phase III, randomized controlled trial (ESTEEM 2). British Journal of Dermatology. 2015;173(6):1387–1399.
85. Bissonnette R, Pariser DM, Wasel NR, Goncalves J, Day RM, Chen R, et al. Apremilast, an oral phosphodiesterase-4 inhibitor, in the treatment of palmoplantar psoriasis: Results of a pooled analysis from phase II PSOR-005 and phase III Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis (ESTEEM) clinical . J Am Acad Dermatol. 2016;75(1):99–105.
86. Rich P, Gooderham M, Bachelez H, Goncalves J, Day RM, Chen R, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with difficult-to-treat nail and scalp psoriasis: Results of 2 phase III randomized, controlled trials (ESTEEM 1 and ESTEEM 2). J Am Acad Dermatol. 2016;74(1):134–142.
87. Thaçi D, Kimball A, Foley P, Poulin Y, Levi E, Chen R, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, improves patient-reported outcomes in the treatment of moderate to severe psoriasis: results of two phase III randomized, controlled trials. Journal of the European Academy of Dermatology and Venereology. 2017;31(3):498–506.
88. Armstrong AW, Betts KA, Sundaram M, Thomason D, Signorovitch JE. Comparative efficacy and incremental cost per responder of methotrexate versus apremilast for methotrexate-naïve patients with psoriasis. J Am Acad Dermatol. 2016;75(4):740–746.
89. Crowley J, Thaçi D, Joly P, Peris K, Papp KA, Goncalves J, et al. Long-term safety and tolerability of apremilast in patients with psoriasis: Pooled safety analysis for ≥156 weeks from 2 phase 3, randomized, controlled trials (ESTEEM 1 and 2). J Am Acad Dermatol. 2017;77(2):310-317.e1.
90. Gisondi P, Del Giglio M, Girolomoni G. Treatment approaches tomoderate to severe psoriasis. Int J Mol Sci. 2017;18(11):2427.
91. Cosentyx (secukinumab) EPAR. European Medicines Agency. 2023. https://www.ema.europa.eu/en/medicines/human/EPAR/cosentyx. Accessed 3 July 2023.
92. Tremfya (guselkumab). Summary of product characteristics. 2017. Last updated 2022. https://www.ema.europa.eu/documents/product-information/tremfya-epar-product-information_en.pdf. Accessed 3 July 2023.
93. Skyrizi (risankizumab). Summary of product characteristics. 2019. Last updated 2023. https://www.ema.europa.eu/documents/product-information/skyrizi-epar-product-information_en.pdf. Accessed 3 July 2023.
94. Ilumetri (tildrakizumab). Summary of product characteristics. 2018. Last updated 2023. https://www.ema.europa.eu/documents/product-information/ilumetri-epar-product-information_en.pdf. Accessed 3 July 2023.
95. Cosentyx (secukinumab). Summary of product characteristics. 2015. Last updated 2023. https://www.ema.europa.eu/documents/product-information/cosentyx-epar-product-information_en.pdf. Accessed 3 July 2023.
96. Taltz (ixekizumab). Summary of product characteristics. 2016. Last updated 2023. https://www.ema.europa.eu/documents/product-information/taltz-epar-product-information_en.pdf. Accessed 3 July 2023.
97. Sotyktu (deucravacitinib). Summary of product characteristics. 2023. https://www.ema.europa.eu/documents/product-information/sotyktu-epar-product-information_en.pdf. Accessed 3 July 2023.
98. Spevigo (spesolimab). Summary of product characteristics. 2023. https://www.ema.europa.eu/documents/product-information/spevigo-epar-product-information_en.pdf. Accessed 3 July 2023.
99. Kyntheum (brodalumab). Summary of product characteristics. 2017. Last updated 2023. https://www.ema.europa.eu/documents/product-information/kyntheum-epar-product-information_en.pdf. Accessed 3 July 2023.
100. Benepali (etanercept). Summary of product characteristics. 2016. Last updated 2023. https://www.ema.europa.eu/documents/product-information/benepali-epar-product-information_en.pdf. Accessed 3 July 2023.
101. Remsima (infliximab). Summary of product characteristics. 2013. Last updated 2023. https://www.ema.europa.eu/documents/product-information/remsima-epar-product-information_en.pdf. Accessed 3 July 2023.
102. European Medicines Agency. Stelara (ustekinumab) EPAR. Last updated 2023. https://www.ema.europa.eu/en/medicines/human/EPAR/stelara. Accessed 3 July 2023.
103. Cimzia (certolizumab pegol). Summary of product characteristics. 2010. Last updated 2023. https://www.ema.europa.eu/documents/product-information/cimzia-epar-product-information_en.pdf. Accessed 3 July 2023.
104. Hukyndra (adalimumab). Summary of product characteristics. 2022. Last updated 2023. https://www.ema.europa.eu/documents/product-information/hukyndra-epar-product-information_en.pdf. Accessed 3 July 2023.
105. Bimzelx (bimekizumab). Summary of product characteristics. 2021. Last updated 2022. https://www.ema.europa.eu/documents/product-information/bimzelx-epar-product-information_en.pdf. Accessed 3 July 2023.
106. Menter A, Tyring SK, Gordon K, Kimball AB, Leonardi CL, Langley RG, et al. Adalimumab therapy for moderate to severe psoriasis: A randomized, controlled phase III trial. J Am Acad Dermatol. 2008;58(1):106–115.
107. Papp KA, Yang M, Sundaram M, Jarvis J, Betts KA, Bao Y, et al. Comparison of Adalimumab and Etanercept for the Treatment of Moderate to Severe Psoriasis: An Indirect Comparison Using Individual Patient Data from Randomized Trials. Value in Health. 2018;21(1):1–8.
108. Papp KA, Armstrong AW, Reich K, Karunaratne M, Valdecantos W. Adalimumab Efficacy in Patients with Psoriasis Who Received or Did Not Respond to Prior Systemic Therapy: A Pooled Post Hoc Analysis of Results from Three Double-Blind, Placebo-Controlled Clinical Trials. Am J Clin Dermatol. 2016;17(1):79–86.
109. Menter A, Thaçi D, Wu JJ, Abramovits W, Kerdel F, Arikan D, et al. Long-Term Safety and Effectiveness of Adalimumab for Moderate to Severe Psoriasis: Results from 7-Year Interim Analysis of the ESPRIT Registry. Dermatol Ther (Heidelb). 2017;7(3):365–381.
110. Wu JJ, Abramovits W, Valdecantos WC, Servin OR, Bereswill M, Arikan D, et al. 14030 Ten-year interim results from the ESPRIT registry: Real-world safety, effectiveness, and patient-reported outcomes of adalimumab for moderate to severe psoriasis. J Am Acad Dermatol. 2020;83(6):AB17.
111. Gisondi P, Geat D, Pizzolato M, Girolomoni G. State of the art and pharmacological pipeline of biologics for chronic plaque psoriasis. Curr Opin Pharmacol. 2019;46:90–99.
112. ClinicalTrials.gov. NCT02326272 - A Study to Evaluate the Efficacy and Safety of Two Dose Levels of Certolizumab Pegol (CZP) in Subjects With Plaque Psoriasis (PSO). 2018. https://clinicaltrials.gov/ct2/show/NCT02326272. Accessed 24 February 2021.
113. Cochrane Central Register of Controlled Trials (CENTRAL). Efficacy and Safety Study of Sirukumab in Subjects With Polymyalgia Rheumatica. 2016.
114. Rutkowski D, Chinoy H, Warren RB. The Potential Benefits of Certolizumab Pegol in Patients with Concurrent Psoriatic Arthritis and Chronic Plaque Psoriasis: A Case Series and Review of the Literature. Dermatol Ther (Heidelb). 2019;9(2):373–381.
115. Gottlieb AB, Blauvelt A, Thaçi D, Leonardi CL, Poulin Y, Drew J, et al. Certolizumab pegol for the treatment of chronic plaque psoriasis: Results through 48 weeks from 2 phase 3, multicenter, randomized, double-blinded, placebo-controlled studies (CIMPASI-1 and CIMPASI-2). J Am Acad Dermatol. 2018;79(2):302-314.e6.
116. Lebwohl M, Blauvelt A, Paul C, Sofen H, Węgłowska J, Piguet V, et al. Certolizumab pegol for the treatment of chronic plaque psoriasis: Results through 48 weeks of a phase 3, multicenter, randomized, double-blind, etanercept- and placebo-controlled study (CIMPACT). J Am Acad Dermatol. 2018;79(2):266-276.e5.
117. Curtis JR, Mariette X, Gaujoux-Viala C, Blauvelt A, Kvien TK, Sandborn WJ, et al. Long-term safety of certolizumab pegol in rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis, psoriasis and Crohn’s disease: A pooled analysis of 11 317 patients across clinical trials. RMD Open. 2019;5(1). doi:10.1136/rmdopen-2019-000942.
118. Blauvelt A, Paul C, van de Kerkhof P, Warren RB, Gottlieb AB, Langley RG, et al. Long-term safety of certolizumab pegol in plaque psoriasis: pooled analysis over 3 years from three phase III, randomized, placebo-controlled studies. British Journal of Dermatology. 2021;184(4):640–651.
119. Mariette X, Förger F, Abraham B, Flynn AD, Moltó A, Flipo RM, et al. Lack of placental transfer of certolizumab pegol during pregnancy: Results from CRIB, a prospective, postmarketing, pharmacokinetic study. Ann Rheum Dis. 2018;77(2):228–233.
120. Clowse ME, Förger F, Hwang C, Thorp J, Dolhain RJ, Van Tubergen A, et al. Minimal to no transfer of certolizumab pegol into breast milk: Results from CRADLE, a prospective, postmarketing, multicentre, pharmacokinetic study. Ann Rheum Dis. 2017;76(11):1890–1896.
121. Lee JY, Kang S, Park JS, Jo SJ. Prevalence of psoriasis in Korea: A population-based epidemiological study using the Korean national health insurance database. Ann Dermatol. 2017;29(6):761–767.
122. Luger T, Schopf RE, Schwanke A, Langhammer S, Meng T, Löschmann PA. An observational study to evaluate the long-term outcomes of treatment with etanercept in patients with plaque-type psoriasis. Journal of the European Academy of Dermatology and Venereology. 2016;30(10):1730–1741.
123. Leonardi CL, Powers JL, Matheson RT, Goffe BS, Zitnik R, Wang A, et al. Etanercept as Monotherapy in Patients with Psoriasis. New England Journal of Medicine. 2003;349(21):2014–2022.
124. Papp KA. The long-term efficacy and safety of new biological therapies for psoriasis. Arch Dermatol Res. 2006;298(1):7–15.
125. Kimball AB, Rothman KJ, Kricorian G, Pariser D, Yamauchi PS, Menter A, et al. OBSERVE-5: Observational postmarketing safety surveillance registry of etanercept for the treatment of psoriasis final 5-year results. J Am Acad Dermatol. 2015;72(1):115–122.
126. Subedi S, Gong Y, Chen Y, Shi Y. Infliximab and biosimilar infliximab in psoriasis: Efficacy, loss of efficacy, and adverse events. Drug Des Devel Ther. 2019;13:2491–2502.
127. Reich K, Wozel G, Zheng H, Van Hoogstraten HJF, Flint L, Barker J. Efficacy and safety of infliximab as continuous or intermittent therapy in patients with moderate-to-severe plaque psoriasis: Results of a randomized, long-term extension trial (RESTORE2). British Journal of Dermatology. 2013;168(6):1325–1334.
128. Shear NH, Hartmann M, Toledo-Bahena M, Katsambas A, Connors L, Chang Q, et al. Long-term efficacy and safety of infliximab maintenance therapy in patients with plaque-type psoriasis in real-world practice. British Journal of Dermatology. 2014;171(3):631–641.
129. Kim WB, Marinas JEC, Qiang J, Shahbaz A, Greaves S, Yeung J. Adverse events resulting in withdrawal of biologic therapy for psoriasis in real-world clinical practice: A Canadian multicenter retrospective study. J Am Acad Dermatol. 2015;73(2):237–241.
130. Landells I, Marano C, Hsu MC, Li S, Zhu Y, Eichenfield LF, et al. Ustekinumab in adolescent patients age 12 to 17 years with moderate-to-severe plaque psoriasis: Results of the randomized phase 3 CADMUS study. J Am Acad Dermatol. 2015;73(4):594–603.
131. Papp K, Gottlieb AB, Naldi L, Pariser D, Ho V, Goyal K, et al. Safety surveillance for ustekinumab and other psoriasis treatments from the psoriasis longitudinal assessment and (PSOLAR). Journal of Drugs in Dermatology. 2015;14(7):706–714.
132. Strober BE, Bissonnette R, Fiorentino D, Kimball AB, Naldi L, Shear NH, et al. Comparative effectiveness of biologic agents for the treatment of psoriasis in a real-world setting: Results from a large, prospective, observational study (Psoriasis Longitudinal Assessment and Registry [PSOLAR]). J Am Acad Dermatol. 2016;74(5):851-861.e4.
133. Menter A, Papp KA, Gooderham M, Pariser DM, Augustin M, Kerdel FA, et al. Drug survival of biologic therapy in a large, disease-based registry of patients with psoriasis: results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR). Journal of the European Academy of Dermatology and Venereology. 2016;30(7):1148–1158.
134. Egeberg A, Rosenø NAL, Aagaard D, Lørup EH, Nielsen ML, Nymand L, et al. Drug survival of biologics and novel immunomodulators for rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis, and psoriasis - A nationwide cohort study from the DANBIO and DERMBIO registries. Semin Arthritis Rheum. 2022;53:151979.
135. Augustin M, Abeysinghe S, Mallya U, Qureshi A, Roskell N, McBride D, et al. Secukinumab treatment of plaque psoriasis shows early improvement in DLQI response - Results of a phase II regimen-finding trial. Journal of the European Academy of Dermatology and Venereology. 2016;30(4):645–649.
136. Zweegers J, Groenewoud JMM, van den Reek JMPA, Otero ME, van de Kerkhof PCM, Driessen RJB, et al. Comparison of the 1- and 5-year effectiveness of adalimumab, etanercept and ustekinumab in patients with psoriasis in daily clinical practice: results from the prospective BioCAPTURE registry. British Journal of Dermatology. 2017;176(4):1001–1009.
137. Bagel J, Blauvelt A, Nia J, Hashim P, Patekar M, de Vera A, et al. Secukinumab maintains superiority over ustekinumab in clearing skin and improving quality of life in patients with moderate to severe plaque psoriasis: 52-week results from a double-blind phase 3b trial (CLARITY). Journal of the European Academy of Dermatology and Venereology. 2021;35(1):135–142.
138. Reich K, Papp KA, Blauvelt A, Langley RG, Armstrong A, Warren RB, et al. Bimekizumab versus ustekinumab for the treatment of moderate to severe plaque psoriasis (BE VIVID): efficacy and safety from a 52-week, multicentre, double-blind, active comparator and placebo controlled phase 3 trial. Lancet. 2021;397(10273):487–498.
139. Hawkes JE, Chan TC, Krueger JG. Psoriasis pathogenesis and the development of novel targeted immune therapies. Journal of Allergy and Clinical Immunology. 2017;140(3):645–653.
140. Kim J, Krueger JG. Highly Effective New Treatments for Psoriasis Target the IL-23/Type 17 T Cell Autoimmune Axis. Annu Rev Med. 2017;68:255–269.
141. Chan TC, Hawkes JE, Krueger JG. Interleukin 23 in the skin: role in psoriasis pathogenesis and selective interleukin 23 blockade as treatment. Ther Adv Chronic Dis. 2018;9(5):111–119.
142. European Medicines Compendium. Tremfya. Summary of Product Characteristics. 2021. https://www.medicines.org.uk/emc/product/9587. Accessed 19 February 2021.
143. European Medicines Compendium. Ozurdex. Summary of Prescribing Information. 2021. https://www.medicines.org.uk/emc/product/5654/smpc#gref. Accessed 17 February 2021.
144. Sun Pharma. Sun Pharma announces receipt of European Commission approval for ILUMETRI® (tildrakizumab) by Almirall for treatment of moderate-to-severe chronic plaque psoriasis. 2018. www.sunpharma.com/Media/Press-Releases/Press Release European Commission Approval For ILUMETRI.pdf. Accessed 17 February 2021.
145. European Medicines Compendium. Flixabi. Summary of Product Characteristics. 2021. https://www.medicines.org.uk/emc/product/7265/smpc. Accessed 5 January 2022.
146. Nogueira M, Torres T. Guselkumab for the treatment of psoriasis – evidence to date. Drugs Context. 2019;8:212594.
147. Pithadia DJ, Reynolds KA, Lee EB, Liao W, Wu JJ. Tildrakizumab in the treatment of psoriasis: latest evidence and place in therapy. Ther Adv Chronic Dis. 2019;10. doi:10.1177/2040622319865658.
148. Reich K, Warren RB, Iversen L, Puig L, Pau-Charles I, Igarashi A, et al. Long-term efficacy and safety of tildrakizumab for moderate-to-severe psoriasis: pooled analyses of two randomized phase III clinical trials (reSURFACE 1 and reSURFACE 2) through 148 weeks. British Journal of Dermatology. 2020;182(3):605–617.
149. Thaci D, Piaserico S, Warren RB, Gupta AK, Cantrell W, Draelos Z, et al. Five-year efficacy and safety of tildrakizumab in patients with moderate-to-severe psoriasis who respond at week 28: pooled analyses of two randomized phase III clinical trials (reSURFACE 1 and reSURFACE 2)*. British Journal of Dermatology. 2021;185(2):323–334.
150. Drerup KA, Seemann C, Gerdes S, Mrowietz U. Effective and Safe Treatment of Psoriatic Disease with the Anti-IL-23p19 Biologic Tildrakizumab: Results of a Real-World Prospective Cohort Study in Nonselected Patients. Dermatology. 2021. doi:10.1159/000519924.
151. Costanzo A, Llamas-Velasco M, Fabbrocini G, Cuccia A, Rivera-Diaz R, Gaarn Du Jardin K, et al. Tildrakizumab improves high burden skin symptoms, impaired sleep and quality of life of moderate-to-severe plaque psoriasis patients in conditions close to clinical practice. Journal of the European Academy of Dermatology and Venereology. 2023;n/a(n/a). doi:https://doi.org/10.1111/jdv.19229.
152. Thaci D, Piaserico S, Warren RB, Gupta AK, Cantrell W, Draelos Z, et al. Five-year efficacy and safety of tildrakizumab in patients with moderate-to-severe psoriasis who respond at week 28: pooled analyses of two randomized phase III clinical trials (reSURFACE 1 and reSURFACE 2)*. British Journal of Dermatology. 2021;185(2):323–334.
153. Banaszczyk K. Risankizumab in the treatment of psoriasis - Literature review. Reumatologia. 2019;57(3):158–162.
154. Machado Á, Torres T. Spotlight on risankizumab and its potential in the treatment of plaque psoriasis: evidence to date. Psoriasis: Targets and Therapy. 2018;Volume 8:83–92.
155. Strober B, Menter A, Leonardi C, Gordon K, Lambert J, Puig L, et al. Efficacy of risankizumab in patients with moderate-to-severe plaque psoriasis by baseline demographics, disease characteristics and prior biologic therapy: an integrated analysis of the phase III UltIMMa-1 and UltIMMa-2 studies. Journal of the European Academy of Dermatology and Venereology. 2020;34(12):2830–2838.
156. Papp KA, Lebwohl MG, Puig L, Ohtsuki M, Beissert S, Zeng J, et al. Long-term efficacy and safety of risankizumab for the treatment of moderate-to-severe plaque psoriasis: interim analysis of the LIMMitless open-label extension trial beyond 3 years of follow-up. Br J Dermatol. 2021;185(6):1135–1145.
157. Gordon KB, Strober B, Lebwohl M, Augustin M, Blauvelt A, Poulin Y, et al. Efficacy and safety of risankizumab in moderate-to-severe plaque psoriasis (UltIMMa-1 and UltIMMa-2): results from two double-blind, randomised, placebo-controlled and ustekinumab-controlled phase 3 trials. The Lancet. 2018;392(10148):650–661.
158. Yamauchi PS, Bagel J. Next-generation biologics in the management of plaque psoriasis: A literature review of IL-17 inhibition. Journal of Drugs in Dermatology. 2015;14(3):244–250.
159. Koppu S, Singh R, Kaur K, Feldman SR. Review of bimekizumab in the treatment of psoriasis. Hum Vaccin Immunother. 2022;18(6):2119767.
160. Reich K, Warren RB, Lebwohl M, Gooderham M, Strober B, Langley RG, et al. Bimekizumab versus Secukinumab in Plaque Psoriasis. New England Journal of Medicine. 2021;385(2):142–152.
161. Warren RB, Blauvelt A, Bagel J, Papp KA, Yamauchi P, Armstrong A, et al. Bimekizumab versus Adalimumab in Plaque Psoriasis. New England Journal of Medicine. 2021;385(2):130–141.
162. Gordon KB, Foley P, Krueger JG, Pinter A, Reich K, Vender R, et al. Bimekizumab efficacy and safety in moderate to severe plaque psoriasis (BE READY): a multicentre, double-blind, placebo-controlled, randomised withdrawal phase 3 trial. The Lancet. 2021;397(10273):475–486.
163. Reich K, Papp KA, Blauvelt A, Langley RG, Armstrong A, Warren RB, et al. Bimekizumab versus ustekinumab for the treatment of moderate to severe plaque psoriasis (BE VIVID): efficacy and safety from a 52-week, multicentre, double-blind, active comparator and placebo controlled phase 3 trial. The Lancet. 2021;397(10273):487–498.
164. Foulkes AC, Warren RB. Brodalumab in psoriasis: Evidence to date and clinical potential. Drugs Context. 2019;8. doi:10.7573/dic.212570.
165. Pinter A, Bonnekoh B, Hadshiew IM, Zimmer S. Brodalumab for the treatment of moderate-tosevere psoriasis: Case series and literature review. Clin Cosmet Investig Dermatol. 2019;12:509–517.
166. Puig L, Lebwohl M, Bachelez H, Sobell J, Jacobson AA. Long-term efficacy and safety of brodalumab in the treatment of psoriasis: 120-week results from the randomized, double-blind, placebo- and active comparator–controlled phase 3 AMAGINE-2 trial. J Am Acad Dermatol. 2020;82(2):352–359.
167. Bissonnette R, Luger T, Thaçi D, Toth D, Lacombe A, Xia S, et al. Secukinumab demonstrates high sustained efficacy and a favourable safety profile in patients with moderate-to-severe psoriasis through 5 years of treatment (SCULPTURE Extension Study). Journal of the European Academy of Dermatology and Venereology. 2018;32(9):1507–1514.
168. Feldman SR, Gomez B, Meng X, Germino R. Secukinumab rapidly improves EQ-5D health status in patients with psoriasis: Pooled analysis from four phase 3 trials. Journal of Dermatological Treatment. 2021;32(7):709–715.
169. Blauvelt A, Reich K, Tsai TF, Tyring S, Vanaclocha F, Kingo K, et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate-to-severe plaque psoriasis up to 1 year: Results from the CLEAR study. J Am Acad Dermatol. 2017;76(1):60-69.e9.
170. Magnolo N, Kingo K, Laquer V, Browning J, Reich A, Szepietowski JC, et al. A phase 3 open-label, randomized multicenter study to evaluate efficacy and safety of secukinumab in pediatric patients with moderate to severe plaque psoriasis: 24-week results. J Am Acad Dermatol. 2022;86(1):122–130.
171. Van De Kerkhof PCM, Griffiths CEM, Reich K, Leonardi CL, Blauvelt A, Tsai TF, et al. Secukinumab long-term safety experience: A pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis. J Am Acad Dermatol. 2016;75(1):83-98.e4.
172. Khattri S, Goldblum O, Solotkin K, Amir Y, Min MS, Ridenour T, et al. Early onset of clinical improvement with Ixekizumab in a Randomized, open-label study of patients with moderate-to-severe plaque psoriasis. Journal of Clinical and Aesthetic Dermatology. 2018;11(5):33–37.
173. Sekhon S, Jeon C, Nakamura M, Yan D, Afifi L, Bhutani T, et al. Clinical utility of ixekizumab in the treatment of moderate-to-severe plaque psoriasis. Psoriasis: Targets and Therapy. 2017;7:65–72.
174. Strober B, Sigurgeirsson B, Popp G, Sinclair R, Krell J, Stonkus S, et al. Secukinumab improves patient-reported psoriasis symptoms of itching, pain, and scaling: Results of two phase 3, randomized, placebo-controlled clinical trials. Int J Dermatol. 2016;55(4):401–407.
175. Langley RG, Kimball AB, Nak H, Xu W, Pangallo B, Osuntokun OO, et al. Long-term safety profile of ixekizumab in patients with moderate-to-severe plaque psoriasis: an integrated analysis from 11 clinical trials. Journal of the European Academy of Dermatology and Venereology. 2019;33(2):333–339.
176. Boehringer Ingelheim. European Commission approves SPEVIGO® (spesolimab) for generalized pustular psoriasis flares. Press release. 2022. https://www.boehringer-ingelheim.com/human-health/skin-diseases/gpp/european-commission-approves-spevigo-spesolimab-generalized. Accessed 10 May 2023.
177. European Medicines Agency. Spevigo (spesolimab) EPAR. 2023. https://www.ema.europa.eu/en/medicines/human/EPAR/spevigo. Accessed 10 May 2023.
178. Bachelez H, Choon S-E, Marrakchi S, Burden AD, Tsai T-F, Morita A, et al. Trial of Spesolimab for Generalized Pustular Psoriasis. New England Journal of Medicine. 2021;385(26):2431–2440.
179. European Medicines Agency. Sotyktu (deucravacitinib) EPAR. 2023. https://www.ema.europa.eu/en/medicines/human/EPAR/sotyktu. Accessed 11 May 2023.
180. Armstrong AW, Gooderham M, Warren RB, Papp KA, Strober B, Thaçi D, et al. Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis: Efficacy and safety results from the 52-week, randomized, double-blinded, placebo-controlled phase 3 POETYK PSO-1 trial. J Am Acad Dermatol. 2023;88(1):29–39.
181. Strober B, Thaçi D, Sofen H, Kircik L, Gordon KB, Foley P, et al. Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis: Efficacy and safety results from the 52-week, randomized, double-blinded, phase 3 Program fOr Evaluation of TYK2 inhibitor psoriasis second trial. J Am Acad Dermatol. 2023;88(1):40–51.
182. European Medicines Agency. Sotyktu (deucravacitinib) EPAR - Medicine overview. 2023 https://www.ema.europa.eu/documents/overview/sotyktu-epar-medicine-overview_en.pdf. Accessed 11 May 2023.
183. Martin G. Novel Therapies in Plaque Psoriasis: A Review of Tyrosine Kinase 2 Inhibitors. Dermatol Ther (Heidelb). 2023;13(2):417–435.
184. McInnes IB, Byers NL, Higgs RE, Lee J, Macias WL, Na S, et al. Comparison of baricitinib, upadacitinib, and tofacitinib mediated regulation of cytokine signaling in human leukocyte subpopulations. Arthritis Res Ther. 2019;21(1):183.
185. Cohen S, Barer F, Itzhak I, Silverman MH, Fishman P. Inhibition of IL-17 and IL-23 in Human Keratinocytes by the A₃ Adenosine Receptor Agonist Piclidenoson. J Immunol Res. 2018;2018:2310970.
186. Clinicaltrials.gov. 2023. https://clinicaltrials.gov/. Accessed 9 May 2023.
187. EU clinical trials register. 2023. https://www.clinicaltrialsregister.eu/ctr-search/search. Accessed 9 May 2023.
188. Nast A, Altenburg A, Augustin M, Boehncke W-H, Härle P, Klaus J, et al. German S3-Guideline on the treatment of Psoriasis vulgaris, adapted from EuroGuiDerm – Part 2: Treatment monitoring and specific clinical or comorbid situations. JDDG: Journal der Deutschen Dermatologischen Gesellschaft. 2021;19(7):1092–1115.
189. Nast A, Altenburg A, Augustin M, Boehncke W-H, Härle P, Klaus J, et al. German S3-Guideline on the treatment of Psoriasis vulgaris, adapted from EuroGuiDerm – Part 1: Treatment goals and treatment recommendations. JDDG: Journal der Deutschen Dermatologischen Gesellschaft. 2021;19(6):150–934.
190. Lambert JLW, Segaert S, Ghislain PD, Hillary T, Nikkels A, Willaert F, et al. Practical recommendations for systemic treatment in psoriasis according to age, pregnancy, metabolic syndrome, mental health, psoriasis subtype and treatment history (BETA-PSO: Belgian Evidence-based Treatment Advice in Psoriasis; part 1). Journal of the European Academy of Dermatology and Venereology. 2020;34(8):1654–1665.