Comparison of psoriasis guidelines for use of IL-23 inhibitors in the United States and United Kingdom: a critical appraisal and comprehensive review.

PURPOSE: This review article aims to compare global dermatologic organizations and the clinical practice guidelines available for the use of interleukin (IL)-23 inhibitors in the treatment of psoriasis. MATERIALS AND METHODS: A literature review encompassing systemic therapies for the treatment of psoriasis was conducted. Guidelines from the American Academy of Dermatology (AAD)-National Psoriasis Foundation (NPF), the National Institute for Health and Care Excellence (NICE), and the British Association of Dermatologists (BAD) served as the main comparators in this review. RESULTS: Of the American and European guidelines available for use of IL-23 inhibitors, several organizations are in agreement regarding the dosage and indications of guselkumab, tildrakizumab, and risankizumab. However, there are differences as well as insufficient recommendations concerning laboratory monitoring and screenings as well as contraindications to therapy. CONCLUSION: IL-23 inhibitors are safe and efficacious therapeutic options for patients with psoriasis and should be considered as a potential first-line therapy alone or in combination with topical medications, phototherapy, and other systemic non-biologic agents. Consideration should be given to the evidence-based guidelines of global dermatologic organizations to help guide therapeutic decisions.

IL-23 orchestrating immune cell activation in arthritis.

IL-23 is a cytokine member of the IL-12 superfamily. These heterodimeric cytokines offer broad immune regulatory activity with potential effector function in inflammatory arthritis. IL-23 is a pro-inflammatory cytokine secreted by dendritic cells and macrophages. It plays a key role in both innate and adaptive immunity. By promoting and maintaining T cell differentiation into Th17 T cells, IL-23 is a key player in the pathogenesis of rheumatic diseases. Data from pre-clinical IL-23 knockout models show the major importance of IL-23 in development of arthritis. The induction and maintenance of type 17 cells, which secrete IL-17A and other pro-inflammatory cytokines, contributes to local synovial inflammation and skin inflammation in PsA, and perhaps in RA. Commensurate with this, therapeutic strategies targeting IL-23 have proven efficient in PsA in several studies, albeit not yet in RA.

Guselkumab: the First Selective IL-23 Inhibitor for Active Psoriatic Arthritis in Adults.

INTRODUCTION: Guselkumab is a subcutaneously administered human monoclonal antibody, selectively blocking IL-23 through binding to its p19 subunit. It was initially approved for the treatment of patients with moderate-to-severe plaque-psoriasis who are candidates for systemic therapy or phototherapy. Pubmed and Embase databases were searched for publications, using the following search terms: psoriasis, psoriatic arthritis, guselkumab, risankizumab, tildrakizumab, p19, interleukin 23, guidelines, treatment recommendations, DISCOVER, ECLIPSE, and VOYAGE. AREAS COVERED: Accumulating evidence suggests that the IL-23/Th17 pathway is important in the pathogenesis of both psoriasis and psoriatic arthritis. Following a successful development program in psoriasis, guselkumab was evaluated for its efficacy and safety in psoriatic arthritis in a comprehensive clinical trial program, comprising one phase-2 study and two phase-3 studies (DISCOVER-1 and -2). Complementary data on pharmacokinetics and safety exist from pre-clinical experiments and pooled analyses from two long-term studies in psoriasis (VOYAGE-1 and -2). Based on the DISCOVER-1 and -2 data, guselkumab was approved by the FDA for the treatment of active psoriatic arthritis in 2020. EXPERT OPINION: Guselkumab is the first selective IL-23 inhibitor approved to treat adults with active psoriatic arthritis, broadening therapeutic options in the field through a novel mode of action.

Effect of biologics targeting interleukin-23/-17 axis on subclinical atherosclerosis: results of a pilot study.

BACKGROUND: Psoriasis is associated with an increased risk of developing atherosclerotic vascular disease. The hypothesis that treatment of the skin inflammation may decrease the risk of developing atherosclerosis and consequently, cardiovascular disease, is currently a focus of significant attention. AIM: To assess the effect of biologic drugs targeting the interleukin (IL)-23/IL-17 axis on selected subclinical atherosclerosis parameters in patients with psoriatic disease. METHODS: In a series of patients with moderate to severe psoriasis who were eligible for biologic therapy, pulse wave velocity (PWV) and intima-media thickness (IMT) were determined before therapy and after 6 months of treatment with biologics (ustekinumab, secukinumab, ixekizumab). RESULTS: After 6 months of treatment, a marked clinical improvement of skin lesions was observed in all patients. No significant changes in PWV or IMT values were observed before (8.59 ± 1.96 mm and 0.54 ± 0.9 mm, respectively) and after 6 months (8.89 ± 2.02 mm and 0.53 ± 0.9 mm) of therapy (P = 0.16 and P = 0.74). CONCLUSIONS: Systemic treatment of patients with a psoriatic disease with biologics targeting the IL-23/IL-17 axis has a possibly neutral effect on atherosclerosis. Additional studies are needed to assess the impact of newer biologic treatments on atherosclerosis.

Biologic therapies targeting the interleukin (IL)-23/IL-17 immune axis for the treatment of moderate-to-severe plaque psoriasis: a systematic review and meta-analysis.

There are a rapidly increasing number of novel biologic therapies for psoriasis targeting interleukin-23 (IL-23) and interleukin-17 (IL-17). This systematic review and meta-analysis evaluated the efficacy and safety of induction therapy (12-16 weeks) with biologic therapies targeting the IL-23/IL-17 immune axis for the treatment of moderate-to-severe plaque psoriasis. Twenty-seven randomized controlled trials met the specified inclusion criteria. The results showed that ixekizumab q2w had the greatest efficacy in terms of achieving 90% reduction in Psoriasis Area and Severity Index when compared to placebo [risk ratio (RR): 65.01, 95% confidence intervals (CI): 13.97-302.56, P < 0.00001], etanercept (RR: 3.14, 95% CI: 2.22-4.45) and ustekinumab (RR: 1.73, 95% CI: 1.41-2.12). The IL-17 inhibitors were overall shown to have a higher efficacy than the IL-23 inhibitors during induction therapy. However, the IL-17 inhibitors had an increased risk of adverse events when compared to placebo, while there was no increased risk with any of the IL-23 inhibitors. In conclusion, induction therapy with IL-17 inhibitors is highly efficacious but carries a higher risk of adverse events than induction therapy with IL-23 inhibitors.

Cost-Effectiveness of Targeted Pharmacotherapy for Moderate to Severe Plaque Psoriasis.

BACKGROUND: Newer classes of targeted drugs for moderate to severe plaque psoriasis are more effective and more expensive than older classes, posing a difficult and potentially costly decision about whether to use them as initial targeted treatments. OBJECTIVE: To estimate the clinical and economic outcomes of initial targeted treatment for the following drugs: adalimumab, etanercept, and infliximab (TNFα inhibitors); apremilast (PDE4 inhibitor); ustekinumab (IL-12/23 inhibitor); and ixekizumab, secukinumab, and brodalumab (IL-17 inhibitors). METHODS: We developed a Markov model to simulate patient outcomes as measured by quality-adjusted life-years (QALYs) and health care costs over a 10-year period. We assumed that patients who fail initial targeted treatment either proceed to subsequent therapy or discontinue targeted treatment. Effectiveness estimates for initial treatment were defined as improvement in Psoriasis Area and Severity Index (PASI) from baseline and derived from a 2018 network meta-analysis. Wholesale acquisition drug costs were discounted by a class-specific, empirically derived rebate percentage off of 2016 costs. We conducted one-way and probabilistic sensitivity analyses to assess uncertainty in results. RESULTS: The incremental benefits compared with no targeted treatment were, in descending order: ixekizumab 1.68 QALYs (95% credible range [CR] = 1.11-2.02), brodalumab 1.64 QALYs (95% CR = 1.08-1.98), secukinumab 1.51 QALYs (95% CR = 1.00-1.83), ustekinumab 1.43 QALYs (95% CR=0.94-1.74), infliximab 1.27 QALYs (95% CR = 0.89-1.55), adalimumab 1.15 QALYs (95% CR = 0.76-1.44), etanercept 0.97 QALYs (95% CR = 0.61-1.25), and apremilast 0.87 QALYs (95% CR = 0.52-1.17). Costs of care without targeted treatment totaled $66,451, and costs of targeted treatment ranged from $137,080 (apremilast) to $255,422 (ustekinumab). Probabilistic sensitivity analysis results indicated that infliximab and apremilast are likely to be the most cost-effective initial treatments at willingness-to-pay thresholds around $100,000 per QALY, while IL-17 drugs are more likely to be cost-effective at thresholds approaching $150,000 per QALY. Acquisition cost of the initial targeted drug and utility of clinical response were the most influential parameters. CONCLUSIONS: Our findings suggest that initial targeted treatment with IL-17 inhibitors is the most effective treatment strategy for plaque psoriasis patients who have failed methotrexate and phototherapy. Apremilast, brodalumab, infliximab, ixekizumab, and secukinumab are cost-effective at different willingness-to-pay thresholds. Additional research is needed on whether the effectiveness of targeted agents changes when used after previously targeted agents. DISCLOSURES: Funding for this study was contributed by the Institute for Clinical and Economic Review (ICER). Ollendorf, Chapman, Pearson, and Kumar are current employees, and Loos and Liu are former employees, of ICER, an independent organization that evaluates the evidence on the value of health care interventions, which is funded by grants from the Laura and John Arnold Foundation, Blue Shield of California Foundation, and the California HealthCare Foundation. ICER's annual policy summit is supported by dues from Aetna, AHIP, Anthem, Alnylam, AstraZeneca, Blue Shield of California, Cambia Health Solutions and MedSavvy, CVS Caremark, Editas, Express Scripts, Genentech, GlaxoSmithKline, Harvard Pilgrim Health Care, Health Care Service Corporation, OmedaRx, United Healthcare, Johnson & Johnson, Kaiser Permanente, Premera Blue Cross, Merck, National Pharmaceutical Council, Takeda, Pfizer, Novartis, Lilly, Humana, Prime Therapeutics, Sanofi, and Spark Therapeutics. Linder owns stock in Amgen, Biogen, and Eli Lilly; has contingent value rights in Sanofi Genzyme (related to alemtuzumab for multiple sclerosis); has received grant support from Astellas Pharma not related to this study and Clintrex, which was supported by AstraZeneca on an unrelated topic; and has received an honorarium from the Society of Healthcare Epidemiology of America (SHEA) as part of the SHEA Antimicrobial Stewardship Research Workshop Planning Committee, an educational activity supported by Merck. No other authors have potential conflicts of interest.

Emerging therapies in psoriasis: a systematic review.

Many new biologics are being studied for use in psoriasis. In this review, we evaluate and summarize findings about emerging biologic therapies for psoriasis. We reviewed published data from phase 2 and 3 clinical trials of 2 IL-17 inhibitors (ixekizumab and brodalumab); 3 IL-23 inhibitors (guselkumab, tildrakizumab, and risankizumab); and 1 tumor necrosis factor (TNF) inhibitor (certolizumab pegol). Janus kinase inhibitors were not included in our review, as they currently are not approved by the US Food and Drug Administration (FDA) and there are no plans to further develop this class for treatment of psoriasis. Overall, the clinical improvement provided by and the safety profiles of these agents are promising; they may be equal to or more efficacious than available therapeutic options for treating the symptoms of psoriasis. Long-term studies are still needed, however, to further establish safety and efficacy profiles for these biologic agents.

Guselkumab for the treatment of moderate-to-severe plaque psoriasis.

INTRODUCTION: Guselkumab is a human monoclonal antibody targeting the p19 subunit of IL-23 that has been approved for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. This medication blocks the IL-23/IL-17 axis, which has been implicated in playing a key role in the pathogenesis of psoriasis. Areas covered: This review outlines the pharmacologic properties, safety, and efficacy of guselkumab for the treatment of plaque psoriasis. Expert commentary: Guselkumab is the first IL-23 specific inhibitor to be approved for the treatment of plaque psoriasis. Phase II and III clinical trial results have demonstrated excellent safety and efficacy of guselkumab. IL-23 inhibitors may offer potential benefits over existing therapies for moderate-to-severe plaque psoriasis in terms of safety, frequency of administration, and efficacy. Long-term safety data will be critical in evaluating the role of guselkumab in the treatment of psoriasis.

Adverse Reactions to Biologics in Psoriasis.

Psoriasis is a chronic autoimmune disease which affects millions of people worldwide. Not only can psoriasis itself be debilitating and significantly reduce an individual's quality of life, but it is also a risk factor for other systemic disorders, such as metabolic syndrome, cardiovascular disease, and malignancy. Tremendous strides were made in the treatment of psoriasis during the mid-to-late-20th century, including the emergence of topical corticosteroids and vitamin D analogs, methotrexate, systemic retinoids, and phototherapy. However, it was not until 2004 with the advent of systemic biologic agents, which precisely target components of the immune system involved in the pathophysiological process of psoriasis, that the primary treatment benchmark increased from 50% improvement in the Psoriasis Area and Severity Index (PASI 50) to PASI 75, PASI 90, and even PASI 100, or complete resolution of cutaneous disease. Today, many patients receiving biologic therapy routinely experience greater than 75% or 90% reduction in cutaneous disease burden and a significant improvement in overall quality of life. These biologic agents are generally well-tolerated and safe but, like any medication, have associated adverse effects, some of which are predictable based on the effects of immune modulation, animal model studies, and human populations with known cytokine deficiencies. Going forward, it will be important to carefully monitor the safety profiles of these agents in both clinical trials and post-marketing surveillance registries to ensure long-term safety. It is reassuring that large safety registries are consistent in demonstrating an improved safety profile with newer and emerging biologic therapies.

Monoclonal antibodies inhibiting IL-12, -23, and -17 for the treatment of psoriasis.

Psoriasis is a chronic, inflammatory, immune-mediated skin condition that affects 3 to 4% of the adult US population, characterized by well-demarcated, erythematous plaques with silver scale. Psoriasis is associated with many comorbidities including cardiometabolic disease and can have a negative impact on quality of life. The current armamentarium of psoriasis treatment includes topical therapies, phototherapy, oral immunosuppressive therapies, and biologic agents. Over the past 2 decades, there has been rapid development of novel biologic therapies for the treatment of moderate-to-severe plaque psoriasis. This article will review the role of IL-12, IL-23, and IL-17 in the pathogenesis of psoriasis and the monoclonal antibodies (ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, tildrakizumab, and risankizumab) that target these cytokines in the treatment of this disease.

Guselkumab: First Global Approval.

Guselkumab (Tremfya™) is a human monoclonal IgG1λ antibody being developed by Janssen Biotech, Inc. that has been approved in the USA as a treatment for moderate-to-severe plaque psoriasis. Guselkumab inhibits the binding of interleukin 23 (IL-23) to its cell surface receptor, disrupting the type 17 helper T cell/IL-17 pathway. This article summarizes the milestones in the development of guselkumab leading to this first approval for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Biologic Therapy in Psoriasis (Part II): Efficacy and Safety of New Treatment Targeting IL23/IL-17 Pathways.

BACKGROUND: Psoriasis is a chronic immune-mediated inflammatory skin disorder that is estimated to affect 2-3% of the general population. The IL-23/IL-17 axis is currently considered to be crucial in the pathogenesis of psoriasis. METHODS: Biologics licensed for psoriasis include the TNFα inhibitors (infliximab, adalimumab, etanercept), the interleukin (IL)-12/23 monoclonal antibody (ustekinumab), and IL-17 inhibitor (secukinumab, ixekizumab). RESULTS: In this section, we analyse the role of IL-12, IL-23, and IL-17 in psoriasis and evaluated the efficacy and safety of biologic therapies targeting this cytokine. CONCLUSION: Dosing regimens, administration modality, and pharmacodynamics profiles of currently available anti-IL-12/IL-23 and IL-17 inhibitors are also examined.

Biological therapy targeting the IL-23/IL-17 axis in inflammatory bowel disease.

INTRODUCTION: As many inflammatory bowel disease (IBD) patients do not benefit from long-term anti-tumour necrosis factor treatment, new anti-inflammatories are urgently needed. After the discovery of the interleukin (IL) 23/17 axis being pivotal in IBD pathogenesis, many different compounds were developed, targeting different components within this pathway. Areas covered: A literature search to March 2016 was performed to identify the most relevant reports on the role of the IL-23/IL-17 axis in IBD and on the different molecules targeting this pathway. First, the authors briefly summarize the immunology of the IL-23/IL-17 pathway to elucidate the mode of action of all different agents. Second, they describe all different molecules targeting this pathway. Besides discussing efficacy and safety data, they also explore immunogenicity, exposure during pregnancy and pharmacokinetics. Expert opinion: A new era in IBD treatment has recently been initiated: besides immunomodulators and TNF-antagonists, anti-adhesion molecules and monoclonal antibodies targeting the IL-23/IL-17 pathway have been developed. Biomarkers for personalized medicine are urgently needed. This therapeutic (r)evolution will further improve disease-related and patient-reported outcome, though a lot of questions should still be addressed in future years.

Andrographolide alleviates imiquimod-induced psoriasis in mice via inducing autophagic proteolysis of MyD88.

Psoriasis is a chronic inflammatory skin disease with excessive activation of toll-like receptors (TLRs), which play important roles in developing psoriasis. Targeting TLR signaling remains a challenge for treating psoriasis. Here, we found that andrographolide (Andro), a small-molecule natural product, alleviated imiquimod- but not interleukin 23 (IL-23)-induced psoriasis in mice with reducing expressions of IL-23 and IL-1ß in the skin. The improvement in imiquimod-induced psoriasis by Andro was not observed in microtubule-associated protein 1 light chain 3 beta (MAP1LC3B) knockout mice. Furthermore, Andro inhibited mRNA expressions of IL-23, IL-6 and IL-1ß but not CD80 and CD86 in bone-marrow derived dendritic cells (BMDCs) treated with lipopolysaccharide (LPS) in a MAP1LC3B-dependent manner. In addition, Andro inhibited imiquimod-induced mRNA expressions of IL-23, IL-6, IL-1ß, CD80 and CD86 in BMDCs from mice. Interestingly, Andro induced a degradation of myeloid differentiation factor 88 (MyD88) and blocked the recruitment of TNF receptor-associated factor 6 (TRAF6) to MyD88 upon LPS stimulation in BMDCs from mice. Blockade of autophagic proteolysis using NH4Cl or MAP1LC3B(-/-) BMDCs abolished the Andro-induced MyD88 degradation. In conclusion, Andro controls activation of MyD88-dependent cytokines and alleviates psoriasis in mice via inducing autophagic proteolysis of MyD88, which could be a novel strategy to treat psoriasis.

New and emerging biologic therapies for moderate-to-severe plaque psoriasis: mechanistic rationales and recent clinical data for IL-17 and IL-23 inhibitors.

The development of effective and well-tolerated biologic therapies has advanced the management of psoriasis by enabling clinicians to treat underlying disease mechanisms. Biologics approved for the treatment of moderate-to-severe psoriasis include three tumor necrosis factor alpha inhibitors and an interleukin-12/interleukin-23 inhibitor. The establishment of the immunological basis of psoriasis has led to the development of biologic agents targeting specific downstream mediators in the psoriatic cascade. These drugs inhibit cytokines and cytokine signaling/transcription mediators like interleukin-17, which plays an important role in immunopathogenesis. Several interleukin-17 inhibitors are undergoing phase 3 clinical studies. In addition, biologics that selectively inhibit interleukin-23 have been assessed in phase 2 studies. This review describes how the dissection of pathways in the immunopathogenesis of psoriasis has led to the development of therapeutic agents and highlights the latest clinical efficacy, safety and tolerability data on new and emerging biologic therapies that selectively target interleukin-17 or interleukin-23.

Monoclonal gammopathy of undetermined significance in patients with psoriasis: is it really a side effect of biological therapy?

Moderate-to-severe psoriasis is treated using biological drugs targeting cytokines involved in the pathogenesis of the disease, such as tumor necrosis factor alpha (TNF-α) (adalimumab, infliximab, etanercept) and interleukin 12/23 (IL 12/23) (ustekinumab). There is a slight risk of developing hematological malignancies, such as monoclonal gammopathy of undetermined significance (MGUS) with anti TNF-α agents. There are no data available on anti-IL12/23 drugs. This retrospective study of data from 191 patients describes the appearance and follow-up of MGUS in three patients with psoriasis receiving long-term biological therapy. Since the appearance of MGUS occurred after about 6 years of anti-TNFα treatment in only three subjects, it was deemed unlikely to be due to the biological treatment. The decision not to suspend biological therapy after the appearance of MGUS was taken after careful assessment of the possible risks and benefits.

Structural basis of IL-23 antagonism by an Alphabody protein scaffold.

Protein scaffolds can provide a promising alternative to antibodies for various biomedical and biotechnological applications, including therapeutics. Here we describe the design and development of the Alphabody, a protein scaffold featuring a single-chain antiparallel triple-helix coiled-coil fold. We report affinity-matured Alphabodies with favourable physicochemical properties that can specifically neutralize human interleukin (IL)-23, a pivotal therapeutic target in autoimmune inflammatory diseases such as psoriasis and multiple sclerosis. The crystal structure of human IL-23 in complex with an affinity-matured Alphabody reveals how the variable interhelical groove of the scaffold uniquely targets a large epitope on the p19 subunit of IL-23 to harness fully the hydrophobic and hydrogen-bonding potential of tryptophan and tyrosine residues contributed by p19 and the Alphabody, respectively. Thus, Alphabodies are suitable for targeting protein-protein interfaces of therapeutic importance and can be tailored to interrogate desired design and binding-mode principles via efficient selection and affinity-maturation strategies.

Multiple lentigines in areas of resolving psoriatic plaques after ustekinumab therapy.

The development of lentigines in areas previously involved by psoriasis has been reported in the literature, classically related to phototherapy but also to topical products. More recently, some authors have described several cases of lentigines appearing in resolving psoriatic plaques during or after treatment with anti-tumour necrosis factor (TNF) drugs used to treat severe plaque psoriasis, including adalimumab, etanercept, and infliximab. We report the case of a patient that developed multiple lentigines after clearance of the plaques of psoriasis receiving treatment with ustekinumab for his psoriasis.

Role of IL-23 in the pathogenesis of psoriasis: a novel potential therapeutic target?

INTRODUCTION: Psoriasis is a chronic inflammatory skin disorder determined by the activation of several immune cells and resident tissue cells. Various cytokines mediate inflammatory signals, including IL-23, which is an important factor involved in the differentiation of T helper (Th17) cells. AREAS COVERED: Increasing evidence suggests that IL-23 is a central cytokine to the pathogenesis of psoriasis. An overview on both experimental and human data will be reported in order to support the hypothesis of a key pathogenic role of IL-23/Th17 axis. EXPERT OPINION: Targeting IL-23 might be a more selective, valid and effective therapeutic approach, which, potentially, may show important advantages in terms of long-term efficacy and safety in the treatment of psoriasis.

Does treatment of psoriasis reduce the risk of cardiovascular disease?

Psoriasis is an inflammatory disease associated with multiple comorbidities and cardiovascular risk factors. Patients with psoriasis have an increased risk of cardiovascular disease (CVD) and cardiovascular death. It has been proposed that overlapping mechanisms of systemic inflammation contribute to the link between psoriasis and cardiovascular disease. Some psoriasis treatments decrease systemic inflammation, but the effect of psoriasis treatments on heart disease is unknown. In this review of 23 original research publications, we present preliminary evidence that some psoriasis therapies improve cardiovascular biomarkers and the incidence of cardiovascular risk. Phototherapy may reduce some inflammatory cytokines, but there is little evidence for a decreased risk of CVD outcomes. Both methotrexate and tumour necrosis factor-α inhibitors improve cardiovascular inflammatory biomarkers and improve CVD outcomes. Short-term data on interleukin-12/23 inhibitors are varied, but most data suggest there is not an increase in cardiovascular events.