IL-23 Inhibitors: The Gold Standard in Psoriasis Treatment

Understanding Psoriasis and Why Treatment Must Be Targeted

Psoriasis is more than a skin disease; it is a chronic, immune-mediated inflammatory disorder that primarily affects the skin but also significantly increases the risk of comorbid conditions like psoriatic arthritis, metabolic syndrome, cardiovascular diseases, and mental health disorders. Affecting around 2–3% of the global population, psoriasis demands lifelong management. Over the past decade, the therapeutic landscape has transformed—biological treatments have revolutionized outcomes for many patients. Still, individualized care remains crucial, and non-biologic therapies still hold relevance.

Biologic Therapies: Redefining Psoriasis Management

Biologic drugs are bioengineered proteins derived from human genes that target specific components of the immune system. They have set a new standard in managing moderate to severe psoriasis, particularly in patients unresponsive to conventional systemic agents or those with contraindications.

1. TNF-Alpha Inhibitors: The First Wave

Tumor necrosis factor-alpha (TNF-α) plays a central role in psoriasis pathogenesis. Drugs targeting this cytokine include:

• Etanercept: A fusion protein that inhibits TNF-α. Administered subcutaneously, it's often used in both psoriasis and psoriatic arthritis.
• Infliximab: A chimeric monoclonal antibody requiring IV infusion. It shows rapid and significant PASI score reductions.
• Adalimumab: A fully human monoclonal antibody with both dermatologic and rheumatologic indications.

While effective, TNF inhibitors are now being replaced in many cases by newer biologics due to concerns about long-term immunogenicity and relatively slower onset of action.

2. IL-12/23 Inhibitors: Bridging the Immune Axis

• Ustekinumab: Targets the shared p40 subunit of interleukin (IL)-12 and IL-23, reducing Th1 and Th17 cell-mediated inflammation. It is dosed every 12 weeks, making it patient-friendly.

This class provided significant improvements in moderate-to-severe plaque psoriasis but was gradually superseded by selective IL-23 blockers due to superior efficacy.

3. IL-17 Inhibitors: Fast-Acting Precision

Interleukin-17 (IL-17) is pivotal in psoriasis pathogenesis.

• Secukinumab and Ixekizumab: Both target IL-17A. They show rapid onset and high skin clearance rates.
• Brodalumab: Targets the IL-17 receptor A (IL-17RA), offering a broader blockade of the IL-17 pathway but comes with psychiatric risk warnings (notably suicidality).

This class is associated with high rates of complete skin clearance (PASI 90 and even PASI 100 responses), making it a top-tier option for patients seeking fast relief.

4. IL-23 Inhibitors: The New Gold Standard

• Guselkumab, Tildrakizumab, and Risankizumab: These target the p19 subunit of IL-23, selectively modulating the Th17 axis without affecting IL-12.

IL-23 inhibitors are long-acting, well-tolerated, and exhibit durable efficacy with dosing every 8–12 weeks, making them the current benchmark in biologic therapy.

5. JAK Inhibitors: Oral Targeted Therapies Emerging

Though not biologics in the classical sense, Janus kinase (JAK) inhibitors such as Deucravacitinib (a TYK2 inhibitor) represent the frontier of oral targeted therapy for psoriasis, offering biologic-like effects in pill form. They are particularly attractive for patients with needle aversion or unstable access to injection services.

How to Choose the Right Biologic?

Factors include:

• Phenotype of Psoriasis: Erythrodermic or pustular variants may respond differently.
• Presence of Psoriatic Arthritis: TNF-α or IL-17 inhibitors have dual efficacy.
• Comorbidities: E.g., avoid TNF inhibitors in demyelinating disorders.
• Patient Lifestyle and Preference: Frequency of dosing, route of administration.
• Previous Treatment Response: Primary or secondary failure.
• Insurance and Cost Factors: Accessibility can dictate therapy options.

Other Best Treatment Approaches Beyond Biologics

While biologics dominate headlines, non-biologic therapies still play a vital role, especially for mild to moderate disease or in combination with biologics.

1. Topical Treatments: First-Line for Mild Psoriasis

• Corticosteroids: Still the most commonly used topical agents. Potency must be matched to site.
• Vitamin D Analogues: Calcipotriol, often in combination with steroids.
• Coal Tar and Salicylic Acid: Effective for scale reduction but less cosmetically elegant.

These are ideal for localized disease or maintenance therapy between biologic injections.

2. Phototherapy: Light as a Medicine

• Narrowband UVB: Widely used for moderate psoriasis with excellent safety and efficacy.
• Excimer Laser: For localized plaques.
• PUVA Therapy: Less commonly used now due to carcinogenic potential.

Phototherapy remains a cost-effective, safe option, especially in resource-limited settings.

3. Traditional Systemic Agents: Still Holding Their Ground

• Methotrexate: Cheap, effective, with dual benefit in arthritis. But hepatotoxicity, teratogenicity, and bone marrow suppression limit its use.
• Cyclosporine: Rapid onset but nephrotoxicity and hypertension are concerns.
• Acitretin: A systemic retinoid helpful in pustular and erythrodermic variants, though teratogenic.

These agents are also used as bridging therapy while initiating biologics.

Emerging Therapies and Future Perspectives

1. RNA-Based Therapies

Antisense oligonucleotides and RNA interference are being explored to silence key inflammatory mediators.

2. Microbiome Modulation

Alterations in skin and gut microbiota have been linked to psoriasis. Probiotic and microbiome-targeted therapies may become part of the future armamentarium.

3. Personalized Immunotherapy

Advanced immunophenotyping may soon allow tailored biologic regimens based on individual immune signatures.

4. Vaccine-Based Approaches

Still in preclinical stages, antigen-specific immune modulation could someday offer a disease-modifying cure.

Psychodermatology and Holistic Care

Managing psoriasis is not just about clearing plaques—it’s about improving quality of life.

• Cognitive Behavioral Therapy (CBT): Useful in stress-triggered flares.
• Dietary Interventions: Gluten-free, anti-inflammatory diets show promise in select patients.
• Weight Reduction: Obesity is a major comorbidity that exacerbates inflammation and reduces biologic efficacy.

Combination Therapy: Optimizing Outcomes

Biologics combined with topical agents, phototherapy, or traditional systemics may provide synergistic benefits, especially in:

• Partial responders
• Flare control
• Resistant anatomical areas (e.g., scalp, nails, genitals)

This multi-modal strategy can minimize doses, reduce side effects, and enhance patient satisfaction.

Patient Education and Long-Term Monitoring

Regardless of the treatment chosen, adherence and realistic expectations are key. Many biologics take weeks to months for full effect. Patients must be screened for infections (e.g., TB, hepatitis), and monitored periodically for adverse effects.

Vaccinations, reproductive counseling, and drug interaction checks are integral to safe therapy, especially for younger patients.