What are the recent therapeutic advances in the management of psoriasis, including first‑line topical treatments and newer biologic and small‑molecule systemic agents?

Recent Therapeutic Advances in Psoriasis Management

The treatment landscape for psoriasis has been revolutionized by IL-17 and IL-23 inhibitors, which demonstrate superior efficacy compared to traditional TNF inhibitors, while topical corticosteroids combined with vitamin D analogs remain the cornerstone of first-line therapy for limited disease. 1, 2

First-Line Topical Treatments

Topical agents are strongly recommended as first-line treatment for patients with limited body surface area involvement (typically <10% BSA or PASI <10). 1

• Combination therapy with topical corticosteroids and vitamin D analogs (calcipotriol) represents the most effective topical approach, offering synergistic anti-inflammatory and antiproliferative effects. 1

• Topical tacrolimus is conditionally recommended for sensitive areas including facial and intertriginous psoriasis where corticosteroid side effects are problematic. 1

• For nail psoriasis specifically, calcipotriol and glucocorticoid preparations are conditionally recommended as topical options, though biologics show superior efficacy. 1

Biologic Therapy Advances: The New Standard

IL-23 Inhibitors: The Most Recent Breakthrough

IL-23 inhibitors (guselkumab, risankizumab, tildrakizumab) represent the newest class of biologics and demonstrate the highest efficacy rates for skin clearance. 1, 2, 3

• Risankizumab and guselkumab achieve PASI 90 responses in 70-80% of patients, exceeding the efficacy of earlier biologics. 2, 3

• These agents target the p19 subunit of IL-23 specifically, offering more precise immunomodulation than the dual IL-12/23 inhibitor ustekinumab. 1, 2

• Dosing intervals are extended (every 12 weeks after loading), improving patient convenience compared to TNF inhibitors requiring every 2-week dosing. 2

IL-17 Inhibitors: High Efficacy Established

Secukinumab, ixekizumab, and brodalumab demonstrate superior skin clearance compared to TNF inhibitors, with PASI 90 responses in 60-70% of patients. 1, 3

• Secukinumab is recommended as a first-line biologic agent for adults with psoriasis, with or without psoriatic arthritis. 1

• Bimekizumab, a dual IL-17A and IL-17F inhibitor, represents the latest advancement in this class with potentially enhanced efficacy. 2

• IL-17 inhibitors show particular efficacy for dactylitis and enthesitis in psoriatic arthritis patients. 1

IL-12/23 Inhibitor: Ustekinumab

Ustekinumab is strongly recommended as a first-line biologic agent for adults with moderate-to-severe psoriasis. 1

• Standard dosing is 45 mg for patients <100 kg and 90 mg for patients ≥100 kg, administered at weeks 0,4, then every 12 weeks. 1

• Dose escalation strategies include increasing to 90 mg for patients <100 kg or shortening the interval to every 8 weeks for inadequate responders. 1

• Ustekinumab demonstrates 60% PASI 90 response rates and shows efficacy across multiple psoriasis variants including palmoplantar (67% clearance with 90 mg dose), nail (100% NAPSI improvement by week 40), and pustular psoriasis. 1

TNF Inhibitors: Still Essential

Despite newer agents, TNF inhibitors (adalimumab, infliximab, etanercept, certolizumab pegol) remain critical first-line options, particularly when psoriatic arthritis or cardiovascular comorbidities are present. 1, 4

• Adalimumab is specifically recommended as first-line therapy when psoriatic arthropathy is a consideration. 1

• TNF inhibitors demonstrate significant cardioprotective effects, reducing major adverse cardiovascular events with a hazard ratio of 0.50 (95% CI 0.32-0.79, P=.003) compared to other systemic therapies. 4

• Infliximab should be reserved for very severe disease or where other biologic agents have failed, given its intravenous administration and immunogenicity concerns. 1

Small Molecule Oral Therapies: The Newest Frontier

JAK Inhibitors

JAK inhibitors represent a major advance as oral alternatives to injectable biologics, with deucravacitinib (a selective TYK2 inhibitor) showing particular promise. 1, 2

• Deucravacitinib demonstrates efficacy comparable to biologics while offering oral administration convenience. 2

• JAK inhibitors show strong efficacy for dactylitis in psoriatic arthritis, with similar improvements to adalimumab at week 24. 1

PDE4 Inhibitors

Apremilast is strongly recommended for skin psoriasis and shows efficacy for dactylitis, though with lower skin clearance rates than biologics. 1

• Apremilast can be combined with ustekinumab, though long-term safety data for this combination are limited. 1

Traditional Systemic Agents: Still Relevant

Methotrexate remains the most commonly prescribed traditional systemic therapy worldwide and continues to play an important role despite biologic advances. 1, 5

• Methotrexate demonstrates 60% PASI 75 response at 16 weeks and is particularly effective for acute generalized pustular psoriasis, psoriatic erythroderma, and psoriatic arthritis. 5

• Dosing typically ranges from 7.5-25 mg weekly, with subcutaneous administration offering improved bioavailability over oral dosing. 1, 5

• Methotrexate can be combined with biologics (particularly TNF inhibitors and ustekinumab) to suppress antibody formation and potentially enhance efficacy, though this increases immunosuppression risk. 1

Cyclosporine is one of the most effective treatments for acute severe flares but is limited to 1 year in the US (2 years in UK) due to nephrotoxicity risk. 1

Acitretin is conditionally recommended and shows particular efficacy for pustular psoriasis, though limited as monotherapy for plaque psoriasis. 1

Treatment Selection Algorithm

Step 1: Define Disease Severity

• Mild disease: <10% BSA or PASI <10 → Topical therapy
• Moderate-to-severe disease: ≥10% BSA or PASI ≥10 AND DLQI >10 → Consider systemic therapy 1, 6

Step 2: Biologic Eligibility Criteria

Patients must meet ALL of the following before initiating biologics: 6

• DLQI >10 AND (PASI ≥10 OR BSA >10%)
• Disease severe for ≥6 months
• Documented failure, intolerance, or contraindication to BOTH methotrexate AND cyclosporine (or PUVA)

Earlier biologic initiation is justified when: 6

• Active psoriatic arthritis requiring treatment
• Rapidly relapsing disease
• Severe unstable life-threatening disease (PASI ≥20 or DLQI ≥18)
• Significant drug-related toxicity risk with traditional agents

Step 3: First-Line Biologic Selection

For skin-predominant disease without arthritis: 1

• First choice: IL-23 inhibitors (guselkumab, risankizumab) for highest skin clearance rates
• Alternative: Ustekinumab or secukinumab

For psoriasis with psoriatic arthritis: 1

• First choice: Adalimumab or other TNF inhibitors
• Alternatives: IL-17 inhibitors (secukinumab), IL-23 inhibitors, or JAK inhibitors

For patients with cardiovascular comorbidities: 4

• Strongly favor: TNF inhibitors for cardioprotective effects

Step 4: Assessing Treatment Response

Define response at drug-specific timepoints: 1, 6

• Infliximab: 14 weeks
• Etanercept: 12 weeks
• Adalimumab: 16 weeks
• Ustekinumab: 12 weeks

Minimum response criteria: 1

• ≥50% reduction in baseline PASI (PASI 50) AND
• ≥4-point improvement in DLQI

Optimal response: PASI 75 or greater 1

Step 5: Managing Inadequate Response

If primary failure (inadequate initial response): 1

• Consider dose escalation if feasible (e.g., ustekinumab 45→90 mg or every 12→8 weeks)
• Switch to alternative biologic class (e.g., TNF inhibitor → IL-23 inhibitor)
• Add adjunctive topical therapy or optimize methotrexate (oral → subcutaneous)

If secondary failure (loss of response): 1

• Check for antibody formation (particularly with monoclonal antibodies)
• Switch to different biologic class
• Consider adding methotrexate to suppress immunogenicity

Critical Safety Considerations

Mandatory pre-treatment screening: 4, 6

• Tuberculosis testing is mandatory before starting any biologic therapy due to reactivation risk with TNF inhibitors and other immunosuppressants
• Hepatitis B and C screening
• HIV testing in high-risk patients

Absolute contraindications to biologics: 4

• Active infections
• First-degree relatives with multiple sclerosis (for TNF inhibitors)
• Active tuberculosis

Relative contraindications requiring caution: 4

• Congestive heart failure (TNF inhibitors can worsen CHF)
• History of malignancy (individualize risk-benefit)
• Chronic infections

Registry enrollment: 6

• Enroll all patients starting biologics in long-term safety registries (BADBIR in UK/Ireland) for post-marketing surveillance

Common Pitfalls to Avoid

• Do not use biologics as first-line therapy without documented failure of traditional systemic agents (methotrexate and cyclosporine), except in specific circumstances outlined above. 6

• Do not assess treatment response too early—allow adequate time for each agent to demonstrate efficacy (12-16 weeks depending on drug). 1

• Do not overlook psoriatic arthritis—screen all psoriasis patients for joint symptoms, as this fundamentally changes treatment selection toward TNF inhibitors or IL-17/IL-23 inhibitors with arthritis indications. 1

• Do not ignore cardiovascular risk factors—TNF inhibitors offer unique cardioprotective benefits that should influence selection in high-risk patients. 4

• Do not combine biologics with each other—there is insufficient evidence for safety and unknown risk of serious adverse events. 1