What is the recommended treatment for an adult with severe plaque psoriasis?

Treatment for Severe Psoriasis

For adults with severe plaque psoriasis, initiate biologic therapy with infliximab, bimekizumab, ixekizumab, or risankizumab as first-line systemic treatment, as these agents achieve the highest clearance rates (PASI 90 in 70-80% of patients) with high-certainty evidence. 1, 2

Defining Severe Psoriasis

Severe psoriasis is defined by the FDA as extensive or disabling plaque psoriasis, typically involving:

• Body surface area ≥10% 1
• PASI score ≥10 combined with DLQI >10 1
• High-impact anatomic sites (face, scalp, palms/soles, nails, genitalia) even with limited body surface area, as these markedly impair quality of life 3

Patients qualify for systemic therapy when they have failed to respond to at least one prior systemic therapy, or when other systemic therapies are contraindicated or cannot be tolerated. 1

First-Line Biologic Therapy: Specific Agents and Dosing

Highest Efficacy Biologics (Ranked by PASI 90 Achievement)

Infliximab (anti-TNF-α):

• Dosing: 5 mg/kg IV at weeks 0,2,6, then every 8 weeks 1, 4
• Efficacy: 79-80% achieve PASI 75 by week 10; 50-70% achieve PASI 75 by weeks 8-16 1, 3, 2
• Critical consideration: Concomitant methotrexate is required to limit immunogenicity; without it, approximately 19% develop anti-infliximab antibodies 3
• Specific indication: First-line for generalized pustular psoriasis due to rapid and often complete disease clearance 5

Bimekizumab (anti-IL-17):

• Efficacy: PASI 90 in 84% (RR 30.27 vs placebo) with high-certainty evidence 2

Ixekizumab (anti-IL-17):

• Efficacy: PASI 90 in 84% (RR 30.19 vs placebo) with high-certainty evidence 2

Risankizumab (anti-IL-23):

• Efficacy: PASI 90 in 80% (RR 28.75 vs placebo) with high-certainty evidence 2

Alternative First-Line Biologics

Adalimumab (anti-TNF-α):

• Dosing: 80 mg at week 0, then 40 mg at week 1, then 40 mg every 2 weeks 1, 4
• Efficacy: 71% achieve PASI 75 at week 16 vs 7% with placebo 3
• Dose escalation: Can increase to 40 mg weekly for better control 6, 4
• Dual indication: Treats both skin and joint symptoms in psoriatic arthritis; inhibits radiographic joint damage 3

Ustekinumab (anti-IL-12/23):

• Dosing: 45 mg SC at weeks 0,4, then every 12 weeks for patients ≤100 kg; 90 mg SC at weeks 0,4, then every 12 weeks for patients >100 kg 1, 6
• Dose optimization: For inadequate response, escalate to 90 mg or shorten interval to every 8 weeks 1
• Site-specific efficacy: For palmoplantar psoriasis, 90 mg achieves 67% clearance vs 9% with 45 mg 1, 3; for nail psoriasis, median 100% NAPSI improvement by week 40 1, 3

Etanercept (anti-TNF-α):

• Dosing: 50 mg SC twice weekly for 12 weeks, then 50 mg weekly 1, 6, 3
• Efficacy: 48-66% achieve PASI 75 at week 12 3, 2

Traditional Systemic Agents (When Biologics Are Not Available)

Cyclosporine (Most Rapid Onset)

• Indication: Severe, recalcitrant psoriasis; particularly effective for erythrodermic and generalized pustular psoriasis 1, 5
• Dosing: 2.5-5.0 mg/kg/day in two divided doses 1, 6
• Efficacy: At 5 mg/kg/day, 65% achieve clear or almost clear result after 8 weeks; 50-70% achieve PASI 75 after 8-16 weeks 1
• Duration: Optimally used as interventional therapy for short 3-4 month courses; US approval for 1 year continuous treatment 1, 5
• Dose adjustment: Reduce by 0.5-1.0 mg/kg when clearance is achieved or when hypertension or decreased renal function occurs 1

Critical monitoring requirements:

• Blood pressure and serum creatinine every 2 weeks for first 3 months, then monthly 1
• Monthly CBC, LFTs, lipid profile, magnesium, uric acid, potassium 1
• Baseline PPD testing 1

Absolute contraindications:

• Abnormal renal function, uncontrolled hypertension, malignancy 1
• Concomitant PUVA/UVB, methotrexate, other immunosuppressives 1

Methotrexate (Preferred First-Line Oral Agent)

• Dosing: Initial 0.2 mg/kg body weight; maintenance 15 mg weekly initially, maximum 25-30 mg weekly 6
• Response time: 2 weeks 5
• Safety profile: Lower incidence of serious adverse events compared with most biologic agents, though evidence is of very low certainty 3, 2

Acitretin (For Pustular Psoriasis)

• Dosing: Starting 0.75 mg/kg/day; maintenance titrated to 0.5 mg/kg/day 6
• Efficacy: 23% achieve PASI 75 at 8 weeks with 50 mg/day; 75% reach PASI 50 at 6 months, 88% at 12 months 1
• Specific indication: Rapid and impressive responses in pustular psoriasis 1
• Critical contraception requirement: Absolute contraception for at least 1 month before, during, and for at least 2 years after stopping treatment 6

Combination Strategies to Enhance Efficacy

Adding topical therapy to biologics accelerates clearance:

• High-potency topical corticosteroid + etanercept for 12 weeks (Level I evidence, Strength A) 1, 3
• Calcipotriene/betamethasone dipropionate + adalimumab for 16 weeks accelerates plaque clearance (Strength B) 1, 3
• Topical calcipotriene + methotrexate improves outcomes (Level I evidence, Strength A) 5, 3

Combining biologics with conventional systemics:

• Ustekinumab + methotrexate may improve therapeutic outcomes 1, 3
• Ustekinumab + acitretin may augment efficacy 1, 3

Treatment Failure and Switching

Primary failure (initial nonresponse):

• Primary failure to one TNF-α inhibitor does not preclude successful response to a different TNF-α inhibitor, though it may portend reduced efficacy 1
• Failure of another biologic does not preclude successful response to ustekinumab 1

Secondary failure (loss of efficacy):

• All biologics may lose efficacy in patients who initially respond favorably 1
• One reason is antidrug antibodies; concomitant methotrexate with biologics increases drug survival 1
• Switching to a different biologic may result in improved efficacy, safety, or tolerability 1

Retreatment after discontinuation:

• Consider repeating loading doses if the patient is flaring and/or if more than 3-4 half-lives have passed since the previous dose 1
• Retreatment may result in a small percentage of patients not recapturing their previous robust response 1

Critical Safety Considerations

Tuberculosis screening mandatory before all biologics:

• Perform PPD or interferon-gamma release assay; if positive, start TB treatment prior to starting biologic 1, 6
• Monitor all patients for active TB during treatment, even if initial latent TB test is negative 1, 4

Serious infection risk:

• Increased risk of serious infections leading to hospitalization or death, including bacterial sepsis, invasive fungal infections (histoplasmosis), and opportunistic pathogens 4
• Discontinue biologic if patient develops serious infection or sepsis 4
• For patients who develop systemic illness on biologics and reside or travel to endemic mycoses regions, consider empiric antifungal therapy 1

Malignancy concerns:

• Lymphoma and other malignancies, some fatal, reported in children and adolescents treated with TNF blockers 4
• Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL) in adolescent and young adults with inflammatory bowel disease treated with TNF blockers 4
• Incidence of malignancies was greater in biologic-treated patients than controls 4

IL-17 inhibitor-specific caution:

• Avoid in patients with inflammatory bowel disease or at risk for it, as they may cause paradoxical worsening 6

Long-term safety data:

• Long-term safety data (beyond 6 months) for biologics remain limited 3, 7
• Biologics are generally well tolerated in long-term studies and offer a viable alternative to conventional non-biologic agents 7

Common Pitfalls to Avoid

• Never use systemic corticosteroids for psoriasis; abrupt withdrawal can precipitate severe, potentially fatal erythrodermic or pustular flares 5, 3
• Do not continue cyclosporine long-term due to toxicities; rapid relapse occurs after abrupt discontinuation 1
• Avoid live vaccinations during cyclosporine or biologic therapy 1
• Do not underdose biologics based solely on body surface area; high-impact sites warrant systemic therapy even with limited BSA 3
• Avoid grapefruit juice with cyclosporine as it alters drug metabolism 1