Introduction to Ustekinumab

Ustekinumab (brand name Stelara) is a fully human IgG1κ monoclonal antibody that targets the p40 subunit of interleukin-12 (IL-12) and interleukin-23 (IL-23). It was first approved by the FDA in 2009 for the treatment of moderate to severe plaque psoriasis. Since then, its indications have expanded to include psoriatic arthritis, Crohn's disease, and ulcerative colitis.

Mechanism of Action

Ustekinumab works by binding to the p40 protein subunit used by both IL-12 and IL-23. This binding prevents these cytokines from interacting with their cell surface receptors, effectively inhibiting their biological activity. The inhibition of IL-12 and IL-23 signaling disrupts key pathways in the pathogenesis of several immune-mediated inflammatory disorders.

Key points:

• Binds with high affinity and specificity to the p40 subunit of IL-12 and IL-23
• Prevents IL-12 and IL-23 from binding to their cell surface IL-12Rβ1 receptor
• Inhibits T cell differentiation, particularly Th1 and Th17 cells
• Reduces production of inflammatory cytokines such as IFN-γ, IL-17A, IL-17F, and IL-22
• Modulates immune responses involved in psoriasis, psoriatic arthritis, and inflammatory bowel diseases

Indications

Ustekinumab is FDA-approved for the following indications:

1. Moderate to severe plaque psoriasis in patients 6 years and older who are candidates for phototherapy or systemic therapy
2. Active psoriatic arthritis in adults
3. Moderately to severely active Crohn's disease in adults
4. Moderately to severely active ulcerative colitis in adults

Off-label uses include:

• Hidradenitis suppurativa
• Pityriasis rubra pilaris
• Atopic dermatitis
• Refractory systemic lupus erythematosus

Dosage and Administration

Ustekinumab is administered subcutaneously or intravenously, depending on the indication. The dosage varies based on the condition being treated and patient weight:

For Plaque Psoriasis (subcutaneous):

• Adults weighing ≤100 kg: 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks
• Adults weighing >100 kg: 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks
• Pediatric patients (6-17 years): Weight-based dosing, ranging from 0.75 mg/kg to 90 mg, administered at weeks 0 and 4, then every 12 weeks

For Psoriatic Arthritis (subcutaneous):

• 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks
• 90 mg may be used in patients with co-existent moderate-to-severe plaque psoriasis weighing >100 kg

For Crohn's Disease and Ulcerative Colitis:

• Initial intravenous weight-based dose:
  • ≤55 kg: 260 mg
  • >55 kg to ≤85 kg: 390 mg
  • >85 kg: 520 mg
• Followed by 90 mg subcutaneous injection 8 weeks after initial dose, then every 8 weeks thereafter

Efficacy

Plaque Psoriasis:

• Approximately 66-76% of patients achieve PASI 75 (75% improvement in Psoriasis Area and Severity Index) at week 12
• Sustained efficacy observed in long-term studies up to 5 years
• Significant improvement in quality of life measures

Psoriatic Arthritis:

• ACR20 response (20% improvement in American College of Rheumatology criteria) achieved in 42-50% of patients at week 24
• Improves physical function and inhibits radiographic progression

Crohn's Disease:

• Clinical response observed in 55-60% of patients at week 6
• Maintenance of remission in about 50% of responders at week 52

Ulcerative Colitis:

• Clinical remission achieved in 15-16% of patients at week 8
• Maintenance of remission in 43-44% of responders at week 44

Side Effects

Common side effects (≥1% incidence) include:

• Nasopharyngitis (7-9%)
• Upper respiratory tract infections (5-7%)
• Headache (5-6%)
• Fatigue (3-5%)
• Injection site reactions (1-2%)
• Nausea (3% in IBD patients)
• Arthralgia (3% in psoriasis patients)

Serious side effects:

• Infections (including tuberculosis and opportunistic infections)
• Malignancies (slightly increased risk, causal relationship not established)
• Reversible posterior leukoencephalopathy syndrome (rare)
• Anaphylaxis and other hypersensitivity reactions
• Non-infectious pneumonia

Precautions and Monitoring

• Screen for tuberculosis before initiating therapy and monitor for active TB during treatment
• Evaluate patients for helminth infections before starting treatment in endemic areas
• Live vaccines should not be given concurrently with ustekinumab
• Monitor for signs and symptoms of malignancy
• Use with caution in patients with a history of malignancy
• Pregnancy Category B: Use only if clearly needed
• Monitor liver function tests in patients with Crohn's disease, as ustekinumab may increase the risk of hepatotoxicity
• Consider discontinuation if a serious hypersensitivity reaction occurs
• Advise patients to seek immediate medical attention if they experience any symptoms of RPLS (headache, seizures, confusion, visual disturbances)