What are the considerations for using ustekinumab (a monoclonal antibody) in a patient with moderate to severe psoriatic arthritis and a history of severe infections or malignancies?

Ustekinumab in Psoriatic Arthritis with History of Severe Infections or Malignancies

Ustekinumab can be used in patients with moderate to severe psoriatic arthritis who have a history of solid tumor malignancy or severe infections, provided specific screening and monitoring protocols are followed, though it is considered less effective than TNF inhibitors for joint disease. 1

Efficacy Considerations for Psoriatic Arthritis

• Ustekinumab has FDA approval for active psoriatic arthritis but does not carry the label for prevention of joint destruction that TNF-α inhibitors possess. 1
• Ustekinumab is considered less effective than TNF-α inhibitors specifically for psoriatic arthritis manifestations. 1
• Patients switched from an effective biologic for PsA to ustekinumab may experience worsening of arthritis and other musculoskeletal symptoms. 1
• Despite lower efficacy for joints, ustekinumab remains a valuable option when TNF inhibitors have failed or are contraindicated due to safety concerns. 2, 3

Use in Patients with History of Malignancy

Patients with a history of solid tumor malignancy who have failed other therapies (ultraviolet phototherapy, methotrexate, acitretin) may receive ustekinumab without expectation of increased risk of tumor recurrence. 1

Key Evidence on Malignancy Risk:

• There is no definitive evidence that ustekinumab increases the risk of solid tumor or lymphoreticular malignancy. 1
• Pooled analysis of 3,117 patients treated with ustekinumab for up to 3 years showed malignancy rates comparable to the general US population based on SEER database. 1, 4
• Standardized incidence ratios for cancers excluding non-melanoma skin cancer were 0.98 (95% CI 0.74-1.29), demonstrating no increased risk. 1
• For patients with history of malignancy in the last 5 years requiring biologics, ustekinumab may be considered based on currently available evidence. 1

Critical Distinction from Other Biologics:

• TNF inhibitors carry theoretical concerns about malignancy recurrence, particularly in patients with recent malignancy history. 1
• Ustekinumab's mechanism (IL-12/IL-23 blockade) does not appear to alter malignancy risk in the same way as TNF inhibition. 1

Use in Patients with History of Severe Infections

Ustekinumab can be used in patients with history of severe infections, but requires careful screening for active infection and tuberculosis before initiation. 1

Infection Risk Profile:

• During placebo-controlled periods, overall infection rates per 100 patient-years were similar between placebo (121.0), ustekinumab 45 mg (145.7), and ustekinumab 90 mg (132.2). 4
• Serious infection rates remained stable or decreased over 3 years of treatment. 4
• Serious opportunistic infections (including tuberculosis) are rarely observed in clinical trials or practice. 1
• Throughout long-term treatment, serious infections occurred rarely and rates were comparable to the US psoriasis population. 4, 3

Comparative Safety Advantage:

• In patients with recurrent or serious infections, IL-12/IL-23 inhibitors like ustekinumab may be preferred over TNF or IL-17 inhibitors. 5
• This represents a conditional recommendation based on lower infection risk compared to TNF inhibitors. 5

Mandatory Pre-Treatment Screening

Tuberculosis Screening:

• Pretreatment test for latent TB is required using PPD, QuantiFERON-Gold, or T-Spot. 1
• Chest radiography is required if TB test is positive. 1
• Referral to infectious disease specialist should be considered on a case-by-case basis. 1

Hepatitis Screening:

• Serologic tests for hepatitis B and C are required: HB surface antigen, anti-HB surface antibody, anti-HB core antibody, and hepatitis C antibody. 1
• Patients with history of hepatitis B (confirmed resolved infection) do not need specialist follow-up but require monitoring for reactivation risk. 1
• Patients with active or history of hepatitis C may receive ustekinumab. 1

Additional Baseline Testing:

• Complete blood count with differential. 1
• Complete metabolic panel. 1
• HIV testing at practitioner's discretion based on patient-specific risk factors. 1

Ongoing Monitoring Requirements

Tuberculosis Monitoring:

• Yearly testing for latent TB (PPD, T-Spot, or QuantiFERON-Gold) is required in high-risk patients (those in contact with active TB due to travel, work, or family relationships, and patients with selected underlying medical conditions). 1
• For patients not at high risk, TB screening should be done at dermatologist's discretion. 1
• Exercise caution when using QuantiFERON-Gold test as it can remain positive after treatment of latent TB. 1

General Monitoring:

• Periodic history and physical examination, including screening for non-melanoma skin cancer. 1
• Screening for adverse effects at each visit. 1
• CBC with differential and CMP are not supported by evidence for routine ongoing monitoring. 1

Absolute and Relative Contraindications

Absolute Contraindications:

• History of allergic reaction to ustekinumab or vehicle. 1

Relative Contraindications:

• Untreated hepatitis B infection. 1
• History of lymphoreticular malignancy (use extreme caution). 1
• Active infection including TB or sepsis (initiation requires infectious disease consultation). 1

Dosing Considerations

Standard Dosing:

• Response to treatment is best ascertained after 12 weeks of continuous therapy. 1
• Overweight or obese patients often require the higher dose (90 mg) to achieve response equivalent to 45 mg in lower-weight patients. 1
• Serum concentrations are affected by weight, with lower concentrations in heavier patients at each dose. 1

Dose Escalation Options:

• Consider increasing dosing frequency to every 8 weeks. 1
• Consider increasing dose from 45 mg to 90 mg based on clinical response. 1

Temporary Discontinuation

Ustekinumab must be temporarily discontinued in the presence of febrile illness, especially illness requiring treatment. 1

• Treatment can be restarted after full resolution of symptoms/signs of infection and completion of any antibiotic course. 1
• Consider repeating loading doses upon restarting if the patient is flaring and/or if more than 3-4 half-lives have passed since the previous dose. 1

Special Populations

HIV-Positive Patients:

• Patients with HIV may receive ustekinumab if they are on HAART that has effectively normalized CD4+ T-cell counts, show undetectable viral load, and have no recent history of opportunistic infection. 1, 6
• Consultation with the patient's infectious disease provider is mandatory before initiating therapy. 1, 6

Pregnancy and Lactation:

• The safety of ustekinumab during pregnancy and lactation is uncertain. 1
• Ustekinumab is acceptable for men attempting conception with their partner. 1

Common Pitfalls to Avoid

• Do not assume ustekinumab has equivalent efficacy to TNF inhibitors for joint manifestations of psoriatic arthritis—it is FDA-approved but lacks the joint destruction prevention label. 1
• Do not skip tuberculosis screening even in patients with prior negative tests if they are now high-risk. 1
• Do not restart therapy during active infection—wait for complete resolution and antibiotic course completion. 1
• Do not overlook weight-based dosing requirements—heavier patients typically need 90 mg dosing. 1
• Do not combine with other potent immunosuppressants without careful consideration of infection risk. 1