Is upadacitinib (Rinvoq) safe in patients with advanced age, specifically those aged 78 years?

Upadacitinib Safety in 78-Year-Old Patients

Upadacitinib should only be used in a 78-year-old patient when no suitable alternative treatments are available, due to significantly elevated risks of serious infections, major adverse cardiovascular events, malignancies, and venous thromboembolism in this age group. 1, 2

Age-Specific Contraindications and Warnings

The European Medicines Agency specifically recommends using tofacitinib (and by extension, JAK inhibitors as a class) in patients with rheumatoid arthritis "above the age of 65 only when there is no alternative treatment." 3 This recommendation stems from safety data showing increased risks in older populations across multiple JAK inhibitors.

For patients aged ≥65 years, upadacitinib should only be prescribed when no suitable alternatives exist, based on increased risk of major cardiovascular events, serious infections, and malignancy. 1 The FDA label specifically notes higher rates of serious infections and malignancies in patients 65 years and older receiving the 30 mg dose in long-term atopic dermatitis trials. 2

Evidence from Clinical Trials in Older Adults

Rheumatoid Arthritis and Psoriatic Arthritis

• Of 4,381 patients treated across five RA trials, 906 were ≥65 years and 146 were ≥75 years 2
• Of 1,827 patients in two PsA trials, 274 were ≥65 years and 34 were ≥75 years 2
• No differences in effectiveness were observed between older and younger patients, but there was a higher rate of overall adverse events, including serious infections, in patients ≥65 years 2

Atopic Dermatitis

• Of 2,583 patients in three Phase 3 trials, 120 were ≥65 years and only 6 were ≥75 years 2
• Higher rates of serious infections and malignancies occurred in patients ≥65 years in the 30 mg dosing group in long-term trials 2

Specific Safety Risks in Advanced Age

Venous Thromboembolism Risk

Age is a major independent risk factor for VTE with JAK inhibitors, with patients older than 65 years at higher risk. 3 The risk may be up to 10-fold for patients with a history of VTE and twofold for those taking COX-2 inhibitors. 3

• VTEs occurred primarily in patients with risk factors including advanced age, obesity, immobility, surgery, COX-2 inhibitor use, and prior VTE history 3
• Numerically increased rates of VTEs were observed in double-blind phases of upadacitinib trials, primarily with the 15 mg once-daily dose 3
• Patients aged ≥50 years with cardiovascular risk factors should not receive JAK inhibitors as first-line therapy when TNF inhibitors remain an option 3, 1

Cardiovascular Events

The ORAL Surveillance study (tofacitinib in RA patients ≥50 years with cardiovascular risk factors) demonstrated increased risk of major adverse cardiovascular events over a median 4-year follow-up, particularly at higher doses. 3 While this was a tofacitinib study, regulatory agencies have applied class-wide warnings to all JAK inhibitors. 3

Patients aged ≥50 years with cardiovascular risk factors (prior cardiovascular disease, current/past smoking, hypertension, diabetes, family history of premature coronary disease) require cautious use of JAK inhibitors. 3

Serious Infections

Higher rates of serious infections were detected in upadacitinib-treated patients at higher cardiovascular risk, which correlates with advanced age. 4 The EMA restricted tofacitinib use in people older than 65 years due to increased risk of serious infections. 3

Malignancy Risk

History of malignancy within the past 5 years requires careful risk-benefit assessment, particularly given ORAL Surveillance data showing increased malignancy risk with JAK inhibitors. 1 Rates of malignancy (excluding NMSC) were 0.3-0.5 events per 100 patient-years across upadacitinib studies, with higher rates in older populations. 5, 6

Clinical Decision Algorithm for 78-Year-Old Patients

Step 1: Assess Absolute Contraindications

• Active tuberculosis, sepsis, or opportunistic infections 1
• Current malignancy (except adequately treated NMSC or cervical carcinoma in situ) 1
• Decompensated liver disease (Child-Pugh C) 1
• Severe renal impairment (CrCl <15 mL/min for AD/UC/CD) 2
• History of unprovoked or recurrent VTE 1

Step 2: Evaluate Alternative Treatments

If TNF inhibitors, IL-23 inhibitors, or other biologics are viable options, these should be prioritized over upadacitinib in a 78-year-old patient. 3, 1 The 2024 AGA guideline for ulcerative colitis specifically recommends cautious use of JAK inhibitors in patients at high risk of major adverse cardiovascular events. 3

Step 3: Assess Cardiovascular Risk Factors

• Prior cardiovascular disease (heart attack, stroke) 3
• Current or previous long-term smoking 3, 1
• Hypertension, diabetes, dyslipidemia 3
• Family history of premature coronary disease 3

If ≥1 cardiovascular risk factor is present in addition to age ≥78 years, alternative treatments are strongly preferred. 3, 1

Step 4: Evaluate VTE Risk Factors

• History of VTE (10-fold increased risk) 3
• Obesity (2-fold increased risk) 3
• Recent surgery or prolonged immobility 3
• COX-2 inhibitor use (2-fold increased risk) 3
• Hereditary thrombophilia 3

If multiple VTE risk factors are present, upadacitinib should be avoided. 3

Step 5: Pre-Treatment Screening (If Proceeding)

• TB testing (interferon-gamma release assay or tuberculin skin test) and chest X-ray 1
• Hepatitis B and C screening 1
• Complete blood count with differential 1
• Comprehensive metabolic panel (liver and renal function) 1
• Lipid panel 1
• Cardiovascular risk assessment 1
• Skin examination for NMSC in at-risk patients 1

Step 6: Dosing Considerations

For atopic dermatitis in patients with severe renal impairment, the maximum dose is 15 mg once daily. 2 For ulcerative colitis or Crohn's disease with severe renal impairment, use 30 mg once daily for induction and 15 mg once daily for maintenance. 2

No dose adjustment is needed for mild-to-moderate hepatic impairment (Child-Pugh A/B), but severe hepatic impairment (Child-Pugh C) is not recommended. 2

Monitoring Requirements

Laboratory Monitoring

• CBC with differential and comprehensive metabolic panel at baseline, 4-8 weeks after starting, then every 3 months 7
• Lipid panel at baseline, 4-8 weeks after starting, then annually 7

Clinical Monitoring

• Monitor for signs of infection, particularly herpes zoster 7
• Counsel on warning signs of VTE (leg swelling, pain, sudden shortness of breath, chest pain) 3, 7
• Regular skin examinations for NMSC 1

Common Pitfalls to Avoid

Do not use upadacitinib as first-line therapy in a 78-year-old patient when biologics are available and appropriate. 3, 1, 8 The FDA approved upadacitinib for use after failure of other systemic therapies (pills or injections, including biologics) or when use of those therapies is inadvisable. 3, 8

Do not overlook the cumulative effect of multiple risk factors. A 78-year-old patient with obesity, hypertension, and prior smoking history has substantially elevated risk that may make upadacitinib inappropriate even if no single absolute contraindication exists. 3

Do not fail to vaccinate before starting therapy. Patients should receive recombinant zoster vaccine (Shingrix) before initiating treatment, as herpes zoster rates are elevated with upadacitinib (2.4-6.6 events per 100 patient-years across indications). 7, 6 Live vaccines are contraindicated during therapy. 1