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 4, 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. 4 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. 4
Serious Infections
Higher rates of serious infections were detected in upadacitinib-treated patients at higher cardiovascular risk, which correlates with advanced age. 5 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. 6, 7
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. 4, 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. 4
Step 3: Assess Cardiovascular Risk Factors
- Prior cardiovascular disease (heart attack, stroke) 4
- Current or previous long-term smoking 4, 1
- Hypertension, diabetes, dyslipidemia 4
- Family history of premature coronary disease 4
If ≥1 cardiovascular risk factor is present in addition to age ≥78 years, alternative treatments are strongly preferred. 4, 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 8
If multiple VTE risk factors are present, upadacitinib should be avoided. 3, 8
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 9
- Lipid panel at baseline, 4-8 weeks after starting, then annually 9
Clinical Monitoring
- Monitor for signs of infection, particularly herpes zoster 9
- Counsel on warning signs of VTE (leg swelling, pain, sudden shortness of breath, chest pain) 8, 9
- 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. 4, 1, 10 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. 11, 10
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, 4, 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). 9, 7 Live vaccines are contraindicated during therapy. 1