What are the potential side effects of Upadacitinib (Rinvoq) in patients, particularly those with a history of cardiovascular disease or other comorbidities?

Upadacitinib Side Effects

Upadacitinib carries significant cardiovascular and thrombotic risks that require careful patient selection, particularly avoiding use in patients ≥65 years, current/former smokers, or those with cardiovascular risk factors unless no alternatives exist. 1

Serious Cardiovascular and Thrombotic Risks

Black box warnings exist for venous thromboembolism (VTE) and major adverse cardiovascular events (MACE) in higher-risk patients. 2, 3

Venous Thromboembolism

• Numerically increased rates of VTE observed in clinical trials, primarily with the 15 mg once daily dose 1
• Risk factors include age, high BMI, immobilization, surgery, Cox-2 inhibitor use, and prior VTE history 1
• Patients with prior VTE history have up to 10-fold increased risk 1
• Patients should seek immediate medical attention for signs of deep venous thrombosis or pulmonary embolism 3

Major Adverse Cardiovascular Events

• MACE rates (myocardial infarction, stroke, cardiovascular death) were similar to adalimumab in controlled trials 1
• However, increased risk observed in patients ≥50 years with cardiovascular risk factors 4
• Current or past smokers and patients with other cardiovascular risk factors should be monitored closely 3

Regulatory Restrictions for High-Risk Patients

• The European Medicines Agency cautions that JAK inhibitors should only be used in the following patients if no suitable alternatives exist: 1
  • Patients aged ≥65 years 1
  • Those at increased risk of major cardiovascular problems 1
  • Current or long-term past smokers 1
  • Those at increased risk of cancer 1

Infectious Complications

Serious Infections

• Serious infection rates with upadacitinib 15 mg were similar to adalimumab but higher than methotrexate 5
• Higher rates observed in patients ≥65 years and those with cardiovascular risk factors 4
• Patients should contact their healthcare provider immediately if signs of infection develop 3

Herpes Zoster

• Significantly elevated risk compared to adalimumab and methotrexate 5, 6, 4
• Rates of 4.0-7.2% reported in maintenance therapy 2
• Can be serious in some cases 3
• Recombinant zoster vaccine (Shingrix) should be administered before initiating therapy 7

Opportunistic Infections

• Higher rates with upadacitinib versus adalimumab (excluding tuberculosis, herpes zoster, and oral candidiasis) 6
• Mandatory screening for latent tuberculosis before initiation using interferon-gamma release assay or tuberculin skin test 7
• Screen for viral hepatitis before treatment 7

Malignancy Risk

• Rates of malignancies (excluding non-melanoma skin cancer) were similar across upadacitinib, methotrexate, and adalimumab 5, 4
• Non-melanoma skin cancer rates were higher with upadacitinib versus comparators 4
• Almost all malignancies occurred in patients aged ≥53 years 8
• Periodic skin examinations should be performed and sun exposure limited with protective clothing and broad-spectrum sunscreen 3

Gastrointestinal Complications

Gastrointestinal Perforation

• Reported in clinical trials, possibly a class effect of JAK inhibitors 1
• Use with caution in patients at increased risk: 1
  • History of diverticulitis 1
  • Concomitant NSAID use 1
  • Concomitant glucocorticoid use 1
• Patients should seek immediate medical care for new onset abdominal pain, fever, chills, nausea, or vomiting 1, 3
• Fever and acute phase reactants may be blunted by JAK inhibitor therapy, complicating diagnosis 1

Laboratory Abnormalities

Creatine Phosphokinase (CPK) Elevations

• Commonly observed, usually without clinical sequelae 1, 5
• Occasionally associated with myalgia but rarely with weakness 1
• One case of rhabdomyolysis reported 1
• CPK testing only necessary if symptoms develop 1

Hematologic Changes

• Interrupt treatment if absolute neutrophil count <1000 cells/mm³ 2, 7
• Interrupt treatment if absolute lymphocyte count <500 cells/mm³ 2, 7
• Hemoglobin decreases ≤20 g/L and levels ≥90 g/L do not require dose adjustment 1
• Hemoglobin <80 g/L (confirmed by repeat testing) should lead to dose interruption 1

Hepatic and Renal Changes

• Creatinine increases observed without organ dysfunction or clinical sequelae 1
• Transaminase elevations can occur 1

Lipid Elevations

• Dose-dependent lipid elevations occur with JAK inhibitors 7
• Lipid profile should be checked at baseline and at 3 months 1, 7

Common Adverse Events

The most frequently reported treatment-emergent adverse events include: 5, 9, 6

• Upper respiratory tract infection 5, 6
• Nasopharyngitis 5, 6
• Urinary tract infection 5
• Increased creatine phosphokinase 6

Monitoring Requirements

Mandatory laboratory monitoring schedule: 1, 7

• Baseline: Complete blood count with differential, comprehensive metabolic panel (liver enzymes, renal function), lipid profile 7
• At 1 month: Full blood count with differential, transaminases, renal function 1
• At 3 months: Full blood count with differential, transaminases, renal function, lipid levels 1
• Every 3 months thereafter: Full blood count with differential, transaminases, renal function 1

Special Populations

Pregnancy and Lactation

• Contraindicated in pregnancy; teratogenic in animal studies 1
• Effective contraception required during treatment and for 4 weeks after final dose 3
• Do not breastfeed during treatment and for 6 days after last dose 3

Severe Organ Dysfunction

• Do not use with severe hepatic disease (Child-Pugh C) 1
• Baricitinib not recommended if creatinine clearance <30 mL/min; tofacitinib requires dose reduction 1
• No dosage reduction currently recommended for upadacitinib with renal impairment, though 20% undergoes renal excretion 1

Retinal Complications

• Retinal detachment reported in clinical trials 3
• Patients should immediately inform healthcare provider of sudden vision changes 3

Critical Pitfalls to Avoid

• Do not initiate in patients with active serious infections 7
• Do not use live vaccines during treatment 3
• Do not overlook cardiovascular risk assessment in older patients 8
• Do not fail to complete tuberculosis screening and hepatitis screening before initiation 7
• Do not assume absence of symptoms equals absence of latent tuberculosis 7