Why are Janus kinase (JAK) inhibitors, such as baricitinib (baricitinib), not preferred in patients with a first-degree relative history of cancer?

JAK Inhibitors and Family History of Cancer: Clarifying the Confusion

The concern about JAK inhibitors in patients with a first-degree relative history of cancer stems from regulatory caution based on the ORAL Surveillance trial, but this restriction specifically applies to the patient's own history of cancer, not family history alone. 1

Understanding the Actual Regulatory Restrictions

The European Medicines Agency recommends cautious use of JAK inhibitors as first-line agents in patients with "a history of cancer" - meaning the patient themselves, not their relatives. 1 The FDA similarly restricts first-line use but does not specifically cite family history as a contraindication. 1

The key risk factors identified for JAK inhibitor caution include: 1

• Age ≥65 years
• Current or previous long-term smoking
• History of cardiovascular disease (heart attack or stroke)
• History of cancer (in the patient)

The Evidence Behind Cancer Concerns

The ORAL Surveillance trial in rheumatoid arthritis patients aged ≥50 years with cardiovascular risk factors showed increased cancer risk with tofacitinib (particularly 10 mg twice daily) compared to TNF antagonists over 4 years of follow-up. 1 Notably, this included an imbalance in lung cancer cases, many in patients with current or past smoking history. 1

However, the actual cancer risk in dermatology populations appears substantially lower: 2

• Non-melanoma skin cancer rates: 0-0.9% versus 0% in placebo
• Other malignancies: 0-0.7% versus 0-0.6% in placebo
• Most patients who developed malignancies had pre-existing risk factors

Distinguishing Personal vs. Family History

The 2025 expert consensus statement on JAK inhibitors lists "current (or history of) malignancies" as a contraindication, explicitly referring to the patient's own cancer history, not family history. 1 The statement notes that patients with previous malignancies (typically within the last 5 years) are usually excluded from clinical trials. 1

Family history of cancer (such as "family history of premature coronary heart disease") was mentioned in the ORAL Surveillance trial as one of multiple cardiovascular risk factors, not as an independent cancer risk factor. 1

Practical Clinical Algorithm

For patients with first-degree relative history of cancer but no personal cancer history:

• JAK inhibitors are NOT contraindicated based on family history alone 1
• Assess the patient's own cancer risk factors: age, smoking status, cardiovascular disease, immunosuppression history 1
• Perform baseline skin examination for non-melanoma skin cancer in at-risk patients 1, 3
• Consider age-specific cancer screening (particularly for patients ≥53 years) 4

For patients with personal history of cancer:

• Carefully evaluate risk-benefit ratio, particularly if cancer occurred within the last 5 years 1
• Consider alternative therapies such as vedolizumab or anti-IL therapies, which may have lower malignancy risk 1
• If JAK inhibitor use is necessary, ensure close monitoring and multidisciplinary consultation 1

Common Pitfalls to Avoid

Do not conflate family history with personal history - the regulatory warnings and clinical evidence specifically address patients with their own cancer history, not familial predisposition. 1

Do not overlook non-melanoma skin cancer risk - this is the most consistently elevated malignancy risk across JAK inhibitor trials, with reporting odds ratios of 1.67-5.40 depending on the specific agent. 5, 2

Do not ignore the dose-dependent relationship - higher doses (particularly tofacitinib 10 mg twice daily) showed greater cancer risk than lower doses or 2 mg formulations. 1, 6

Monitoring Recommendations

For all patients on JAK inhibitors, regardless of family history: 4, 2

• Baseline screening: hepatitis B/C, tuberculosis, complete blood count, liver enzymes, renal function
• Ongoing monitoring: CBC with differential and comprehensive metabolic panel at 4-8 weeks, then every 3 months
• Annual skin examinations for patients with risk factors for skin cancer 1, 3
• Age-appropriate cancer screening per standard guidelines 4