Drug Update · Rheumatology

FDA Requires Warnings for JAK Inhibitors: Higher Heart, Cancer, Clot, Death Risk vs TNF

August 27, 2026

LITFULO recommended dosage

50 mg orally once daily [1]

XELJANZ RA recommended dosage

XELJANZ tablets 5 mg twice daily or XELJANZ XR 11 mg once daily [2]

FDA safety conclusion

Increased risk of serious heart-related events, cancer, blood clots, and death with XELJANZ versus TNF blockers in RA based on a large randomized safety clinical trial [6][7][2]

ORAL Surveillance VTE signal

Higher cumulative probabilities for VTE and PE with tofacitinib 10 mg BID, but not 5 mg BID, versus TNFi [8]

Clinical Perspective

Rheumatologists, specialists, pharmacists, and primary care clinicians prescribing JAK inhibitors for patients with rheumatoid arthritis should be aware that FDA review found higher rates of serious heart‑related events, malignancy, blood clots, and death with tofacitinib versus TNF blockers and that these findings are reflected in revised boxed warnings and prescribing information for JAK inhibitors ^[3]^[4]^[2]^[1]. The source‑confirmed data support careful assessment of cardiovascular and malignancy risk factors, and consideration of the benefits and risks of initiating or continuing JAK inhibitor therapy compared with TNF blockers in individual RA patients ^[1]^[2]^[3]^[4]. What specific patient selection criteria or monitoring strategies will most effectively mitigate these risks in routine rheumatology practice?

Dr. Deepak Nair, MBBS, MD (General Medicine), DM (Clinical Immunology & Rheumatology) · Rheumatology

The FDA is requiring boxed‑warning and prescribing information revisions for JAK inhibitors after review of a large randomized safety clinical trial that found increased risks of serious heart‑related events, cancer, blood clots, and death with XELJANZ (tofacitinib) versus tumor necrosis factor (TNF) blockers in rheumatoid arthritis (RA) patients ^[3]^[4]^[2]. The LITFULO (ritlecitinib) prescribing information was revised 06/2026 to include warnings referencing higher rates of mortality, malignancy, MACE, and thrombosis observed with another JAK inhibitor versus TNF blockers in RA patients ^[1].

Clinical Context

Janus kinase (JAK) inhibitors are oral kinase inhibitors used to treat inflammatory conditions; XELJANZ (tofacitinib) is an approved JAK inhibitor for moderately to severely active rheumatoid arthritis and other indications, and LITFULO (ritlecitinib) is a kinase inhibitor approved for severe alopecia areata ^[2]^[1]. The FDA review and communications address classwide safety concerns after a large randomized postmarketing safety study compared tofacitinib with TNF blockers in RA patients aged 50 years or older with at least one cardiovascular risk factor, prompting boxed warning revisions for XELJANZ and requirements for labels of other JAK inhibitors ^[3]^[4]. LITFULO labeling explicitly notes the safety signals observed with another JAK inhibitor versus TNF blockers in RA patients and includes boxed warnings for infections, mortality, malignancy, MACE, and thrombosis ^[1].

Key Findings

The FDA concluded that XELJANZ/XELJANZ XR increased the risk of serious heart‑related events, cancer, blood clots, and death versus TNF blockers in RA patients based on a completed large randomized safety clinical trial ^[3]^[4]^[2].
LITFULO labeling was revised (06/2026) to include warnings that malignancies occurred in patients treated with ritlecitinib and that a higher rate of all‑cause mortality, including sudden cardiovascular death, was observed with another JAK inhibitor versus TNF blockers in RA patients ^[1].
The LITFULO label also states that a higher rate of lymphomas and lung cancers was observed with another JAK inhibitor versus TNF blockers in RA patients, and that higher rates of MACE (cardiovascular death, myocardial infarction, stroke) and thrombosis were observed with another JAK inhibitor versus TNF blockers in RA patients ^[1].
ORAL Surveillance analyses reported higher cumulative probabilities for venous thromboembolism (VTE) and pulmonary embolism (PE) with tofacitinib 10 mg twice daily, but not 5 mg twice daily, versus TNF inhibitors; incidence rates were generally consistent over time ^[5].
Clinicians should consult current prescribing information for full dosing guidance.

Safety & Tolerability

Serious infections, including tuberculosis and opportunistic infections, leading to hospitalization or death are included in boxed warnings for both LITFULO and XELJANZ/XELJANZ XR ^[1]^[2].
Higher rate of all‑cause mortality, including sudden cardiovascular death, was observed with another JAK inhibitor versus TNF blockers in RA patients (LITFULO label) and with XELJANZ versus TNF blockers in the FDA safety review ^[1]^[2]^[3]^[4].
Malignancies (including lymphomas and lung cancers) were reported with ritlecitinib; a higher rate of lymphomas and lung cancers with another JAK inhibitor versus TNF blockers in RA patients is noted ^[1].
Major adverse cardiovascular events (MACE: cardiovascular death, myocardial infarction, stroke) were observed at higher rates with another JAK inhibitor versus TNF blockers in RA patients ^[1].
Thromboembolic events including pulmonary embolism, deep venous thrombosis, and arterial thrombosis have occurred with JAK inhibitors; a PE was reported in a patient receiving ritlecitinib and higher rates of thrombosis were observed with another JAK inhibitor versus TNF blockers in RA patients ^[1]^[2]^[5].
Commonly reported adverse reactions for LITFULO include headache, diarrhea, acne, rash, urticaria, folliculitis, pyrexia, atopic dermatitis, dizziness, increased blood creatine phosphokinase, herpes zoster, decreased red blood cell count, and stomatitis ^[1].
Common adverse reactions for XELJANZ in RA, PsA, and AS include upper respiratory tract infection, nasopharyngitis, diarrhea, and headache; for ulcerative colitis additional reactions listed include elevated cholesterol and herpes zoster ^[2].

Study Design

The FDA safety conclusions were based on a large randomized postmarketing safety study (ORAL Surveillance) that enrolled patients with rheumatoid arthritis aged 50 years or older with at least one cardiovascular risk factor and compared tofacitinib 5 mg or 10 mg twice daily versus tumor necrosis factor (TNF) blockers; subgroup and post hoc analyses of VTE/PE and MACE informed labeling changes and warnings ^[3]^[4]^[5]^[6]. Clinicians should consult current prescribing information for full dosing guidance. Sample sizes reported in analyses included tofacitinib 5 mg BID (N = 1455), tofacitinib 10 mg BID (N = 1456), and TNFi (N = 1451) in ORAL Surveillance publications ^[6]. Details on endpoints, adjudication, and follow‑up are reported in the cited ORAL Surveillance analyses ^[5]^[6]^[7].

FAQ

Q1 What is XELJANZ (tofacitinib) approved for?

XELJANZ tablets and XELJANZ XR are Janus kinase (JAK) inhibitors indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more TNF blockers. XELJANZ is also indicated for psoriatic arthritis, ankylosing spondylitis, polyarticular course juvenile idiopathic arthritis, and ulcerative colitis in specified populations as described in the prescribing information.

Q2 How does XELJANZ work?

XELJANZ is a Janus kinase (JAK) inhibitor; the prescribing information describes XELJANZ and XELJANZ XR as members of the JAK inhibitor class and provides clinical pharmacology and mechanism of action details in the full prescribing information.

Q3 What is the recommended dose of XELJANZ for RA?

Recommended dosages for adult patients with rheumatoid arthritis are XELJANZ tablets 5 mg twice daily or XELJANZ XR extended‑release tablets 11 mg once daily, with specific dosing recommendations and contraindications detailed in the full prescribing information; certain higher doses are not recommended for RA and other indications as noted in the label.

Q4 What are the side effects of XELJANZ?

Boxed warnings for XELJANZ include serious infections, increased risk of mortality, malignancy, major adverse cardiovascular events (MACE), and thrombosis; commonly reported adverse reactions include upper respiratory tract infection, nasopharyngitis, diarrhea, and headache in RA and related indications, and ulcerative colitis labeling lists additional reactions such as elevated cholesterol and herpes zoster.

Clinicians should consult current prescribing information for complete dosing guidance.

FDA Requires Warnings for JAK Inhibitors: Higher Heart, Cancer, Clot, Death Risk vs TNF

Direct Clinical Takeaway & Evidence Summary

FDA Requires Warnings for JAK Inhibitors: Higher Heart, Cancer, Clot, Death Risk vs TNF

Clinical Perspective

Clinical Context

Key Findings

Safety & Tolerability

Study Design

FAQ

References

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