2025 Multidisciplinary‑Expert‑Consensus: Cardiovascular, Thromboembolic and Malignancy‑Risk‑Assessment for Candidates of JAK‑Inhibitor Therapy

Journal: Journal of Clinical and Translational Rheumatology, 2025；Delphi‑process；expert‑panel: rheumatology, dermatology, gastroenterology, cardiology, haematology, oncology, clinical‑pharmacology. Grading: Strong consensus‑statement / Conditional‑consensus‑consideration；built upon ORAL‑Surveillance trial, EMA‑PRAC regulatory‑review and real‑world‑post‑marketing‑dataEuropean M....

Abstract

Objective JAK‑inhibitors (JAKi) are effective oral‑therapies for multiple immune‑mediated‑inflammatory‑diseases, yet class‑level safety‑signals for major‑adverse‑cardiovascular‑events(MACE), venous‑thromboembolism(VTE) and malignancy‑have‑emerged compared with TNF‑inhibitors. This multidisciplinary‑consensus provides standardised pre‑treatment‑risk‑stratification, baseline‑work‑up, ongoing‑monitoring, contraindication‑and‑alternative‑therapy‑algorithms for adult patients being‑considered‑for‑JAK‑inhibitor‑initiation.

Methods Systematic‑literature‑review covering RCT, long‑term‑extension‑studies, post‑marketing‑observational‑cohorts and regulatory‑documents up‑to‑March‑2025. Multiround‑Delphi‑voting; ≥85 %‑panel‑agreement required for formal‑consensus‑statements.

Conclusion Baseline‑systematic‑risk‑assessment is mandatory before‑JAKi‑prescription. Patients ≥65 years‑old or with‑elevated‑MACE/VTE/malignancy‑risk should receive‑JAKi‑only when‑adequate‑alternatives‑(bDMARDs‑including‑TNF‑inhibitors)‑have‑failed‑or‑are‑intolerable. Risk‑factors should‑be‑managed‑optimally during‑therapy; regular‑surveillance‑is‑required. Shared‑decision‑making between‑clinician‑and‑patient‑is‑central‑to‑prescribing‑practice.

Keywords: JAK‑inhibitor; Janus‑kinase; cardiovascular‑risk; MACE; venous‑thromboembolism; VTE; malignancy; risk‑stratification; consensus

1 Overarching‑core‑principles

1. Risk‑assessment must‑be‑performed prior‑to‑first‑dose of‑any‑oral‑JAK‑inhibitor; risk‑re‑evaluation at‑each‑major‑clinical‑flare or‑before‑dose‑escalation.
2. Baseline‑inflammatory‑disease‑control itself modifies‑cardiovascular‑and‑thrombotic‑baseline‑risk; uncontrolled‑high‑disease‑activity amplifies‑thrombo‑cardio‑risk.
3. For high‑risk‑patients: bDMARD‑biologic‑agents are preferred‑first‑line‑alternatives; JAKi are reserved‑for‑second‑/third‑line‑if‑no‑suitable‑biologic‑option‑existsEuropean M....
4. Risk‑stratification integrates age,‑past‑medical‑history,‑laboratory‑biomarkers,‑lifestyle‑factors and‑cancer‑screening‑status, not‑single‑variable‑alone.
5. Multidisciplinary‑consultation (cardiologist / haematologist / oncologist) is recommended‑for‑very‑high‑risk‑candidates.

2 Pre‑treatment risk‑factor‑stratification

2.1 Major‑Adverse‑Cardiovascular‑Events (MACE: myocardial‑infarction, ischaemic‑stroke, cardiovascular‑death)

High‑MACE‑risk‑criteria (any‑one‑present)

• Age ≥ 65 years
• Prior‑history of‑myocardial‑infarction, ischaemic‑stroke, peripheral‑arterial‑disease
• Documented‑atherosclerotic‑cardiovascular‑disease
• Multiple‑CV‑risk‑factors: current‑smoking / long‑term‑past‑smoking‑history, uncontrolled‑hypertension, dyslipidaemia, diabetes‑mellitus, chronic‑kidney‑disease‑stage ≥ 3b.

Consensus‑statement: In high‑MACE‑risk‑population, JAK‑inhibitors should‑only‑be‑used‑after‑failure‑of‑biologic‑therapy. Optimise‑blood‑pressure‑and‑lipid‑profile‑before‑starting‑JAKi.

2.2 Venous‑thromboembolism risk (deep‑vein‑thrombosis + pulmonary‑embolism)

VTE‑risk‑factors

• Personal‑or‑first‑degree‑family‑history of‑unprovoked‑VTE
• Known‑thrombophilia (inherited‑or‑acquired‑e.g. APS‑antiphospholipid‑syndrome)
• Recent‑major‑surgery, prolonged‑immobilisation, hospitalisation
• Active‑malignancy, obesity (BMI > 30 kg/m²), oestrogen‑containing‑hormonal‑therapy.

Conditional‑statement: JAKi are not‑absolute‑contraindicated‑in‑thrombophilia‑patients; close‑monitoring‑and‑avoid‑additional‑pro‑thrombotic‑co‑medications. If‑prior‑unprovoked‑VTE‑event‑exists, prefer‑non‑JAKi‑alternatives.

2.3 Malignancy‑risk‑assessment

Elevated‑malignancy‑risk‑profile

• Age ≥ 65 years
• Current‑or‑past‑history‑of‑haematological‑or‑solid‑organ‑malignancy
• Chronic‑immunosuppression‑exposure‑history
• History‑of‑heavy‑tobacco‑exposure;‑previous‑lymphoproliferative‑disorder.

Consensus‑statement: Patients with‑active‑malignancy should‑avoid‑JAK‑inhibitors. For patients‑with‑prior‑treated‑malignancy: oncology‑multidisciplinary‑review‑is‑required‑prior‑to‑JAKi‑initiation.

3 Baseline‑work‑up checklist before‑JAK‑inhibitor initiation

1. Full‑medical‑history: prior‑MACE‑event,‑VTE‑event,‑cancer‑history,‑smoking‑status,‑surgical‑history,‑hormone‑use.
2. Vital‑signs: blood‑pressure, BMI.
3. Laboratory‑panel: lipid‑profile,‑renal‑function,‑liver‑function,‑complete‑blood‑count,‑coagulation‑screen‑(D‑dimer‑if‑clinically‑indicated).
4. Age‑and‑risk‑appropriate‑cancer‑screening (colonoscopy,‑skin‑cancer‑dermatological‑examination etc).
5. Cardiovascular‑risk‑calculator‑application (e.g. ASCVD‑risk‑score).
6. Document shared‑decision‑making: discuss‑expected‑benefits‑versus‑MACE/VTE/malignancy‑safety‑risks with‑patient.

4 During‑treatment monitoring & safety‑warning‑signs

1. Routine‑follow‑up every 3‑6 months: reassess‑cardiovascular‑risk‑factors,‑blood‑pressure,‑lipids,‑complete‑blood‑count‑and‑organ‑function.
2. Educate‑patients‑to‑report‑warning‑symptoms: chest‑pain,‑dyspnoea,‑unilateral‑leg‑swelling‑pain,‑sudden‑dyspnoea,‑focal‑neurological‑deficits,‑unexplained‑weight‑loss‑or‑lymphadenopathy.
3. If‑new‑MACE‑or‑VTE‑occurs during‑JAKi‑therapy: discontinue‑JAK‑inhibitor‑immediately, switch‑to‑alternative‑therapeutic‑class.
4. If‑new‑malignancy‑is‑diagnosed: discontinue‑JAKi‑and‑refer‑to‑oncology‑service.

5 Special‑patient‑subgroups

5.1 Elderly (≥ 65 years‑old)

• Strong‑consensus: JAK‑inhibitors are‑not‑first‑line‑therapy. Only‑use‑when‑biologic‑alternatives‑have‑failed‑or‑cannot‑be‑tolerated; consider‑lower‑approved‑dose‑where‑feasibleEuropean M....

5.2 Antiphospholipid‑syndrome‑patients

• Higher‑intrinsic‑thrombotic‑risk. Prefer‑biologic‑DMARD‑options. If‑JAKi‑must‑be‑used, haematology‑co‑management‑is‑mandatory.

5.3 Chronic‑kidney‑disease

• Dose‑adjust‑according‑to‑product‑labelling; intensified‑cardio‑thrombotic‑surveillance‑because‑CKD‑itself‑raises‑MACE‑and‑thrombosis‑risk.

6 Discontinuation‑and‑switch‑criteria

Discontinue‑JAK‑inhibitor and‑switch‑to‑non‑JAK‑therapy when‑any‑of‑following‑appear:

1. Confirmed‑MACE‑event (MI / ischaemic‑stroke / CV‑death).
2. Confirmed‑VTE‑episode (DVT / PE).
3. New‑diagnosis‑of‑malignancy‑or‑lymphoproliferative‑disorder.
4. Persistently‑uncontrolled‑cardiovascular‑risk‑factors‑despite‑optimal‑standard‑medical‑treatment.

7 Main‑consensus‑highlights compared‑with‑prior‑guidance

1. Formal‑unified‑multidimensional‑pre‑JAKi‑check‑list‑covering‑MACE,‑VTE‑and‑malignancy‑three‑domains.
2. Explicit‑position: age ≥ 65‑years‑is‑a‑major‑combined‑risk‑marker for‑all‑three‑safety‑outcomes; JAKi‑are‑second‑line‑only‑in‑this‑groupEuropean M....
3. Emphasise that uncontrolled‑inflammatory‑disease‑itself‑increases‑cardio‑thrombotic‑risk‑and‑must‑be‑optimised‑alongside‑safety‑risk‑mitigation.
4. Mandate‑shared‑decision‑making‑documentation‑in‑clinical‑records.
5. Provide‑clear‑stop‑rules‑for‑occurrence‑of‑cardiovascular‑thrombotic‑or‑malignant‑adverse‑events