Which one is safer upadacitinib or biologics
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upadacitinib safety biologics comparison cardiovascular malignancy
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upadacitinib vs biologics safety comparison 2024 2025
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https://pmc.ncbi.nlm.nih.gov/articles/PMC12474609
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upadacitinib JAK inhibitor biologic safety cardiovascular malignancy
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PMID: 38216757
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PMID: 41826212
Here is a thorough, evidence-based comparison of upadacitinib vs. biologics safety:
Upadacitinib vs. Biologics: Safety Comparison
The honest answer is: it depends on the patient and the specific biologic being compared. Biologics (particularly TNF inhibitors) have a longer track record and are generally preferred first-line in patients with cardiovascular risk factors, older age, or history of malignancy. Upadacitinib is effective but carries specific risks that require patient selection.
1. The Pivotal Safety Signal - ORAL Surveillance
The entire debate stems from the ORAL Surveillance trial, which studied tofacitinib (another JAK inhibitor) vs. TNF inhibitors in RA patients aged ≥50 with ≥1 cardiovascular risk factor. Tofacitinib had a statistically higher rate of MACE and malignancy vs. TNF inhibitors. Based on this, the FDA and EMA issued class-wide warnings for all JAK inhibitors, including upadacitinib.
However, this trial studied a specifically enriched high-risk population and involved tofacitinib - not upadacitinib directly.
2. Upadacitinib's Own Data (27,000+ Patient-Years)
A major 2025 integrated analysis across 16 studies (8,600+ patients, >27,000 patient-years across RA, PsA, axSpA, AD, and IBD) [PMC12474609] found:
| Safety Event | Upadacitinib | vs. Active Comparator (adalimumab/MTX) |
|---|---|---|
| MACE | 0-0.5 per 100 PY | Similar to adalimumab |
| Malignancy (excl. NMSC) | 0.2-0.9 per 100 PY | Similar to adalimumab |
| VTE | 0-0.9 per 100 PY | Similar to adalimumab |
| Serious infections | 1.3-4.6 per 100 PY | Comparable |
| Herpes zoster | 2.4-6.6 per 100 PY | Higher than adalimumab |
| NMSC | 0-1.4 per 100 PY | Higher than adalimumab |
| Elevated creatine kinase | 0-9.2 per 100 PY | Higher than adalimumab |
Key takeaway: In upadacitinib's own program, MACE, serious malignancy, and VTE rates were comparable to adalimumab (a biologic). Herpes zoster and NMSC occurred more frequently with upadacitinib.
3. Where Biologics Are Safer
- Cardiovascular disease / MACE risk: TNF inhibitors (biologics) remain preferred in patients with established CV disease, age ≥65, or significant CV risk factors. The FDA guidance specifically says JAK inhibitors should be reserved for patients who have had inadequate response or intolerance to ≥1 TNF inhibitor (Harrison's 22E, 2025).
- Malignancy history: Patients with prior or active malignancy should avoid JAK inhibitors if possible - biologics are preferred.
- History of smoking + age ≥65: This combination dramatically increases JAK inhibitor-related cancer and MACE risk; biologics are safer in this profile.
- Established long-term data: Biologics (especially anti-TNF agents like adalimumab, etanercept) have 20+ years of post-marketing data.
4. Where Upadacitinib Is Comparable or Has Advantages
- In younger patients without CV risk factors, upadacitinib's MACE/malignancy rates are not significantly different from biologics.
- Efficacy: Upadacitinib is one of the most effective agents for RA, PsA, axSpA, and atopic dermatitis - in some trials outperforming adalimumab for disease control.
- Oral administration - avoids injection-site reactions, infusion reactions, and immunogenicity issues seen with biologic injections/infusions.
- TNF inhibitors carry their own specific risks: demyelinating disease, worsening CHF, paradoxical psoriasis, and latent TB reactivation. IL-17 inhibitors risk leukopenia and triggering/worsening IBD. IL-6 inhibitors raise infection and lipid risks. No biologic is risk-free.
5. Shared Risks (Both Classes)
- Serious infections (bacterial, opportunistic)
- Latent TB reactivation (higher with TNF inhibitors; requires screening before both)
- Hepatitis B reactivation
- Immunosuppression-related concerns in general
6. Current Guideline Positioning (2025 EULAR, 2026 update)
The 2025 EULAR RA recommendations (Smolen et al., Ann Rheum Dis 2026) state:
- Start with methotrexate +/- short-term glucocorticoids
- Upon inadequate response, add a bDMARD (biologic) first
- JAK inhibitors may also be considered after careful weighing of MACE, malignancy, and thromboembolic risks
- If one bDMARD fails, switch to another bDMARD or a JAK inhibitor (considering risks)
Bottom Line
| Factor | Biologics (e.g., TNFi) | Upadacitinib |
|---|---|---|
| CV risk / age ≥65 | Safer (preferred) | Higher caution required |
| Malignancy history | Safer (preferred) | Avoid if possible |
| Herpes zoster risk | Lower | Higher (consider VZV vaccination) |
| NMSC risk | Lower | Slightly higher |
| Demyelinating disease | Risk (TNFi) | Lower risk |
| IBD risk | IL-17i risk | Less of a concern |
| TB reactivation | Higher (TNFi) | Lower |
| Efficacy (RA, AD, PsA) | High | Often superior |
| Route | Injection/infusion | Oral |
In low-to-moderate CV risk patients without malignancy history, upadacitinib and biologics have broadly comparable serious safety profiles. In older, high-CV-risk, or post-malignancy patients, biologics - especially TNF inhibitors - are the safer first choice per FDA guidance and international guidelines.
Sources: Harrison's Principles of Internal Medicine 22E (2025); Burmester et al., Adv Ther 2025, PMID: 40875187; Szekanecz et al., Nat Rev Rheumatol 2024, PMID: 38216757; EULAR 2025 RA Recommendations, PMID: 41826212
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