Tofacitinib vs Upadacitinib

## Overview

Upadacitinib (Rinvoq) is a highly selective JAK1 inhibitor — the most selective of approved JAK inhibitors. This selectivity may improve its therapeutic window vs. tofacitinib, which inhibits JAK1 and JAK3. Upadacitinib has the broadest indication set among JAK inhibitors (RA, PsA, AS, nr-axSpA, AD, UC, Crohn's).

## Mechanism of Action

Tofacitinib: JAK1 + JAK3 (with some JAK2 at high doses). Upadacitinib: preferentially inhibits JAK1. JAK1 mediates signaling for IL-6, IFN-γ, and IL-4 family cytokines relevant to inflammatory disease. JAK3 selectivity in tofacitinib affects lymphocyte development.

## Pharmacokinetics

Upadacitinib: once daily (15 mg RA; higher doses for other indications), half-life ~9–14 h, CYP3A4 metabolism. Tofacitinib: BID (IR) or QD (XR), CYP3A4 + 2C19.

## Clinical Evidence

SELECT-COMPARE (upadacitinib vs. adalimumab vs. methotrexate in RA): upadacitinib superior to adalimumab in ACR50 at 12 weeks. Multiple SELECT trials establish upadacitinib efficacy across indications. Tofacitinib's ORAL Surveillance raised concerns about MACE/malignancy vs. TNFi; upadacitinib's post-marketing surveillance (ORAL SELECT equivalent) is ongoing.

## Indication Breadth

Upadacitinib: FDA-approved for RA, PsA, AS, nr-axSpA, AD, UC, Crohn's — the most approved JAK inhibitor by indication count. Tofacitinib: RA, PsA, UC, JIA.

## Key Takeaways

- Upadacitinib: most JAK1-selective among approved JAKi; broadest indications
- Tofacitinib: first-in-class; more cytokine pathway selectivity through JAK3 inhibition
- Both carry class-wide boxed warnings; upadacitinib ORAL Select surveillance ongoing