Drug Monograph
Upadacitinib (Rinvoq)
upadacitinib — selective Janus kinase 1 (JAK1) inhibitor
Pharmacokinetic Profile
Half-Life
8–14 h (terminal)
Metabolism
CYP3A4 (major), CYP2D6 (minor)
Protein Binding
52%
Bioavailability
~76% (ER relative to IR); high absolute (no significant first-pass)
Volume of Distribution
~294 L (Vss/F)
Clinical Information
Drug Class
Selective JAK1 Inhibitor
Available Doses
15 mg, 30 mg, 45 mg ER tablets
Route
Oral, once daily
Renal Adjustment
None for RA (all severities)
Hepatic Adjustment
Avoid in severe (Child-Pugh C)
Pregnancy
Contraindicated (teratogenic in animals)
Lactation
Not recommended
Schedule
Prescription only (not scheduled)
Generic Available
No
Black Box Warning
Yes — infections, mortality, malignancy, MACE, thrombosis
Approved Indications & Off-Label Uses
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Moderately to severely active rheumatoid arthritis | Adults with inadequate response or intolerance to ≥1 TNF blocker | Monotherapy or with conventional DMARDs (e.g., methotrexate) | FDA Approved |
| Active psoriatic arthritis | Adults and patients ≥2 years after TNF blocker failure | Monotherapy or with conventional DMARDs | FDA Approved |
| Active ankylosing spondylitis | Adults after TNF blocker failure | Monotherapy | FDA Approved |
| Active nr-axial spondyloarthritis | Adults with objective signs of inflammation after TNF blocker failure | Monotherapy | FDA Approved |
| Refractory moderate-to-severe atopic dermatitis | Adults and patients ≥12 years | Monotherapy or with topical therapies | FDA Approved |
| Moderately to severely active ulcerative colitis | Adults after TNF blocker failure or when TNF blockers are inadvisable | Monotherapy | FDA Approved |
| Moderately to severely active Crohn’s disease | Adults after TNF blocker failure or when TNF blockers are inadvisable | Monotherapy | FDA Approved |
| Giant cell arteritis | Adults | Monotherapy or adjunctive | FDA Approved |
| Active polyarticular juvenile idiopathic arthritis | Patients ≥2 years after TNF blocker failure | Monotherapy or with conventional DMARDs | FDA Approved |
Upadacitinib occupies a second-line position in the RA treatment algorithm for patients who have failed or cannot tolerate at least one TNF-blocking agent. The 2021 FDA label revision restricted the RA indication to post-TNF-blocker use following the ORAL Surveillance study findings with tofacitinib. Upadacitinib should not be combined with biologic DMARDs, other JAK inhibitors, or potent immunosuppressants such as azathioprine or ciclosporin.
Off-Label Uses Under Investigation
Systemic lupus erythematosus: Phase III trials ongoing. Evidence quality: Low (Phase II data only).
Hidradenitis suppurativa: Phase III trials ongoing. Evidence quality: Low (Phase II data only).
Alopecia areata: Phase III trials ongoing. Evidence quality: Low.
Takayasu arteritis: Phase III trial underway. Evidence quality: Very low.
Vitiligo: Phase III trial underway. Evidence quality: Very low.
Dosing by Clinical Scenario
Primary Dosing — Rheumatoid Arthritis
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Active RA — post-TNF blocker, with background MTX | 15 mg once daily | 15 mg once daily | 15 mg/day | No titration required; take with or without food Swallow whole — do not crush, split, or chew |
| Active RA — post-TNF blocker, monotherapy (without MTX) | 15 mg once daily | 15 mg once daily | 15 mg/day | Efficacy demonstrated as monotherapy in SELECT-MONOTHERAPY and SELECT-EARLY trials Can be used without background DMARDs |
| Active RA — concurrent strong CYP3A4 inhibitor use | 15 mg once daily | 15 mg once daily | 15 mg/day | No dose reduction needed at 15 mg level for RA Strong CYP3A4 inhibitors increase upadacitinib exposure by ~75% |
| Renal impairment (mild / moderate / severe) — RA | 15 mg once daily | 15 mg once daily | 15 mg/day | No dosage adjustment needed for any degree of renal impairment in RA Not recommended in ESRD (eGFR <15) |
| Hepatic impairment — RA | 15 mg once daily | 15 mg once daily | 15 mg/day | No adjustment for mild-moderate (Child-Pugh A/B) Not recommended in severe hepatic impairment (Child-Pugh C) |
Dosing for Other Approved Indications (Reference)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Psoriatic arthritis / AS / nr-axSpA | 15 mg once daily | 15 mg once daily | 15 mg/day | Identical to RA dosing |
| Atopic dermatitis — adults <65 years | 15 mg once daily | 15–30 mg once daily | 30 mg/day | Increase to 30 mg if inadequate response; 15 mg max in ≥65 years or severe renal impairment |
| Ulcerative colitis — induction | 45 mg once daily | 45 mg daily × 8 weeks | 45 mg/day | Then transition to 15 mg maintenance |
| Ulcerative colitis — maintenance | 15 mg once daily | 15–30 mg once daily | 30 mg/day | 30 mg for refractory/severe disease; use lowest effective dose |
| Crohn’s disease — induction | 45 mg once daily | 45 mg daily × 12 weeks | 45 mg/day | Longer induction than UC (12 vs 8 weeks) |
Clinical Pearl — Pre-Treatment Checklist
Before initiating upadacitinib, complete the following: (1) TB screening (QuantiFERON-Gold or tuberculin skin test), (2) hepatitis B and C serologies, (3) CBC with differential (ensure ANC ≥1000, ALC ≥500, Hb ≥8 g/dL), (4) liver function tests, (5) lipid panel at baseline, (6) pregnancy test in patients of childbearing potential, and (7) update immunizations including consideration of recombinant zoster vaccine (Shingrix). Avoid live vaccines during or immediately before treatment.
Pharmacology & Mechanism of Action
Mechanism of Action
Upadacitinib is a second-generation, selective Janus kinase 1 inhibitor that blocks intracellular JAK-STAT signalling downstream of multiple pro-inflammatory cytokine receptors. By preferentially targeting JAK1 over JAK2, JAK3, and TYK2, it interrupts signalling through type I and type II cytokine receptors that drive the pathogenesis of rheumatoid arthritis — notably IL-6, IFN-gamma, and the common gamma-chain cytokines. In functional cell-based assays, upadacitinib demonstrates approximately 74-fold selectivity for JAK1 over JAK2 and 58-fold selectivity over JAK3. This selectivity profile is designed to preserve JAK2-mediated erythropoietin and thrombopoietin signalling while suppressing JAK1-dependent inflammatory cascades. The downstream effect is a reduction in pro-inflammatory mediators, inhibition of T-cell activation, and suppression of the acute-phase response, reflected clinically by rapid improvements in CRP and disease activity scores within the first weeks of treatment.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Tmax 2–4 h (ER tablet); no significant first-pass effect; food does not affect exposure clinically | Can be taken with or without meals; steady state reached by Day 4 |
| Distribution | Vss/F ~294 L; protein binding 52%; parent drug accounts for 79% of circulating drug-related material | Moderate distribution into tissues; low protein binding reduces displacement interaction risk |
| Metabolism | Primarily CYP3A4; minor CYP2D6 contribution; main metabolite M4 (oxidation + glucuronidation) — pharmacologically inactive | Strong CYP3A4 inhibitors increase exposure ~75%; strong inducers decrease exposure ~50% — co-administration with strong inducers not recommended |
| Elimination | Terminal t½ 8–14 h; excreted unchanged in feces (38%) and urine (24%); functional half-life ~4 h | Once-daily dosing with ER formulation; washout complete within ~3 days after discontinuation |
Side Effects & Adverse Reactions
Adverse reaction data below are from the Phase III RA clinical programme (SELECT trials), primarily from placebo-controlled comparisons with RINVOQ 15 mg (N=1035) versus placebo (N=1042) over 12–14 weeks, supplemented by the integrated 12-month safety dataset (FDA PI).
≥10%
Very Common
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Upper respiratory tract infections | 13.5% | Includes nasopharyngitis, sinusitis, pharyngitis, tonsillitis; generally mild and self-limiting (vs 9.5% placebo) |
1–10%
Common
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Nausea | 3.5% | Generally mild; rarely leads to discontinuation (vs 2.2% placebo) |
| Herpes zoster (shingles) | 3.0/100 PY | Higher than adalimumab (1.1/100 PY) and MTX (0.8/100 PY); Asian patients and those with prior HZ at highest risk; consider Shingrix pre-treatment |
| Cough | 2.2% | Mild; no specific management usually needed (vs 1.0% placebo) |
| Elevated creatine phosphokinase (CPK) | 1.6% (>5×ULN) | Higher than placebo (0.3%) and active comparators; generally transient and asymptomatic; distinguish from rhabdomyolysis clinically |
| Herpes simplex infections | <1–2% | Includes oral herpes reactivation; usually self-limiting |
| Pyrexia | 1.2% | Low-grade; evaluate to exclude infection (vs 0% placebo) |
| Bronchitis | ~1% | Monitor for worsening; generally mild |
| Headache | ~1–2% | Usually transient; not typically a reason for discontinuation |
| Hepatic transaminase elevations (ALT/AST ≥3×ULN) | 0.8–1.5% | Most elevations transient; monitor LFTs and interrupt if drug-induced liver injury is suspected |
| Hyperlipidaemia (LDL/total cholesterol increase) | Common (class effect) | LDL cholesterol typically increases within 2–4 weeks; responds to statin therapy; assess lipids at ~12 weeks |
| Neutropenia (ANC <1000) | ~1–2.4% | Interrupt if ANC <1000; may restart once above threshold |
Serious
Serious Adverse Effects (Regardless of Frequency)
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Serious infections (pneumonia, cellulitis) | 3.7/100 PY (UPA 15 mg) | Any time during treatment | Interrupt treatment; initiate appropriate antimicrobials; resume only when infection controlled |
| Opportunistic infections (TB, disseminated herpes zoster, cryptococcosis) | 0.6/100 PY (UPA 15 mg) | Variable; TB may present months to years into therapy | Discontinue; evaluate fully; initiate targeted anti-infective therapy; TB requires full course of antimycobacterials |
| Malignancy (excluding NMSC) | 1.2/100 PY (UPA 15 mg) | After prolonged exposure (months–years) | Discontinue; refer to oncology; higher risk in smokers per JAK class-wide data |
| Major adverse cardiovascular events (MACE) | ~0.3–0.4/100 PY | Variable | Discontinue after MI or stroke; class-wide concern from ORAL Surveillance; assess CV risk factors at baseline |
| Venous thromboembolism (DVT, PE) | <0.1–0.4/100 PY | Variable | Discontinue promptly; initiate anticoagulation; avoid in patients with thrombotic risk factors |
| Gastrointestinal perforation | Rare (<0.1/100 PY at 15 mg) | Variable; higher risk with concurrent NSAIDs/corticosteroids | Immediate surgical evaluation; discontinue; exercise caution in patients with diverticulitis history |
| Anaphylaxis / serious hypersensitivity | Rare | Any time | Discontinue permanently; emergency treatment; upadacitinib is contraindicated in known hypersensitivity |
| Hepatitis B reactivation | Rare | Variable | Screen before initiation; consult hepatologist if HBV DNA detected; consider antiviral prophylaxis |
| Non-melanoma skin cancer (NMSC) | 0.5–0.8/100 PY | After prolonged exposure | Periodic skin examination; sun protection; refer dermatology for suspicious lesions |
Discontinuation
Discontinuation Rates
Adults (RA — 15 mg)
4.5–5.4/100 PY TEAE leading to discontinuation
Top reasons: Infections, hepatic events, herpes zoster
Comparator — Adalimumab (RA)
~4.0/100 PY similar discontinuation profile
Note: Overall discontinuation rates are generally comparable between upadacitinib 15 mg and adalimumab across the SELECT programme
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Infections | Most common reason | Serious infections (pneumonia, cellulitis) accounted for the majority; herpes zoster also contributed |
| Hepatic disorders | Uncommon | Transaminase elevations; most were transient and did not require discontinuation |
| Malignancy | Rare | Long-term discontinuation trigger; requires oncological evaluation |
Managing Herpes Zoster Risk
Herpes zoster is the most clinically distinctive adverse effect of upadacitinib compared to other RA therapies, occurring at roughly 3-fold the rate seen with adalimumab. Prior to initiating treatment, strongly consider vaccination with recombinant zoster vaccine (Shingrix), which can be given as it is non-live. If herpes zoster develops during treatment, temporarily interrupt upadacitinib until the episode resolves. Patients from Asia and those with a personal history of shingles carry the highest risk.
Drug Interactions
Upadacitinib is primarily metabolised by CYP3A4. It does not inhibit or induce major CYP enzymes or common drug transporters (P-gp, BCRP, OATPs, OCTs, OATs, MATEs) at therapeutic concentrations, which limits its perpetrator interaction potential. The key interactions centre on drugs that alter CYP3A4 activity or those that compound the immunosuppressive risk.
Major
Strong CYP3A4 Inducers (rifampicin, phenytoin, carbamazepine)
MechanismInduction of CYP3A4 metabolism
EffectReduces upadacitinib AUC by approximately 50%, potentially leading to loss of efficacy
ManagementCo-administration not recommended (FDA PI). Use alternative non-inducing agents where possible
FDA PI
Major
Strong CYP3A4 Inhibitors (ketoconazole, clarithromycin, itraconazole)
MechanismInhibition of CYP3A4-mediated clearance
EffectIncreases upadacitinib AUC by ~75%, raising the risk of dose-dependent adverse effects
ManagementFor RA (15 mg dose): no dose adjustment needed per FDA PI. For indications using 30 or 45 mg doses: dose reduction applies — see indication-specific guidance. Avoid grapefruit products
FDA PI
Major
Other JAK Inhibitors (tofacitinib, baricitinib, ruxolitinib)
MechanismOverlapping pharmacological immunosuppression
EffectAdditive immunosuppression; potential for amplified infection and malignancy risk
ManagementCombination is contraindicated per the label — never combine JAK inhibitors
FDA PI
Major
Biologic DMARDs (adalimumab, etanercept, tocilizumab, abatacept)
MechanismCompounded immunosuppression via distinct pathways
EffectSignificantly increased risk of serious infections without established additional efficacy
ManagementCombination not recommended per label. Allow appropriate washout when switching from biologics
FDA PI
Major
Potent Immunosuppressants (azathioprine, ciclosporin)
MechanismAdditive immune suppression
EffectEnhanced risk of infections and cytopenias
ManagementCombination not recommended. Methotrexate at conventional doses is acceptable and studied
FDA PI
Moderate
Live Vaccines (MMR, varicella, oral polio, yellow fever)
MechanismImpaired immune response to live pathogens
EffectRisk of vaccine-strain infection; diminished vaccine efficacy
ManagementAvoid live vaccines during treatment and immediately prior. Complete all live vaccinations ≥2 weeks before starting upadacitinib. Inactivated and recombinant vaccines can be given during therapy
FDA PI
Moderate
NSAIDs / Corticosteroids (long-term)
MechanismAdditive GI mucosal risk
EffectIncreased risk of gastrointestinal perforation, especially in patients with diverticulitis
ManagementUse the lowest effective NSAID dose for the shortest duration; taper corticosteroids when feasible; monitor for new abdominal pain
FDA PI / Clinical Practice
Minor
Methotrexate
MechanismNo pharmacokinetic interaction; complementary pharmacodynamic immunosuppression
EffectCombination studied in the SELECT programme; no dose adjustment needed for either drug
ManagementAcceptable and well-studied combination for RA; standard MTX monitoring applies
SELECT-COMPARE (Phase III)Monitoring Parameters
-
TB Screening
Baseline; periodic re-screening
Routine QuantiFERON-Gold or TST prior to initiation. Re-screen if new TB exposure risk factors develop. Treat latent TB before starting upadacitinib. Monitor for signs/symptoms of active TB throughout therapy. -
Complete Blood Count
Baseline; per routine management
Routine Evaluate ANC, ALC, and haemoglobin. Do not initiate if ANC <1000, ALC <500, or Hb <8 g/dL. Interrupt if these thresholds are breached during therapy; may restart once values recover. -
Hepatic Function (LFTs)
Baseline; per routine management
Routine Monitor ALT/AST. Interrupt if drug-induced liver injury is suspected. Most elevations are transient; investigate promptly if ≥3×ULN persists. -
Lipid Panel
~12 weeks after start; then per guidelines
Routine Total cholesterol, LDL, and HDL typically increase. LDL responds to statin therapy. Manage according to cardiovascular risk guidelines. -
Viral Hepatitis
Baseline screening
Routine Screen for HBV (HBsAg, anti-HBc, HBV DNA) and HCV. Do not initiate in active hepatitis B or C. Cases of HBV reactivation have been reported; consult hepatology if HBV DNA is detected during treatment. -
Skin Examination
Periodic
Routine Screen for NMSC, particularly in patients at increased risk (fair skin, prior NMSC, prolonged sun exposure). Advise sun protection and protective clothing. -
Signs of Infection
Every visit
Trigger-based Evaluate for new fever, cough, dyspnoea, abdominal pain, skin lesions, or vesicular rash (herpes zoster). Interrupt treatment for any serious infection until controlled. -
Cardiovascular Risk
Baseline; ongoing
Trigger-based Assess CV risk factors (smoking, hypertension, diabetes, hyperlipidaemia). Discontinue after MI or stroke. The class-wide boxed warning is based on the ORAL Surveillance study of tofacitinib; direct MACE data for upadacitinib in RA are limited. -
Pregnancy Status
Baseline; as needed
Trigger-based Verify negative pregnancy test before initiation. Counsel on effective contraception during treatment and for at least 4 weeks after discontinuation. Upadacitinib is teratogenic in animals.
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity to upadacitinib or any excipient (includes anaphylaxis, angioedema reported in trials)
- Pregnancy — teratogenic in animal studies; verify negative test before starting; use effective contraception during treatment and for 4 weeks after
- Active serious infection — including active TB; do not initiate until infection is controlled
- Severe hepatic impairment (Child-Pugh C) — not recommended
Relative Contraindications (Specialist Input Recommended)
- Active or recent malignancy (other than successfully treated NMSC) — weigh benefits vs cancer risk; smokers are at additional increased risk (class-wide warning)
- Patients ≥50 years with ≥1 cardiovascular risk factor — increased MACE and mortality risk identified with another JAK inhibitor (tofacitinib) vs TNF blockers; discuss risk-benefit thoroughly
- Current or past smokers — additional increased risk of malignancies and MACE per class-wide data
- History of VTE or active thrombotic risk factors — DVT, PE, and arterial thrombosis reported; avoid if thrombosis risk is elevated
- Latent TB (untreated) — must complete appropriate TB treatment before initiating upadacitinib
- Active hepatitis B or C — not studied; HBV reactivation reported; consult hepatology
Use with Caution
- Elderly patients (≥65 years) — higher incidence of serious infections and malignancies observed in older patients across JAK inhibitor studies
- History of diverticulitis — increased GI perforation risk, particularly with concomitant NSAIDs or corticosteroids
- Chronic or recurrent infections — closely monitor; interrupt treatment for serious infections
- Pre-existing cytopenias — do not initiate if ANC <1000, ALC <500, or Hb <8 g/dL
- Breastfeeding — not recommended; upadacitinib is excreted in animal milk with exposure ~30-fold higher in milk than plasma; advise discontinuation of breastfeeding during treatment and for 6 days after last dose
- Concomitant strong CYP3A4 inhibitors — monitor closely, particularly at higher doses used for other indications
FDA Boxed Warning
Serious Infections, Mortality, Malignancy, MACE, and Thrombosis
Patients treated with upadacitinib are at increased risk for serious infections that may lead to hospitalisation or death (including TB, invasive fungal infections, and opportunistic infections). A higher rate of all-cause mortality (including sudden cardiovascular death), malignancies (including lymphoma and lung cancer in smokers), major adverse cardiovascular events (MI, stroke, CV death), and thrombosis (DVT, PE) was observed with another JAK inhibitor compared to TNF blockers in RA patients ≥50 years with cardiovascular risk factors.
Carefully consider the benefits and risks before initiating or continuing upadacitinib, particularly in patients ≥50 years with CV risk factors, current or past smokers, and patients with thrombotic risk factors. Test for latent TB before and during therapy. Discontinue after MI or stroke. Promptly evaluate patients with symptoms of thrombosis.
Patient Counselling
Purpose of Therapy
Upadacitinib is a targeted medicine that works by blocking a specific enzyme (JAK1) involved in the inflammatory process that drives rheumatoid arthritis. It reduces joint pain, swelling, and stiffness and can slow joint damage progression. It is prescribed after a different type of anti-inflammatory medication (a TNF blocker) has not worked well enough or could not be tolerated.
How to Take
Take one 15 mg tablet by mouth once daily, with or without food. Swallow the tablet whole — do not break, crush, or chew it, as it is designed to release the medicine slowly over 24 hours. If a dose is missed, take it as soon as remembered on the same day; then return to the normal schedule. Do not take two tablets to make up for a missed dose.
Infection Risk
Tell patient
This medicine lowers the immune system’s activity, which can increase susceptibility to infections. Good hand hygiene and avoiding close contact with people who are unwell can reduce this risk. It is important to receive recommended vaccinations, including the shingles vaccine, before starting treatment.
Call prescriber
If you develop fever, persistent cough, difficulty breathing, burning on urination, painful skin sores, unexplained fatigue, or a painful blistering rash (possible shingles), contact your prescriber immediately. Treatment may need to be paused.
Blood Clots & Heart Problems
Tell patient
There is a small risk of blood clots in the legs or lungs and heart-related events with this class of medicine, particularly in patients over 50 with heart disease risk factors. If you are a smoker, discuss this with your doctor — quitting smoking reduces this risk.
Call prescriber
Seek immediate medical attention for sudden shortness of breath, leg swelling or pain, chest pain, weakness on one side of the body, or sudden difficulty speaking.
Cancer Risk & Skin Checks
Tell patient
There may be a slightly higher risk of certain cancers, particularly skin cancers. Protect skin from excess sun exposure by using sunscreen (SPF 30+) and wearing protective clothing. Attend regular skin checks as recommended by your doctor.
Call prescriber
Report any new or changing skin lesions, moles, or unexplained lumps to your prescriber promptly.
Pregnancy & Contraception
Tell patient
Upadacitinib may cause harm to an unborn baby based on animal studies. Reliable contraception must be used during treatment and for at least 4 weeks after the last dose. Breastfeeding is not recommended during treatment and for 6 days after the last dose.
Call prescriber
If you become pregnant or suspect pregnancy during treatment, stop the medicine and contact your prescriber immediately.
Laboratory Monitoring
Tell patient
Regular blood tests are needed, particularly in the first few months, to check blood counts, liver function, and cholesterol levels. These tests help detect problems early, before symptoms occur.
Call prescriber
If you notice unusual bruising or bleeding, yellowing of the skin or eyes, dark urine, or persistent nausea, contact your prescriber — these may indicate blood count or liver problems.
Tablet Residue in Stool
Tell patient
Occasionally, the ghost shell of the tablet may be visible in the stool. This is normal for extended-release tablets and does not mean the medicine was not absorbed. However, in patients with shortened GI transit (e.g., those with an ileostomy), this may affect absorption.
Call prescriber
If you see the tablet residue in your stool repeatedly and feel the medicine is not working as expected, inform your prescriber.
Sources
Regulatory (PI / SmPC)
- RINVOQ (upadacitinib) [prescribing information]. North Chicago, IL: AbbVie Inc.; Most recent revision 10/2025. Available via FDA Drugs@FDA Primary regulatory source for dosing, adverse reactions, warnings, and PK data. RA indication and safety data stable since 05/2023; GCA added 04/2025; UC/CD indication updated 10/2025.
- European Medicines Agency. Rinvoq (upadacitinib): EPAR – Product information. EMA Product Page EU regulatory perspective including SmPC dosing and safety; aligns with FDA data with minor regional differences in indication wording.
Key Clinical Trials
- Fleischmann R, Pangan AL, Song IH, et al. Upadacitinib versus placebo or adalimumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase III, double-blind, randomized controlled trial (SELECT-COMPARE). Arthritis Rheumatol. 2019;71(11):1788-1800. doi:10.1002/art.41032 Pivotal head-to-head trial demonstrating superiority of upadacitinib 15 mg over adalimumab on ACR50 at week 12 in MTX-IR patients.
- van Vollenhoven R, Takeuchi T, Pangan AL, et al. Efficacy and safety of upadacitinib monotherapy in methotrexate-naive patients with moderately-to-severely active rheumatoid arthritis (SELECT-EARLY): a multicenter, multi-country, randomized, double-blind, active comparator-controlled trial. Arthritis Rheumatol. 2020;72(10):1607-1620. doi:10.1002/art.41384 SELECT-EARLY trial showing upadacitinib monotherapy was superior to MTX in treatment-naive RA patients on radiographic progression and clinical endpoints.
- Genovese MC, Fleischmann R, Combe B, et al. Safety and efficacy of upadacitinib in patients with active rheumatoid arthritis refractory to biologic disease-modifying anti-rheumatic drugs (SELECT-BEYOND): a double-blind, randomised controlled phase 3 trial. Lancet. 2018;391(10139):2513-2524. doi:10.1016/S0140-6736(18)31116-4 Demonstrated efficacy of upadacitinib in biologic-refractory RA patients, the population most relevant to the current FDA indication.
- Smolen JS, Pangan AL, Emery P, et al. Upadacitinib as monotherapy in patients with active rheumatoid arthritis and inadequate response to methotrexate (SELECT-MONOTHERAPY): a randomised, placebo-controlled, double-blind phase 3 study. Lancet. 2019;393(10188):2303-2311. doi:10.1016/S0140-6736(19)30419-2 Supports the use of upadacitinib as monotherapy (without background MTX) in MTX-inadequate responders.
Guidelines
- Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res. 2021;73(7):924-939. doi:10.1002/acr.24596 ACR 2021 guideline conditionally recommends JAK inhibitors over other DMARDs only after TNF inhibitor failure, reflecting the post-ORAL Surveillance positioning.
- Smolen JS, Landewé RBM, Bergstra SA, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis. 2023;82(1):3-18. doi:10.1136/ard-2022-223356 EULAR 2022 update positions JAK inhibitors as a treatment option after failure of a first bDMARD, with preference for use in patients without elevated cardiovascular or malignancy risk.
Mechanistic / Basic Science
- Parmentier JM, Voss J, Graff C, et al. In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494). BMC Rheumatol. 2018;2:23. doi:10.1186/s41927-018-0031-x Details the JAK1 selectivity profile of upadacitinib versus JAK2, JAK3, and TYK2, establishing the pharmacological basis for its differentiated safety profile.
Pharmacokinetics / Special Populations
- Mohamed MEF, Klünder B, Engel N, Othman AA. Clinical pharmacokinetics of upadacitinib: review of data relevant to the rheumatoid arthritis indication. Clin Pharmacokinet. 2020;59(5):531-544. doi:10.1007/s40262-019-00855-0 Comprehensive PK review covering absorption, distribution, metabolism, elimination, and covariate effects of upadacitinib in RA patients.
- Cohen S, van Vollenhoven R, Winthrop KL, et al. Safety profile of upadacitinib in rheumatoid arthritis: integrated analysis from the SELECT phase III clinical programme. Ann Rheum Dis. 2021;80(3):304-311. doi:10.1136/annrheumdis-2020-218510 Integrated safety analysis of all SELECT RA trials (3834 patients); source for comparative adverse event rates versus adalimumab and methotrexate.
- Winthrop KL, Tanaka Y, Engel N, et al. Incidence and risk factors for herpes zoster in patients with rheumatoid arthritis receiving upadacitinib: a pooled analysis of six phase III clinical trials. Ann Rheum Dis. 2022;81(2):206-213. doi:10.1136/annrheumdis-2021-221101 Detailed analysis of herpes zoster risk with upadacitinib (5306 patients); identifies Asian ancestry and prior HZ history as key risk factors.
- Burmester GR, Deodhar A, Irvine AD, et al. Safety profile of upadacitinib over 15 000 patient-years across rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and atopic dermatitis. RMD Open. 2023;9(1):e002735. doi:10.1136/rmdopen-2022-002735 Largest integrated safety analysis at time of publication; provides long-term exposure-adjusted rates for adverse events of special interest across multiple indications.