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Upadacitinib in dermatology: A systematic review of mechanism, current applications, efficacy, safety, and emerging evidence
Corresponding author: Dr. Sunil Dogra, Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India. sundogra@hotmail.com
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Received: ,
Accepted: ,
How to cite this article: Dogra S, Prarthana T, Sudharani G, Chhabra S. Upadacitinib in dermatology: A systematic review of mechanism, current applications, efficacy, safety, and emerging evidence. Indian J Dermatol Venereol Leprol. doi: 10.25259/IJDVL_133_2025
Abstract
Upadacitinib, a second-generation oral Janus kinase (JAK) inhibitor, selectively targets the JAK 1 non-receptor protein kinase, effectively modulating downstream inflammatory pathways implicated in a range of dermatological diseases. Its JAK 1 selectivity mitigates unwanted side effects associated with broader JAK inhibition. FDA approval for moderate to severe atopic dermatitis (AD) in January 2022 marked a significant milestone, expanding treatment options in dermatology. Since then, upadacitinib has demonstrated efficacy in various dermatological disorders, contributing to improved patient outcomes. This review aims to spotlight its use in AD, as well as off-label indications in dermatology, its safety and efficacy profile, and pertinent information regarding side effects and contraindications.
Keywords
Atopic dermatitis
JAK-STAT inhibitor
oral small molecule
upadacitinib
Introduction
Upadacitinib (ABT494) is a reversible, selective Janus kinase (JAK) 1 inhibitor. It belongs to the second generation of oral small molecules, specifically targeting the closed glycine-rich P-loop of JAK 1, unlike the open confirmation of JAK 2. This interaction is achieved through tight Vander Waals interaction facilitated by its small and highly polar trifluoroethyl group, enhancing both metabolic and membrane permeability.1 Upadacitinib has been approved by the Food and Drug Administration (FDA) for treating various conditions, such as moderate to severe rheumatoid arthritis (RA, 2019), psoriatic arthritis (PsA, 2021), moderate to severe atopic dermatitis (AD), ulcerative colitis (UC)2, ankylosing spondylitis (AS), non-radiographic axial spondyloarthritis (nr-axSpA), Crohn's disease and giant cell arteritis (GCA). Upadacitinib was approved in January 2022 for the treatment of refractory, moderate to severe AD in adults and children aged 12 years and older who weighed at least 40 kg. The drug is available in two dosage strengths: 15 mg and 30 mg. This approval was based on compelling efficacy and safety findings from a large phase 3 trial. Figure 1 shows the timeline of FDA approval in different diseases. As of April 2025, upadacitinib has received regulatory approval in various indications, including AD in the United States, European Union, United Kingdom, and several other regions, and is anticipated to be launched in the Indian market in the near future.
- Timeline depicting Food and Drug Administration (FDA) approval of upadacitinib in various diseases. “Created with BioRender.com”
Search strategy
A systematic literature search was performed to identify studies on the use of upadacitinib in both dermatological and non-dermatological conditions, conducted between 2016 and December 2024. The Medline database was searched through PubMed using the search term "Upadacitinib." Abstracts were reviewed to select studies published in English. From a total of 1,192 results, 451 studies relevant to dermatology were included in the review.
Pharmacology
Upadacitinib is an oral small molecule with selective JAK1 inhibition. It belongs to the second generation of JAK inhibitors.
i. Pharmacokinetics
The chemical formula of upadacitinib is C17H19F3N6O and it has a molecular weight of 380.368 Da.
1. Absorption and distribution
Upadacitinib demonstrates dose-proportional absorption within its therapeutic range. A median time of 2 to 4 hours is required to reach peak plasma concentration (Cmax) after oral administration. After 4 days of once-daily dosing, steady-state plasma levels are reached. It is offered in both immediate-release (IR) and extended-release (ER) formulations. The ER formulation is estimated to have an oral bioavailability of approximately 80%, which is higher than the IR form. The pharmacokinetics of the ER formulation are not significantly affected by food intake. Additionally, upadacitinib is 52% plasma protein bound.
2. Metabolism
Upadacitinib, metabolised by CYP3A4, is notably affected by potent CYP3A4 inhibitors and inducers. It also undergoes metabolism to a lesser extent via CYP2D6. For example, the strong CYP3A inhibitor ketoconazole led to a 75% increase in upadacitinib area under the curve (AUC), while the CYP inducer rifampicin decreased upadacitinib AUC by 60%.3
3. Elimination
Upadacitinib has a terminal elimination half-life (t½) that typically ranges from 6 to 15 hours across most doses. Approximately 43% of the total dose is excreted in the urine, with 24% of that being in the unchanged parent drug form. Patients with mild to moderate renal or hepatic impairment do not require any dose adjustments.
ii. Pharmacodynamics
JAKs are a family of cytoplasmic tyrosine kinases that include four isotypes: JAK1, JAK2, JAK3, and TYK2, the latter being a non-receptor tyrosine kinase. They are linked with membrane cytokine receptors, which transmit signals downstream from various cytokines and growth factors. Activation of these JAK pathways lead to the production of survival factors and other molecules that drive the proliferation and migration of leukocytes, playing a key role in the development of various inflammatory and autoimmune conditions. The first-generation JAK inhibitors (JAKnibs) include tofacitinib (JAK1/3), ruxolitinib (JAK1/2), and baricitinib (JAK1/2). In contrast, the second-generation JAK inhibitors exhibit greater selectivity, such as JAK1 inhibitors like abrocitinib and upadacitinib, JAK3 inhibitors like ritlecitinib, and TYK2 inhibitors like brepocitinib and deucravacitinib.
Upadacitinib acts by inhibiting JAK1, which plays a central role in the signalling pathways of cytokine transduction and has been extensively studied due to its pivotal role in B and T-cell differentiation, as well as its involvement in the acute phase response during inflammation.
iii. Dosage
Extended-release tablets: 15 mg, 30 mg, and 45 mg
Approved and off-label indications of upadacitinib
AD is the only FDA-approved dermatological indication for the use of upadacitinib. Other FDA approved and off-label indications of upadacitinib are detailed in Table 1.
| FDA approved indications | Off label indications in dermatology |
|---|---|
|
Moderate to severe active RA (August 2019) |
Eczematous disorders: Atopic hand eczema, allergic contact dermatitis,16 dyshidrotic eczema,17 chronic actinic dermatitis,18 Netherton syndrome.19 |
|
Psoriatic arthritis (December 2021) |
Papulosquamous and lichenoid disorders: Plaque psoriasis, psoriasiform drug eruption and pustular psoriasis,20 palmoplantar pustulosis,21 generalised pustular psoriasis,22 Pityriasis rubra pilaris,23 nail psoriasis,24 erosive oral lichen planus,25 lichen planus,26 |
|
Atopic dermatitis in adults and children 12 years and older with refractory, moderate to severe disease (January 2022): only FDA approved dermatological indication • Paediatric patients (≥12 years, ?40 kg) and adults (<65 years): Initiate with 15 mg once daily, consider 30 mg if needed. • Adults (≥65 years) and severe renal impairment (eGFR 15 to <30 mL/min/1.73m2): Recommended dosage is 15 mg once daily |
Autoimmune bullous disease and Connective tissue diseases: Bullous pemphigoid,27,28 pemphigus foliaceous,29 amyopathic dermatomyositis,30 discoid lupus erythematosus,31 lupus tumidus,32 adult-onset Still's disease,33 |
|
Ulcerative colitis (March 2022) |
Alopecia: Alopecia areata,34 alopecia universalis (Phase 3 trial) |
|
Ankylosing spondylitis (April 2022) |
Appendageal diseases: Hidradenitis suppurativa,35,36 acne keloidalis nuche,37 dissecting cellulitis of scalp38 |
| Adults with non-radiographic axial spondylarthritis (October 2022) |
Prurigo: Chronic prurigo,39 prurigo nodularis40 |
|
Crohn's disease (May 2023) |
Pigmentary disorders: Recalcitrant vitiligo41 |
|
Giant cell arteritis (April 2025) |
Others: Lichen amyloidosis,42 epidermolysis bullosa pruriginosa,43 disseminated granuloma annulare,44 erythema multiforme,45 multicentric reticulohistiocytosis,46 erythrodermic mycosis fungoides,47 granulomatous cheilitis,48 Hailey-Hailey disease,49 pyoderma gangrenosum,50 Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis (SAPHO) syndrome.51 |
Upadacitinib in AD
1. Pathogenesis of AD and the mechanism of action of upadacitinib in AD
AD is a chronic inflammatory condition with a compromised skin barrier, leading to persistent pruritus, xerosis, and eczematous lesions. Its complex pathophysiology involves genetic, environmental, and immune factors. Epidermal barrier dysfunction is partly driven by a decrease in the expression of proteins and lipids, which results from the upregulation of interleukins IL-4, IL-13, and IL-33.4,5 AD is associated with T-cell activation, specifically Th2 and Th 22-centred pathways in acute lesions, and Th1 and Th17-centred pathways in chronic lesions.
In genetically predisposed individuals, exposure to allergens activates langerhans cells, which process and present the allergen to naive T cells in the lymph nodes. This results in the differentiation of Th2 cells and the release of Th2 cytokines such as IL-4, IL-5, and IL-13. These cytokines bind to the receptors (subunits IL-4R? and IL-13R?1) on keratinocytes, activating the downstream JAK1/JAK2 and STAT6/STAT3 pathways. This signalling impairs the translocation of transcription factors (OVOL1 and AHR) from the cytoplasm to the nucleus, thereby blocking AHR- and OVOL1-mediated transcription of epidermal differentiation markers (FLG, LOR, and IVL), resulting in barrier dysfunction. By inhibiting JAK1 in this axis, upadacitinib releases the inhibition, facilitates the nuclear translocation of OVOL1 and AHR, restoring the expression of barrier proteins and improving the epidermal barrier. Additionally, IL-4 binding to receptors (subunits; IL-4R? and the common ?-chain) on haematopoietic cells (Th2 cells and Innate lymphoid cells) activates downstream signalling, promoting production of various chemokines (CCL-26, CCL-17, CCL-22) and cytokines including IL-31, which triggers itching by acting on sensory nerve endings. IL-5 and CCL-26 recruit eosinophils, while CCL-17 and CCL-22 recruit Th2 cells. IL-4 and IL-13 further drive the class switching of B cells to produce IgE, which binds to mast cells and triggers the release of histamine, contributing to pruritus. By inhibiting JAK1, upadacitinib reduces the production of these inflammatory mediators, thus alleviating both inflammation and itch in AD as illustrated in Figure 2.
- Illustration depicting mechanism of action of Upadacitinib in atopic dermatitis. “Created with BioRender.com”. (Th2 cells: T helper-2 cells, IL: Interleukin, JAK: Janus kinase, STAT: Signal transducer and activator of transcription, OVOL1: Ovo-like 1, AHR: Aryl hydrocarbon receptor, FLG: Filaggrin, LOR: Loricrin, IVL: Involucrin, CCL: Chemokine ligand, ILC: Innate lymphoid cell).
2. Dosing in AD
Upadacitinib is approved for use in children aged ?12 years and those weighing ?40 kg, up to 65 years of age, with the following recommended dosage. Adults ?65 years or patients with severe renal impairment require dose modification.
• Adults (<65 years) and children (?12 years, ?40 kg): Start with 15 mg once daily and increase to 30 mg if necessary.
• Adults (≥65 years) and patients with severe renal impairment (estimated Glomerular Filtration Rate, eGFR 15 to <30 mL/min/1.73m2): 15 mg once daily dose is recommended.
3. Efficacy and safety of upadacitinib in AD comparison to other JAK inhibitors and immunosuppressants
The US FDA and the European Medicines Agency (EMA) have approved upadacitinib for the treatment of moderate-to-severe AD in adults and children aged 12 years and older, based on findings from three large, global phase 3 randomised clinical trials. The details of the trial have been provided in Table 2.
| Disease | Trial | Trial type, number of patients | Inclusion criteria | Treatment groups | Trial duration and study end points | Results | Adverse events |
|---|---|---|---|---|---|---|---|
| Atopic dermatitis (AD) | AD up study52 | Multicentre, phase 3, randomised, double blind, placebo-controlled study in 171 clinical centres globally (901 patients) | Adults and adolescents (12–75 years) with chronic AD that was moderate to severe | UPA 15 mg/UPA 30 mg/placebo OD, all in combination with TCS (1:1:1) for 16 weeks, re-randomisation of placebo group to UPA15mg/30mg (1:1) | 52-week, (EASI-75) from baseline, (vIGA-AD) and (WP-NRS) | EASI-75 response- 50.8% for 15mg dose and 69.0% for 30mg dose | Acne, nasopharyngitis, URTI, oral herpes, elevation of blood CPK levels, headache, AD. No deaths were reported. MACE and VTE events were infrequent (?0.2/100 patient-years). |
| Measure up 1 and 253 | Multicentre, double-blind, placebo-controlled, replicate phase 3 randomised controlled trial (RCT) conducted in 151 and 154 centres in Measure Up 1 and Measure Up 2, respectively. (total of 1609 patients) | 12 to 75 years with moderate to severe AD | Randomised 1:1:1 to receive once-daily oral UPA 15 mg, 30 mg, or placebo | 52-week, safety, efficacy, and proportion of patients who had achieved EASI-75 | EASI-75 was achieved by 82.0% and 79.1% of patients continuing the 15-mg dose and 84.9% and 84.3% of patients continuing the 30-mg dose (for Measure Up 1 and Measure Up 2, respectively) | Frequently reported TEAEs were acne, cough, headache, herpes zoster, oral herpes, UTI, URTI, nasopharyngitis, AD & elevation in blood CPK levels, transaminase, anemia, lymphopenia. Most common serious infections were pneumonia & eczema herpeticum in Measure Up 1 and 2, respectively. All OI's (excluding TB and herpes zoster) were cases of eczema herpeticum, except for an esophageal candidiasis in patient taking UPA 30 mg. 1 adjudicated MACE (nonfatal stroke) (UPA-15), 1 case of DVT (UPA-15) and 1 PE (UPA-30) were reported-events were deemed serious & unrelated. | |
| Rising up54 | Phase 3, randomised, multicentre study in Japan (272 patients) | Moderate-to-severe AD in adults and adolescents | Randomised 1:1:1 to TCS plus UPA 15 mg, UPA 30 mg or placebo | 112-week, EASI 75/90 | At week 112, 69.5% and 74.4% of patients achieved EASI 75 with UPA15 mg and 30 mg, respectively, while 37.8% and 56.4% of patients achieved EASI 90 | Most common AEs included acne, nasopharyngitis and herpes zoster. One event each of rectal cancer and cerebellar hemorrhage was reported in the UPA15 group; no thrombotic events were observed. | |
| Heads up8 | 24-week, head-to-head, phase 3b, multicentre, randomised, double-blinded, double-dummy, active-controlled clinical trial, 673 adults | Comparing the safety and efficacy of UPA with dupilumab in moderate-to-severe AD | Oral UPA, 30 mg OD or S.C dupilumab, 300 mg every other week (1:1) | At week 24 included EASI75, EASI90, EASI100, and improvement of 4 points or more in WP- NRS from baseline | Efficacy in the intent-to-treat population revealed superior effectiveness of UPA compared to dupilumab during the initial 16 weeks | Most frequent AE among patients treated with UPA was acne (16.1%), whereas in dupilumab group was conjunctivitis (8.8%). Rates of serious infection (1.1% vs 0.6%), eczema herpeticum (0.3% vs 0%) and herpes zoster (2.0% vs 0.9%) were higher for patients treated with UPA than those treated with dupilumab. No cases of adjudicated VTE, MACE, active tuberculosis or gastrointestinal perforation were reported in either treatment group. |
|
| Vitiligo | Passeron et al55 | Phase 2b multicentre, randomised, double-blind, placebo-controlled dose-ranging study | 18–65 years with extensive non-segmental vitiligo (NSV) | In period 1: UPA 22 mg, UPA 11 mg, UPA 6 mg, or placebo (PBO) for 24 weeks, OD Period 2: In a 28-week blinded extension, patients receiving PBO in period 1 were pre-assigned to either UPA11 or UPA22. | Efficacy endpoints evaluated through week 36 included (%CFB) in F-VASI, F-VASI 50 and F-VASI 75, %CFB in T-VASI and T-VASI 50 | At week 36, F-VASI 50 was achieved with UPA6, UPA11, & UPA22 by 34.2%, 54.3% and 61.5% of patients and F-VASI 75 by 15.8%, 40.0% and 30.8%, respectively. %CFB in T-VASI for UPA6, UPA11 & UPA22 were ?24.3%, ?32.0% and ?37.6% with 10.5%, 20.0% & 19.2% of patients, respectively, achieving T-VASI 50. | TEAE rates were generally similar with UPA and PBO in period 1 and across treatment arms in period 2. Most common TEAEs: COVID-19, acne, fatigue, and headache One death adjudicated as unknown cause in the UPA22 group (period 1). One adjudicated event of nonfatal ischemic stroke occurred with UPA11 (period 2). There were no adjudicated events of VTE, gastrointestinal perforation or events of opportunistic infection, active tuberculosis or malignancy. |
UPA: Upadacitinib, EASI: Eczema activity and severity score, URTI: Upper respiratory tract infection, CPK: Creatinine phosphokinase, UTI: Urinary tract infection, OI: Opportunistic infection, TB: Tuberculosis, DVT: Deep vein thrombosis, PE: Pulmonary embolism, TCS: Topical corticosteroids, WP- NRS: Worst pruritus numerical rating scale, AE: Adverse effects, %CFB: Percent change from baseline, F-VASI: Facial vitiligo area scoring index, T-VASI: Total vitiligo area scoring index, T-VASI 50: At least a 50% improvement in T-VASI, vIGA-AD: Validated investigator global assessment for AD, PBO: Placebo.
• Upadacitinib vs. abrocitinib, baricitinib
Wan et al.6 (2022) conducted a network meta-analysis comparing abrocitinib, baricitinib, and upadacitinib for moderate-to-severe atopic dermatitis. They reported that upadacitinib 30?mg was superior to all other regimens, upadacitinib 15?mg was superior to all except abrocitinib 200?mg, and that abrocitinib 200?mg outperformed abrocitinib 100?mg and all baricitinib doses in terms of efficacy outcomes like Investigator's global assessment (IGA) and Eczema Area and Severity Index (EASI) response.
Direct meta-analysis suggested that abrocitinib was associated with a significantly higher incidence of treatment-emergent adverse events (TEAEs) compared to placebo (OR 2.25, 95% CI 1.59 to 3.41). Upadacitinib also had a higher incidence of TEAEs vs. placebo (OR 1.48, 95% CI 1.02 to 2.27). A subgroup network meta-analysis showed that upadacitinib at 30 mg markedly increased the risk of TEAEs (OR 6.71, 95% CI 1.48 to 30.83).6
• Upadacitinib vs. dupilumab
A network meta-analysis indicates that upadacitinib (30 mg) and abrocitinib (200 mg) are more effective than dupilumab and baricitinib as second-line systemic therapies in adults with AD. Upadacitinib (15 mg) or abrocitinib (200 and 100 mg) are more effective than dupilumab in adolescents.7 A 24-week head-to-head comparison of upadacitinib (30 mg once daily) with dupilumab (300 mg subcutaneous every other week) (Heads Up trial) showed superior efficacy of upadacitinib in disease control and reduction in pruritus in patients with moderate to severe AD.8
• Upadacitinib vs. conventional immunosuppressants
Upadacitinib (30 and 15 mg) are likely to be more effective than ciclosporin A as first-line therapy in moderate to severe AD.7
Contraindications
Upadacitinib is contraindicated under the following conditions
1. History of hypersensitivity to upadacitinib or any of the ingredients in the formulation.
2. Pregnancy and breastfeeding, children less than 12 years or <40kg
3. Active local or systemic infections HIV, Hepatitis, active/latent tuberculosis
4. Laboratory abnormalities like anaemia ( <8 g/dL), Lymphocytopenia (<500 cells/mm3), neutropenia (1000 cells/mm3)
5. Severe hepatic (Child-Pugh C) and renal (eGFR <15mL/min/1.7m2) dysfunction
6. Close monitoring of patients at risk for gastrointestinal perforations and evaluate for any symptoms.
Baseline investigations and monitoring
Prior to starting upadacitinib, a thorough history and examination to look for any past or active infections and organ dysfunctions are required. It is recommended that adult patients receive their pneumococcal and herpes zoster vaccines. Details regarding baseline workup and monitoring are outlined in Table 3.9
| Baseline work up | ||
| Complete blood count (CBC) with differential | Contraindicated if haemoglobin is <8 g/dL, absolute neutrophil count is <1000/mm3 and absolute lymphocyte count is <500/mm3 | |
| Liver function tests (LFT) | Not recommended for patients with severe hepatic impairment (Child-Pugh C) | |
| Renal function tests (RFT) | Contraindicated if estimated glomerular filtration rate (eGFR) <15 mL/min/1.7m2 | |
| Screen for active or latent TB | If positive, treat for tuberculosis prior to use | |
| Screen for viral infections | Contraindicated if active hepatitis B or hepatitis C | |
| Pregnancy status | Contraindicated | |
| Monitoring | ||
| CBC | - At 1 month after treatment - Every 3–6 months thereafter |
Stop if • Haemoglobin drops > 2 g/dL or is < 8 g/dL, absolute neutrophil count (ANC) is <1000/mm3, absolute lymphocyte count is < 500/mm3 |
| LFT | Depending on prior laboratory results and risk factors | Stop if - drug-induced liver injury is suspected, until this diagnosis is excluded. |
| RFT | Depending on prior laboratory results and risk factors | Stop if - Creatinine clearance is 30–60 or<30 mL/min |
| Lipid profile | 3 months after initial screening | Manage similarly to hyperlipidaemia of any cause. |
| Tuberculosis | Screening should also be performed annually | |
Use in special populations
1. Pregnancy/lactation and children less than 12 year or ?40kg: Contraindicated
2. Elderly: In adults ≥65 years, 15 mg once daily (recommended dosage)
3. Hepatic dysfunction
• Mild to moderate hepatic disease: No dose adjustment required
• Severe hepatic impairment (Child-Pugh C): Contraindicated
4. Renal dysfunction
Dose modification according to eGFR is required in patients with renal impairment
• Mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73m2): No dosage adjustment is needed
• Severe renal impairment (eGFR 15 to <30 mL/min/1.73m2): Recommended dosage is 15 mg once daily
• End-stage renal disease (eGFR <15 mL/min/1.73m2): Contraindicated
5. Vaccinations: Avoid use with live vaccines
6. Combination:
Upadacitinib should not be combined with other JAK inhibitors, biologics, or other potent conventional immunosuppressants like cyclosporine and azathioprine.
Adverse effects
Clarity is still needed to distinguish whether side effects are specific to the drug, the disease, or particular patient characteristics, as opposed to being general class effects. Treatment emergent adverse effects include acne (14%), most common, nasopharyngitis (12%), upper respiratory tract infection (8%), oral herpes (8%), blood creatinine phosphokinase elevation (6%), headache (5%), and exacerbation of AD (1%). Other side effects of special interest include serious infections, eczema herpeticum, herpes zoster (2.2%), active tuberculosis, non-melanoma skin cancer (NMSC), hepatic and renal dysfunction; haematological side effects like anaemia, neutropenia, and lymphopenia in a few. The increased risk of herpes zoster is observed with both nonselective and selective JAK inhibitors, indicating the need for consistent vaccination strategies for prevention across all medications in this class. The details have been given in Table 4.
| Cutaneous | |
| Infections | Herpes reactivation* |
| Others | Acne* Pruritus Urticaria |
| Malignancies | Non melanoma skin cancers Melanoma |
| Systemic | |
| Hypersensitivity | - |
| Infections | Upper respiratory tract infection (URTI), Nasopharyngitis* |
| Opportunistic infections | Activation of latent TB* Reactivation of hepatitis B and C* Pulmonary cryptococcosis Histoplasmosis |
| Gastrointestinal AE | Nausea, gastritis, dyspepsia, vomiting, diarrhoea, abdominal pain, gastrointestinal perforation |
| Lab abnormalities | Haematological (reversible, dose dependent)Decrease in Haemoglobin, RBC count, absolute neutrophil count, absolute lymphocyte count* Increase of creatine phosphokinase (CPK), Serum Glutamic Oxaloacetic Transaminase (SGOT), Serum Glutamic Pyruvic Transaminase (SGPT)* |
| Dyslipidaemia | Increase in low-density lipoprotein (LDL), triglycerides, total cholesterol, and decrease in high-density lipoprotein (HDL)* |
| General symptoms | Pyrexia, fatigue, peripheral oedema |
| Musculoskeletal | Arthralgia, pain, tendinitis, joint swelling |
| Nervous system | Headache, dizziness, insomnia |
| Vascular effects | Hypertension, major adverse cardiac events (MACE), thromboembolism* |
| Solid organ malignancy | Carcinoma of the lung, prostate, breast, pancreas, lymphoma, EBV-induced lymphoproliferative disease* |
Venous thromboembolism (VTE) and major adverse cardiovascular events (MACE) were infrequent (?0.2/100 patient-years) in the Atopic dermatitis-upadacitinib trial (AD-UP) trial.10,11 The risk factors identified for adjudicated VTE and MACE in this study included individuals aged over 60, with uncontrolled hypertension, and a previous history of severe deep vein thrombosis or pulmonary embolism related to a COVID-19 diagnosis. However, the exact magnitude of this potential risk increase has not been quantified. Sporadic instances of VTE have been reported with more selective JAK1 inhibitors, including upadacitinib.12 Theoretically, JAK2 is primarily associated with elevated platelet counts and thrombosis risk. Hence, it is conceivable that the level of VTE risk associated with JAK1-selective inhibitors, such as upadacitinib, might be lower compared to non-selective inhibitors, such as tofacitinib.13
Boxed warnings associated with upadacitinib include the following
1. Serious infections: Pulmonary and extra-pulmonary TB, invasive fungal infections, bacterial and viral infections, including herpes zoster.
2. Mortality: The presence of at least one cardiovascular risk factor in patients 50 years or older is associated with an increased rate of all-cause mortality.
3. Malignancy: Lymphoma and other malignancies (other than non-melanoma skin cancer) are increased compared to tumor necrosis factor (TNF) inhibitors.
4. MACE: Non-fatal myocardial infarction, cardiovascular death, and non-fatal stroke.
5. Thrombosis: Patients with symptoms of thrombosis should discontinue upadacitinib and should undergo evaluation.
A study on the long-term safety of upadacitinib across rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylosis (AS), and atopic dermatitis (AD) noted varying adverse event rates: deaths (0 to 0.8%), serious infections (0 to 3.9%), MACE (0 to 0.4%), VTE (less than 0.1 to 0.4%), and malignancies (0.3 to 1.4%). Lower rates were generally seen in AS and AD patients. AD patients had increased acne rates compared to others.14 Upadacitinib usage across RA, PsA, and AS in phase 2b/3 clinical trials revealed that in patients with RA and PsA, MACE rates (0.3–0.6 E/100 PY) and VTE rates (0.2–0.4 E/100 PY) were similar across upadacitinib doses, and rates were also comparable to those seen with active comparators such as adalimumab and methotrexate utilised in these trials. For AS patients, no MACEs were reported, with only one VTE event. Screening for multiple cardiovascular risk factors, including chronic inflammation associated with uncontrolled immune-mediated inflammatory diseases (IMIDs), may help prevent MACE and VTE, as these conditions are commonly present in affected patients. Additionally, monitoring for inflammatory changes in lipid parameters, which can elevate the risk of atherosclerotic cardiovascular disease, may further aid in reducing the incidence of MACE and VTE in patients receiving upadacitinib. Individuals with IMIDs face up to twice the risk of cardio-vascular morbidity and mortality and a threefold increased risk of VTE.15
Conclusion
Upadacitinib has shown promising efficacy and a favourable safety profile in the treatment of various dermatological disorders. By selectively inhibiting specific JAK pathways, it provides targeted therapeutic effects while minimising off-target activity. Clinical trials have demonstrated its sustained efficacy over long-term treatment, particularly in moderate to severe AD, with manageable safety outcomes. Overall, upadacitinib represents a significant and well-tolerated addition to the dermatologic therapeutic armamentarium, offering an effective option for patients with severe, treatment-refractory inflammatory skin disorders.
Declaration of patient consent
Patient's consent not required as there are no patients in this study.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
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