Ustekinumab (STELARA®)
Drug class: CDK4/6 inhibitor
Mechanism of Action
Interleukin 12 (IL 12) and interleukin 23 (IL 23) are key drivers of chronic inflammation. Ustekinumab, a fully human immunoglobulin G1 (IgG1) monoclonal antibody, targets the p40 subunit shared by IL 12 and IL 23 heterodimers. By blocking this subunit, ustekinumab prevents IL 12/IL 23 binding to the IL 12 receptor β1 (IL 12Rβ1) on immune cell surfaces. This inhibition disrupts downstream differentiation and activation of T helper type 1 (Th1) and T helper type 17 (Th17) cells, thereby attenuating dysregulated inflammatory and immune responses (1).
Approved Indications
Adult and pediatric
Plaque psoriasis (1)
Psoriatic Arthritis (PsA) (1)
Ulcerative Colitis (UC) (1)
Crohn’s Disease (CD) (1)
Dosage and Administration
Psoriasis and PSA SC Injection - Adults:
≤ 100 kg: Initial 45 mg and 4 weeks later, followed by 45 mg Q12 week (1)
>100 kg: Initial 90 mg and 4 weeks later, followed by 90 mg Q12 week (1)
Pediatric (6 to17 year old):
<60 kg: 0.75 mg/kg; 60 to 100 kg: 45 mg; >100 kg:90 mg
Crohn’s Disease and Ulcerative Colitis IV Infusion, adults:
Initial: ≤55 kg: 260 mg, >55 kg to 85 kg: 390 mg;>85 kg to 520 mg, followed by SC 90 mg dose Q8 weeks (1)
Key clinical benefits
Demonstrated efficacy in the treatment of moderate to severe psoriasis (2, 3).
Significant improvement in axial symptoms, physical function, and inhibition of structural damage in psoriatic arthritis (PsA) (4, 5).
Sustained disease control and clinical improvement in ulcerative colitis (UC) patients with inadequate response to anti TNF agents or vedolizumab (6, 7).
Provided rapid symptom relief and durable remission in Crohn’s disease (CD) with long term use (8).
Key clinical trials
PHOENIX 1and PHOENIX 2
PHOENIX 1 was a randomized, phase 3 trial involving 766 patients with moderate to severe psoriasis treated with ustekinumab. The primary endpoint was achievement of PASI 75, with difference rates of 63·9% (95% CI 57·8–70·1, p<0·0001) in patients receiving 45 mg and 63·3% (57·1–69·4, p<0·0001) in patients treated with 90 mg at weeks 0 and 4, followed by ustekinumab every 12 weeks, compared with placebo. Patients who maintained long term response at week 40 and continued maintenance dosing for up to one year demonstrated superior PASI outcomes compared with those who discontinued therapy (2).
PHOENIX 2, with a similar design, evaluated 1,230 patients and met its primary endpoints. The PASI 75 response rates versus placebo were 63.1% (95% CI 58.2–68.0; p<0.0001) for the 45 mg group and 72.0% (95% CI 67.5–76.5; p<0.0001) for the 90 mg group. From week 28, partial responders escalated to ustekinumab 90 mg every 8 weeks achieved PASI 75 at week 52 more frequently than those maintained on 90 mg every 12 weeks (68.8% vs 33.3%; difference 35.4%, 95% CI 12.7–58.1; p=0.004). Adverse and serious adverse events occurred across both ustekinumab and placebo groups. These findings confirm that ustekinumab every 12 weeks sustains long term efficacy, while dose escalation to 90 mg every 8 weeks can induce complete responses in partial responders (3).
Landmark Phase 3 Trials in Psoriatic Arthritis (PsA)
The pivotal randomized, multicentre, double blind, placebo-controlled studies established the efficacy and safety of subcutaneous ustekinumab (45 mg or 90 mg at weeks 0 and 4, followed by dosing every 12 weeks), leading to its approval for plaque PsA.
PSUMMIT 1
Among 615 patients, 42.4% and 49.5% of those treated with ustekinumab 45 mg and 90 mg, respectively, achieved ACR20 at week 24, compared with 22.8% in the placebo group (4).
PSUMMIT 2
In 312 patients, including 180 with prior anti TNF exposure, ustekinumab demonstrated ACR20 and PASI75 response rates at week 24 of 35.6% and 47.1%, respectively, versus 14.5% and 2.0% with placebo. The median HAQ DI change was −0.13 for ustekinumab versus 0.0 for placebo. At week 52, ustekinumab maintained efficacy with ACR20 of 38.9%, PASI75 of 43.4%, and a median HAQ DI change of −0.13 (5).
Ulcerative Colitis (UC) – UNIFI Trials
In this randomized phase 3 study, investigators evaluated ustekinumab as induction and maintenance therapy in 961 patients with moderate to severe UC. An intravenous (IV) induction dose of either 130 mg or 6 mg/kg, compared with placebo, achieved clinical remission in 15.6% and 15.5% of patients versus 5.3% with placebo (p<0.001).
Subcutaneous (SC) maintenance dosing of 90 mg every 8 or 12 weeks further enhanced clinical remission at week 44 in 43.8% (p<0.001) and 38.4% (p=0.002) of patients, respectively, compared with 24.0% with placebo (6).
UNIFI Jr (Pediatric UC) A phase 3 study in 112 pediatric patients (aged 2 to <18 years) with moderate to severe UC demonstrated that ustekinumab was effective and safe through week 52, with clinical remission achieved in 40.5% [95% CI: 30.4%–51.5%] (7).
Crohn’s Disease – UNITI Trials
The UNITI 1 and UNITI 2 randomized trials evaluated ustekinumab as intravenous (IV) induction followed by subcutaneous (SC) maintenance therapy in patients with moderate to severe Crohn’s disease (CD).
UNITI 1: Enrolled 741 patients with prior non response or unacceptable side effects to anti TNF therapy. Clinical response rates were 34.3% and 33.7% with ustekinumab versus 21.5% with placebo (p≤0.003).
UNITI 2: Included 628 patients with failed therapeutic response or intolerance to prior therapies. Clinical response rates were 51.7% and 55.5% with ustekinumab versus 28.7% with placebo (p<0.001).
IM UNITI (Maintenance): In 397 patients, SC ustekinumab every 8 or 12 weeks achieved remission rates of 53.1% (p=0.005) and 48.8% (p=0.04), respectively, at week 44. (8)
UNITI Jr (Pediatric CD) An extended phase 3 study evaluated induction and maintenance therapy in pediatric patients aged ≤18 years and weighing ≥40 kg. Following a single IV induction dose, SC ustekinumab 90 mg every 8 or 12 weeks was effective and safe through 52 weeks, with sustained clinical benefit. (9)
Common Adverse Events
Psoriasis and PsA: Headache, fatigue, nasopharyngitis, URTI (1).
CD induction: Bronchitis, Injection site erythema, nasopharyngitis, pruritus, sinusitis, urinary tract infection, vomiting, vulvovaginal candidiasis/mycotic infection (1).
UC: Abdominal pain, diarrhea, fatigue, fever, headache, influenza, nasopharyngitis, nausea, sinusitis (1).
Contraindications/Precautions
Use of ustekinumab is contraindicated in patients with:
Known clinical hypersensitivity to ustekinumab (1)
Active infection or increased risk of infection (1)
Posterior reversible encephalopathy syndrome (PRES) (1)
Tuberculosis (TB) (1)
Requirement for immunizations during therapy (1)
Non infectious pneumonia (1)
Special Notes for Clinician
Screen for TB and infections before initiation (1).
Avoid live vaccines during treatment (1).
Monitor for serious infections, PRES, and non-infectious pneumonia (1).
Discontinue immediately if hypersensitivity or severe allergic reactions occur (1).
Assess long term disease control and adverse events regularly with maintenance dosing (1).
Use caution in pediatric patients; efficacy and safety established in UC/CD, but infection risk requires close monitoring (1).
Abbreviations
IL-12: Interleukin-12; IL-23: interleukin-23; IgG1: immunoglobulin G1, mAb: monoclonal antibody, PsA: psoariatic arthritis; UC: ulcerative colitis; CD: Crohn’s disease; SC: subcutaneous; IV: Intravenous (IV) Infusion; Q12: every 12 weeks; Q8: every 8 weeks; TNF: Tumor Necrosis Factor; PASI: psoriasis area and severity index; ACR: American college of rheumatology; CI: confidence interval; HAQ-DI: Health assessment questionnaire-Disability index; PRES:Posterior reversible encephalopathy syndrome; TB: Tuberculosis.
References
U.S. Food and Drug Administration. Stelara: US Prescribing Information; 2023 Mar [cited 2024 May 22]. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/125261s158,761044s009lbl.pdf(Assesses on 12 (September 2026).
Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008; 17;371(9625):1665–1674.
Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. 2008;17;371(9625):1675–1684.
McInnes IB, Kavanaugh A, Gottlieb AB, et al. PSUMMIT 1 Study Group. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1-year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet. 2013 ;382(9894):780-9.
Ritchlin C, Rahman P, Kavanaugh A et al. PSUMMIT 2 Study Group. Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial. Ann Rheum Dis. 2014; 73(6):990-9.
Sands BE, Sandborn WJ, Panaccione R, et al. Ustekinumab as induction and maintenance therapy for ulcerative colitis. N Eng J Med. 2019; 26;381(13):1201-14.
De Greef E, Turner D, Russell RK, et al. P1154 Safety and efficacy of ustekinumab in paediatric ulcerative colitis (UC): Results from the phase 3 UNIFI Jr study. Journal of Crohn’s and Colitis. 2026 Jan;20 (Supplement_1): jjaf231-1335.
Feagan BG, Sandborn WJ, Gasink C, et al.. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Eng J Medicine. 2016; 17;375(20):1946-60.
De Greef E, Turner D, Kierkuś J, et al. Ustekinumab therapy for moderately to severely active pediatric Crohn’s disease: UNITI Jr study safety and efficacy results in patients weighing at least 40 kg. J Crohn's and Colitis. 2026;20(3):jjag011.
About the Author
Jaimee George holds a PhD in Microbiology and has published extensively in peer reviewed journals. As a scientific writer, she has developed systematic reviews, book chapters, review articles, and original research papers. Her professional interests include regulatory writing, medical communication tools, and case report development.
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