Stelara (Ustekinumab)
ustekinumab — human anti-IL-12/23 p40 monoclonal antibody
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Moderate-to-severe plaque psoriasis | Adults and pediatric patients ≥6 years | Monotherapy; candidates for phototherapy or systemic therapy | FDA Approved |
| Active psoriatic arthritis | Adults and pediatric patients ≥6 years | Monotherapy or with methotrexate | FDA Approved |
| Moderately-to-severely active Crohn’s disease | Adults | IV induction then SC maintenance | FDA Approved |
| Moderately-to-severely active ulcerative colitis | Adults | IV induction then SC maintenance | FDA Approved |
Ustekinumab occupies a unique niche among biologics as the only agent targeting the shared p40 subunit of both IL-12 and IL-23. This dual blockade is relevant across dermatologic and gastroenterologic conditions driven by Th1 and Th17 pathways. In psoriasis, it serves as a first-line biologic option for patients with moderate-to-severe disease who have failed topical therapy. In inflammatory bowel disease, it is typically positioned after anti-TNF failure, though it may be used earlier in certain clinical settings.
Ankylosing spondylitis: A proof-of-concept open-label study (TOPAS) showed clinical response, but efficacy was modest and no phase 3 trials have been completed. Evidence quality: Low.
Hidradenitis suppurativa: Case series and small retrospective studies suggest benefit; no large controlled data. Evidence quality: Very low.
Pediatric Crohn’s disease: Retrospective data in adolescent patients show steroid-free remission in approximately 58% at 52 weeks, though not yet FDA-approved for this age group. Evidence quality: Low.
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Plaque psoriasis — body weight ≤100 kg | 45 mg SC at Weeks 0 and 4 | 45 mg SC q12w | 45 mg q12w | Self-injection after training is appropriate Rotate injection sites each dose |
| Plaque psoriasis — body weight >100 kg | 90 mg SC at Weeks 0 and 4 | 90 mg SC q12w | 90 mg q12w | 45 mg is efficacious in this group but 90 mg provides greater response rates FDA PI notes superior efficacy at 90 mg for >100 kg |
| Psoriatic arthritis — standard | 45 mg SC at Weeks 0 and 4 | 45 mg SC q12w | 45 mg q12w | Can use with or without methotrexate No dose escalation to q8w studied for PsA |
| PsA with coexistent moderate-severe PsO, >100 kg | 90 mg SC at Weeks 0 and 4 | 90 mg SC q12w | 90 mg q12w | Higher dose targets concomitant psoriasis burden |
| Crohn’s disease — induction | Weight-based IV: ≤55 kg = 260 mg; >55–85 kg = 390 mg; >85 kg = 520 mg | — | 520 mg IV (single dose) | Single infusion over ≥1 hour; use 0.2 µm in-line filter Approximately 6 mg/kg body weight |
| Crohn’s disease — maintenance | 90 mg SC 8 weeks after IV induction | 90 mg SC q8w | 90 mg q8w | Some patients require dose escalation to q4w in clinical practice for loss of response |
| Ulcerative colitis — induction | Weight-based IV: same tiers as CD | — | 520 mg IV (single dose) | Same IV weight-based protocol as Crohn’s disease |
| Ulcerative colitis — maintenance | 90 mg SC 8 weeks after IV induction | 90 mg SC q8w | 90 mg q8w | Steady-state trough ~3.3 µg/mL at q8w |
Pediatric Dosing (≥6 years — Psoriasis and Psoriatic Arthritis)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Psoriasis / PsA — <60 kg | 0.75 mg/kg SC at Weeks 0 and 4 | 0.75 mg/kg SC q12w | 0.75 mg/kg q12w | Withdraw calculated volume from 45 mg/0.5 mL vial Refer to PI weight-based volume table |
| Psoriasis — 60–100 kg | 45 mg SC at Weeks 0 and 4 | 45 mg SC q12w | 45 mg q12w | Adult-equivalent fixed dosing |
| Psoriasis — >100 kg | 90 mg SC at Weeks 0 and 4 | 90 mg SC q12w | 90 mg q12w | Follows adult weight-tier approach |
Ustekinumab uses a unique dual-dosing paradigm: fixed-dose weight tiers for SC administration in psoriasis and PsA, but a true mg/kg-based IV induction for IBD. The IBD induction dose (~6 mg/kg) is substantially higher than SC doses, reflecting the need for rapid serum levels in active luminal disease. In patients with psoriasis who weigh just above 100 kg, some clinicians start with 45 mg to minimize immunosuppression, escalating to 90 mg if response is suboptimal.
Pharmacology
Mechanism of Action
Ustekinumab is a fully human IgG1κ monoclonal antibody that targets the p40 protein subunit shared by both interleukin-12 (IL-12) and interleukin-23 (IL-23). By binding to p40, the drug prevents these cytokines from engaging their cell-surface receptor complex (IL-12Rβ1), thereby blocking downstream signaling through the Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathway. IL-12 drives differentiation of naïve T cells toward a Th1 phenotype with interferon-gamma production, while IL-23 sustains and expands Th17 cells that produce IL-17A, IL-17F, and IL-22. By simultaneously inhibiting both axes, ustekinumab dampens the inflammatory cascades central to plaque psoriasis, psoriatic arthritis, and inflammatory bowel disease. Serum reductions in C-reactive protein and other acute-phase reactants are observed within weeks of induction dosing.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | SC bioavailability ~57% (psoriasis), ~78% (CD); Tmax 7–13.5 days (SC) | Slow absorption allows q12w or q8w dosing; food does not affect SC administration |
| Distribution | Vdss 4.4–4.6 L; confined largely to vascular and interstitial compartments | Small Vd typical of monoclonal antibodies; limited tissue penetration outside of blood and lymph |
| Metabolism | Degraded via catabolic pathways into peptides and amino acids (same as endogenous IgG); not CYP-mediated | No hepatic CYP interactions; however, normalizing IL-12/23 may restore suppressed CYP450 activity in inflamed patients |
| Elimination | Terminal half-life ~15–46 days (psoriasis SC); ~19 days (CD/UC); clearance ~0.19 L/day | Long half-life supports extended dosing intervals; body weight is the principal determinant of clearance |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Nasopharyngitis | 8% (45 mg); 7% (90 mg) vs 8% placebo | Similar to placebo in psoriasis trials; higher in UC maintenance (~24%) |
| Nasopharyngitis (UC maintenance) | 24% vs 20% placebo | Most frequently reported adverse effect in long-term UC studies; likely reflects longer trial duration |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Upper respiratory tract infection | 4–5% | Comparable to placebo in psoriasis trials; monitor for progression |
| Headache | 5% (psoriasis); 10% (UC maintenance) | Usually mild and self-limiting; significantly higher in ulcerative colitis long-term data |
| Fatigue | 3% (psoriasis); 4% (UC maintenance) | Dose-independent in psoriasis; may overlap with underlying disease symptoms |
| Injection site erythema | 1–2% (psoriasis); 5% (CD maintenance) | Local reaction; rotate injection sites; cold compress may reduce discomfort |
| Back pain | 1–2% | Reported more often with 90 mg in psoriasis trials |
| Dizziness | 1–2% | More frequent with 90 mg dose; usually transient |
| Pruritus | 1–2% (psoriasis); 4% (CD maintenance) | May also reflect underlying dermatologic disease activity |
| Vulvovaginal candidiasis / mycotic infection | 5% (CD maintenance) vs 1% placebo | Consistent with immunosuppressive mechanism; treat with antifungals as needed |
| Bronchitis | 5% (CD maintenance) vs 3% placebo | Monitor for progression to lower respiratory tract infection |
| Sinusitis | 3–4% (CD/UC maintenance) | Expected with any immunosuppressive biologic |
| Vomiting | 4% (CD induction) vs 3% placebo | May relate to IV infusion or active disease; generally transient |
| Arthralgia | 3% (PsA) vs 1% placebo | Paradoxical joint pain reported; distinguish from underlying PsA flare |
| Nausea | 3% (PsA/UC) | May be related to IV induction or disease activity |
| Abdominal pain | 7% (UC maintenance) vs 3% placebo | Distinguish drug-related effect from underlying colitis symptoms |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Serious infections (pneumonia, cellulitis, diverticulitis, sepsis) | 0.3% (psoriasis); 0.01/patient-year | Any time during treatment | Hold ustekinumab; initiate appropriate antimicrobial therapy; reassess before re-initiating |
| Anaphylaxis / serious hypersensitivity | Rare (~0.1% in CD trials) | Within hours of dose; reported after first IV infusion | Discontinue permanently; emergency treatment; one fatal postmarketing case reported |
| Malignancy (non-melanoma skin cancer) | 0.52/100 patient-years (psoriasis long-term data) | Months to years; monitor continually | Annual dermatologic screening; heightened vigilance in patients >60 years, prior PUVA, or prior immunosuppression |
| Posterior reversible encephalopathy syndrome (PRES) | Very rare (2 cases in clinical trials; postmarketing reports) | Days to months after initiation; some cases >1 year | Discontinue ustekinumab immediately; supportive care; imaging; most cases reversible |
| Tuberculosis reactivation | Rare | Any time during treatment | Screen with TB test before initiation; treat latent TB before starting; hold drug if active TB develops |
| Noninfectious pneumonia (interstitial, eosinophilic, COP) | Very rare (postmarketing) | After 1–3 doses | Discontinue ustekinumab; corticosteroids may be required; imaging and pulmonology consultation |
| Exfoliative dermatitis / erythrodermic psoriasis | Very rare (postmarketing) | Variable | Assess causality; may require hospitalization and alternative therapy |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Serious infection | 0.01/patient-year | Most frequent cause of safety-driven withdrawal across all indications |
| Malignancy | Rare | New diagnosis triggers reassessment; discontinuation is individualized |
| Hypersensitivity | <0.1% | Permanent discontinuation after confirmed anaphylaxis or angioedema |
| Loss of response (IBD) | ~38% require dose escalation before discontinuation at 1 year | Interval shortening (q4w) is often attempted before formal switch |
The overall infection rate with ustekinumab (27% in controlled psoriasis data) is comparable to placebo (24%). Serious infections are uncommon (0.01/patient-year). In clinical practice, mild upper respiratory tract infections and nasopharyngitis do not require dose interruption. For clinically significant infections requiring hospitalization or systemic antibiotics, ustekinumab should be held until the infection has fully resolved. The long half-life means drug levels decline slowly after the last dose, which should be factored into infection management timelines.
Drug Interactions
Ustekinumab is not metabolized by cytochrome P450 enzymes and does not directly inhibit or induce CYP isoforms. However, because chronic inflammation suppresses CYP450 activity (particularly CYP1A2, CYP2C9, CYP2C19, and CYP3A4), resolving inflammation with ustekinumab may normalize hepatic enzyme function. This is clinically relevant for patients receiving narrow-therapeutic-index drugs metabolized by CYP pathways. No formal in vivo drug interaction studies have been performed. Population pharmacokinetic analyses indicate that methotrexate, NSAIDs, and oral corticosteroids do not affect ustekinumab clearance.
Monitoring
-
TB Screening
Baseline (before first dose)
Routine Tuberculin skin test or interferon-gamma release assay (QuantiFERON, T-SPOT). Treat latent TB before initiating ustekinumab. Repeat annually or if new exposure risk factors emerge. -
Infection Signs
Every visit
Routine Assess for fever, cough, wound changes, urinary symptoms. Hold therapy for clinically significant infections until resolution. Counsel patients to report symptoms promptly. -
Skin Cancer Screening
Baseline, then annually
Routine Full skin examination for non-melanoma skin cancer. Increased vigilance in patients over 60 years, those with prior PUVA exposure, or prolonged immunosuppressant use. -
Hepatitis B Status
Baseline
Routine Screen with HBsAg, anti-HBc, and anti-HBs before initiation. Reactivation is possible with immunosuppression. Co-manage with hepatologist if positive. -
Neurological Symptoms
As needed
Trigger-based Assess for headache, visual disturbance, seizures, or confusion that may suggest PRES. Prompt imaging (MRI) if clinical suspicion arises. -
CYP Substrate Levels
At initiation / discontinuation
Trigger-based Monitor narrow-therapeutic-index drugs (warfarin, cyclosporine, theophylline) when starting or stopping ustekinumab, as CYP normalization may alter drug levels. -
Immunogenicity (Drug Levels)
If loss of response
Trigger-based Anti-drug antibodies develop in 2.9–12.4% of patients. Consider trough level and antibody measurement before switching agents. Low-titer antibodies may not be clinically significant.
Contraindications & Cautions
Absolute Contraindications
- Clinically significant hypersensitivity to ustekinumab or any excipient (L-histidine, L-histidine monohydrochloride monohydrate, polysorbate 80, sucrose)
- Active tuberculosis — must treat latent TB before initiation
Relative Contraindications (Specialist Input Recommended)
- Active serious infection — delay initiation until infection resolves or is adequately treated
- History of or known malignancy — safety not evaluated in this population; document risk-benefit discussion
- Chronic or recurrent infection — weigh benefits against infection risk; close monitoring required
- Latex sensitivity — the prefilled syringe needle cover contains dry natural rubber (a latex derivative); use vial formulation instead
Use with Caution
- Patients >60 years — increased baseline risk of malignancy and infection
- History of PUVA therapy or prolonged immunosuppression — heightened non-melanoma skin cancer risk
- Hepatitis B carriers — risk of reactivation; co-manage with hepatology
- Patients scheduled for surgery — consider the long half-life when planning perioperative drug holidays
- Pregnancy — limited human data; use if benefit outweighs risk; no teratogenicity in animal studies at >100 times MRHD exposure
Ustekinumab does not carry a formal FDA Boxed Warning, but the prescribing information contains prominent warnings regarding serious infections (including TB reactivation), malignancy risk, and the theoretical vulnerability to mycobacterial and salmonella infections in patients with pharmacologic IL-12/23 blockade. These warnings are consistent with the class-wide safety profile of biologic immunosuppressants and warrant pre-treatment screening and ongoing surveillance.
Patient Counselling
Purpose of Therapy
Ustekinumab works by targeting two specific immune-system messengers (IL-12 and IL-23) that drive the inflammation responsible for psoriasis, psoriatic arthritis, Crohn’s disease, and ulcerative colitis. Unlike corticosteroids, which broadly suppress the immune system, ustekinumab selectively blocks a defined pathway, resulting in a more targeted approach with fewer systemic side effects. Full benefits may take 12 to 16 weeks to become apparent, and treatment is typically long-term to maintain disease control.
How to Take
For psoriasis and psoriatic arthritis, injections are given at Weeks 0 and 4, then every 12 weeks. For Crohn’s disease and ulcerative colitis, the first dose is an intravenous infusion in a clinic, followed by self-administered subcutaneous injections every 8 weeks. Patients who are trained in self-injection technique may administer subcutaneous doses at home. Injections should be given in the thigh, abdomen, or upper arm, rotating sites each time. The prefilled syringe should be removed from refrigeration 30 minutes before injection and allowed to reach room temperature. Do not shake or expose to direct sunlight.
Sources
- Stelara (ustekinumab) prescribing information. Janssen Biotech, Inc. Revised 11/2025. Full Prescribing Information Primary source for all dosing, indications, adverse reactions, warnings, and pharmacokinetic data in this monograph.
- Stelara (ustekinumab) European Medicines Agency Summary of Product Characteristics. EMA SmPC Provides European regulatory perspective and supplementary safety data including long-term registries.
- 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;371(9625):1665–1674. DOI Pivotal phase 3 trial establishing ustekinumab efficacy in moderate-to-severe psoriasis with long-term follow-up.
- 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;371(9625):1675–1684. DOI Second pivotal psoriasis trial; provided key data on partial responders and dose escalation strategy.
- Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2016;375(20):1946–1960. DOI UNITI-1/2 and IM-UNITI trials establishing IV induction and SC maintenance dosing for Crohn’s disease.
- Sands BE, Sandborn WJ, Panaccione R, et al. Ustekinumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2019;381(13):1201–1214. DOI UNIFI trial providing regulatory basis for the ulcerative colitis indication.
- McInnes IB, Kavanaugh A, Gottlieb AB, et al. 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):780–789. DOI Phase 3 trial establishing ustekinumab for psoriatic arthritis with or without methotrexate.
- Feuerstein JD, Ho EY, Shmidt E, et al. AGA clinical practice guidelines on the medical management of moderate to severe luminal and perianal fistulizing Crohn’s disease. Gastroenterology. 2021;160(7):2496–2508. DOI AGA guideline positioning ustekinumab in the treatment algorithm for Crohn’s disease.
- Singh S, Loftus EV Jr, Limketkai BN, et al. AGA living clinical practice guideline on pharmacological management of moderate-to-severe ulcerative colitis. Gastroenterology. 2024;167(7):1307–1343. DOI Updated AGA guideline incorporating ustekinumab as a treatment option for ulcerative colitis management.
- Benson JM, Peritt D, Scallon BJ, et al. Discovery and mechanism of ustekinumab: a human monoclonal antibody targeting interleukin-12 and interleukin-23 for treatment of immune-mediated disorders. MAbs. 2011;3(6):535–545. DOI Definitive paper on ustekinumab’s molecular mechanism of action and IL-12/23 p40 binding characteristics.
- Adedokun OJ, Xu Z, Marano CW, et al. Population pharmacokinetics and exposure–response analyses of ustekinumab in patients with moderately to severely active Crohn’s disease. Clin Ther. 2022;44(10):1336–1355. DOI Population PK model confirming Vdss, clearance, bioavailability, and covariate effects including body weight in Crohn’s disease.
- Drugs and Lactation Database (LactMed). Ustekinumab. National Institute of Child Health and Human Development. Last revised September 2025. LactMed Entry Authoritative resource for ustekinumab safety during breastfeeding, including breast milk concentration data.
- Mahadevan U, Robinson C, Bernasko N, et al. Inflammatory bowel disease in pregnancy clinical care pathway. Gastroenterology. 2019;156(5):1508–1524. DOI AGA IBD Parenthood Project clinical pathway with guidance on biologic use during pregnancy including ustekinumab.