Guselkumab (Tremfya)
guselkumab — fully human anti-interleukin-23p19 monoclonal antibody (IgG1λ)
Approved Indications & Off-Label Uses
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Moderate-to-severe plaque psoriasis | Adults (and pediatric ≥6 years per recent label) who are candidates for systemic therapy or phototherapy | Monotherapy | FDA Approved |
| Active psoriatic arthritis | Adults | Monotherapy or with conventional DMARDs | FDA Approved |
| Moderately to severely active ulcerative colitis | Adults | Monotherapy; may continue immunomodulators/corticosteroids | FDA Approved (Sep 2024) |
| Moderately to severely active Crohn’s disease | Adults | Monotherapy; may continue immunomodulators/corticosteroids | FDA Approved (Mar 2025) |
Guselkumab was the first IL-23p19 inhibitor approved by the FDA (July 2017 for plaque psoriasis). It selectively targets the p19 subunit of IL-23, sparing IL-12 signalling. Unlike IL-17 inhibitors, guselkumab does not worsen inflammatory bowel disease — it is now approved to treat both UC and CD, making it the first and only IL-23 inhibitor offering both SC and IV induction for IBD. It carries no boxed warning and has an exceptionally favourable long-term safety profile with over 8,600 patient-years of exposure data.
Palmoplantar pustulosis: Phase III data available. Evidence quality: Moderate.
Hidradenitis suppurativa: Phase II trials. Evidence quality: Low.
Dosing by Clinical Scenario
Plaque Psoriasis & Psoriatic Arthritis (Subcutaneous Only)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Plaque psoriasis — adults | 100 mg SC at Wk 0 & 4 | 100 mg SC every 8 weeks | 100 mg Q8W | Q8W maintenance — longest dosing interval of any IL-23 inhibitor for PsO Trough ~1.2 μg/mL at steady state |
| Psoriatic arthritis — adults | 100 mg SC at Wk 0 & 4 | 100 mg SC every 8 weeks | 100 mg Q8W | May be used alone or with cDMARDs (e.g., MTX) Same regimen as PsO |
Ulcerative Colitis (Induction + Maintenance)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| UC — IV induction option | 200 mg IV at Wk 0, 4, 8 | Then transition to SC maintenance (see below) | Infuse over ≥1 hour; use in-line 0.2 μm filter Peak Wk 8 Cmax ~68 μg/mL | |
| UC — SC induction option | 400 mg SC at Wk 0, 4, 8 | Then transition to SC maintenance (see below) | Given as 2 × 200 mg injections; AUC similar to IV induction Peak ~29 μg/mL | |
| UC — SC maintenance | 200 mg SC Q4W or 100 mg SC Q8W | Starting at Wk 12 | 200 mg Q4W | Use lowest effective dose; 200 mg Q4W for patients needing higher exposure |
Crohn’s Disease (Induction + Maintenance)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| CD — IV induction option | 200 mg IV at Wk 0, 4, 8 | Then transition to SC maintenance | Approved Mar 2025; first IL-23i with IV induction for CD | |
| CD — SC induction option | 400 mg SC at Wk 0, 4, 8 | Then transition to SC maintenance | Given as 2 × 200 mg SC injections | |
| CD — SC maintenance | 200 mg SC Q4W starting at Wk 12 | 200 mg SC Q4W | 200 mg Q4W | Or 100 mg SC Q8W for patients who respond to induction Use lowest effective maintenance dose |
Guselkumab is the first and only IL-23 inhibitor offering both IV and SC induction for UC and CD. The total systemic exposure (AUC) after induction is similar with either route, giving clinicians flexibility. IV induction may be preferred for patients in clinic-based settings or those with high disease burden, while SC induction suits patients who prefer self-administration from the outset. For PsO/PsA, only SC dosing is used — no IV induction is needed.
Pharmacology & Mechanism of Action
Mechanism of Action
Guselkumab is a fully human IgG1λ monoclonal antibody that selectively binds to the p19 subunit of interleukin-23 (IL-23). By blocking IL-23 binding to its receptor, guselkumab prevents activation of the IL-23/Th17 axis without affecting IL-12-mediated Th1 signalling (since IL-12 shares only the p40, not the p19, subunit). This selective blockade reduces downstream production of IL-17A, IL-17F, and IL-22 — cytokines that drive keratinocyte proliferation, neutrophil recruitment, and mucosal inflammation. In IBD, IL-23 plays a central role in maintaining pathogenic Th17 and innate lymphoid cell responses in the gut mucosa. Unlike IL-17 inhibitors, IL-23p19 blockade does not impair the protective role of IL-17 in mucosal antifungal and antibacterial defence, which explains the absence of candidiasis and the therapeutic benefit in UC and CD.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | SC: Tmax ~5.5 days; absolute bioavailability ~49%; linear PK; steady-state trough ~1.2 μg/mL (100 mg Q8W) | Lower bioavailability than IL-17 mAbs but compensated by potent target engagement; Q8W dosing adequate for PsO/PsA |
| Distribution | Vd 13.5 L (PsO), 10.1 L (UC), 11.4 L (CD); limited extravascular distribution typical for IgG1; body weight affects exposure but no dose adjustment needed | Vd larger than typical IgG1 mAbs; patients <90 kg have ~38% higher AUC than those ≥90 kg but no dose adjustment warranted |
| Metabolism | Expected intracellular catabolism to amino acids; no CYP involvement; exploratory study showed low interaction potential for CYP3A4, CYP2C9, CYP2C19, CYP1A2 substrates; potential interaction with CYP2D6 substrates (single outlier observed) | Minimal drug interaction risk overall; monitor narrow-TI CYP2D6 substrates when initiating guselkumab |
| Elimination | CL ~0.516 L/day (PsO), ~0.531 L/day (UC); t½ ~15–18 days (PsO), ~17 days (CD) | Q8W maintenance for PsO/PsA; Q4W for IBD due to higher exposure requirements in gut inflammation |
Side Effects & Adverse Reactions
Data below are primarily from pooled Phase III PsO trials (VOYAGE 1 & 2; TREMFYA N=823 vs placebo N=422) through 16 weeks, supplemented by long-term safety data of up to 5 years (8,662 patient-years, FDA PI revised 03/2025). IBD-specific safety data from QUASAR (UC) and GALAXI/ASTRO (CD) trials are also incorporated.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Upper respiratory infections | 14.3% | Includes nasopharyngitis, URTI, pharyngitis; mild, self-limiting (vs 12.2% placebo) |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Headache | 4.6% | Includes tension headache (vs 3.7% placebo) |
| Injection site reactions | 4.5% | Erythema, bruising, pain; mild; much lower than ixekizumab (17%) (vs 3.4% placebo) |
| Arthralgia | 2.7% | Joint pain; may be pre-existing PsA symptom (vs 2.2% placebo) |
| Diarrhoea | 1.6% | Generally mild (vs 1.3% placebo) |
| Gastroenteritis | 1.3% | Includes viral gastroenteritis (vs 0.9% placebo) |
| Tinea infections | 1.1% | Lower than IL-17 inhibitors; includes tinea pedis, cruris (vs 0.3% placebo) |
| Herpes simplex infections | 1.1% | Includes oral herpes, genital herpes (vs 0.6% placebo) |
| Bronchitis | ~1.6–2.9% (PsA data) | Observed in the PsA programme; mild |
| Elevated liver enzymes | 2.6% | ALT/AST elevations more common than placebo (1.9%); check LFTs before UC/CD initiation per updated label |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Serious infections | 1.1/100 PY (short-term); 0.9/100 PY (long-term, 5 yr) | Any time | Discontinue until resolved; comparable to placebo rates in PsO programme (1.2/100 PY) |
| Hepatotoxicity (UC/CD) | Uncommon; highlighted in March 2025 label update | Variable | Obtain liver enzymes and bilirubin before initiating for UC/CD; monitor as clinically indicated; evaluate elevations promptly |
| Anaphylaxis / serious hypersensitivity | Rare (postmarketing); some required hospitalisation | Any injection/infusion | Discontinue permanently; initiate emergency therapy |
| Malignancy | 0.7/100 PY long-term (comparable to placebo) | After prolonged exposure | No increased signal vs placebo in 5-year data; standard age-appropriate cancer screening |
| MACE | 0.3/100 PY (comparable to placebo) | Variable | No increased signal; standard CV risk management |
Guselkumab’s 5-year integrated safety analysis (2,891 patients, 8,662 PY) is among the most reassuring in the biologic class for psoriatic disease. Unlike IL-17 inhibitors, guselkumab was not associated with IBD, candidiasis, or significant neutropenia. Rates of serious infections, malignancy, and MACE were comparable to placebo and remained stable or declined over time. This profile supports its use as a first-line biologic across PsO, PsA, and now IBD.
Drug Interactions
Guselkumab is eliminated by intracellular catabolism. An exploratory drug interaction study in PsO patients showed low potential for interactions with CYP3A4, CYP2C9, CYP2C19, and CYP1A2 substrates. However, one outlier showed a 2.9-fold increase in dextromethorphan AUC (CYP2D6 substrate), so CYP2D6 interactions cannot be ruled out.
Monitoring Parameters
- TB ScreeningBaseline
RoutineEvaluate for latent/active TB before initiating. Treat latent TB before starting guselkumab. No cases of active TB were reported in the 5-year PsO safety pool, but standard vigilance applies. - Liver Enzymes & BilirubinBaseline (UC/CD); if indicated (PsO/PsA)
RoutinePer the March 2025 label update: obtain liver enzymes and bilirubin prior to initiating guselkumab for UC or CD. For PsO/PsA, obtain if clinically indicated. Elevated LFTs were more common with guselkumab (2.6%) than placebo (1.9%) in PsO trials. - Signs of InfectionEvery visit
Trigger-basedOverall infection rate 23% vs 21% placebo through 16 weeks. Monitor for URTI, gastroenteritis, tinea, herpes simplex. Serious infection rate was very low and comparable to placebo. Discontinue for serious infections. - ImmunisationsBaseline
RoutineComplete age-appropriate vaccinations before initiating. Avoid live vaccines during treatment. - IBD Response (UC/CD)Wk 12 (end of induction); then per clinical judgement
Trigger-basedAssess clinical response at end of induction. If inadequate response, consider the higher maintenance dose (200 mg Q4W). Endoscopic assessment as per standard IBD practice.
Contraindications & Cautions
Absolute Contraindications
- Known serious hypersensitivity to guselkumab or any excipient — anaphylaxis reported postmarketing
Relative Contraindications (Specialist Input Recommended)
- Active serious infection — do not initiate until infection resolves or is adequately treated
- Active tuberculosis — treat latent TB before initiating
Use with Caution
- Chronic or recurrent infections — slightly higher infection rate vs placebo (23% vs 21%)
- Hepatic concerns — elevated LFTs observed; check liver enzymes before UC/CD treatment per 2025 label
- Pregnancy — limited human data; neonatal deaths in monkey offspring at high doses (4–18× human exposure); IgG crosses placenta increasingly in third trimester; pregnancy registry available (1-877-311-8972)
- Lactation — guselkumab not detected in monkey milk; unknown in human milk; weigh benefit-risk
- Combination with other biologics — not studied; not recommended
The March 2025 label revision added a requirement to obtain liver enzymes and bilirubin levels prior to initiating guselkumab for ulcerative colitis or Crohn’s disease. For plaque psoriasis and psoriatic arthritis, liver function testing should be performed if clinically indicated. Elevated liver enzyme levels (2.6% vs 1.9% placebo) were observed in PsO trials, and the IBD population may carry additional hepatic risk factors. Monitor as clinically indicated during treatment.
Patient Counselling
Purpose of Therapy
Guselkumab is a biologic medicine that targets a specific immune protein called IL-23, which drives the inflammation responsible for skin plaques, joint symptoms, and bowel inflammation. By blocking IL-23, it calms the immune response at its source, reducing skin disease, joint pain, and intestinal inflammation.
How to Take
For skin or joint conditions, guselkumab is given as a subcutaneous injection at weeks 0 and 4, then every 8 weeks — one of the longest intervals between doses of any biologic. For bowel conditions, a higher-dose induction phase (either IV infusions or SC injections at weeks 0, 4, and 8) is followed by ongoing SC injections. Patients or caregivers can learn to self-inject at home after proper training.
Sources
- TREMFYA (guselkumab) [prescribing information]. Horsham, PA: Janssen Biotech, Inc.; Revised 03/2025. FDA Label (PDF)Primary source for dosing (including UC/CD), adverse reactions, PK data, and the 2025 hepatotoxicity monitoring update.
- European Medicines Agency. Tremfya (guselkumab): EPAR — Product information. EMA Product PageEU regulatory perspective; includes SmPC with CD and UC dosing and updated pregnancy/lactation guidance.
- Blauvelt A, Papp KA, Griffiths CEM, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: results from the phase III, double-blinded, placebo- and active comparator-controlled VOYAGE 1 trial. J Am Acad Dermatol. 2017;76(3):405-417. doi:10.1016/j.jaad.2016.11.024VOYAGE 1 pivotal trial: guselkumab superior to adalimumab on PASI 90 and IGA 0/1 at week 16; sustained through 48 weeks.
- Reich K, Armstrong AW, Foley P, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: results from the phase III, double-blind, placebo- and active comparator-controlled VOYAGE 2 trial. J Am Acad Dermatol. 2017;76(3):418-431. doi:10.1016/j.jaad.2016.11.042VOYAGE 2: demonstrated durability of response and superiority to adalimumab; informed withdrawal/retreatment strategy.
- Deodhar A, Helliwell PS, Boehncke WH, et al. Guselkumab in patients with active psoriatic arthritis who were biologic-naive or had previously received TNFα inhibitor treatment (DISCOVER-1): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet. 2020;395(10230):1115-1125. doi:10.1016/S0140-6736(20)30265-8DISCOVER-1: guselkumab 100 mg Q8W significantly improved ACR20/50, enthesitis, dactylitis, and skin outcomes in PsA.
- Mease PJ, Rahman P, Engel N, et al. Guselkumab in biologic-naive patients with active psoriatic arthritis (DISCOVER-2): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet. 2020;395(10230):1126-1136. doi:10.1016/S0140-6736(20)30263-4DISCOVER-2: confirmed PsA efficacy in a larger biologic-naive population including inhibition of structural joint damage.
- Rubin DT, Allegretti JR, Panés J, et al. Guselkumab in patients with moderately to severely active ulcerative colitis (QUASAR): phase 3 double-blind, randomised, placebo-controlled induction and maintenance studies. Lancet. 2025;405(10472):33-49. doi:10.1016/S0140-6736(24)01927-5QUASAR Phase 3 UC trial supporting the Sep 2024 FDA approval; demonstrated clinical remission and endoscopic improvement vs placebo with both IV and SC induction.
- Gossec L, Kerschbaumer A, Ferreira RJO, et al. EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2023 update. Ann Rheum Dis. 2024;83(6):706-719. doi:10.1136/ard-2024-225531EULAR 2023 PsA update positions IL-23 inhibitors as biologic options, particularly when skin involvement is prominent.
- Feuerstein JD, Isaacs KL, Schneider Y, et al. AGA clinical practice guideline on the management of moderate to severe ulcerative colitis. Gastroenterology. 2020;158(5):1450-1461. doi:10.1053/j.gastro.2020.01.006AGA UC management guideline; IL-23 inhibitors are emerging options referenced in subsequent updates.
- Gaffen SL, Jain R, Garg AV, Cua DJ. The IL-23–IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol. 2014;14(9):585-600. doi:10.1038/nri3707Key review of the IL-23/IL-17 axis explaining the upstream rationale for targeting IL-23p19 over IL-17 directly.
- Zhuang Y, Calderon C, Marciniak SJ Jr, et al. First-in-human study to assess guselkumab (anti-IL-23 mAb) pharmacokinetics/safety in healthy subjects and patients with moderate-to-severe psoriasis. Eur J Clin Pharmacol. 2016;72(11):1303-1310. doi:10.1007/s00228-016-2110-5First-in-human PK study characterising dose-proportional PK, ~49% SC bioavailability, and ~15-day half-life that informed clinical dosing.
- Griffiths CEM, Papp KA, Song M, et al. Safety of guselkumab treatment for up to 5 years in patients with moderate-to-severe psoriasis: pooled analyses across seven clinical trials with more than 8600 patient-years of exposure. Br J Dermatol. 2023;189(1):42-52. doi:10.1093/bjd/ljad097Definitive 5-year integrated safety analysis (2891 patients, 8662 PY); demonstrates favourable long-term safety with no IBD, opportunistic infection, or TB signal.
- Langley RG, Tsai TF, Flavin S, et al. Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: results of the randomized, double-blind, phase III NAVIGATE trial. Br J Dermatol. 2018;178(1):114-123. doi:10.1111/bjd.15750NAVIGATE trial showing guselkumab benefit in patients with inadequate response to ustekinumab (IL-12/23 inhibitor).