Introduction

Janus kinase (JAK) inhibitors have emerged as an important therapeutic class for the management of several immune-mediated conditions, including inflammatory bowel disease (IBD), but they are associated with several side effects. A renewed attention to the safety profile of this drug class has been driven by increasing reports of JAK inhibitor-induced acneiform eruptions seen in clinical trials and real-life practice.

Aims & Methods

We aimed to investigate the epidemiology, clinical characteristics, and treatment outcomes of this condition in patients with IBD. This was an international, multicenter, retrospective cohort study that consecutively enrolled patients with IBD who were treated with JAK inhibitors and subsequently developed acne. The primary objective was to evaluate the clinical characteristics of acne presentation. Secondary objectives included determining acne prevalence, assessing its impact on quality of life, and evaluating the effectiveness of treatments.

Results

Of the 2,183 JAK inhibitor-treated patients with IBD screened, 272 developed acne and were included in the study. The crude prevalence rates of acne were 15.9% for upadacitinib, 4.3% for tofacitinib, and 1.9% for filgotinib, with dose-dependent relationships observed for upadacitinib and tofacitinib. Acne predominantly affected patients aged 30–50 years, with most cases being mild to moderate in severity. Acneiform eruptions most frequently involved the face (89%), followed by the back (33%) and chest (27%). Lesion characteristics were documented in 159 patients; papules (82%), pustules (52%), and comedones (42%) were the most frequently reported. In contrast, nodules (19%) and cysts (18%) – features associated with more severe disease – were less commonly observed. Among the 213 patients with available time-to-onset data, the median time to acne onset following JAK inhibitor initiation was 47 days (IQR: 28–98 days). Patients with a previous history of acne vulgaris were significantly more likely to develop severe drug-induced acne (p<0.0001). Although corticosteroids are known to contribute to acne, our data did not demonstrate an association between concomitant steroid use and increased acne severity. There was also no difference in time to onset or resolution of acne between the steroid-treated and non-steroid treated groups. A third of patients reported a negative impact on psychosocial well-being, and 40% required pharmacological intervention. Topical therapies were required for 106 patients (39%), with 52 (49%) showing acne improvement or resolution. Systemic oral agents were required for 38 patients (14%), including 25 patients who did not respond or had a partial response to topical therapies. Antibiotics were prescribed to 29 patients (most commonly from the tetracycline class), leading to acne improvement or resolution in 14 patients (48%). Oral isotretinoin was required for 8 patients (3%) and was effective in all but one patient. Eighteen percent of patients who developed acne (2.2% of total cohort) required a JAK inhibitor dose reduction or discontinuation, although most did not have severe disease.

Conclusion

This study is the first to characterise this adverse event in JAK inhibitor-treated patients with IBD and presents the largest cohort of JAK inhibitor-induced acne cases to date across all immune-mediated diseases. JAK inhibitor-induced acne is a common adverse effect resulting in significant psychological burden. Early identification, proactive counselling, and timely interventions, such as dose reduction or referral to dermatology, are crucial in managing this side effect.

Introduction

There is a lack of guidance regarding clinical trial design for advanced combination treatment (ACT) in patients with inflammatory bowel disease (IBD). Key uncertainties remain regarding aspects such as eligibility criteria, pharmacotherapy regimens, safety considerations, and standardised trial design configurations for both induction and maintenance phases.

Aims & Methods

We aimed to formulate expert recommendations regarding the design of ACT clinical trials in IBD. ACT was defined as the concomitant administration of 2 biological therapies, a biological plus an oral small molecule, or 2 small molecules.^1,2 A total of 17 gastroenterologists and precision medicine experts were invited to participate in a Modified RAND/University of California, Los Angeles Appropriateness Methodology (RAM) exercise, based on publication record, experience in clinical trial design, and/or expertise in personalised treatment strategies for IBD. The process began with development of a draft survey drawing from a previously published systematic review that identified 10 randomised controlled trials comparing ACT with advanced monotherapy for the treatment of immune-mediated diseases.² The survey covered 6 domains: (1) general considerations, (2) pharmacotherapies utilised in ACT regimens, (3) trial design configurations, (4) outcome timepoints, (5) outcome measures, and (6) precision medicine considerations. The RAM study evaluated 287 statements related to the design of ACT clinical trials in patients with IBD. The multidisciplinary panel of experts rated statement appropriateness on a 9-point Likert scale. Statements were subsequently categorised as appropriate, uncertain, or inappropriate based on the median panel rating and the presence of disagreement.

Results

ACT should consist of drugs with distinct mechanisms of action, avoiding combinations targeting the same biological pathway (Table 1). Panellists favoured combining therapies with distinct mechanisms of action and deemed the use of 2 drugs targeting the same pathway (eg, 2 anti-tumour necrosis factors) inappropriate. Combinations such as sphingosine-1-phosphate receptor modulators with α4β7 inhibitors were classified as appropriate, while the addition of thiopurines required case-specific consideration. Appropriate eligibility criteria included prior treatment failure and high risk for disease complications. Safety considerations were prioritised, with short-term use of high-risk regimens acceptable for induction therapy. Trial designs should compare ACT to monotherapy and allow for longitudinal evaluation. Co-primary endpoints of clinical remission and endoscopic response were endorsed, with safety outcomes including adverse events and infections. Precision medicine approaches, guided by biomarker analysis, were considered essential for further defining mechanistic pathways and monitoring treatment response.

Conclusion

Implementing standardised design elements for eligibility criteria, pharmacotherapy regimens, safety considerations, and trial design configurations will facilitate the conduct of efficient clinical trials of ACT.

References

1. Danese S, Solitano V, Jairath V, Peyrin-Biroulet L. The future of drug development for inflammatory bowel disease: the need to ACT (advanced combination treatment). Gut. 2022;71(12):2380-2387. Doi: 10.1136/gutjnl-2022-327025
2. Solitano V, Yuan Y, Singh S, Ma C, Nardone OM, Fiorino G, et al. Efficacy and safety of Advanced Combination Treatment in immune-mediated inflammatory disease: A systematic review and meta-analysis of randomized controlled trials. J Autoimmun. 2024;149:103331. Doi: 10.1016/j.jaut.2024.103331

Disclosure

Jurij Hanžel has received consultancy fees from Alimentiv Inc
Christopher Ma has received consulting fees and speaker’s fees from Alimentiv Inc.
Laurent Peyrin-Biroulet has received consulting fees from Alimentiv Inc.
Bram Verstockt has received consultancy fees from Alimentiv Inc.
Geert D'Haens reports consulting fees from Alimentiv Inc
Malcolm Hogan and Claire E. Parker are employees of Alimentiv Inc.
Federica Ungaro has nothing to declare.
Julian Panés has received consultancy fees/honorarium from Alimentiv Inc., and has served on data safety monitoring boards for Alimentiv Inc.
Remo Panaccione has received consultant fees and advisory board fees from Alimentiv Inc. (formerly Robarts).
Bruce E. Sands reports consulting fees from Alimentiv Inc.
Brian G. Feagan is the Senior Scientific Director at Alimentiv Inc.
Silvio Danese has received consultancy fees from Alimentiv Inc.
Vipul Jairath has received consultancy/advisory board fees from Alimentiv Inc.
Virginia Solitano, Robert Battat, Tim Raine, Britta Siegmund, Joana Torres, Saurabh Mehandru, and Raja Atreya report no conflicts of interest with Alimentiv Inc.

Introduction

Guselkumab (GUS) is a dual-acting IL-23p19 subunit inhibitor that potently neutralizes IL-23 and binds to CD64, a receptor on cells that produce IL-23.¹ In the Phase 3 QUASAR maintenance study (NCT04033445), both the GUS 100mg every 8 weeks (q8w) and 200mg q4w subcutaneous (SC) maintenance dose regimens were efficacious.² Here, we evaluated efficacy of these dose regimens in clinically relevant subgroups of participants (pts) with and without extensive ulcerative colitis (UC) disease or high inflammatory burden.

Aims & Methods

Clinical responders after 12 weeks of GUS intravenous (IV) induction were randomized 1:1:1 to GUS 100mg SC q8w, GUS 200mg SC q4w or placebo (PBO) (GUS withdrawal) at start of the maintenance study (M-0). Efficacy endpoints were analyzed at Week (W)44 in the primary analysis population of pts randomized and treated in the maintenance study who had a modified Mayo score of 5-9 at induction baseline (I-0). Subgroup analyses were conducted by (1) extent of UC disease (limited to left side of colon vs extensive) based on screening endoscopy and/or medical history at I-0 and (2) inflammatory burden based on serum C-reactive protein (CRP) levels (≤3 vs >3mg/L) at M-0.

Results

Of 568 pts in the primary analysis population, 257 (45.2%) had extensive UC disease at I-0 and 182 (32.0%) had serum CRP >3mg/L at M-0.
Proportions of pts achieving W44 clinical and histologic-endoscopic efficacy endpoints were greater with both GUS dose regimens vs PBO across subgroups (Table). For pts with extensive UC disease, the proportion of pts achieving clinical remission at W44 was numerically greater with GUS 200mg q4w (62.7%) relative to GUS 100mg q8w (49.4%) (PBO, 11.6%). For those with elevated CRP (>3mg/L) at M-0, clinical remission at W44 was achieved by 48.2% of GUS 200mg q4w vs 30.2% of GUS 100mg q8w pts (PBO, 14.3%). Proportions of pts achieving endoscopic improvement, histo-endoscopic improvement, endoscopic remission, and maintenance of clinical remission were also greater with GUS 200mg q4w in these subgroups. Among pts with disease limited to the left side of the colon or CRP ≤3mg/L at M-0, proportions of pts achieving these efficacy endpoints were similar with GUS 100mg q8w and GUS 200mg q4w.

Conclusion

For pts with moderately to severely active UC with extensive disease or high inflammatory burden, greater efficacy rates were observed with GUS 200mg SC q4w compared with GUS 100mg SC q8w.

References

1. Sachen KL et al. Guselkumab binding to CD64+ IL-23–producing myeloid cells enhances potency for neutralizing IL-23 signaling. Front. Immunol. 2025;16:1532852.
2. Rubin DT 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.

Disclosure

Study support: Johnson & Johnson.​
JRA: Abbvie, Bristol Myer Squibb, Ferring, Finch, Iterative Scopes, Johnson & Johnson, Merck, Pfizer, Roivant, Seres Therapeutics and Roivant Adiso
TH: AbbVie, Bristol Myers Squibb, Daiichi-Sankyo, EA Pharma Co, Ltd., JIMRO, Eli Lilly, Gilead Sciences, Johnson & Johnson, Kissei Pharmaceutical Co, Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Inc and Takeda Pharmaceutical Co., Ltd
BB: AbbVie, Alimentiv, Allergan, Amgen, AMT, Bausch Health, Bristol Myers Squibb, Business Intelligence, Celgene, Celltrion, Eupraxia Fresenius Kabi, Ferring, Genentech/Roche, Gilead, Iterative Scopes, GlaxoSmithKline, Jamp, Johnson & Johnson, Merck, Microbiome Insights, Mylan, Novartis, Organon, Pendopharm, Pfizer, Protagonist, Qu Biologic, Sandoz, Takeda, and Viatris
LPB: AbbVie, Abivax, Adacyte, Alimentiv, Alma, Amgen, Applied Molecular Transport, Arena, Biogen, Bristol Myers Squibb, Celltrion, Connect, Cytoki, Eli Lilly, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech/Roche, Gilead, Gossamer Bio, GlaxoSmithKline, HAC-Pharma, IAG, InDex, Inotrem, Johnson & Johnson, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Nordic Pharma, Novartis, OM, ONO, OSE, Pandion, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Roivant, Samsung, Sandoz, Sanofi, Takeda, Theravance, Thermo Fisher, Tigenix, Tillots, Vectivbio, Ventyx, Viatris, Vifor, and Ysopia
MG, SY, NS, YM: Johnson & Johnson.
BES: AbbVie, Abivax, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, AstraZeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Celltrion, Equillium, Enthera, Enveda Biosciences, Evommune, Ferring, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Johnson & Johnson, Kaleido, Kallyope, Lilly, Merck, Microba, Mirador Therapeutics, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biopharma, Sanofi, Sorriso Pharmaceuticals, Spyre Therapeutics, Sun Pharma, Surrozen, Takeda, Target RWE, Teva, TLL Pharmaceutical, Tr1X, Union Therapeutics, Ventyx Biosciences, and Vividion Therapeutics
DTR: Abbvie, Altrubio, Apex, Avalo Therapeutics, Bristol-Myers Squibb, Buhlmann Diagnostics Corp, Celgene, Connect BioPharma, Intouch Group, Iterative Health, Johnson & Johnson, Lilly, Pfizer, Samsung Neurologica, and Takeda.
AD: Abivax, AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, CED Service GmbH, Celltrion, Dr Falk Foundation, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Gilead, High5MD, Johnson & Johnson, Lilly, Materia Prima, MedToday, MSD, Pfizer, Pharmacosmos, Roche, Sandoz, Stada, Takeda, Thieme, Tillotts, UniMed Verlag and Vifor Pharma