Introduction

Apelin (APL), originally isolated from alimentary tract, has been defined as the endogenous ligand for APJ, which is a known G protein-coupled receptor. It has been reported that APL is upregulated in the colonic tissues of an animal model of acute colitis induced by dextran sodium sulfate (DSS), and it is suggested to be associated with the pathogenesis of inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, in humans. However, the mechanism and function of APL in the context of IBD remain unclear.

Aims & Methods

The aim of this study was to define the function of APL in the pathogenesis of IBD. To this end, each cell type in the colonic tissue, including epithelial cells and lamina propria lymphocytes, were first isolated from wild-type C57BL6 mice (WT) to assess APL expression. Next, naïve T cells isolated from WT were adoptively transferred into Rag deficient mice (Rag^-/-) to induce chronic colitis, followed by isolation of splenic and colonic CD4⁺ T cells from these T cell-reconstituted Rag^-/- to compare with those of WT. In addition, WT naïve T cells were differentiated into either Th1, Th2 or Th17 in vitro to analyze APL expression. Finally, the Rag^-/- receiving naïve T cells were administered synthetic APL peptide, APL-13, to assess the severity of colitis.

Results

Semi-quantitative PCR (qPCR) revealed that CD4⁺ T cells express relatively higher level of APL when compared to other cell types including the epithelial cells in colonic tissue from WT. However, APL expression in the colonic tissues from the Rag^-/- induced chronic colitis was unexpectedly downregulated compared to those without colitis, which is not consistent with the previous report using acute DSS colitis model. Subsequently, qPCR revealed significantly decreased APL expression in the splenic and colonic T cells from Rag^-/- induced colitis compared to that of WT. APL expressions in all of the differentiated T cells in vitro, such as Th1, Th2 and Th17, were also significantly downregulated compared to that of non-differentiated control T cells. Given these results, APL-13 was injected into the Rag^-/- that underwent T cell reconstitution to antagonize the APL downregulation. This resulted in reduced severity of colitis compared to that of vehicle control-injected mice.

Conclusion

Our results indicate that T cells can be one of the major sources of APL in colonic tissues, and the downregulated APL expression in effecter T cells may lead to the development of chronic colitis. In addition, our current study also suggests that APL may be a novel therapeutic target for IBD.

Clinical Case Summary

An 18-year-old female was diagnosed with very early-onset Crohn’s disease (CD) in 2008. Due to steroid dependence, adalimumab 40 mg biweekly was initiated in 2019, with escalation to 40 mg weekly in February 2023 following secondary loss of response. In November 2023, despite clinical and biochemical remission (CRP <0.5 mg/L, fecal calprotectin <50 µg/g), the patient developed painful purpuric and ulcerated lesions on both lower limbs. Histological examination of a skin biopsy confirmed leukocytoclastic vasculitis (LCV), revealing perivascular neutrophilic infiltrates, nuclear debris, and fibrinoid necrosis in post-capillary venules. Infectious and autoimmune screening, including ANA, antiphospholipid antibodies, p-ANCA, and c-ANCA, were negative. Following consultation with an immunologist, adalimumab was discontinued, and oral prednisone 25 mg/day was initiated. However, the clinical course was complicated by a skin abscess, which was treated with oral amoxicillin/clavulanate (1 g three times daily for 3 days). As vasculitic lesions worsened, the patient was hospitalized, and prednisone was increased to 50 mg/day. Intravenous cefazolin (2 g every 8 hours for 5 days) was also administered, resulting in stabilization and partial clinical improvement. A multidisciplinary team, including a gastroenterologist, immunologist, and dermatologist, opted to initiate off-label treatment with upadacitinib 30 mg/day, a selective Janus kinase 1 (JAK1) inhibitor. After four weeks, the patient showed improvement in the vasculitic lesions, and corticosteroid therapy was tapered. At the six-month follow-up, the patient remained on upadacitinib monotherapy, with sustained clinical and biochemical remission of both CD and LCV, without any adverse events. This case highlights the potential of JAK1 inhibition as an effective and safe therapeutic option for leukocytoclastic vasculitis in patients with Crohn’s disease.

References

Photographic documentation of the clinical case:
1. Images showing the initial presentation of petechial and purpuric lesions on the lower limbs.
2. Images of severe vasculitis characterized by confluent and ulcerated lesions.
3. Images documenting cutaneous healing following upadacitinib treatment.

Introduction

Mirikizumab is a monoclonal antibody directed against the p19 subunit of interleukin (IL)-23 approved for the management of patients with moderate-to-severe ulcerative colitis (UC). Currently, there is no large study supporting the effectiveness of mirikizumab in UC in a real-life setting.

Aims & Methods

This study aims to evaluate the effectiveness and safety of mirikizumab in real-life setting. This was a retrospective multicenter cohort study of a prospectively collected database including adult patients with confirmed diagnosis of UC treated with mirikizumab according to clinical practice. Patients were enrolled in three third-level italian centers (San Raffaele Hospital, Humanitas Research Hospital, and Federico II Hospital) from June 2024 to February 2025. All patients with at least 3 months of follow-up after therapy initiation were eligible. The primary outcome was the clinical remission rate (defined as partial Mayo Score (pMS) < 2 with a rectal bleeding subscore of 0) at week 12. Secondary outcomes included changes in bowel urgency (measured by the Numeric Rating Scale (NRS) urgency score), changes in serum C-reactive protein (CRP) and fecal calprotectin (FC) levels from week 0 to 12, safety profile of mirikizumab during induction therapy.

Results

In total 100 patients (60% male, with median age 48.53 ± 15.36) with UC were included. Most patients had a left-sided colitis (55, 55%) or a pancolitis (41, 41%). Most patients (81, 81%) were already treated with at least one advanced therapy before starting mirikizumab (including 28 patients treated with ustekinumab, 28%). A fifth of patients (19, 19%) were exposed to ≥ 4 advanced therapies. A significant reduction in pMS was observed from baseline to week 12 (median [IQR]: 4.0 [1.75–6.0] vs. 2.0 [0.0–4.0]; Wilcoxon signed-rank test: W = 312, Z = -5.35, p < 0.00001, n = 69) with 48 (48%) patients reaching clinical remission at week 12. Moreover, a significant improvement in bowel urgency was observed from baseline to week 12 (t(98) = 6.58, p = 2.28×10⁻⁹), with a moderate-to-large effect size (g = 0.66). From baseline to week 12, both FC and CRP levels showed significant reductions following treatment (FC: V = 1153.00, p = 2.4×10⁻⁵, r = 0.67; CRP: V = 680.00, p = 0.03, r = 0.37). Effect sizes were large for FC and moderate for CRP with paired data from 53 and 47 patients being analyzed, respectively. In total, 39 patients (39%) underwent extended induction while 3 patients (3%) discontinued the drug at week 12. There were no adverse events leading to discontinuation or death. Two mild adverse events were reported (upper respiratory tract infection in 1 patient and pyrexia in 1 patients). No significant changes were observed in liver aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels over time (AST: χ²(2) = 0.21, p = 0.90, W = 0.005; ALT: χ²(2) = 3.73, p = 0.16, W = 0.08).

Conclusion

This is the largest study demonstrating the effectiveness and safety of mirikizumab in inducing clinical remission in patients with UC in a real-life setting. Patients treated with mirikizumab achieved a significant reduction in bowel urgency, FC and CRP levels. No statistically significant increase in liver toxicity was detected during the induction treatment.

Disclosure

F. D'Amico. OM Nardone, A. Zilli, M. Allocca, S. Danese, L. Peyrin-Biroulet and A. Armuzzi have served as speaker and advisory board member for Lilly

Introduction

Guselkumab (GUS) is a dual-acting IL-23p19 subunit inhibitor that was efficacious in double-blind, placebo-controlled, treat-through trials in participants (pts) with moderately to severely active Crohn’s disease (CD) using IV induction and SC maintenance (GALAXI 2 & 3) or SC induction and maintenance (GRAVITI). Assessment of histologic disease activity is becoming increasingly important as a measure of treatment efficacy. Here we report histologic outcomes at Weeks (W) 12 & 48 from GRAVITI.

Aims & Methods

Pts were randomized 1:1:1 to GUS 400 mg SC every 4 weeks (q4w)→200 mg SC q4w, GUS 400 mg SC q4w→100 mg SC every 8 weeks (q8w), or placebo (PBO). Biopsies were obtained from the most affected area (or if no disease activity present, from normal-appearing mucosa) in 5 segments: terminal ileum, ascending colon, transverse colon, descending colon, and rectum. Histologic response, histologic remission, and the composite endpoints of histo-endoscopic response and histo-endoscopic remission were evaluated using Robarts Histopathology Index (RHI), Global Histologic Activity Score (GHAS), and Geboes scoring. Histologic response was assessed in pts with baseline histologic disease; histologic remission, histo-endoscopic response, and histo-endoscopic remission were assessed in the full analysis set (see definitions in table legend). Pts who met rescue criteria at W16 were considered non-responders at W48. Histologic endpoints in GRAVITI were exploratory and not controlled for multiple comparisons; p-values are nominal.

Results

Of the 347 pts in the full analysis set, 273 (78.7%) had baseline histologic disease per RHI score. SC induction with GUS (400 mg SC at W0, W4, & W8) resulted in greater rates of histologic response, histologic remission, histo-endoscopic response, and histo-endoscopic remission compared to placebo at W12 (Table). At W48, greater proportions of pts receiving GUS 100 mg SC q8w or GUS 200 mg SC q4w maintenance also achieved histologic response, histologic remission, histo-endoscopic response, and histo-endoscopic remission compared to PBO. Comparable outcomes were observed using GHAS or Geboes scoring criteria.

Conclusion

Compared to PBO, pts with moderately to severely active CD receiving SC induction and maintenance treatment with GUS achieved greater rates of histologic response, histologic remission, histo-endoscopic response, and histo-endoscopic remission through W48. These results support the use of histologic and composite histologic and endoscopic endpoints as a measure of CD activity, and the efficacy of SC guselkumab in CD.

Disclosure

GRD’H: consultancy activities for AbbVie, Agomab, Alimentiv, AstraZeneca, AMT, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom, Galapagos, GlaxoSmithKline, Gossamerbio, Immunic, Index, Johnson & Johnson, Kaleido, Origo, Pfizer, Polpharma, Procise Diagnostics, Prometheus Laboratories, Prometheus Biosciences, Progenity, and Protagonist Therapeutics Inc.; speaker’s bureau for AbbVie, Bristol Myers Squibb, Galapagos, Pfizer, and Takeda; and data monitoring board activities for AbbVie, AstraZeneca, Galapagos, and Seres Health.
ALH: lecturer and/or advisory board member for Bristol Myers Squibb, Celltrion, Falk, AbbVie, Johnson & Johnson, Takeda, Pfizer, Galapagos, MSD, and GSK.
RP: consulting fees from Abbivax, Abbott, AbbVie, Alimentiv (formerly Robarts), Amgen, AnaptsyBio, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, JAMP Bio, Johnson & Johnson, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Spyre Therapeutics, Sublimity Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Union Biopharma, Viatris, Ventyx, and UCB; speaker’s fees from AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Gilead Sciences, Johnson & Johnson, Merck, Organon, Pfizer, Roche, Sandoz, Shire, and Takeda Pharmaceuticals; and participation in Advisory Boards for AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Johnson & Johnson, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Shire, Sublimity Therapeutics, Takeda Pharmaceuticals, and Ventyx.
FS: consultant, speaker, or researcher for AbbVie, Amgen, Celltrion, Ferring, Johnson & Johnson, Pfizer, Sandoz, and Takeda.
QC: steering committee adviser for Bristol Myers Squibb and Johnson & Johnson; research grants from Takeda and Johnson & Johnson.
SD: consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring, Gilead, Hospira, Inotrem, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity, Takeda, TiGenix, UCB and Vifor; and lecture fees from AbbVie, Amgen, Ferring, Gilead, Johnson & Johnson, Mylan, Pfizer and Takeda
TH: grant support from Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Mochida Pharmaceutical Co. Ltd., Boston Scientific Corporation, and Kissei Pharmaceutical Co. Ltd.; consulting fees from Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, Johnson & Johnson, Pfizer Inc., Eli Lilly, Gilead Sciences, Bristol Myers Squibb, and Abivax; lecture fees from Mitsubishi Tanabe Pharma Corporation, AbbVie GK, EA pharma Co. Ltd., Kyorin Pharmaceutical Co. Ltd., JIMRO Co., Johnson & Johnson, Mochida Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., and Kissei Pharmaceutical Co. Ltd.
BES: consulting fees from AbbVie, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, AstraZeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Celltrion, Equillium, Enthera, Enveda Biosciences, Evommune, Ferring, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, Microba, Mirador Therapeutics, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biopharma, Sanofi, Sorriso Pharmaceuticals, Spyre Therapeutics, Sun Pharma, Surrozen, Target RWE, Teva, TLL Pharmaceutical, Tr1X, Union Therapeutics, Ventyx Biosciences, and Vividion Therapeutics; consulting and speaking fees from Abivax; consulting and speaking fees and other support from Lilly; research grants, consulting and speaking fees and other support from Bristol Myers Squibb, Johnson & Johnson, Pfizer, and Takeda; and stock/stock options from Ventyx Biopharma.
MO, LS, PB, WvD, NT: employees and shareholders of Johnson & Johnson

Clinical Case Summary

Immunotherapy with checkpoint inhibitors (CPI) has transformed oncology management, achieving durable remissions. However, its widespread has also led to significant immune-mediated side effects, whose treatment is a challenge in today's medicine.
We present the case of a 59-year-old man diagnosed with non-small-cell lung cancer who started treatment with Nivolumab(anti-PD1). After 6 months, the patient was admitted for 3 weeks diarrhoea(4 liquid stools/day).
A colonoscopy was done, identifying severe pancolitis with oedema, erythema, nodularity and superficial ulcers. PA revealed diffuse non-specific colitis with CMV IHC -. Given the suspicion of immune-mediated colitis vs de novo IBD, treatment was started with iv GCC, with no improvement.
Given the contraindication of long-term use of anti-TNF in IBD patients with active malignancies, induction with IV Ustekinumab (anti-IL12/23) was decided. Ustekinumab 390 mg iv was given, after which the patient showed clinical improvement until complete resolution. He continued with Ustekinumab 90 mg/8 weeks. A follow-up colonoscopy showed pancolic scarring with pseudopolyps and no inflammatory activity. Given these findings Ustekinumab was discontinued after 1 year, with the patient remaining asymptomatic and without oncologic progression.
Immune-mediated colitis is a common side effect, being mild in most cases. When severe cases occur, CPI should be discontinued indefinitely, and high-dose iv GCC (up to 2 mg/kg) should be initiated. Up to one-third of GCC-treated patients don't respond and are candidates for immunosuppressive therapy with biologic drugs.
Although clinical guidelines recommend Infliximab/Vedolizumab for induction as 2º line treatment, the therapeutic decision should be individualized, as they are contraindicated in IBD patients with active malignancies. Therefore, in this context of complex differential diagnosis, Ustekinumab (with lower rate of oncological side effects) appears to be an effective option.

References

Photo 1: Initial colonoscopy: severe pancolitis with erythema, oedema, superficial ulcers and mucosal nodularity.
Photo 2: Abdominal CT: Diffuse thickening of the colon with increased uptake of the wall.
Photo 3: Follow-up colonoscopy: Chronic scar changes without signs of acute activity.

Clinical Case Summary

Introduction: Infliximab, an anti-TNF agent, has revolutionized the management of inflammatory bowel disease (IBD), promoting long-term remission and improving quality of life. However, paradoxical immune-mediated reactions, including autoimmune dermatologic conditions, have been increasingly recognized.
Aims & Methods: We report a rare case of paradoxical development of giant pyoderma gangrenosum (PG) in a patient with Crohn’s disease during Infliximab maintenance therapy.
Case Report: A 26-year-old female with Crohn’s disease (A2, L3, B1), in clinical remission under Infliximab, developed a pustular erythematous nodule (~5 cm) on the right popliteal region after the third maintenance dose. The lesion rapidly expanded to a painful ulcerative plaque with inflammatory borders, reaching 15 cm in diameter within 8 days. Histopathology revealed dense neutrophilic dermatosis, confirming pyoderma gangrenosum.
Results: This case exemplifies a paradoxical reaction induced by anti-TNF therapy. Although PG is more commonly associated with ulcerative colitis, it may occur in Crohn’s disease and be exacerbated by immunomodulation. The lesion was managed with corticosteroids and discontinuation of Infliximab, with partial improvement.
Conclusion: Paradoxical PG during anti-TNF therapy is rare but significant. Clinicians should be alert to unusual dermatologic manifestations in IBD patients on biologics. Early recognition and multidisciplinary management are essential to mitigate morbidity.

References

1) Paradoxical pyoderma gangrenosum induced by infliximab in a patient with Crohn’s disease.
• Autores: Llamas-Velasco M, García-Diez A, Daudén E.J Crohns Colitis. 2013;7(10):e479-81.
2) Paradoxical skin reactions to anti-TNFα agents: a study of 118 cases.
• Autores: Ramos-Casals M, Brito-Zerón P, Muñoz S, Soto MJ.Br J Dermatol. 2010;163(5):1159-65.
3) Paradoxical psoriasis and pyoderma gangrenosum induced by anti-TNF therapy in inflammatory bowel disease: a case series.
• Autores: Navarini AA, Trüeb RM, Imhof L, French LE.J Crohns Colitis. 2011;5(5):457-62.

Introduction

Upadacitinib has shown to be more effective than placebo for treating extraintestinal manifestations (EIM) in post-hoc analyses. However, real-world data on the effectiveness of upadacitinib in patients with inflammatory bowel disease (IBD) and EIMs are lacking.

Aims & Methods

A multicenter, retrospective and observational study was conducted at 19 Spanish hospitals. Patients with IBD and active EIMs when initiating upadacitinib were eligible. The primary outcome was EIM improvement at weeks 8-12. The EIM assessment was based on the physician's subjective evaluation and categorized into clinical remission, partial response, nonresponse and worsening. EIM improvement was defined as either clinical remission or partial response. Axial arthropathy, peripheral arthropathy, pyoderma gangrenosum, erythema nodosum, sweet syndrome, aphthous stomatitis, uveitis, episcleritis, primary sclerosing cholangitis and bronchiectasis were considered. In patient experiencing >1 EIM, all had to be resolved or improved to be considered. If not, the worst outcome was recorded. Patients’ visits were scheduled at weeks 0, 8-12, and 6 months. Multivariate analysis was performed to find factors associated with EIM improvement at w8-12.

Results

A total of 160 patients were included, 120 patients with Crohn’s Disease (75.6%), 90 females (56.3%) with a median age of 46.6 years (IQR 37.9-56.7). Upadacitinib was initiated in one hundred twenty-six (78.8%) patients due to EIMs and luminal activity and 35 patients (21.3%) exclusively due to EIMs. All patients were bio-experienced with 84 patients previously treated with ≥3 biologics (52.5%). Baseline EIMs assessment was for at least 1 EIM in 107 patients (66.9%), 42 patients presented 2 EIMs (26.3%) while 11 patients (6.9%) experienced ≥ 3 EIMs.
At w8-12, 99 patients (61.9%) achieved EIM improvement, 40 patients (25 %) clinical remission, 58 patients (36.9%) partial response, 58 patients (36.5 %) nonresponse and worsening in 3 patients. Patients initiating Upadacitinib due to exclusively active EIMs was associated with EIM improvement at weeks 8-12 (OR 2.99 95% CI 1.06-8.42; p=0.04). IBD clinical remission at w8-12 was achieved in 75 patients (61%).
Evaluation at 6 months was available for 103 patients, 73 patients (70.9%) presented EIM improvement, 41 patients (39.8%) clinical remission, 32 patients (31.1%) partial response, 20 patients (19.4%) nonresponse and 10 patients (9.7%) worsening. IBD clinical remission at 6 months was achieved in 51 patients (62.2%).
During the follow-up, Upadacitinib was ceased in 27 patients (16.9%). Adverse events were detected in 39 patients (24.3%) and 7 patients (4.4%) experienced worsening of previous inactive EIMs.

Conclusion

Upadacitinib was highly effective in the short term for treating bio-experienced patients with active EIMs, particularly for patients without luminal activity

Disclosure

No conflict