Introduction

Increased blood pressure (BP) and hypertension are known adverse effects of sphingosine 1-phosphate (S1P)_1,4,5 receptor modulators. Etrasimod is an investigational, oral, once-daily, selective S1P_1,4,5 receptor modulator in development for the treatment of moderately to severely active ulcerative colitis (UC).

Aims & Methods

We assessed the impact of etrasimod on BP and hypertension development among patients (pts) in the etrasimod UC clinical programme. Pivotal (placebo [PBO]-controlled phase [p]3 [NCT03945188; NCT03996369] studies) and All UC (PBO-controlled plus open-label extension [OLE]; p2 [NCT02447302], p3 and OLE [NCT03950232 and NCT04176588, data snapshot Jan 31, 2022; NCT02536404] studies) cohort data were analysed. BP was assessed at each visit and at 2 and 4 weeks (wks) post‑treatment cessation. Proportions and exposure-adjusted incidence rates (EAIRs; pts with AEs divided by the total pt‑years [PY] at risk for AEs, per 1 PY) of treatment‑emergent Hypertension (Medical Dictionary for Regulatory Activities preferred term [PT]) AEs among pts receiving etrasimod (2 mg once daily; both cohorts) or PBO (Pivotal UC cohort) were assessed. Characteristics of pts with Hypertension AEs that met sponsor-designated events of interest (SDEI) criteria (related to hypertension associated with sustained increases in BP [systolic/diastolic: ≥ 160/100 mmHg], or requiring new or increased antihypertensive therapy) were analysed descriptively.

Results

In the Pivotal and All UC cohorts, 11/527 (2.1%; EAIR, 0.04; PBO: 2/260 [0.8%; EAIR, 0.02]) and 20/942 (2.1%; EAIR, 0.03) etrasimod-treated pts had PT Hypertension, respectively; none led to study treatment discontinuation. In the All UC cohort, 19/942 (2.0%; EAIR, 0.02) etrasimod-treated pts had hypertension-related SDEIs. Of these events, 6 were in pts with hypertension history; none were serious or led to treatment discontinuation; 6 resolved (5 with intervention), 8 were resolving/unknown outcome and 5 were unresolved. Etrasimod‑treated pts had minimal changes in BP over time (All UC cohort, mean change in systolic/diastolic BP at Wk52: 2.9/1.2 mmHg, respectively; Table). In the All UC cohort, at Wk104, no etrasimod-treated pts had a systolic/diastolic BP > 160/100 mmHg, respectively.

Conclusion

Hypertension events were infrequent among etrasimod-treated pts. No clinically meaningful changes in BP with etrasimod 2 mg over time or following treatment discontinuation were observed up to 2 years. Data interpretations are limited by small pt numbers.

Disclosure

SV: lecture/speaker fees: AbbVie, Dr. Falk Pharma, Ferring Pharmaceuticals, Hospira, MSD, Takeda, Tillotts; consultancy/advisory fees: AbbVie, AbolerIS, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Dr. Falk Pharma, Eli Lilly, Ferring Pharmaceuticals, Galapagos, Genentech/Roche, Gilead Sciences, Hospira, Imidomics, Janssen, Johnson & Johnson, Materia Prima, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer Inc, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance Biopharma, Tillotts, Zealand Pharma; grant/research support: AbbVie, MSD, Pfizer Inc, Galapagos, Takeda.
DTR: grant support: Takeda, Helmsley Charitable Trust and GastroIntestinal Research Foundation; consultancy fees/advisory boards: AbbVie, AltruBio, ASLAN Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chronicles, Syneos, ClostraBio, Connect Biopharma, EcoR1, Genentech/Roche, Gilead Sciences, Iterative Health, Janssen Pharmaceuticals, Kaleido Biosciences, Eli Lilly, Pfizer, Prometheus, Reistone, Seres Therapeutics, Takeda, Target RWE, Trellus Health; Board of Trustees: Crohn’s & Colitis Foundation and Cornerstones Health, Inc; stock options: Alike Health, AltruBio, Datos Health, Iterative Health.
LP-B: grant/research support: Takeda, Fresenius Kabi, Celltrion; lecture/speaker fees: Galapagos, AbbVie, Janssen, Genentech, Ferring Pharmaceuticals, Tillotts, Celltrion, Takeda, Pfizer, Sandoz, Biogen, MSD, Amgen, Vifor, Arena Pharmaceuticals, Lilly, Gilead Sciences, Viatris, Medac, Sanofi; consultancy fees: AbbVie, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Biogen, Bristol-Myers Squibb, Celltrion, CONNECT Biopharm, Cytoki Pharma, Enthera, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, Gossamer Bio, GSK, HAC-Pharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par'Immune, Pfizer, Prometheus, Protagonist, Roche, Sandoz, Takeda, Theravance, Thermo Fisher, TiGenix, Tillotts, Viatris, Vifor, Ysopia, Abivax; stockholder: CTMA.
MCD: consultancy fees: AbbVie, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Genentech, Gilead Sciences, Janssen Pharmaceuticals, Pfizer Inc, Prometheus Laboratories, Takeda, Trellus Health, UCB; grant/research support: Janssen; shares/royalties: Trellus Health; directorship/ownership interests: Trellus Health.
MR: Unrestricted Educational Grants: Abbvie, BMS, Janssen, UCB, Pfizer, Takeda, Celgene, Genentech, Gilead; advisory boards/Consultant: Abbvie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, S.p.A., Bristol-Myers Squibb (BMS), CME Companies: CME Outfitters, Imedex, GI Health Foundation (GiHF), Cornerstones, Remedy, MJH life sciences; royalties: Wolters Kluwer Health: Author/Editor of UpToDate.
PMI: grant support: Celltrion, Janssen, MSD, Takeda; lecture fees: AbbVie, Bristol-Myers Squibb, Celgene, Celltrion, Dr. Falk Pharma, Ferring Pharmaceuticals, Galapagos, Gilead Sciences, MSD, Janssen, Pfizer, Takeda, Tillotts, Sapphire Medical, Sandoz, Shire, Warner Chilcott; advisory fees: AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Genentech, Gilead Sciences, Hospira, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Prometheus, Roche, Sandoz, Samsung Bioepis, Takeda, Topivert, VH2, Vifor, Warner Chilcott.
MG and KL: employees & shareholders of Pfizer AG.
JW, IM, JCW, CR: employees & shareholders of Pfizer Inc.
AM: employee of Pfizer Ltd and shareholder of Pfizer Inc.
AY: consultancy fees: Pfizer, Arena Pharmaceuticals, Takeda, Bristol-Myers Squibb; lecture/speaker fees: Bristol-Myers Squibb.

Introduction

Secondary loss of response to Infliximab(IFX) occurs in approximately half of patients with Inflammatory Bowel Disease(IBD), due to drug levels falling below the therapeutic range. This study evaluated IFX levels and related clinical and laboratory parameters and their impact on clinical outcomes.

Aims & Methods

Pre-infusion drug levels, associated laboratory data, and clinical parameters were evaluated in IBD patients receiving maintenance doses of IFX(5–15 mg/kg every 4–8 weeks) between Nov2021-Apr2025. Drug levels were measured using a bedside kit capable of quantitatively detecting values between 0.4–20µg/mL.

Results

A total of 1,059 single pre-infusion measurements from 455 patients and consecutive dual measurements at weeks 4 and 8 from 64 patients were evaluated. In the single and double measurement groups, 75.4% and 84.4% of patients had Crohn’s disease(CD), respectively. The most commonly used doses were 5 mg/8 weeks and 10 mg/4 weeks(Table 1) Drug levels were below 5 µg/mL in 33% of the measurements. Antibody positivity was present in 47.5% of 120 available measurements ranging from 0.4-20 µg/mL, showing no significant correlation with drug levels or immunomodulatory(IM) use (p=0.62 and p=0.61) However, for all positive antibody measurements drug levels were ≤ 3.5 µg/mL. CRP differed significantly across drug level groups, whereas albumin did not(Table 1). A weak negative correlation was found between IFX levels and CRP(r = -0.13, p = 0.001), with no correlation for albumin(p=0.54). In UC patients, the correlation between CRP and IFX levels was slightly stronger(r= -0.280, p=0.004).No significant associations were found between IM use and IFX levels >5 µg/mL(p=0.55), >10 µg/mL(p= 0.93), or >20µg/mL(p = 0.87). Abdominal pain was more common in patients with IFX levels <5 µg/mL (p=0.032) and <10 µg/mL (p=0.044). Smoking status was not associated with achieving IFX levels >5 µg/mL( p=0.57), >10 µg/mL (p=0.89), and >20 µg/mL (p=0.633). Among CD patients, those with IFX levels >5 µg/mL had significantly lower CDAI scores (p = 0.039), and lower daily stool frequency (p=0.002).Regression analysis showed that higher BMI (p=0.045), lower CRP(p < 0.001), higher IFX dose(p < 0.001), and CD diagnosis(p =0.014) to be independently associated with achieving IFX levels >5 µg/mL. These factors also predicted levels >10 µg/mL and >20 µg/mL, except for BMI at the >20 µg/mL threshold. In the dual measurement group, the median CRP levels at weeks 4 and 8 were 2.1(5.1) and 2.5(6.3), respectively (p = 0.108). Among patients with IFX >20 µg/mL at week 4, 75% maintained levels >5 µg/mL at week 8, whereas this rate was 64% for those with levels >10 µg/mL. Only 59.6% of those with >5 µg/mL at week 4 retained >5 µg/mL at week 8(all p <0.001). Week 4 IFX levels was 7.3 times higher than at week 8 for cases within measurable range.

Conclusion

One-third of patients demonstrated sub-therapeutic drug levels, which were associated with elevated CRP levels and worse clinical outcomes. Notably, the 5mg/4 weeks group exhibited higher drug concentrations compared to the 10mg/8 weeks group, suggesting that increased infusion frequency may contribute to achieving higher levels. Moreover, maintaining sufficient drug levels at week 8 requires substantially higher levels at week 4. Measurement of anti-TNF antibodies may not be fruitful if drug level is > 3.5µg/mL. These findings support the drug monitoring and personalized dosing to reduce the risk of loss of response and improve outcomes.

Introduction

The treatment of complex perianal fistulas (cPAF) in Crohn’s disease remains challenging. Diversion stoma is typically reserved for patients with advanced disease and for palliation. However, data regarding its contribution to radiological remission (RR) in the era of biologic therapies are limited. This study aimed to evaluate effects of diversion stoma on RR.

Aims & Methods

After identifying RR-associated factors in entire cPAF cohort(n:236), a control group was generated using propensity score matching(PSM), accounting for these variables. Stoma(n:60) and control(n:59) groups were assessed for demographic and treatment-related characteristics. In the study group (n:60+59) univariate time-dependent anlayses were conducted for RR. Than, RR-related factors (p<0.1 in univariate analyses) were evaluated in multivariate Cox regression analysis. Cinical remission (CR) was defined as the absence of fistula drainage ≥3 months, confirmed by gentle compression. RR was defined as fibrotic closure of all fistula tracts in MRI. MRI assessments were reevaluated and confirmed by two radiologists.

Results

Among 236 patients with cPAF, factors associated with RR included multiple fistulas, branched morphology, trans-sphincteric fistulas (TSF), frequent need for antibiotics, and use of multiple anti-TNF agents. A total of 60 patients who underwent stoma formation were matched via PSM to 59 patients in the control cPAF group.
Stoma creation occurred at a relatively late stage, with a median fistula duration of 29 months (IQR: 69). The median stoma duration was 24 months (IQR:46). With stoma, CR was achieved in 77% and RR in 60% of patients. The median time to CR was 20 months (range: 3–196; IQR:13), and the median time to RR was 29 months (range: 6–208; IQR:28). The stoma was reversed in 45.8% of cases (n:27).
While multiple fistulas, TSF, and a history of multiple anti-TNF use were associated with RR in the entire cohort, their distribution was similar between stoma and control groups. However, the stoma group had a higher proportion of females (51.7% vs. 32.2%), more frequent history of seton use (53.3% vs. 35.6%), and longer IBD duration at the time of fistula development (30 vs. 5 months). These factors may be considered negative influencers in IBD and could compromise the success of the stoma group from the beginning. Both radiologic response and RR rates were significantly higher in the stoma group. In Kaplan-Meier analysis, diversion stoma was significantly associated with RR (log-rank: 0.02) (Table 1). Cox regression analysis showed that the presence of multiple fistulas and TSF were independently associated with poor RR, while diversion stoma was independently associated with achieving RR (Table 1). Among patients with a stoma, only multiple fistulas (p = 0.03) and TSF (p = 0.004) were associated with poor RR.

Conclusion

Diversion stoma in patients with cPAF, after adjusting for key prognostic factors, was independently associated with RR. Despite having unfavorable prognostic features such as TSF, multiple fistula tracts, and other negative influencers, the success of even relatively late-stage stoma formation may encourage consideration of earlier stoma creation to achieve RR.

Clinical Case Summary

27-year-old male with penetrating Crohn's disease (CD; A1, L2, pB3), diagnosed at the age of 9, with multiple hospitalizations. The patient was treated with infliximab + azathioprine for three years. Colonoscopy at 16 years showed pancolitis and was complicated with perforation, being submitted to total colectomy with rectal preservation and ileostomy. Therapy was switched to adalimumab+methotrexate, with partial clinical response. After seven years, due to severe complex fistulizing perianal disease, adalimumab was switched to ustekinumab. After 2 years of Ustekinumab monotherapy, he presented disabling symptoms and developed an enterocutaneous fistula peri-ileostomy. Combination therapy with ustekinumab+vedolizumab was started. The patient still maintained discharge from the enterocutaneous and perianal fistulas. After 1 year, a painful circumferential penile ulcer with swelling and seropurulent discharge was noted. Other causes, namely infections were excluded. Biopsies were performed and revealed non-caseous granulomatous inflammation with lymphocytic and eosinophilic infiltrates, compatible with CD. Topical therapy with tacrolimus ointment was applied, with no response. Ustekinumab+vedolizumab was switched to upadacitinib. There was a substantial improvement of the penile lesion, the enterocutaneous fistula discharge reduced, and perianal symptoms resolved on maintenance therapy with Upadacitinib.
Genital metastatic CD is uncommon and mainly occurs in the setting of colonic involvement and perianal disease. Treatment options for MCD remain underwhelming due to the limited available evidence and varying responses of reported therapeutic methods. Optimization of biologic therapy is mandatory.

References

For this case we'll include:
- Pictures ​of the penile ulcers before and during maintenance therapy with upadacitinib
- Endoscopic evaluation during follow-up
- Histological specimen of colectomy and from multiple endoscopic evaluations performed
- Radiological evidence of perianal and peri-ileostomy enterocutaneous fistula