Clinical Case Summary

A 78-year-old patient with known non-ischaemic dilated cardiomyopathy with reduced left ventricular ejection fraction, asthma and type 2 diabetes mellitus was treated with amiodarone from 2019. In April 2023, he developed hypersensitivity pneumonitis due to amiodarone and methylprednisolone (0.5 mg/kg body weight) was initiated along with prophylactic osteoporosis treatment and trimethoprim with sulphamethoxazole. On the 18th day of methylprednisolone treatment, an Addisonian crisis resulted from acute gastroenteritis. Subsequent investigations revealed Herpes simplex virus type 1 infection and elevated serum Cytomegalovirus (CMV) DNA levels. Gastrointestinal complications included fungal esophagitis, Helicobacter pylori chronic gastritis and mild chronic duodenitis. Ischemic colitis and coeliac disease was ruled out. Despite negative findings for inflammatory bowel disease and parasitic infections, CMV infection was histologically confirmed in the terminal ileum and colonic mucosa samples. Abdominal CT confirmed infectious enteritis involving the entire small bowel. Treatment with valganciclovir (900 mg BID) for six weeks was successful, leading to clinical improvement and a disappearance of CMV DNA. Follow-up endoscopic and histological examinations did not confirm the persistence of CMV infection. Regular follow-ups with a cardiologist and a pulmonologist continue, with the patient still receiving low-dose methylprednisolone. Further hematological evaluation is planned due to persistent monoclonal gammopathy, however until now we didn't proof lymphoma, myeloma or other hematological malignancy.
The case underscores the challenges in managing CMV infections in non-traditionally immunocompromised patients, necessitating vigilance in diagnosis and treatment despite limited reported cases in the literature.

References

Reference Illustrative material:

• Table of patient laboratory findings
• Endoscopic image of CMV ulcer in terminal ileum
• Histological image of CMV infection in terminal ileum

Introduction

Precision medicine aims to expand upon the summary average treatment effects reported in clinical trials by providing more refined, individualised estimates of treatment effects. The phase IIb TUSCANY-2 study (NCT04090411), which examined the efficacy and safety of afimkibart (RO7790121/RG6631; previously PF-06480605/RVT-3101), an anti-TL1A antibody, in patients (pts) with moderate to severe ulcerative colitis (UC), previously reported clinically meaningful treatment effects at UEGW 2024.¹ Here, we report post hoc analyses of the relationship between baseline clinical characteristics and Week 14 efficacy in pts enrolled in TUSCANY-2.

Aims & Methods

Pts were randomised to receive subcutaneous afimkibart 50mg, 150mg, 450mg or matched placebo (PBO) monthly during induction. In this post hoc analysis, all afimkibart doses were pooled, and the endpoint of interest was clinical remission by modified Mayo score (mMS; defined as stool frequency subscore=0 or 1; rectal bleeding subscore=0; and endoscopic subscore [ES]=0 or 1) at Week 14. Our investigation of more patient-specific treatment effects was guided by the Predictive Approaches to Treatment effect Heterogeneity (PATH) statement.² We developed a regularised logistic regression model to predict the probability of Week 14 remission and to help examine heterogeneity of treatment effects based on the following baseline characteristics: mMS, C-reactive protein (CRP), serum albumin, Robart’s Histopathology Index (RHI), number of failed advanced therapy classes, corticosteroid use, disease extent, disease duration, age and sex. Baseline faecal calprotectin (FCP) was investigated separately due to the extent of missing data.

Results

The proportion of pts achieving clinical remission by mMS at Week 14 in the afimkibart pooled dose arm was 32.5% (65/200; 90% confidence interval [CI]: 27.3 to 38.1) compared with 13.3% (6/45; 90% CI: 7.1 to 23.8) of pts in the PBO arm (treatment delta: 19.2%; 90% CI: 7.6 to 27.9). Based on calibrated predictions from the multivariate model, all of the individual TUSCANY-2 pts (both treated with PBO and afimkibart) had anywhere between a 2–76% probability of Week 14 remission at baseline. The clinical characteristics included in the model explained ~10% of the variability in the observed outcomes. There was no evidence that the clinical characteristics were associated with heterogeneous treatment effects on the relative scale (odds ratios appeared to be constant; p-value >0.5). On the clinically meaningful absolute scale, the treatment delta in the top 50% of pts with a higher baseline probability of remission (27–76%) was 28.5% (90% CI: 8 to 42; 45.2% in afimkibart pooled dose arm vs 16.7%, in PBO arm), compared with a treatment delta of 7.6% (90% CI: –7 to 18; 18.8% in afimkibart pooled dose arm vs 11.1%, in PBO arm) in pts with a lower baseline probability of remission (2–27%). Lower baseline CRP, lower RHI and higher serum albumin contributed to a greater probability of remission and absolute benefit from treatment with afimkibart.

Conclusion

Pts with inflammatory bowel disease (IBD) have diverse baseline characteristics that are associated with variability of treatment outcomes, yet clinicians rely on reported averages from clinical trials to make individual treatment decisions. This analysis demonstrates how precision medicine approaches, that account for diverse characteristics, may improve interpretation of positive IBD clinical trial results. Integrating genetic and novel biomarkers alongside clinical features could help to better predict individual outcomes for pts with IBD.

References

1. Danese S, et al. Presented at UEGW 2024 (Oral presentation OP079).
2. Kent D, et al. The Predictive Approaches to Treatment effect Heterogeneity (PATH) Statement. Ann Intern Med 2020;172:35–45.

Disclosure

This study was sponsored by F. Hoffmann-La Roche Ltd. Third-party medical writing support, under the direction of the authors, was provided by Victoria Dagwell, MSc, of Ashfield MedComms, an Inizio company, and was funded by F. Hoffmann-La Roche Ltd.
LP-B reports consulting or advisory role/board from AbbVie, Abivax, Adacyte, Alimentiv, Amgen, Applied Molecular Transport, Arena, Banook, Biogen, Bristol Myers Squibb, Celltrion, Connect Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Inc., Gilead, Gossamer Bio, GSK, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Nordic Pharma, Novartis, Oncodesign Precision Medicine, ONO Pharma, OSE Immunotherapeutics, Pandion, Par' Immune, Pfizer, Prometheus, Protagonist, F. Hoffmann-La Roche Ltd, Samsung, Sandoz, Sanofi, Satisfay, Takeda, Telavant, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vectivbio, Ventyx and Ysopia; speakers’ bureau from AbbVie, Alfasigma, Amgen, Arena, Biogen, Celltrion, Ferring, Galapagos, Genentech, Inc., Gilead, Janssen, Kern Pharma, Lilly, Medac, MSD, Nordic Pharma, Pfizer, Sandoz, Takeda, Tillots and Viatris. JRA reports consulting or advisory role/board from Janssen, Pfizer, AbbVie, Vedanta, Genentech, Inc., Seres Therapeutics, Ferring, GSK, Merck, Bristol Myers Squibb, Roivant, Celltrion, TRXBio and Shattuck Labs; speakers’ bureau from AbbVie and Janssen. SD reports consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Lilly, Enthera, Ferring Pharmaceuticals, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, F. Hoffmann-La Roche Ltd, Sandoz, Sublimity, Takeda, Teladoc Health, TiGenix, UCB, Vial and Vifor; lecture fees from AbbVie, Amgen, Ferring Pharmaceuticals, Gilead, Janssen, Mylan, Pfizer and Takeda. PSD reports employment at Northwestern University; consulting or advisory role/board from AbbVie, Adiso, Alimentiv, Celltrion, Genentech/Roche, Geneoscopy, Janssen, Shattuck and Takeda; research funding from Takeda and Bristol Myers Squibb. AB reports employment and stockholder from Pfizer. DEC reports employment and stock ownership from Pfizer. EP reports employment, stock or other ownership interests and patents, royalties, other intellectual property from Pfizer. SN reports employment and stock or other ownership interests from Pfizer. MSV reports employment and shareholder from Pfizer. KH reports no conflict of interest. LU reports employment at Genentech, Inc. CS reports employment, stock or other ownership interests from Genentech/Roche. DB reports employment at F. Hoffmann-La Roche Ltd. KL reports employment and stock or other ownership interests from Genentech, Inc. BES reports honoraria for consulting from AbbVie, Adiso, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen, AstraZeneca, Biolojic Design, Biora, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Enveda, Evommune, Ferring, Fresenius Kabi, Fzata, Galapagos, Genentech/Roche, Gilead Sciences, GSK, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, Microbiotica, Mitsubishi Tanabe, Mobius Care, Morphic, MRM Health, Nexus, Nimbus Discovery, Odyssey, OSE Immunotherapeutics, Palisade Bio, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist, Q32 Bio, Rasayana, Recludix, Reistone, Sanofi, Sorriso, Spyre, Surrozen, Target RWE, Teva, TLL Pharmaceutical, Tr1X, Union and Ventyx; consulting/speaking fees from Abivax; consulting/speaking fees/other support from Lilly; research grants/consulting/speaking fees/other support from Bristol Myers Squibb, Lilly, Janssen, Pfizer and Takeda; research grants/consulting fees from Janssen; stock/stock options from Ventyx.

Introduction

While three JAK inhibitors are now available in Ulcerative Colitis (UC), the hierarchy of these treatments according to their effectiveness, remains to be determined.

Aims & Methods

In the JAKARTA study, we aimed to compare the effectiveness of the three available JAK inhibitors (tofacitinib/TOFA, filgotinib/FILGO and upadacitinib/UPA) in bio-exposed patients with UC.
In this retrospective multicenter study (12 centres), we included all consecutive patients with UC ≥18 years-old, partial Mayo score > 2 who had started TOFA, FILGO or UPA after receiving ≥ 1 biologic between JAN2019 and JUN2022. Acute severe UC were excluded.
Following regimen were applied for TOFA (10mg b.i.d until W8 and 5mg or 10 mg b.i.d according to physician’s judgement), FILGO (200mg q.d) and UPA (45mg q.d until W8 and 45mg, 30 mg or 15 mg q.d according to physician’s judgement).
The primary endpoint was symptomatic remission (partial Mayo score ≤ 2) without corticosteroids (CFREM) at W16. Secondary endpoints were clinical and endoscopic remission (CFREM + endoscopic Mayo score ≤ 1), histological and endoscopic mucosal improvement (HEMI) (= clinical-endoscopic and histological remission (Nancy index ≤ 1)), drug retention (treatment discontinuation-free survival using Kaplan-Meier curve), time to colectomy, time to UC-related hospitalization and secondary loss of response among patients in CFREM at W16.
All the comparisons were performed using propensity scores adjustment (IPTW).

Results

A total of 290 patients were included: 150, 79 and 61 in TOFA, FILGO, and UPA arms, respectively. The 3 groups were comparable except for higher proportion of patients with previous exposure to > 3 biologics in UPA group (p < 0.001). TOFA 10 mg b.i.d was continued until W16 in 47.0% of patients. FILGO was maintained at 200 mg in 97.5%. UPA was diminished at 30 mg and 15 mg at W8 in 55.6% and 3.3% of patients, respectively.
After IPTW, CFREM at W16 was higher in UPA (60.1%) compared to TOFA (38.9%) or FILGO groups (36.0%) (p = 0.026 and 0.016, respectively). No predictive factor of efficacy/ failure was identified with these 3 JAK inhibitors.
We failed to show any significant difference regarding clinical-endoscopic remission (UPA:16.5%, TOFA:16.5%, FILGO:12.8%) or HEMI (UPA:11.9%, TOFA: 4.4, FILGO: 12.7%) at W16.
Among patients who reduced the dose to the recommended maintenance regimen (TOFA 5 mg b.i.d and UPA 30 or 15 mg q.d) between W8 and W16, the need for dose re-escalation to the induction dose was 33.8% (27/80) for TOFA, 14.7% (5/34) for UPA30mg and 50.0 % (1/2) for UPA 15 mg. After adjustment, drug retention was longer for UPA compared to TOFA (HR = 0.38 [0.17-0.85], p = 0.019) and FILGO groups (HR = 0.17 [0.08-0.65], p < 0.001) and shorter in FILGO than in TOFA group (HR = 1.57[1.02-2.41], p = 0.038).
No difference was demonstrated in terms of time to hospitalization or surgery between the 3 groups.
Among patients achieving CFREM at W16 (regardless of the dose), secondary loss of response (symptomatic relapse) was similar for TOFA:12.8% (N=47 patients), FILGO: 19.2% (N = 26 patients) and UPA: 10.3% (N = 29 patients) (p=ns after IPTW).

Conclusion

In this real-world evidence multicenter study, UPA was the most effective JAK inhibitor in UC at short and long-term but the large use of off-label maintenance doses in current practice needs further safety investigations.

Disclosure

Consulting fees from: Abbvie, Amgen, Arena, Biocon, Biogen, Celltrion Healthcare, CTMA, Ferring, Galapagos/AlfaSigma, GutyCare/Resilience Janssen, Lilly, MSD, Nexbiome, Pfizer, Roche, Sandoz, Takeda et Tillotts
Lecture fees from : Abbvie, Amgen, Biogen, Celltrion Healthcare Galapagos/AlfaSigma, Ferring, Janssen, Lilly, Mayoli-Spindler, MSD, Nordic Pharma, Norgine, Pfizer, Roche, Takeda, Tillotts and Vifor Pharma
Research grants/fundings from: Abbvie, Celltrion Healthcare, Janssen, Lessaffre, Lilly, Pfizer, Sandoz and Takeda

Introduction

Most inflammatory bowel disease (IBD) randomised controlled trials (RCTs) only permit tapering of corticosteroids after initiating the maintenance period, either as adaptive or forced tapering, resulting in different corticosteroid exposure among participants.¹ These practices result in inappropriately, prolonged, and excessive exposure to corticosteroids that is not consistent with optimal clinical care and may inflate placebo response rates.^2-7

Aims & Methods

We aimed to provide comprehensive standardised recommendations on key aspects of corticosteroid use in RCTs for adults with moderately-to-severely active IBD, through a multi-phase, international expert consensus. The consensus was informed by a systematic review of MEDLINE, EMBASE, and the Cochrane CENTRAL Register of Controlled Trials which determined the corticosteroid management rules used in placebo-controlled trials of advanced therapies in IBD. Expert consensus recommendations for all aspects of corticosteroid management in RCTs were then developed using a modified Delphi process with two rounds of survey questions and a ratification meeting. For the surveys, corticosteroid management practices were divided into several domains describing the key stages of an IBD RCT and were directly reflected in clinical trial protocols: corticosteroid management during screening, induction, and maintenance; and corticosteroid-related endpoints.

Results

The international Delphi panel consisted of 45 IBD RCT experts. The recommendations propose management of corticosteroid intake during screening, induction, and maintenance phases of pharmacologic RCTs in IBD, and define corticosteroid-related endpoints. The need for minimising corticosteroid exposure through expedited tapering and shorter fixed-dosing periods that more closely reflect routine clinical care was emphasised, and recommendations for standardised definitions of corticosteroid-free remission were provided (Table). The panellists recommended a 2-week stable dosing period before screening, and favoured beginning dosage tapering at ≤2 weeks of induction. Panellists supported a unified tapering protocol of 5 mg prednisone equivalents/week, and voted that enteric- and colonic-release corticosteroids do not require tapering. A point of consensus was that both the beginning of tapering and its rate should be mandated by the trial protocol, rather than the investigators’ discretion. Consensus was not reached on the duration of corticosteroid withdrawal prior to the final study visit for defining corticosteroid-free remission. During the ratification meeting, the panellists highlighted the need for meticulous documentation of corticosteroid use during RCTs to avoid underreporting.

Conclusion

This set of internationally guided recommendations will serve to improve optimisation of RCT design and facilitate appropriate, acceptable, and standardised corticosteroid handling practices in RCTs, as well as maximise comparability between trials and minimise steroid-related harm to trial participants.

References

¹George et al. Inflamm Bowel Dis. 2020;26:515-523. DOI:10.1093/ibd/izz193
²Candy et al. Gut. 1995;37:674-678. DOI:10.1136/gut.37.5.674
³D’Haens et al. N Engl J Med. 2023;388:2444-2455. DOI:10.1056/NEJMoa2207940
⁴D’Haens et al. Lancet. 2022;399:2015-2030. DOI:10.1016/S0140-6736(22)00467-6
⁵Feagan et al. Lancet. 2021;397:2372-2384. DOI:10.1016/S0140-6736(21)00666-8
⁶Danese et al. Lancet. 2022;399:2113-2128. DOI:10.1016/S0140-6736(22)00581-5
⁷Almradi et al. J Crohns Colitis. 2022;16:717-736. DOI:10.1093/ecco-jcc/jjab194

Disclosure

JH has received consulting fees from Alimentiv Inc.
SKV has received consulting fees from Alimentiv Inc.
VS, ZR, and VA report no disclosures.
RA, MA, CNB, PB, RVB, BLC, JFC, FDA, AD, MD, RG, PF, SBH, ALH, MK, TK, PL, EL, FM, NN, RWL, TR, MR, WR, SS, AHS, RCU, CJW, TY, DTR, and PD report no disclosures related to Alimentiv Inc.
RP reports being a consultant and on the Advisory Board for Alimentiv Inc.
BES reports consulting fees from Alimentiv Inc.
LPB reports consulting for Alimentiv Inc.
SD reports consultancy fees from Alimentiv Inc.
GRDH reports advisor fees from Alimentiv Inc.
BB reports advisor/speaker fees from Alimentiv Inc.
JP has received consultancy fees/honorarium from Alimentiv Inc., and has served on a data safety monitoring board for Alimentiv Inc.
ST reports receiving consulting fees from Alimentiv Inc.
LJC and MH are employees of Alimentiv Inc.
WJS is a consultant for Alimentiv Inc.
BGF is the Senior Scientific Officer of Alimentiv Inc.
VJ has received consulting/advisory board fees from Alimentiv Inc.
CM has received consulting fees from Alimentiv Inc.

Introduction

Anti-TNF agents play a significant role in the induction and maintenance therapy of moderate to severe ulcerative colitis. However, at least 30% of patients experience loss of response within the first year of treatment.

Aims & Methods

This study aims to compare Tofacitinib versus Vedolizumab in patients with ulcerative colitis in the setting of previous anti-TNF failure. We performed a systematic review in PubMed, Embase and Cochrane databases, searching for randomized and non-randomized studies comparing Tofacetinib versus Vedolizumab in this population. The primary outcome was colectomy rate. The secondary outcomes were thromboembolic event rate and infectious incidence. The odds ratio (OR) was used for binary outcomes with their respective 95% confidence interval (CI). Heterogeneity was assessed using the Cochran Q test and I² statistics.

Results

The meta-analyses included 6 studies and 2,241 patients. There was a significant difference favoring Vedolizumab in colectomy rate (OR 2.03; 95% CI 1.30 to 3.16, p=0.002; I2=0%). There were no difference in thromboembolic event rate (OR 0.90; 95% CI 0.39 to 2.06; p=0.798; I2=0%) and infection incidence (OR 0.83; 95% CI 0.56 to 1.25; p=0.378; I2=0%).

Conclusion

In patients with ulcerative colitis with prior anti-TNF failure, tofacitinib showed higher colectomy rate compared to vedolizumab, with no difference in thromboembolic and infectious events between both groups. Considering this, vedolizumab seems to be a reasonable option in this population.

References

1. Straatmijer T, Biemans V, Visschedijk MC, Hoentjen F, De Vries A, Van Bodegraven AA, et al. SUPERIOR EFFECTIVENESS OF TOFACITINIB COMPARED TO VEDOLIZUMAB IN ANTI-TNF EXPERIENCED ULCERATIVE COLITIS PATIENTS: A NATIONWIDE DUTCH REGISTRY STUDY. United Eur Gastroenterol J. 2022;10((Straatmijer T., t.straatmijer@amsterdamumc.nl; De Boer K.H.N.) Amsterdam UMC, Amsterdam, Netherlands):390–1.
2. Buisson A, Serrero M, Altwegg R, Guilmoteau T, Bouguen G, Nachury M, et al. Real-world comparison of effectiveness between tofacitinib and ustekinumab in patients with ulcerative colitis exposed to at least one anti-TNF agent: Results from the TORUS study. J Crohns Colitis. 2023;17((Buisson A.; Guilmoteau T.) CHU Clermont-Ferrand, IBD Unit, Clermont-Ferrand, France):i707.
3. Adimadhyam S, Lewis JD, Simon AL, Wolfe AE, Smith S, Hou L, et al. Real-world Evidence Comparing Tofacitinib and Vedolizumab in Anti-TNF-experienced Patients With Ulcerative Colitis. Inflamm Bowel Dis. 2024 Apr 3;30(4):554–62.
4. Hyun HK, Zhang HS, Yu J, Kang EA, Park J, Park SJ, et al. Comparative effectiveness of second-line biological therapies for ulcerative colitis and Crohn’s disease in patients with prior failure of anti-tumour necrosis factor treatment. BMC Gastroenterol. 2022 Mar 27;22(1):143.

Introduction

Biologic and small-molecule therapies are widely used for ulcerative colitis (UC), but their comparative effectiveness in TNF-exposed patients remains unclear.

Aims & Methods

This study evaluates the clinical and biomarker responses to Vedolizumab, Tofacitinib, and Ustekinumab over 12 months, adjusting for baseline differences using Inverse Probability of Treatment Weighting (IPTW). A multicenter retrospective cohort of TNF-exposed UC patients treated with Vedolizumab (n = 260), Tofacitinib (n = 149), or Ustekinumab (n = 193) was analyzed. Clinical outcomes, including Partial Mayo Score (pMayo), clinical remission, and biomarker response (CRP, ESR, fecal calprotectin), were assessed at baseline (T0), 8 weeks (T1), 24 weeks (T2), and 52 weeks (T3). IPTW balanced baseline characteristics, and longitudinal changes were analyzed using a repeated-measures general linear model (GLM) with post-hoc corrections for multiple comparisons.

Results

Before IPTW, significant baseline differences existed, with Tofacitinib patients being younger (p < 0.001), more frequently female (p = 0.003), and having higher fecal calprotectin levels (p = 0.005). After IPTW, covariate balance was achieved (SMD < 0.10). pMayo scores significantly declined in all treatment groups over time (p < 0.001, η² = 0.469), with no significant main effect of therapy (p = 0.329). A minor time-by-therapy interaction (p = 0.036, η² = 0.026) indicated slight response variations but lacked clinical significance. Before IPTW, Tofacitinib showed superior pMayo improvement versus Ustekinumab (p = 0.008), but this difference lost significance post-IPTW, suggesting baseline confounding. At 52 weeks, clinical remission was highest with Tofacitinib (57%), followed by Vedolizumab (40%) and Ustekinumab (22%) (p = 0.003). Biomarker remission favored Vedolizumab (48.8%) over Tofacitinib (19.5%) and Ustekinumab (21.2%) (p = 0.002). Adverse events were rare but more frequent with Vedolizumab (p < 0.001).

Conclusion

Over 12 months, all therapies significantly improved clinical and biomarker outcomes, with no significant differences in overall pMayo reduction post-IPTW. Tofacitinib achieved the highest clinical remission, while Vedolizumab demonstrated superior biomarker response. These findings highlight the need for individualized treatment selection in TNF-exposed UC patients.