Introduction

Chronic pancreatitis (CP) is a multifactorial disease. Even though the disease frequency in India and other Asian nations are higher compared to the west, not much published literature with a large cohort exists from this region.

Aims & Methods

Aim: The aim of the study was to develop a database on Chronic Pancreatitis in South-East and South Asia (CPSEASA) to evaluate the demography, environmental risk factors and clinical characteristics of CP in south and southeastern Asia.
Methods: In this ongoing study, 1212 patients were recruited between September 2020 - April 2023 from India (3 sites) and one site each from Bangladesh, Myanmar, Nepal, Malaysia, Sri Lanka and Thailand. We recorded data on demographic details, environmental risk factors, clinical signs and symptoms (including disease duration and pain patterns), family history, morphological finding, patient awareness about the disease, therapeutic interventions and its outcomes in a structured questionnaire. The study approach is mainly based on North American Pancreatitis Study 2 (NAPS2). Continuous data were expressed as mean with standard deviation (SD) and categorical data as proportions.

Results

A total of 1212 patients were included. Mean (SD) age of patients was 37.2 ± 13.91 with males 855 (70.5%). Dravidian 337 (27.5%) was the most prevalent ethnicity, followed by Indo-Aryans 333 (27.5) and North East with 78 (6.4%). Most patients 291 (24.2%) belonged to upper middle. The most common etiology was idiopathic 725 (59.8%), followed by alcohol 365 (30.1%) and smoking 291 (24%). Disease duration of CP (years) was 40 ± 106.05 and acute exacerbations was developed in 406 (33.49%) patients. 1021 (84.24%) of patients had painful CP with a maximum VAS pain score of 7.15 ± 3.02 with the most prominent pain patterns were episodic 387 (31.9%) than continuous 354 (29.2%). Change in character of pain over time was experienced in 192 (15.8%) patients. Other important clinical manifestations included were weight loss 781 (64.4%), back pain 765 (63.3%) and diabetes 497 (41.2%). Dilatation of MPD 928 (76.6%) and parenchymal calcification 699 (57.8%) were the two most frequent morphological abnormalities seen. Normal home-cooked food with frequent fat restriction was commonly consumed in 712 (58.6%) patients. In terms of treatment received, 379 (31.27%) patients reported using analgesics and 254 (20.9%) were prescribed with neuromodulators. Around 557 (45.9%) patients underwent interventions includes endotherapy with ESWL in 454 (37.4%) and surgical procedures in 89 (7.4%) cases. Most patients 912 (75.2%) were adhered to medical treatment. Short-term relief lasting between 3 to 6 months was experienced by 493 (40.7%), while 702 (57.9%) patients experienced pain relapse after initial treatment. Improvement in glycemic control and nutritional status was observed in 557 (46%) and 537 (44.3%) patients respectively.

Conclusion

Our data demonstrate that among the few multicenter study from South and Southeast Asia to report several features of CP is different, which distinguishes the epidemiologic trends from those of the West.

References

1. Whitcomb DC, Yadav D, Adam S, Hawes RH, Brand RE, Anderson MA, Money ME, Banks PA, Bishop MD, Baillie J, Sherman S, DiSario J, Burton FR, Gardner TB, Amann ST, Gelrud A, Lo SK, DeMeo MT, Steinberg WM, Kochman ML, Etemad B, Forsmark CE, Elinoff B, Greer JB, O'Connell M, Lamb J, Barmada MM; North American Pancreatic Study Group. Multicenter approach to recurrent acute and chronic pancreatitis in the United States: the North American Pancreatitis Study 2 (NAPS2). Pancreatology. 2008;8(4-5):520-31. doi: 10.1159/000152001. Epub 2008 Sep 3. PMID: 18765957; PMCID: PMC2790781.

Introduction

In the randomized controlled LADI trial, a subset of patients with Crohn’s disease (CD) maintained clinical remission following extension of the adalimumab dose interval (1). The aim of this study was to assess long-term clinical outcomes for trial participants.

Aims & Methods

The initial LADI trial included CD patients in biochemical and corticosteroid-free clinical remission (CFCR) on adalimumab 40 mg/2 weeks. The intervention group started on a 3-week interval and increased to 4 weeks at week 24, if in clinical and biochemical remission. Controls remained on adalimumab every 2 weeks. In the current long-term study, additional data up to 3 years was collected. The primary endpoint was the proportion of patients in CFCR (Harvey Bradshaw Index (HBI) ≤4 or remission per Physician Global Assessment) without complications at year 3, while maintaining the baseline allocated adalimumab interval. Patients at an adalimumab interval >2 weeks or who discontinued for stable remission were also included in the primary endpoint. Complications were defined as IBD-related surgery or hospitalization, and new-onset or required treatment of fistulizing or penetrating disease. Secondary endpoints included CFCR and/or complications after escalation from randomized dose or discontinuation of adalimumab for reasons other than remission.

Results

Data was extracted for 143/174 initially randomized subjects (intervention: 95; control: 48). The primary endpoint was achieved in 34 of 95 patients (35.8%) in the intervention group and in 41 of 48 patients (85.4%) in the control group (p < 0.001). In the intervention group, 39/95 (41%) patients were on a de-escalated adalimumab dose at year 3: 10 (26%) 4-weekly, 25 (64%) 3-weekly, 4 (10%) stopped for stable remission. 35 (90%) patients were in CFCR, and 37 (95%) had no complications. In the control group, 44/48 (92%) were on the randomized or de-escalated dose at year 3: 30 (68%) 2-weekly, 10 (23%) 3-weekly, and 4 (9%) stopped due to remission. 42 (95%) patients were in CFCR and 42 (95%) had no complications. In the intervention group, another 39/95 (41%) patients required re-escalation of adalimumab at year 3: 33 (85%) 2-weekly, 5 (13%) weekly, and 1 (3%) every 10-days. 35 (90%) were in CFCR and 11 (28%) patients developed complications. In the control group, 2 (4%) patients required re-escalation to a weekly interval, and were in CFCR without complications at year 3. Median time to re-escalation was 6 months (Q1-Q3: 5-7) for the intervention group, and 29 (Q1-Q3: 28-30) for the control group. At year 3, 17/95 (18%) intervention and 2/48 (4%) control patients had discontinued adalimumab. 11 (65%) intervention patients and one control (50%) were in CFCR, and 4 (24%) and no complications occurred, respectively. Median time to adalimumab discontinuation was 19 (Q1-Q3: 8-29) and 24 months (Q1-Q3: 21-27) for the intervention and control patients, respectively.

Table 1. Baseline characteristics

Conclusion

Over one-third of CD patients in stable remission were on a de-escalated adalimumab dose at year 3, while maintaining CFCR without complications. Another quarter required adalimumab re-escalation but regained CFCR at year 3, without developing complications.

References

1. van Linschoten RCA, Jansen FM, Pauwels RWM, Smits LJT, Atsma F, Kievit W, et al. Increased versus conventional adalimumab dose interval for patients with Crohn's disease in stable remission (LADI): a pragmatic, open-label, non-inferiority, randomised controlled trial. Lancet Gastroenterol Hepatol. 2023;8(4):343-55.

Introduction

Immune checkpoint inhibitors (CPI) have revolutionised cancer outcomes, but frequently trigger immune related adverse effects, including life-threatening colitis. Current immunosuppressive treatments for CPI-colitis (CPI-C) incur significant side effects and may compromise CPI efficacy, highlighting the constant need for new therapies.

Aims & Methods

RNA sequencing was performed on colonic biopsies from patients with CPI-C (n=12), CPI (no colitis, n=6), healthy controls (n=13), and UC (n=12). Gene expression, pathway level (GSEA) and cellular composition were analysed. The impact of JAK1 blockade was evaluated in vivo using our pre-clinical model of CPI-C. Clinical readouts and colonic leukocytes were analysed by flow cytometry. Colonic organoids from CPI-C and controls were cultured and treated with IFNγ ± JAK1 inhibition with Upadacitinib. Clinical and endoscopic outcomes were defined in patients with treatment-refractory CPI-C following treatment with Upadacitinib 45mg for 8 weeks. Finally, we used a novel humanised mouse model of CPI-C, whereby mice express the human CTLA4 and PD1 gene, to validate these patient findings. Mice were given Nivolumab (6mg/kg) and Ipilimumab (10mg/kg) every 3 days with and without treatment of Upadacitinib (10mg/kg) and clinical features and flow cytometry were used to assess disease severity in these mice.

Results

Gene expression profiling of colonic biopsies highlighted overactivity of the JAK1-dependent cytokine IFNγ in CPI-C. IFNγ-responsive transcripts, including CXCL9, CXCL10, IDO1, GZMB and STAT1, were among the most upregulated transcripts, with IFNg signalling identified as the top enriched pathway. In vivo administration of Upadacitinib significantly reduced pathological clinical features, with reduced colon mass and infiltrating neutrophils, although no changes in T cell cytokine responses were seen in mice treated with CPI-C. Colonic organoids from CPI-C patients expressed high baseline expression of IFNγ-responsive transcripts and significantly overexpressed these transcripts following ex vivo stimulation with IFNγ, which was corroborated at protein level. Upadacitinib treatment of stimulated organoids were able to dampen these responses. To examine the functional impact of the IFNg/JAK1 pathway in CPI-colitis we blocked IFNg (neutralizing mAbs) or JAK1 (Upadacitinib treatment) in a humanised CTLA4 and PD1 murine model of CPI-colitis, which significantly attenuated disease with reduction in colon mass and fewer infiltrating neutrophils and fewer inflammatory monocytes. Humanised mice treated with Upadacitinib also had fewer CD8⁺ T cells in the colonic lamina propria, which also produced less cytotoxic cytokines. Encouraged by these findings, we treated 8 patients with severe, treatment refractory CPI-C with Upadacitinib. All achieved rapidly resolution of disease and complete mucosal healing.

Conclusion

IFNγ/JAK1 signalling was upregulated in CPI-C patients, which was recapitulated in a novel CPI-C derived colonic organoid model and two in vivo models of disease. Upadacitinib improved organoid morphology, reduced IFNγ targets, and ameliorated CPI-C in mice. Moreover, upadacitinib rapidly rescued treatment refractory patients highlighting its potential as a promising therapeutic approach in patients with severe disease.

References

1. Lo, J.W., Cozzetto, D., Alexander, J.L. et al. Immune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and is dependent on an IL23/IFNγ axis. Nat Commun 14, 6719 (2023). https://doi.org/10.1038/s41467-023-41798-2
2. Luoma A. M. et al. Molecular pathways of colon inflammation induced by cancer immunotherapy. Cell 182, 655-671.e22 (2020).
3. Sasson, S. C. et al. Interferon-gamma-producing CD8(+) tissue resident memory T cells are a targetable hallmark of immune checkpoint inhibitor-colitis. Gastroenterology 161, 1229–1244.e1229 (2021).
4. Gupta T, Antanaviciute A, Hyun-Jung Lee C, et al. Tracking in situ checkpoint inhibitor-bound target T cells in patients with checkpoint-induced colitis. Cancer Cell. 2024 May 13;42(5):797-814.e15. doi: 10.1016/j.ccell.2024.04.010. PMID: 38744246.

Introduction

Rescue treatment is administered to patients with acute severe ulcerative colitis (ASUC) who do not respond sufficiently to the initial treatment with intravenous (iv) corticosteroids. Gastrointestinal ultrasound (GIUS) can be used to detect the degree of inflammation in ulcerative colitis and show response in the treatment of ASUC^1,2, but can it be used to detect treatment response of rescue treatment?

Aims & Methods

Can GIUS be used for early prediction of treatment response in patients receiving rescue treatment for ulcerative colitis?
Patients with ulcerative colitis were included from June 2020 to Nov 2024 at two hospitals in Bergen, Norway and treated with iv corticosteroids. At day 3 to 5 patients with insufficient clinical response were treated with infliximab (10mg/kg) as rescue. The patients were examined with GIUS before rescue treatment (baseline), at the day of the 2nd infusion (after 1-2 weeks) and after 3 months. Bowel wall thickness (BWT), bowel wall vessel density with colour Doppler, loss of haustration and fatty tissue reaction was registered for every segment of the colon as well as an activity score (UC-score) based on these parameters³. The two main outcomes of the study based on the partial MAYO score (pMAYO) at 3 months. Clinical response was defined as a change in pMAYO ≥ 3 points and ≥ 30% and with an absolute reduction in the rectal bleeding score ≥ 1 or with the score for rectal bleeding ≤ 1. Clinical remission was defined as pMAYO ≤2.

Results

68 patients with colitis were recruited and of these 37 failed the initial treatment with iv corticosteroids and were given rescue treatment. At baseline 8 had left-sided colitis while 29 had subtotal or total colitis. After 3 months 3 patients had received surgery, 28/34 had treatment response compared to baseline and 24/34 were in remission. There were significantly more patients with left-sided colitis in remission (p=0.034). At the 2^nd infusion there were no significant differences between responders and non-responders for the GIUS parameters, but patients in remission at 3 months had significantly lower BWT in the ascending colon (1.3 ±0.5 vs 2.9 ±2.2 mm, p=0.002) and the transverse colon (1.7 ±0.9 vs 2.8 ±0.9 mm, p<0.001), lower sum of BWT (9.1 ±3.0 vs 13.1 ±5.0 mm, p=0.005) and UC-score (8.0 ±4.7 vs 12.9 ±7.2, p=0.018). At 3 months there was a significant difference in BWT for all segments, the sum of BWT (7.0 ±2.6 vs 14.0 ±4.5, p<0.001) and the UC-score (3.9 ±4.6 vs 16.3 ±5.6, p<0.001) for responders. For patients in remission similar results were found except for the rectum. The sum of BWT (6.8 ±2.6 vs 11.9 ±4.6 mm, p<0.001) as well as the UC-score (3.8 ±4.6 vs 11.7 ±7.8, p<0.001) was significantly lower.

Conclusion

The significant differences in BWT of the ascending and transverse colon at the 2^nd infusion could reflect prognostic differences between left-sided and total colitis. At 3 months the BWT of all colon segments was lower except for the rectum for patients in remission.

References

1) Ilvemark J, Wilkens R, Thielsen P, et al. Early Intestinal Ultrasound Predicts Intravenous Corticosteroid Response in Hospitalised Patients With Severe Ulcerative Colitis. J Crohns Colitis. Nov 23 2022;16(11):1725-1734. doi:10.1093/ecco-jcc/jjac083
2) Nylund, K., et al. ⟪ Sonorescue⟫-treatment response in acute severe Ulcerative Colitis measured with ultrasound. In: J Crohns Colitis. Great Clarendon St, Oxford OX2 6DP, England: Oxford Univ press, 2025. p. i239-i239.
3) Bots S, Nylund K, Lowenberg M, Gecse K, D'Haens G. Intestinal Ultrasound to Assess Disease Activity in Ulcerative Colitis: Development of a novel UC-Ultrasound Index. J Crohns Colitis. Aug 2 2021;15(8):1264-1271. doi:10.1093/ecco-jcc/jjab002

Disclosure

Odd Helge Gilja has received speaker’s honoraria from AbbVie, Bracco, Allmirall, GE healthcare, Takeda AS, Ferring AS, Allergan and Janssen-Cilag and has served as a consultant for Bracco, GE Healthcare, Takeda and Samsung. ​The other authors have nothing to dislose.