Ulcerative colitis (UC) is a chronic relapsing immune-mediated inflammatory bowel disease known to be associated with diffuse superficial inflammation of the colonic mucosa with a continuous pattern from the rectum up to the colon. In recent years, the aim of therapeutic intervention in modern gastroenterology has changed from symptom control to achieve an objective meaningful structural target, which in the gastrointestinal system is represented by mucosal healing and deep histological remission [2]. Mucosal healing is strongly associated with improved rates of hospitalisation, reduction in steroid usage, less flare, and reduced risk of CRC cancers due to colorectal disease flare [2,3].

Even with the use of conventional medical treatments, including treatments in the 5-aminosalicylate (5-ASA) group, systemic immunomodulators, and first-line biologic therapies, anti-tumor necrosis factor-alpha (anti-TNF-alpha) monoclonal antibodies, up to 40% of individuals will not see a response from the medication or may exhibit primary non-response or secondary loss of response, or they will develop an unacceptable drug-related toxicity profile [4,5].

This specific "refractory" subset of patients is a difficult clinical challenge in tertiary centres of gastroenterology worldwide and especially in developing country where the healthcare access and economic factors play significant role in compliance to treatment. Advanced intracellular small molecule kinase inhibitors and gut selective anti-integrin therapy have become main topics in the treatment of patients refractory to anti-TNF therapy. Vedolizumab is a humanized monoclonal antibodies which specifically binds to the alpha4beta7 integrin heterodimer that is displayed on pathogenic, gut-homing T-lymphocytes [6]. Vedolizumab prevents lymphocyte/leukocyte migration into the inflamed colonic lamina propria through the intestinal endothelium by preventing ligation of the integrin by mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1) expressed on the intestinal endothelial cell, which puts it under no systemic immunosuppressive pressure [6,7]. Although its safety profile and gut specificity is highly beneficial, there are real world data showing that its clinical onset of action can be delayed and a few weeks is needed to see significant structural changes in the gut mucosa [6,7].

In contrast, selective Janus kinase-1 (JAK-1) inhibitors, such as Upadacitinib, on the other hand, offer a paradigm shift in which they use oral medications that are small, low molecular weight small molecules [1]. These compounds are small, non-immunoglobulin (non-monoclonal) and selectively bind to the ATP-binding pocket of the JAK-1 tyrosine kinase enzyme leading to an arrest of the downstream signal transducers and activators of transcription (STAT) phosphorylation and nuclear translocation [8]. These agents block the signaling pathways of several interleukins (including IL-2, IL-6, IL-7, IL-15 and interferon-gamma), directly involved in the inflammatory cascade leading to the destructive transmural inflammation that has been described during UC flares [1, 8]. The selective JAK-1 inhibitors have an exceptionally quick onset of clinical action, and have been proven to be highly effective in randomized clinical trials, including in heavily bio-exposed persons [5,9].

Although randomized controlled trials (RCTs) have proven the basic efficacy, head-to-head clinical data to directly compare both of these advanced treatment strategies in biological-refractory population is lacking [6]. In some South Asian populations, this clinical data gap is even greater as South-Asian specific differences in genetic background, infectious disease and healthcare delivery will have an impact on the treatment outcome [5]. This multicentre study directly compares the real world clinical effectiveness, clinical response, biomarker normalization, and short term safety of selective JAK-1 inhibitors with anti-integrin therapy in achieving mucosal healing in an exhaustive phenotype of patients with ulcerative colitis (UC) who are refractory to conventional therapies from Pakistan.

Study Design and Setting This was a prospective, multicenter, real-world observational cohort study which was conducted on five major tertiary care teaching hospitals in Pakistan, namely: Shaikh Zayed Hospital, Lahore; WAPDA Teaching Hospital Complex, Lahore; Sandeman Provincial Hospital, Quetta; Faisalabad Teaching Hospital, Faisalabad and Al-Khidmat Teaching Mansoorah Hospital, Lahore. The recruitment, treatment and follow-up window covered a six month period starting in July 2025 and ending January 2026. The study protocol was designed and conducted in accordance with the Declaration of Helsinki and has adhered completely to the standardized reporting criteria for observational studies. Patient Selection Criteria The adult subjects who met the inclusion criterion were aged between 18 and 65 years with a histologically and clinically proved diagnosis of moderate-to-severe UC for at least six months. All patients had to have a baseline Mayo Score of 6–12 (including a Mayo Endoscopic Score (MES) of >= 2). Refractory disease was carefully defined as the clinical failure to respond to the best available medical regimen (optimized oral/intravenous corticosteroid, azathioprine, and/or 6 mercaptopurine) and to at least one standard anti-TNFalpha medicine (Infliximab or Adalimumab) under maximum therapeutic dose for a standard induction period. Exclusion criteria comprised: 1. Previous subtotal or total colectomy, or an urgent need for surgical intervention because of toxic megacolon, bowel perforation or severe, fulminant bleeding. 2. Signs and symptoms that may indicate Crohn's disease and indeterminate colitis. 3. Active (untreated) systemic infections, such as hepatitis B surface antigen (HBsAg) positive or hepatitis C virus RNA (HCV RNA) positive disease, human immunodeficiency virus (HIV) positive disease or an interferon-gamma release assay (IGRA) suggestive of latent or active tuberculosis (TB) disease and not yet completed with TB prophylaxis. 4. Severe hepatic impairment (Child-Pugh Class C), severe renal insufficiency (eGFR< 30 mL/min/1.73m2), or prior history of recurrent thromboembolic disease. Treatment Interventions Treatments were allocated based on the clinical judgement, institution availability of treatments and patient choice by treating gastroenterologists (not by randomisation in the context of therapeutic trials) and this approach was used as it was customary and practical in clinical practice.Because in clinical practice it was customary and practical, the therapeutics for each patient were allocated based on clinical judgement, the availability of therapeutics in the institution and patient choice. • Selective JAK-1 Inhibitor Group: Allowed to take oral Upadacitinib at a fixed 45mg dose per day for a continuous 8 weeks of treatment. After the induction phase, patients who had an early clinical response were followed up with one of two maintenance therapies: 15 mg or 30 mg daily for as long as they needed, depending on the residual disease activity grading and on the safety profile and judged by the attending physician. • Anti-Integrin Group: hese patients were treated with intravenous Vedolizumab at 300mg at specific time points weeks 0, 2 and 6 (induction). Maintenance treatment was 300 mg of the drug, given as IV infusion, regularly every 8 weeks after that. If oral 5-ASAs and/or thiopurines had been started at least 8 weeks before baseline, then they could be continued throughout the study. A standardised weight based reduction protocol was used to systematically taper systemic baseline corticosteroids 8-12 weeks after beginning of either advanced therapy. Outcome Assessments and Variables Patients underwent meticulous clinical, biochemical, and endoscopic evaluations at baseline, week 8, week 12, and week 24. The primary endpoint was the proportion of patients achieving complete objective mucosal healing at week 24, which was rigorously defined as a Mayo Endoscopic Score (MES) <= 1 on a repeat flexible sigmoidoscopy or full colonoscopy. Endoscopic findings were evaluated by experienced endoscopists who were blinded to the patient's specific medication group to eliminate observational bias. Secondary endpoints evaluated during the 6-month study timeline included: 1.Clinical Remission Rate at Weeks 8 and 24: Complete PANS and CMS as defined by a PMS of ≤2 and no individual subscore >1 at week 8 and/or week 24 [6]. 2. Biochemical Remission: Defined as a very low level of CRP in the bloodstream (CRP < 5 mg/L) and minimal amounts of calprotectin in the faeces (< 150 \mu g/g) [5]. 3. Speed of Symptomatic Response: Assessed by a standardized diary carried out with the patients daily to record the mean time (in days) to achieve a reduction in mean daily stool frequency and reduction in mean bleeding score in the rectum of at least 50% from baseline. 4. Corticosteroid-Free Clinical Remission: Clinical remission was defined as, absence of systemic corticosteroid administration for at least 12 consecutive weeks before the last week of the follow-up period [6]. 5. Safety and Tolerability Profile: Followed by recording all the treatment-emergent adverse events (TEAEs), adverse events (SAEs) resulting in drug discontinuation, and laboratory abnormalities (laboratory profile including complete blood count, lipid profile and liver function tests) observed at each treatment visit. Statistical Analysis The calculations were made using SPSS software (version 28.0) and MedCalc software packages. Data of variables with normal continuous distribution were presented as means ± SD and analyzed by independent Student's t-test. Medians were used to represent non-normally distributed data points and interquartile ranges (IQR) were used and data were analyzed using the Mann-Whitney U test. Categorical variables were presented in terms of frequencies and percentages and intergroup differences therefore formally calculated with the Chi-squared (\chi 2) test as well as with Fisher's exact test applied where appropriate. All efficacy analyses were performed on all subjects treated, with a modified intention-to-treat (mITT) approach, where those who terminated treatment early for non-response or adverse outcomes were considered to be a failure of that treatment (non-responder imputation). All statistical calculations included a two sided p-value of < 0.05 as statistically significant.

Baseline Demographics and Clinical Characteristics

One hundred and fifty-five (155) patients were initially screen in the participating institutions for whom 142 (92%) were eligible and completed the 24 week follow-up (Fig. 1). Sixty eight (n = 68) patients were treated in the selective JAK-1 inhibitor arm and seventy-four (n = 74) patients in the anti-integrin arm.

We did find objectively measured markers of inflammation to be equally distributed across the two study arms and no statistically significant differences in baseline demographics or disease duration, or prior biological exposure (Table 1). The patients were a very refractory population as 100% had had at least one prior anti-TNF agent and ~33% in both arms had had prior exposure to two different anti-TNF molecules.

Table 1: Baseline Demographics and Pre-treatment Disease Characteristics

Primary Efficacy Endpoint: Mucosal Healing

Endoscopy evaluations at the end of the 6-month study period (Week 24) showed highly significant difference concerning the primary outcome. 47 of 68 patients (69.1%) in the selective JAK-1 inhibitor group had complete mucosal healing. By comparison, only 33 of the 74 (44.6%) patients in the anti-integrin group had a similar endoscopic response. The absolute risk reduction of 24.5% in persistent mucosal inflammation favored the selective JAK-1 inhibitor arm and was highly statistically significant (χ 2 = 8.65, p = 0.003.).

Secondary Efficacy Endpoints

Clinical Remission Timeframes

Selective JAK-1 inhibitor group attained better clinical outcome at the two-time points observed. At the early week 8 evaluation, clinical remission was achieved by 58.8% (n = 40/68) of the JAK-1 cohort compared to 32.4% (n = 24/74) of the anti-integrin cohort (p = 0.002). The difference in performance was sustained through week 24, with 73.5% vs. 51.4% (p = 0.007).clinical remissions, respectively, attributed to the small-molecule JAK-1 inhibitor.

Speed of Clinical Symptomatic Response

Patient-reported daily symptom logs identified a quick onset of response to oral inhibitors of JAK-1. The patients treated with Upadacitinib had a median time to a >= 50% reduction in combined stool frequency, rectal bleeding of 6.0 days (IQR, 4.0 to 11.0 days). By contrast, the anti-integrin group had a less rapid clinical course, with a median of 19.5 days (IQR, 12.0-28.0 days) to reach that level of symptomatic response (p<0.001).

Corticosteroid-Free Clinical Remission

In patients dependent on steroids at baseline, 64.7% (n=44/68) in the selective JAK-1 inhibitor group achieved clinically deep remission and cessation of steroids by week 24 compared with 41.9% (n=31/74) of patients in the anti-integrin group, which represents a statistically significant therapeutic effect (p=0.008).

Biochemical Optimization and Biomarker Response

Endoscopic and clinical findings were well correlated with biochemical evaluation. Eighteen patients (80.9%) of the JAK-1 arm, but only 11 (59.5%) of the anti-integrin arm had complete normalization of serum CRP (< 5 mg/L) at week 24 (p = 0.006). In a similar way, 76.5% of the JAK-1 patients but only 54.1% of anti-integrin patients achieved a deep reduction of local colonic inflammation with a final faecal calprotectin concentration of less than 150 µg/g (p = 0.005).

Table 2: Comparative Summary of Primary and Secondary Efficacy Outcomes at Week 24

Safety and Tolerability Profiles

Both therapeutic agents were generally well tolerated, and the majority of treatment-emergent adverse events (TEAEs) recorded were mild-to-moderate (Grade 1 or 2) in severity. No patient developed deep vein thrombosis (DVT), pulmonary embolism (PE), or major adverse cardiovascular events (MACE) during this 6-month trial window. Furthermore, no deaths or malignancies were reported.

In the selective JAK-1 inhibitor cohort, the most commonly encountered adverse events were metabolic and cutaneous. Dose-dependent, transient elevations in serum lipid profiles (total cholesterol and LDL cholesterol) were noted in 23.5% (n = 16) of patients within 8 weeks of therapy initiation, though none required statin intervention. Mild-to-moderate acneiform eruptions occurred in 14.7% (n = 10) of these patients and were managed effectively with topical therapies without necessitating Upadacitinib discontinuation.

In the anti-integrin cohort, adverse reactions were predominantly respiratory and constitutional. Mild upper respiratory tract infections (URTIs) and nasopharyngitis were documented in 18.9% (n = 14) of patients, followed by transient post-infusion headaches in 10.8% (n = 8).

Serious adverse events (SAEs) prompting absolute drug cessation were low and statistically comparable between the groups: 2.9% (n = 2) in the JAK-1 group due to a severe, localized herpes zoster reactivation and a marked drop in absolute neutrophil count (< 1000 cells/\mu L), and 4.1% (n = 3) in the anti-integrin group secondary to a severe, protracted clinical UC disease exacerbation requiring rescue colectomy.

Table 3: Treatment-Emergent Adverse Events and Safety Parameters

Mucosal healing (MH) with clear and objective criteria has become the most important outcome parameter established as a measure of therapeutic efficacy in moderate to severe ulcerative colitis, and serves as a key endpoint for the long-term clinical prognosis [2]. A multicentre real-world study was conducted that aimed to compare the efficacy of oral selective Janus Kinase 1 (JAK-1) inhibition with intravenous anti-integrin therapy in patients with a highly refractory patient cohort and biological experience from Pakistan over 6 months, which ended in January 2026. The results show selective JAK-1 inhibitor Upadacitinib achieves significantly higher rates of objective mucosal healing (69.1% vs. 44.6%) and clinical remission (73.5% vs. 51.4%) than Vedolizumab at week 24. These findings from this real-world study support those from large-scale global trials, and network meta-analyses [6], demonstrating the superior endoscopic performance of selective JAK-1 inhibitors. Severe endoscopic improvement and high clinical remission rates were quickly achieved with upadacitinib induction in patients resistant to biological agents (phase III U-ACHIEVE and U-ACCOMPLISH) [5]. The biological mechanism underlying these results is related to the unique molecular targets of these drugs. In Refractory UC there is hyper-regulation of several overlapping pro-inflammatory cytokine pathways, such as those of IL-6 and Interferon-gamma [1]. Upadacitinib is a selective inhibitor of the JAK-1 protein complex in cells thereafter blocking the downstream STAT-mediated signaling pathways of a wide range of these inflammatory cytokines simultaneously [1,8].

However, unlike monoclonals that bind to a single extracellular link, this broad intracellular suppression in severe, refractory, disease state is more conclusive anti-inflammatory effect [1]. In contrast, Vedolizumab is a therapeutic targeting agent that binds directly to the alpha4beta7 integrin that is found outside of cells. It is through this mechanism that gut-specific leukocytes do not home to the inflamed intestinal mucosa while avoiding systemic immunosuppression [6,7]. This selective mechanism of action in the gut is associated with a favourable safety profile, but generally demands a longer action time, to remove any pre-existing infiltrates of inflammatory cells in the lamina propria and to permit tissue regeneration [7]. The slowness of this mechanism may account for this significant variation in speed of clinical onset in our study. When it came to symptom reduction, those given the JAK-1 inhibitors reduced their symptoms by 50% within a median of 6.0 days while the anti-integrin group reduced their symptoms by 50% within a median of 19.5 days. This quick onset is especially beneficial in acute on chronic exacerbations, severe steroid dependent states to reduce systemic steroid exposure and likelihood of emergency surgery. Our biochemical marker data obtained in this study corroborates with our clinical and endoscopic findings. Fecal calprotectin is a very sensitive and specific non-invasive biomarker of localised gastrointestinal tract inflammation with high correlation with objective gastrointestinal tract endoscopic disease activity indices [5].

At 24 weeks, 76.5% of the selective JAK-1 inhibitor group and 54.1% of the anti-integrin group had complete normalization of fecal calprotectin (FCP) levels (FCP < 150 \mu g/g). This remarkable difference truly emphasizes the effect the fast clinical response shows on objective mucosal inflammatory activity. The safety data of this cohort confirm the known safety profile of both therapeutic classes, and no new or unexpected safety signals were found. Selective JAK inhibitors' lack of safety is a major consideration in clinics, given the concern about deep vein thrombosis, pulmonary embolus and major adverse cardiac event (MACE) associated with pan-JAK inhibitors, such as tofacitinib. Upadacitinib is specifically targeted at the JAK-1 subunit, with favorable separation from the activity of the JAK-2/JAK-3 mediated pathway, limiting interference with signaling pathways responsible for the regulation of production of erythropoietin and lipid homeostasis [1].

During the 6 months follow-up in this study, no case of thromboembolic events or MACE was observed in either group. This included transient hypercholesterolemia (observed in 23.5% of cases treated with JAK-1) and mild acne (observed in 14.7% of cases treated with JAK-1) and were generally self-limited and did not commonly necessitate change of treatment. Vedolizumab showed an extremely favourable systemic safety profile with the most common adverse event being upper respiratory infection; this facilitates its use for long-term maintenance treatment in the patient who cannot accept systemic immunosuppression [7].

Although this study offers valuable real world data for the comparative analysis of these smart drugs in a south Asian context, it has some limitations. The non-randomized, observational design allowed for selection bias since the selection of drug treatment depended upon the preference of the clinician and the financial means of the patient. Furthermore, the 24-week duration of the study is somewhat too short to draw conclusions about long-term maintenance efficacy, and about rare adverse events or events that manifest themselves at a later stage, such as malignancies. Further, prospective, randomized comparisons with longer-term follow-up will serve to validate these results and ensure that further options for sequencing advanced therapy are explored in the Pakistani population of refractory ulcerative colitis. Finally, selective JAK-1 inhibitors offer greater clinical benefit than anti-integrin therapy after offering much faster clinical symptom relief, higher objective mucosal healing rates, and greater biomarker normalization at 24 weeks in patients with moderate-to-severe refractory ulcerative colitis who have been non-responsive to conventional immunomodulators/anti-TNF therapy.

1. Harris, C., & Cummings, J. R. F. (2021). JAK1 inhibition and inflammatory bowel disease. Rheumatology, 60(Suppl. 2), ii45–ii51. https://doi.org/10.1093/rheumatology/keaa896
2. Veltkamp, S. H. C., & Voorneveld, P. W. (2025). Cell-specific effects of JAK1 inhibitors in ulcerative colitis. Journal of Clinical Medicine, 14(2), 608. https://doi.org/10.3390/jcm14020608
3. Ferrante, M., & Sabino, J. (2019). Use of JAK inhibitors in ulcerative colitis. Journal of Crohn's and Colitis, 14(Suppl. 2), S737–S745. https://doi.org/10.1093/ecco-jcc/jjz202
4. Irving, P. M., Hur, P., Gautam, R., Guo, X., & Vermeire, S. (2024). Systematic literature review of evidence for real-world effectiveness and safety of advanced therapies for the treatment of moderate-to-severe ulcerative colitis. Journal of Managed Care & Specialty Pharmacy, 30(9), 1026–1040. https://doi.org/10.18553/jmcp.2024.30.9.1026
5. Mao, Y. (2026). The efficacy and safety of upadacitinib in refractory inflammatory bowel disease: A multicenter real-world observational study. Drug Design, Development and Therapy, 20(1), 585–594.
6. Sror, N. (2026). Comparative effectiveness and safety of upadacitinib and vedolizumab in biologic-exposed patients with ulcerative colitis: A retrospective study. Inflammatory Bowel Diseases, 32(2), 204–212.
7. Feagan, B. G., Rutgeerts, P., Sands, B. E., et al. (2013). Vedolizumab as induction and maintenance therapy for ulcerative colitis. New England Journal of Medicine, 369(8), 699–710. https://doi.org/10.1056/NEJMoa1215734
8. Herrera-deGuise, C., Serra-Ruiz, X., Lastiri, E., & Borruel, N. (2023). A new dawn for oral drugs in inflammatory bowel diseases: JAK inhibitors. Frontiers in Medicine, 10, 1089099. https://doi.org/10.3389/fmed.2023.1089099
9. Gilmore, R. (2026). Upadacitinib induction is effective and safe in ulcerative colitis patients including those with prior exposure to tofacitinib: A multicenter real-world cohort study. Intestinal Research, 24(2), 112–121.