Bridging the Treatment Access Gap: Janus Kinase Inhibitors as First-line Advanced Therapy for Inflammatory Bowel Disease in Resource-variable Settings

Abstract

Aims and background

Janus kinase (JAK) inhibitors have reshaped the pharmacotherapeutic armamentarium for inflammatory bowel disease (IBD), distinguished by oral dosing, ambient-temperature stability, immunity from anti-drug antibody formation, and a characteristically brisk pharmacodynamic onset, properties that collectively set them apart from injectable biologic agents. The epidemiological footprint of IBD is expanding at an accelerating pace across Eastern Europe, Central Asia, and the Middle East, yet meaningful access to biologic therapies remains starkly uneven, constrained by coldchain dependencies, infusion-facility prerequisites, immunogenicity monitoring demands, and financial barriers. Prior reviews have been anchored to Western regulatory paradigms without examining the qualitatively distinct therapeutic roles JAK inhibitors could assume in resource-variable healthcare environments. This narrative review synthesizes comparative efficacy, tolerability, and logistical evidence for JAK inhibitors vs biologic agents and proposes a regionally grounded framework for their integration into the Euroasian IBD treatment pathway.

Methods

A structured literature search of PubMed, MEDLINE, and the Cochrane Central Register of Controlled Trials was performed through March 2026, targeting randomized controlled trials (RCTs), network meta-analyses (NMAs), comparative effectiveness investigations, real-world cohort analyses, and contemporary clinical practice guidelines [American College of Gastroenterology (ACG) 2025, American Gastroenterological Association (AGA) 2024–2025, and European Crohn's and Colitis Organization (ECCO) 2025] addressing JAK inhibitors and biologic agents in moderate-to-severe ulcerative colitis (UC) and Crohn's disease (CD). Endpoints of interest spanned clinical remission, endoscopic improvement, histologic remission, rapidity of symptomatic relief, and safety parameters encompassing herpes zoster reactivation, major adverse cardiovascular events (MACE), and venous thromboembolism (VTE).

Results

Multiple NMAs position upadacitinib at the apex for clinical remission induction in UC (p-score 0.98–0.99), with sustained superiority across both biologic-naïve and biologic-experienced subpopulations. Pivotal phase III data in CD demonstrated clinical remission in 38.9–49.5% of upadacitinib-treated patients vs 21.1–29.1% receiving placebo (p < 0.001). With respect to onset kinetics, JAK inhibitors outpace every biologic class; upadacitinib produced symptomatic remission in 68% by week 2, contrasted with 15.7–22% for vedolizumab, ustekinumab, and tumor necrosis factor (TNF) antagonists. Among heavily pretreated real-world patients (median four prior advanced therapies), 64% achieved clinical remission by week 12, and dose re-escalation recaptured therapeutic response in 60%. Herpes zoster incidence is appreciably elevated [number needed to harm (NNH) 83–97], reinforcing the imperative for pre-treatment immunization. Cardiovascular and thromboembolic signals from the ORAL surveillance rheumatoid arthritis trial have not been substantiated in IBD-specific populations [hazard ratio (HR) 0.50–1.08 for MACE; HR 0.66–1.06 for VTE vs anti-TNF therapy].

Conclusion

Within resource-variable Euroasian healthcare systems, JAK inhibitors may merit a substantially earlier position in the IBD treatment sequence than Western algorithms currently prescribe, by virtue of logistical attributes that circumvent the infrastructure constraints impeding biologic utilization. This review presents the first regionally anchored framework for deploying JAK inhibitors in clinical contexts where the operative decision is not between a JAK inhibitor and a biologic, but between a JAK inhibitor and the total absence of advanced therapy.

Clinical significance

For gastroenterologists practicing throughout the Euroasian region under conditions of restricted biologic availability, limited infusion capacity, and absent therapeutic drug monitoring (TDM), this review furnishes an evidence-grounded rationale for deploying JAK inhibitors as first-line advanced therapy, supported by efficacy data, safety evidence, and pragmatic considerations tailored to resource-variable healthcare systems.

Introduction

The worldwide geography of inflammatory bowel disease (IBD) is undergoing a sweeping realignment. Incidence has largely plateaued across affluent Western nations, yet newly industrializing territories spanning Eastern Europe, Central Asia, and the Middle East are charting steeply ascending disease trajectories.^1,2 A pooled analysis encompassing Eastern Mediterranean Region Organization (EMRO) member states placed ulcerative colitis (UC) incidence at 2.65 per 1,00,000 person-years and Crohn's disease (CD) incidence at 1.16 per 1,00,000 person-years.³ The Global Burden of Disease initiative corroborated that East Asia registered the steepest mean annual growth in agestandardized IBD prevalence at 2.54%.⁴ In Türkiye, a multicenter investigation spanning 24 gastroenterology referral centers documented a greater than twofold surge in annual IBD diagnoses from 2010 through 2021, with the preponderance of patients diagnosed during early adulthood (median age 30–32 years).⁵

This epidemiological acceleration is colliding with a stark therapeutic reality: The advanced pharmacotherapies that have fundamentally improved IBD outcomes in high-income countries remain operationally inaccessible to the majority of patients across the Euroasian corridor. Biologic agents mandate parenteral delivery, refrigerated storage maintained at 2–8°C, purpose-built infusion facilities, and immunogenicity-based therapeutic drug monitoring (TDM)—each requirement amplifying access barriers in resource-constrained environments.^6,7 The proportion of CD patients receiving biologic therapy spans from roughly 40% in Japan to as little as 1% in India, with numerous Euroasian nations clustered toward the lower bound.⁸ The 2025 European Crohn's and Colitis Organization (ECCO) consensus addressing IBD management in low- and middle-income countries (LMICs) designated delayed access to advanced therapies as a pivotal unmet need.⁹ Throughout much of the Euroasian region, corticosteroids endure as the therapeutic backbone for moderate-to-severe disease, a circumstance dictated not by clinical judgment but by the unavailability of superior alternatives.⁶

Janus kinase (JAK) inhibitors represent a mechanistically distinct category of orally administered small molecules poised to fundamentally alter this equation. Unlike biologic agents, they impose no coldchain requirement, no infusion infrastructure, no patient injection education, and no immunogenicity-driven TDM.¹⁰ Tofacitinib obtained Food and Drug Administration (FDA) approval for UC in 2018 based on the OCTAVE trial program, and upadacitinib holds regulatory authorization for both UC and CD.^11–13 Both agents carry FDA labeling that recommends deployment following prior tumor necrosis factor (TNF) antagonist inadequacy, whereas the European Medicines Agency (EMA) counsels cautious first-line use in patients harboring cardiovascular risk.¹⁴

No prior review has systematically interrogated the qualitatively different therapeutic niche these agents could occupy in environments where the clinical decision is not between a JAK inhibitor and a biologic, but between a JAK inhibitor and the complete absence of advanced therapy. This narrative review consolidates comparative efficacy, tolerability, and logistical evidence for JAK inhibitors relative to biologic agents and advances a regionally informed framework for their placement within the Euroasian IBD treatment algorithm.

Methods

This work represents a narrative synthesis of published literature addressing JAK inhibitors and biologic therapies in moderate-to-severe UC and CD, augmented by data pertaining to IBD epidemiology, treatment accessibility, and healthcare delivery across LMICs. No systematic review protocol was registered, no original meta-analytic computation was performed, and no independent data analysis was undertaken. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework was not applied. Because no human participants or patient-level data were involved, institutional ethics committee oversight was not warranted.

Electronic databases, specifically PubMed, MEDLINE, and the Cochrane Central Register of Controlled Trials, were interrogated through March 2026. Source material encompassed RCTs, published systematic reviews, network meta-analyses (NMAs), large-scale observational cohort investigations, and contemporary clinical practice guidelines. Every quantitative datum presented herein is extracted verbatim from its original publication; no independent recalculation or verification was performed by the authorship team.

The guideline corpus reviewed comprised the ECCO consensus on IBD management in LMICs (2025), American Gastroenterological Association (AGA) living clinical practice guideline (2024), American College of Gastroenterology (ACG) clinical guideline update for UC (2025), ACG clinical guideline for CD (2025), and AGA evidence synthesis (2024).^9,14–17 Endpoints of primary interest included clinical remission, endoscopic improvement, histologic remission, rapidity of symptomatic response, and safety outcomes spanning herpes zoster reactivation, major adverse cardiovascular events (MACE), venous thromboembolism (VTE), and serious infections.

Results

The Treatment Access Disparity across the Euroasian Region

Inflammatory bowel disease incidence continues its upward trajectory throughout Eastern Europe, Turkey, Iran, and the broader Eastern Mediterranean basin.^1,3,5 Notwithstanding this mounting disease burden, access to advanced pharmacotherapy remains profoundly inequitable. A targeted assessment of Central and Eastern Europe pinpointed constrained availability of advanced therapies, an insufficient gastroenterology workforce, and fragmented care delivery as cardinal obstacles.¹⁸ A 2026 ECCO-commissioned evaluation reaffirmed that patients in LMICs confront specialist shortages, circumscribed diagnostic capacity, and deficient access to advanced treatments.¹⁹

Barriers to biologic utilization extend considerably beyond drug acquisition cost. Coldchain interruptions can degrade biologic potency or introduce safety concerns.⁷ Infusion-dependent biologics demand facilities staffed by trained nursing personnel and outfitted for emergency intervention, resources that remain scarce across much of the Euroasian landscape.⁶ Therapeutic drug monitoring requires laboratory capacity for quantifying drug trough concentrations and anti-drug antibodies, an infrastructure largely absent in resource-limited nations.⁸ The cumulative result is that a substantial proportion of patients remain dependent on protracted corticosteroid courses because advanced therapies are operationally unattainable.⁶

Janus kinase inhibitors, by contrast, are thermostable oral tablets that eliminate the need for refrigerated supply chains, infusion facilities, injection training, and immunogenicity-based TDM. Their manufacture as small molecules entails inherently lower complexity and cost relative to monoclonal antibody production, potentially enabling more affordable importation or regional synthesis.¹⁰

Comparative Efficacy of JAK Inhibitors

NMAs in UC

Within the NMA conducted by Burr et al., upadacitinib 45 mg once daily secured the premier ranking for clinical remission induction [relative risk (RR) of failure 0.73; 95% confidence interval (CI) 0.68–0.80, p-score 0.98], retaining superiority across both biologic-naïve (p-score 0.99) and biologic-exposed (p-score 0.99) subgroups.²⁰ The 2024 AGA evidence synthesis substantiated that upadacitinib exhibited greater efficacy than every other evaluated agent apart from ozanimod and risankizumab.¹⁷ A 2025 NMA by Shehab et al. placed upadacitinib at the summit for clinical remission induction [surface under the cumulative ranking curve (SUCRA) 99.6%], endoscopic improvement (SUCRA 99.2%), and maintenance of histological remission (SUCRA 93.1%).²¹

For maintenance therapy, Barberio et al. documented that upadacitinib 30 mg once daily attained the top position for sustained clinical remission (RR of failure 0.52; 95% CI 0.44–0.61, p-score 0.99) and endoscopic improvement (p-score 0.99).²²

Phase III Trial Evidence in UC

The OCTAVE induction 1 and 2 trials yielded remission at 8 weeks in 18.5 and 16.6% of patients allocated to tofacitinib 10 mg twice daily vs 8.2 and 3.6% with placebo (p = 0.007 and p < 0.001, respectively).¹¹ In OCTAVE Sustain, 52-week remission was attained by 40.6% receiving tofacitinib 10 mg twice daily compared with 11.1% receiving placebo (p < 0.001).¹¹

Upadacitinib produced numerically higher remission rates: Week 8 clinical remission reached 26 and 33% with upadacitinib 45 mg vs 5 and 4% with placebo (p < 0.0001).¹³ At week 52, clinical remission was observed in 42% (15 mg) and 52% (30 mg) vs 12% with placebo (p < 0.0001).¹³ The 2025 ACG guideline provides strong endorsement for both agents.¹⁵

Phase III Trial Evidence in CD

In U-EXCEL, week 12 clinical remission was documented in 49.5% receiving upadacitinib vs 29.1% receiving placebo, with endoscopic response rates of 45.5 vs 13.1% (p < 0.001).¹² In U-EXCEED (enrolling exclusively biologic-experienced patients), clinical remission was 38.9 vs 21.1%, and endoscopic response was 34.6 vs 3.5% (p < 0.001).¹²

Definitive U-ENDURE maintenance results confirmed Crohn's disease activity index (CDAI) clinical remission in 51.5% receiving 30 mg vs 15.2% receiving placebo, alongside endoscopic response in 40.7 vs 7.2% (p < 0.001).^23,24 Notably, no deaths, active tuberculosis (TB), lymphoma, adjudicated MACE, or VTE events were recorded throughout the trial program.^23,24 The 2025 ACG guideline recognizes upadacitinib as an efficacious therapeutic option, with the 30 mg daily dose preferred for treatment-refractory presentations.¹⁶ Principal efficacy outcomes are consolidated in Table 1.

Table 1.

Comparative efficacy of JAK inhibitors and biologic therapies in moderate-to-severe IBD

Study/source	Design	Disease	Agent	Key efficacy outcome	Result	Comparator	p-value/ranking
Burr et al.20	NMA (Gut)	UC	Upadacitinib 45 mg QD	Clinical remission (induction)	RR of failure 0.73 (95% CI 0.68–0.80)	Placebo	P-score 0.98 (overall); 0.99 (bio-naïve and bio-exposed)
Shehab et al.21	NMA (Clin Gastroenterol Hepatol)	UC	Upadacitinib 45 mg QD	Clinical remission (induction)	SUCRA 99.6%	All advanced therapies	Ranked 1st
Shehab et al.21	NMA (Clin Gastroenterol Hepatol)	UC	Upadacitinib 45 mg QD	Endoscopic improvement (induction)	SUCRA 99.2%	All advanced therapies	Ranked 1st
Shehab et al.21	NMA (Clin Gastroenterol Hepatol)	UC	Upadacitinib 30 mg QD	Histological remission (maintenance)	SUCRA 93.1%	All advanced therapies	Ranked 1st
Barberio et al.22	NMA (Aliment Pharmacol Ther)	UC	Upadacitinib 30 mg QD	Clinical remission (maintenance)	RR of failure 0.52 (95% CI 0.44–0.61)	Placebo	P-score 0.99
Ananthakrishnan et al.17	NMA (Gastroenterology)	UC	Upadacitinib	Clinical remission (bio-naïve)	More efficacious vs all except ozanimod and risankizumab	All advanced therapies	Low-to-moderate certainty
Sandborn et al.11	Phase III RCT (OCTAVE)	UC	Tofacitinib 10 mg BID	Clinical remission at wk 8	18.5% (induction 1); 16.6% (induction 2)	Placebo: 8.2%; 3.6%	0.007; <0.001
Sandborn et al.11	Phase III RCT (OCTAVE Sustain)	UC	Tofacitinib 10 mg BID	Clinical remission at wk 52	40.6%	Placebo: 11.1%	<0.001
Danese et al.13	Phase III RCT (U-ACHIEVE/U-ACCOMPLISH)	UC	Upadacitinib 45 mg QD	Clinical remission at wk 8	26%; 33%	Placebo: 5%; 4%	<0.0001
Danese et al.13	Phase III RCT (U-ACHIEVE maintenance)	UC	Upadacitinib 30 mg QD	Clinical remission at wk 52	52%	Placebo: 12%	<0.0001
Loftus et al.12	Phase III RCT (U-EXCEL)	CD	Upadacitinib 45 mg QD	Clinical remission at wk 12	49.5%	Placebo: 29.1%	<0.001
Loftus et al.12	Phase III RCT (U-EXCEED)	CD	Upadacitinib 45 mg QD	Clinical remission at wk 12 (bio-experienced)	38.9%	Placebo: 21.1%	<0.001
Panaccione et al.23	Phase III RCT (U-ENDURE final)	CD	Upadacitinib 30 mg QD	CDAI clinical remission at wk 52	51.5%	Placebo: 15.2%	<0.001
Ahuja et al.25	NMA (Am J Gastroenterol)	UC	Upadacitinib 45 mg QD	Symptomatic remission at wk 2	68%	VDZ: 15.7%; UST: 18.4%; IFX: 23.7%	RR range 2.85–6.27 vs all agents
García et al.27 (UREAL)	Real-world multicenter	UC/CD	Upadacitinib 15–30 mg QD	Clinical remission at wk 12 (median 4 prior therapies)	64%	—	Dose re-escalation recaptured response in 60%

BID, twice daily; bio, biologic; CD, Crohn's disease; CDAI, Crohn's disease activity index; CI, confidence interval; IFX, infliximab; NMA, network meta-analysis; QD, once daily; RCT, randomized controlled trial; RR, relative risk; SUCRA, surface under the cumulative ranking curve; UC, ulcerative colitis; UST, ustekinumab; VDZ, vedolizumab; wk, week

Speed of Symptomatic Response

The characteristically rapid onset of JAK inhibitors carries heightened clinical relevance in resource-variable environments, where patients frequently present with advanced disease and expeditious corticosteroid withdrawal is imperative. Ahuja et al. demonstrated that upadacitinib elicited symptomatic remission by week 2 in 68% of patients vs 15.7–23.9% across all biologic classes (RR range 2.85–6.27).²⁵ In CD, Colombel et al. documented a median interval to daily clinical remission of 13 days with upadacitinib vs 32 days with placebo, with discernible improvement emerging by day 5–6.²⁶

Janus Kinase Inhibitors in Multiply-refractory Disease

The UREAL study evaluated upadacitinib in 100 patients with IBD who had received a median of four prior advanced therapies.²⁷ Clinical remission was observed in 64% at week 12 and 42% at week 52. Among UC patients with antecedent tofacitinib exposure, clinical remission reached 78% at week 12, substantiating the therapeutic viability of intra-class switching within the JAK inhibitor category. Dose escalation recaptured remission in 60% of patients experiencing secondary efficacy attenuation, and 80% of those harboring active extraintestinal manifestations demonstrated measurable improvement.²⁷

The preserved efficacy of JAK inhibitors following biologic failure reflects their broader pharmacologic mechanism: Concurrent blockade of intracellular signaling cascades downstream of multiple cytokine receptors, thereby overriding the pathway redundancy that constrains sequential biologic strategies. The intrinsic absence of immunogenicity eliminates anti-drug antibody formation, a prevalent driver of secondary treatment failure that mandates TDM infrastructure largely unavailable throughout the Euroasian region.⁸

Safety Considerations Pertinent to the Euroasian Context

Herpes Zoster

Din et al. reported that tofacitinib 10 mg twice daily [RR 6.90; 95% CI 1.56–30.63, number needed to harm (NNH) 97] and upadacitinib 45 mg once daily (RR 7.89; 95% CI 1.04–59.59, NNH 83) were each independently associated with a significantly heightened risk of herpes zoster reactivation.²⁸ The AGA recommends administration of the recombinant zoster vaccine (RZV) to every patient commencing JAK inhibitor therapy.²⁹ Nonetheless, patients receiving JAK inhibitors may generate attenuated vaccine responses, with seroconversion rates of 74 vs 100% among healthy controls; selective JAK-1 inhibitors yielded higher seroconversion (83%) than non-selective agents (64%).³⁰ In environments where RZV remains unavailable, clinicians must weigh this risk against the cumulative toxicity of sustained corticosteroid dependence. Where the vaccine is accessible, completion of the immunization series should precede treatment initiation.

Cardiovascular and Thromboembolic Safety

The ORAL surveillance trial, enrolling rheumatoid arthritis patients aged ≥50 years with established cardiovascular risk factors, detected elevated rates of MACE, VTE, and malignancy with tofacitinib.³¹ Critically, participants younger than 65 years without a smoking history demonstrated no excess risk.³¹

Evidence derived specifically from IBD populations has been consistently reassuring. Ahuja et al. identified no differential risk of VTE [hazard ratio (HR) 0.66; 95% CI 0.28–1.57] or MACE (HR 0.50; 95% CI 0.19–1.30) when comparing 856 JAK inhibitor-treated with 9,422 anti-TNF-treated IBD patients.³² Alsakarneh et al., utilizing propensity-score matching of 8,942 JAK inhibitor-treated with 8,942 anti-TNF-treated patients, detected no statistically significant divergence in MACE [adjusted HR (aHR) 1.08; 95% CI 0.87–1.33] or VTE (aHR 1.06; 95% CI 0.84–1.36), including among patients aged ≥65 years.³³ Yang et al. corroborated the absence of significantly elevated cardiovascular risk across 26 trials encompassing 10,537 IBD patients.³⁴ The discordance with ORAL surveillance findings likely reflects the younger IBD population (mean age 45–47 years) bearing a lower burden of cardiovascular comorbidities relative to the rheumatoid arthritis cohort.³¹ Principal safety data are presented in Table 2.

Table 2.

Safety of JAK inhibitors in IBD-specific populations

Study/Source	Design	Population	Comparison	Outcome	Result (95% CI)	Significance
Ahuja et al.32	Retrospective cohort	856 JAK vs 9,422 anti-TNF (IBD)	JAK vs anti-TNF	MACE	HR 0.50 (0.19–1.30)	Not significant
Ahuja et al.32	Retrospective cohort	856 JAK vs 9,422 anti-TNF (IBD)	JAK vs anti-TNF	VTE	HR 0.66 (0.28–1.57)	Not significant
Ahuja et al.32	Retrospective cohort	856 JAK vs 9,422 anti-TNF (IBD)	JAK vs anti-TNF	Overall infections	HR 1.60 (1.33–1.93)	Significant
Ahuja et al.32	Retrospective cohort	856 JAK vs 9,422 anti-TNF (IBD)	JAK vs anti-TNF	Serious infections	HR 0.97 (0.66–1.44)	Not significant
Alsakarneh et al.33	Multicenter matched cohort	8,942 JAK vs 8,942 anti-TNF (IBD)	JAK vs anti-TNF	MACE at 1 yr	aHR 1.08 (0.87–1.33)	Not significant
Alsakarneh et al.33	Multicenter matched cohort	8,942 JAK vs 8,942 anti-TNF (IBD)	JAK vs anti-TNF	VTE at 1 yr	aHR 1.06 (0.84–1.36)	Not significant
Alsakarneh et al.33	Multicenter matched cohort	Patients aged ≥65 yr	JAK vs anti-TNF	MACE at 1 yr (≥65 yr)	aHR 0.95 (0.69–1.31)	Not significant
Yang et al.34	Systematic review and NMA	26 trials, 10,537 IBD patients	JAK vs placebo	MACE	No significant increase	Not significant
Yang et al.34	Systematic review and NMA	26 trials, 10,537 IBD patients	JAK vs placebo	VTE	No significant increase	Not significant
Din et al.28	Systematic review and NMA	IBD (all JAK trials)	Tofacitinib 10 mg BID vs placebo	Herpes zoster	RR 6.90 (1.56–30.63); NNH 97	Significant
Din et al.28	Systematic review and NMA	IBD (all JAK trials)	Upadacitinib 45 mg QD vs placebo	Herpes zoster	RR 7.89 (1.04–59.59); NNH 83	Significant
Panaccione et al.;23 Colombel et al.26	Phase III RCT (U-ENDURE integrated)	673 CD patients	Upadacitinib vs placebo	Active TB, lymphoma, NMSC, adjudicated MACE, VTE	0 events in all groups	—
Ytterberg et al.31 (ORAL surveillance)	Open-label post-marketing RCT	RA patients ≥50 yr with CV risk factors	Tofacitinib vs anti-TNF	MACE, VTE, malignancy	Increased risk with tofacitinib	Significant (RA population; not replicated in IBD)
Ytterberg et al.31 (ORAL surveillance)	Subanalysis	RA patients 65 yr, never smokers	Tofacitinib vs anti-TNF	MACE, malignancy, MI, death	No increased risk	Not significant in this subgroup

aHR, adjusted hazard ratio; anti-TNF, tumor necrosis factor antagonist; BID, twice daily; CD, Crohn's disease; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; IBD, inflammatory bowel disease; JAK, Janus kinase; MACE, major adverse cardiovascular events; MI, myocardial infarction; NMA, network meta-analysis; NMSC, nonmelanoma skin cancer; NNH, number needed to harm; QD, once daily; RA, rheumatoid arthritis; RCT, randomized controlled trial; RR, relative risk; VTE, venous thromboembolism; yr, year

Infection Risk in Endemic Regions

Tuberculosis remains endemic throughout numerous Central Asian and Eastern European nations; screening protocols should be applied with equivalent rigor to JAK inhibitors as to biologic agents. The U-ENDURE dataset documented no instances of active TB, although pre-treatment screening was universally mandated within the trial protocol.^23,24 Standard pre-treatment evaluation should encompass tuberculin skin testing or interferon-gamma release assay, hepatitis B surface antigen and core antibody, and hepatitis C antibody testing.

Discussion

A Proposed Framework for JAK Inhibitor Positioning

The prevailing Western treatment algorithm, reserving JAK inhibitors for deployment after TNF antagonist failure, was architected for healthcare systems affording unrestricted access to the complete biologic armamentarium.¹⁴ This paradigm cannot be transplanted wholesale to the Euroasian context. The AGA living guideline itself acknowledges this tension, referencing the varying recommendations for use of JAK inhibitors as first-line treatment in different regions of the world.”¹⁴

A regionally calibrated framework stratified across three tiers of healthcare infrastructure is proposed herein:

Tier 1

Environments with comprehensive biologic availability (e.g., Turkey, Israel, Gulf states, EU-member Eastern European countries). Janus kinase inhibitors can be deployed in alignment with Western guideline recommendations, with individualized selection by the patient's risk profile and preferences.¹⁴

Tier 2

Environments with partial biologic availability [e.g., countries possessing biosimilar anti-TNF access but constrained availability of vedolizumab, ustekinumab, or anti-interleukin (IL)-23 agents]. Janus kinase inhibitors may serve as the principal second-line option following anti-TNF inadequacy, bypassing agents reliant on coldchain and infusion infrastructure.²⁷

Tier 3

Environments with negligible biologic availability (e.g., countries where biologics are obtainable exclusively through out-of-pocket expenditure or are entirely unavailable). Janus kinase inhibitors may be deployed as first-line advanced therapy, representing the sole accessible option beyond corticosteroids and immunomodulators. The NMA evidence establishing upadacitinib's superiority in biologic-naïve populations (p-score 0.99) furnishes robust efficacy justification for this positioning.²⁰

Across all tiers, individualized risk-benefit evaluation remains paramount. Patients aged ≥65 years harboring cardiovascular risk factors warrant counseling regarding theoretical risks, notwithstanding the reassuring IBD-specific data.^32–34 Herpes zoster immunization should be administered wherever feasible.^29,30 Pre-treatment screening for TB and hepatitis B is obligatory irrespective of tier assignment.

Biomarker-guided Therapy Selection: Future Directions

Oncostatin M (OSM), which transduces signals through JAK-dependent cascades, has surfaced as a candidate predictive biomarker.³⁵ Elevated mucosal OSM expression has been linked to anti-TNF non-response, raising the possibility that patients exhibiting high OSM levels may derive preferential benefit from JAK inhibition.³⁵ Prospective validation within clinical cohorts is required before incorporation into routine practice.

Cost-effectiveness Considerations

The production cost of small-molecule JAK inhibitors is inherently lower than that of recombinant monoclonal antibodies.¹⁰ When indirect expenditures are incorporated into infusion center operations, TDM, coldchain maintenance, and immunogenicity-related treatment failures, the aggregate cost differential may favor JAK inhibitors even when drug acquisition prices are comparable. Biosimilar alternatives for vedolizumab, ustekinumab, and anti-IL-23 agents remain distant from market availability.³⁶ The dose re-escalation approach validated in the UREAL study—recapturing response in 60% of patients by increasing upadacitinib from 15–30 mg provides a more straightforward strategy for managing treatment failure than sequential biologic class switching.²⁷

Limitations of the Study

As a narrative synthesis, a formal systematic methodology was not employed, introducing the possibility of selection bias in source identification. Comparative efficacy data derive predominantly from NMAs rather than direct head-to-head trials; the ongoing VIVID-1 trial comparing upadacitinib with ustekinumab in CD has not yet yielded definitive results. Safety data are constrained by relatively abbreviated follow-up durations; the largest cohort investigation reported outcomes over a 1-year observation window.³³ The cardiovascular safety reassurance derived from IBD cohorts warrants contextualization against the younger, healthier demographic profile characteristic of IBD populations; whether these findings extend to older patients with established cardiovascular comorbidities remains an open question.

The proposed three-tier framework has not undergone formal health technology assessment or regional stakeholder validation and is advanced as a foundation for further deliberation rather than a definitive recommendation. Access to advanced therapies varies considerably within individual countries, and the tier designations represent broad generalizations that may not capture local realities. Given the rapidly evolving nature of this therapeutic domain, evidence published after March 2026 may not be captured herein.

Conclusion

Janus kinase inhibitors demonstrate efficacy that is comparable to or surpasses that of biologic therapies in moderate-to-severe UC and CD, with upadacitinib consistently securing the highest ranking across multiple NMAs.^17,20,21 The accelerated onset of symptomatic remission, 68% by week 2 vs 15.7–23.9% for biologic agents, represents a clinically consequential advantage in settings where patients present with advanced disease.²⁵

Herpes zoster risk is appreciably elevated (NNH 83–97) and mandates pre-treatment vaccination where available.^28,29 Cardiovascular and thromboembolic signals from the ORAL surveillance trial have not been reproduced in IBD-specific cohorts.^32–34 Individualized risk-benefit evaluation incorporating age, cardiovascular risk profile, and smoking status remains essential.

For the Euroasian region, JAK inhibitors may warrant a qualitatively different position in the treatment algorithm than that prescribed by Western guidelines. In settings where the operative choice lies between a JAK inhibitor and the total absence of advanced therapy, the pragmatic advantages of oral administration, ambient-temperature stability, and independence from infusion infrastructure position these agents as candidate first-line advanced therapies. The proposed three-tier framework offers a starting point for the development of regionally adapted treatment algorithms.

Research priorities going forward include head-to-head trials (VIVID-1 results pending), extended safety registries, biomarker-guided therapy selection investigations, and formal cost-effectiveness analyses incorporating the indirect costs of biologic infrastructure. Regional IBD registries would furnish essential real-world evidence to validate and refine the proposed framework.

Clinical Significance

Janus kinase inhibitors present a distinctive convergence of high efficacy, rapid onset, and logistical advantages that position them to narrow the treatment access disparity across the Euroasian region. For clinicians managing moderate-to-severe IBD in environments with constrained biologic infrastructure, this review provides an evidence-grounded rationale for considering JAK inhibitors as first-line advanced therapy. The proposed three-tier framework offers a regionally contextualized approach that accommodates the heterogeneity of healthcare infrastructure across the Euroasian landscape.

Ethical Approval

Not applicable. This narrative review involved no human participants, patient-level data, or animal experimentation. Institutional ethics committee oversight was not warranted.

Data Availability Declaration

No original data were generated or analyzed in the course of this narrative review. All data discussed herein are derived from previously published investigations cited in the References section.

Artificial Intelligence (AI) Disclosure

No AI is used in the study performed.

Acknowledgments

None.

Authors’ Contributions

Rowan Bandaranaike contributed to the conception and design of the review, literature search and selection, drafting of the original manuscript, and critical revision for important intellectual content. Benjamin Hewitt contributed to the literature search, data extraction from published sources, drafting of the manuscript, and preparation of tables. Samuel Tarwater contributed to the critical revision of the manuscript for important intellectual content and provided expert clinical input on treatment positioning recommendations. All authors reviewed and approved the final version of the manuscript and agree to be accountable for all aspects of the work.