Azathioprine

證據等級: L5

預測適應症: 10 個

Azathioprine: From Organ Transplantation to Inflammatory Bowel Disease

One-Sentence Summary

Azathioprine is a well-established thiopurine immunosuppressant, originally used for prevention of organ transplant rejection and management of autoimmune conditions including rheumatoid arthritis and autoimmune hepatitis. The TxGNN model predicts it may be effective for Inflammatory Bowel Disease (IBD) — encompassing both Crohn’s disease and ulcerative colitis — with a prediction confidence of 99.52%. This prediction is supported by 50 clinical trials and 20 publications including three Cochrane systematic reviews, confirming azathioprine as an established first-line immunomodulator for IBD maintenance therapy.

Editorial note: The TxGNN model’s highest-ranked prediction (rank 1) for azathioprine is a rare congenital syndrome (colobomatous microphthalmia-rhizomelic dysplasia) identified as a knowledge graph topological false positive with no supporting evidence (L5, Hold). This report focuses on the highest-ranked clinically meaningful prediction with real-world evidence: Inflammatory Bowel Disease (rank 5, L1 evidence), which represents the most actionable finding for UK healthcare professionals.

Quick Overview

Item	Content
Original Indication	Organ transplant rejection prevention; autoimmune conditions (UK-specific licensing data not captured in this evidence pack — please consult MHRA register)
Predicted New Indication	Inflammatory Bowel Disease (Crohn’s disease and ulcerative colitis)
TxGNN Prediction Score	99.52%
Evidence Level	L1
UK Market Status	UK regulatory data not available in this evidence pack
Number of Marketing Authorisations	Not available in this evidence pack
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Currently, detailed mechanism of action data is not available in this evidence pack. Based on established pharmacology, azathioprine is a thiopurine prodrug (in the same drug class as 6-mercaptopurine, or 6-MP) whose efficacy in organ transplant rejection prevention and autoimmune conditions has been extensively proven over more than 45 years of clinical use. Mechanistically, azathioprine is converted in vivo to 6-thioguanine nucleotides (6-TGN), its primary active metabolites, which inhibit T and B lymphocyte proliferation — a mechanism directly applicable to the immune dysregulation underlying inflammatory bowel disease. The active metabolites also inhibit the Rac1/TIAM1 signalling pathway in mucosal T cells, suppressing pro-inflammatory cytokines including TNF-α and IL-12 that are central to intestinal mucosal pathology.

Inflammatory bowel disease is characterised by dysregulated immune activation in the gastrointestinal mucosa. Crohn’s disease is driven primarily by Th1/Th17-mediated transmural granulomatous inflammation, whilst ulcerative colitis involves Th2/Th9-mediated colonic mucosal immune overactivation. Both conditions share the hallmark of excessive lymphocyte proliferation and overproduction of pro-inflammatory cytokines. Azathioprine’s ability to suppress T cell proliferation and downregulate these cytokines directly addresses the core immunopathology of both IBD subtypes.

It is important to note that azathioprine’s use in IBD represents a well-established indication rather than a purely novel repurposing: it is already recognised in international guidelines (ECCO, ACG, BSG) as a first-line immunomodulator for steroid-dependent Crohn’s disease and ulcerative colitis. The TxGNN model’s high prediction confidence reflects this strong mechanistic and clinical alignment. For the UK context, the absence of locally confirmed regulatory data in this evidence pack means the current MHRA marketing authorisation status should be verified before prescribing.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrolment	Key Findings
NCT00094458	Phase 3	Completed	508	Landmark double-blind RCT in treatment-naïve Crohn’s disease comparing azathioprine monotherapy, infliximab monotherapy, and combination therapy; provides direct Phase 3 evidence for AZA efficacy with large sample size
NCT00946946	Phase 3	Completed	78	Double-blind double-dummy RCT comparing azathioprine versus mesalazine for prevention of clinical relapse in post-operative Crohn’s disease with moderate or severe endoscopic recurrence
NCT00976690	Phase 3	Completed	83	Multicentre RCT comparing azathioprine to mesalazine for prevention of post-operative Crohn’s disease recurrence; supports AZA as preferred immunomodulator following intestinal resection
NCT03101800	Phase 3	Unknown	84	Investigator-initiated open RCT evaluating low-dose azathioprine plus allopurinol versus standard-dose AZA monotherapy in ulcerative colitis; explores an optimised dosing strategy to reduce treatment failures and adverse events
NCT00537316	Phase 3	Terminated	242	Three-arm RCT comparing infliximab monotherapy, infliximab plus azathioprine, and azathioprine monotherapy in moderate-to-severe active ulcerative colitis; terminated early but provides comparative safety and efficacy data
NCT05040464	Phase 3	Recruiting	166	Ongoing RCT directly comparing azathioprine versus methotrexate in combination with adalimumab in Crohn’s disease; will define the optimal immunosuppressant partner for anti-TNF combination therapy
NCT01536535	Phase 4	Completed	431	Multicentre open-label study evaluating standardised initial therapy (including AZA) in newly diagnosed paediatric ulcerative colitis; large real-world validation of AZA-containing treatment protocols
NCT02852694	Phase 4	Completed	192	Risk-stratified paediatric Crohn’s disease RCT: AZA versus methotrexate in low-risk patients, AZA versus adalimumab in high-risk patients; informs personalised maintenance strategy selection
NCT00098111	Phase 3	Terminated	31	Double-blind dose-ranging study of azathioprine (IMURAN) in active Crohn’s disease requiring corticosteroids; sought to identify the optimal weight-based dose (terminated before target enrolment reached)
NCT00554710	Phase 4	Completed	129	Prospective Benelux RCT comparing early aggressive therapy (immunomodulators plus biologicals) versus conventional step-up approach (AZA-containing) in newly diagnosed Crohn’s disease

Literature Evidence

PMID	Year	Type	Journal	Key Findings
40013523	2025	Cochrane Systematic Review	Cochrane Database Syst Rev	Updated Cochrane review (2025) on azathioprine and 6-MP for maintenance of remission in ulcerative colitis; incorporates most recent trial data; represents the current gold-standard systematic evidence base
39586616	2025	RCT	Gut	ACTIVE trial: top-down infliximab plus azathioprine versus azathioprine alone as maintenance therapy in acute severe UC (ASUC) responding to intravenous steroids; directly evaluates AZA-based maintenance strategy in ASUC
27192092	2016	Cochrane Systematic Review	Cochrane Database Syst Rev	Cochrane review demonstrating AZA and 6-MP reduce the likelihood of failure to maintain remission in UC; confirms role particularly in steroid-dependent disease
29293971	2018	Comprehensive Review	J Crohn’s Colitis	State-of-the-art expert review of thiopurines in IBD; covers indications, pharmacology, metabolite-guided dosing (6-TGN/6-MMP monitoring), safety, and practical clinical management
22972046	2012	Cochrane Systematic Review	Cochrane Database Syst Rev	Earlier Cochrane review establishing the AZA/6-MP evidence base for UC maintenance; foundational systematic evidence informing current clinical practice guidelines
19392869	2009	Meta-analysis	Aliment Pharmacol Ther	Meta-analysis specifically addressing efficacy of azathioprine and 6-MP in ulcerative colitis; demonstrated statistically significant benefit, resolving the historic debate about thiopurine effectiveness in UC versus Crohn’s
22072847	2011	Clinical Review	World J Gastroenterol	Practical guide to optimising 6-MP and azathioprine therapy in IBD; covers 6-TGN therapeutic drug monitoring, 6-MMP hepatotoxicity thresholds, dose adjustments, and clinical management of treatment failure
19072367	2008	Mechanistic Review	Expert Rev Gastroenterol Hepatol	Molecular mechanisms of azathioprine in IBD including Rac1/TIAM1 pathway inhibition and apoptotic pathways in T cells; provides biological rationale underpinning AZA’s therapeutic effect in gut inflammation
37586320	2023	Mechanistic/Translational	Cell Reports Medicine	Identifies gut commensal Blautia wexlerae as a contributor to azathioprine therapy failure in IBD via reduced 6-MP bioavailability; clinically relevant for understanding primary non-response in thiopurine-treated patients
16048561	2005	Review	J Gastroenterol Hepatol	Comprehensive review of AZA and 6-MP pharmacogenetics and metabolite monitoring in IBD; covers TPMT polymorphisms, 6-TGN therapeutic ranges, and principles of individualised dosing — foundational reference for precision prescribing

Cytotoxicity

Azathioprine is a thiopurine prodrug requiring cytotoxic handling precautions. Whilst classified primarily as an immunosuppressant in current UK clinical practice, it is a cytotoxic compound and its active metabolite (6-mercaptopurine) is used as antineoplastic therapy.

Item	Content
Cytotoxicity Classification	Cytotoxic Immunosuppressant (Thiopurine class) — prodrug of 6-mercaptopurine; antimetabolite with mutagenic and teratogenic potential
Myelosuppression Risk	High — leucopenia, thrombocytopenia, and macrocytic anaemia are well-recognised dose-dependent toxicities; severity strongly influenced by TPMT and NUDT15 genotype; may be severe and life-threatening in poor metabolisers
Emetogenicity Classification	Low to minimal
Monitoring Items	FBC with differential: weekly for the first 8 weeks, then at least every 3 months; liver function tests; renal function; TPMT genotyping or enzyme phenotyping before initiation
Handling Protection	Must follow cytotoxic drug handling regulations — do not crush or split tablets; avoid skin and mucosal contact; cytotoxic waste disposal procedures apply; female staff of childbearing age should take particular care

Safety Considerations

Please refer to the SmPC and BNF for safety information. Report suspected adverse reactions via the Yellow Card Scheme (yellowcard.mhra.gov.uk).

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: Azathioprine has robust Level 1 evidence for inflammatory bowel disease, supported by multiple completed Phase 3 RCTs and three Cochrane systematic reviews confirming its efficacy as a first-line maintenance immunomodulator in both Crohn’s disease and ulcerative colitis. This TxGNN prediction confirms a strong and well-established therapeutic signal; however, the absence of verified UK-specific regulatory data in this evidence pack means formal licensing status must be confirmed before clinical implementation.

To proceed, the following is needed:

Verification of current UK marketing authorisation status via the MHRA register and review of the current azathioprine SmPC
TPMT genotyping or enzyme activity phenotyping prior to initiation, in line with current UK standard practice, to identify patients at risk of severe myelosuppression
Baseline assessment of contraindications: active infection, severe hepatic or renal impairment, prior hypersensitivity to azathioprine or 6-mercaptopurine, concurrent allopurinol use (significant interaction — 75% dose reduction required if co-prescription is unavoidable)
Structured haematological and hepatic monitoring plan as per SmPC, including FBC frequency during initiation phase
Patient counselling on increased infection risk, elevated long-term lymphoma risk (particularly hepatosplenic T-cell lymphoma in young patients on combination biological therapy), and importance of Yellow Card reporting for any suspected adverse reactions
Review of current BSG/ECCO guidelines on optimal duration of combination therapy with anti-TNF biologicals to minimise lymphoproliferative risk whilst maintaining clinical and endoscopic remission
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.