Azathioprine

證據等級: L5

預測適應症: 10 個

AZATHIOPRINE: From Immunosuppressant Therapy to Inflammatory Bowel Disease

One-Sentence Summary

Azathioprine is a thiopurine immunosuppressant; this evidence pack does not record its original approved indication, but pharmacologically it belongs to the purine-analog immunosuppressant class. Among 10 TxGNN-predicted indications, the only one with substantial supporting evidence is Inflammatory Bowel Disease (IBD) — a use already well established in clinical practice — backed by ~47 clinical trials and 20 publications, including multiple Cochrane systematic reviews. The other 9 predictions (mostly rare congenital/genetic syndromes) carry very high TxGNN scores but zero supporting clinical trials or literature, and are flagged by the evidence pack itself as likely model noise.

Quick Overview

Item	Content
Original Indication	Not specified in this evidence pack (drug class: thiopurine/purine-analog immunosuppressant)
Predicted New Indication	Inflammatory Bowel Disease (Crohn's Disease / Ulcerative Colitis)
TxGNN Prediction Score	99.52% (overall model rank 5,720)
Evidence Level	L1
Germany Market Status	✗ Not Marketed
Number of Authorizations	0
Recommended Decision	Hold (pending safety data)

Why is This Prediction Reasonable?

Currently, detailed mechanism-of-action data for azathioprine is not available in this evidence pack (flagged as data gap DG002). Based on the pharmacological information embedded in the evidence records, azathioprine is a purine-analog prodrug that is metabolized to 6-mercaptopurine (6-MP), which inhibits purine synthesis and suppresses the proliferation of activated T- and B-lymphocytes. This antiproliferative, immune-suppressing mechanism is the basis for azathioprine's long-standing, well-established role as a steroid-sparing maintenance therapy in inflammatory bowel disease (both Crohn's disease and ulcerative colitis), where chronic T-cell–mediated mucosal inflammation drives disease activity.

Because IBD pathophysiology is fundamentally an aberrant immune/inflammatory process, azathioprine's mechanism is directly and plausibly applicable — this is reflected in the evidence pack by decades of RCTs, Cochrane systematic reviews, and pharmacogenetic studies (TPMT/NUDT15-guided dosing) specifically evaluating azathioprine in IBD. It should be noted that this is less a "novel repurposing signal" and more a model-validated confirmation of an already-recognized therapeutic use — TxGNN correctly re-derived a known, clinically mainstream indication for this drug.

By contrast, the 8 other top-ranked TxGNN predictions in this pack (e.g., colobomatous microphthalmia-rhizomelic dysplasia syndrome, brachydactyly-syndactyly syndrome, osteoarthritis susceptibility, WHIM syndrome, chronic granulomatous disease variants, acromesomelic dysplasia) are rare congenital/genetic disorders with no mechanistic link, no clinical trials, and no literature support. Several (WHIM syndrome, chronic granulomatous disease) are primary immunodeficiency syndromes where adding an immunosuppressant would plausibly worsen infection risk — the opposite of a therapeutic rationale. These are correctly scored L5/S0/Hold in the pack and should be treated as network-prediction artifacts rather than genuine candidates.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT03101800	Phase 3	Unknown	84	RCT comparing low-dose azathioprine + allopurinol vs. azathioprine monotherapy in ulcerative colitis; tests strategy to reduce treatment failure/adverse events
NCT00094458	Phase 3	Completed	508	Infliximab vs. infliximab+azathioprine vs. azathioprine alone in immunomodulator/biologic-naive Crohn's disease (SONIC-type design)
NCT01015391	N/A (RCT)	Unknown	100	Open-label RCT: T2 vs. azathioprine for maintaining remission after surgical resection in Crohn's disease
NCT03464136	Phase 3b	Completed	386	Ustekinumab vs. adalimumab in biologic-naive Crohn's; azathioprine as prior/background immunomodulator
NCT00577538	N/A	Completed	7	Safety study on lymphoproliferative disease risk associated with azathioprine/6-MP in IBD
NCT02929706	N/A	Unknown	400	NUDT15 R139C genotype-guided thiopurine dose optimization to reduce azathioprine-induced leucopenia in IBD
NCT00113503	Phase 2	Terminated	50	Multi-site trial comparing weight-based vs. metabolite-guided azathioprine dosing in Crohn's disease
NCT05584228	N/A	Not Yet Recruiting	150	SMART trial: azathioprine + subcutaneous infliximab vs. surgical resection in symptomatic small bowel Crohn's disease
NCT07235904	Phase 4	Recruiting	300	MIRACLE trial: top-down mirikizumab vs. standard-of-care azathioprine in newly diagnosed moderate-to-severe ulcerative colitis
NCT00796250	Phase 3	Terminated	9	Infliximab as "bridging therapy" in corticodependent Crohn's disease under standard azathioprine treatment

Literature Evidence

PMID	Year	Type	Journal	Key Findings
29293971	2018	Review	J Crohn's Colitis	State-of-the-art clinical review of thiopurine (azathioprine/mercaptopurine/thioguanine) use in IBD
19072367	2008	Review	Expert Rev Gastroenterol Hepatol	Improved molecular insight into azathioprine's mechanism and clinical implications in IBD
33305616	2021	Review	Pharmacogenomics	Pharmacogenetics of IBD, with focus on thiopurine treatment optimization
30954317	2019	Review	Gastroenterol Hepatol	Evidence review on discontinuing aminosalicylates, thiopurines and methotrexate in IBD
36462311	2023	Cohort/Pharmacogenetics	Biomed Pharmacother	TPMT gene methylation and azathioprine pharmacokinetics in very-early-onset IBD children
16048561	2005	Cohort/Pharmacogenetics	J Gastroenterol Hepatol	Azathioprine/6-MP pharmacogenetics and metabolite monitoring in IBD
37586320	2023	Mechanism study	Cell Reports Medicine	Gut commensal bacteria (Blautia wexlerae) linked to azathioprine therapy failure via reduced 6-MP bioavailability
10499471	1999	Clinical review	Scand J Gastroenterol Suppl	Update on azathioprine clinical efficacy and safety in IBD
40126153	2025	Epidemiology	Scand J Gastroenterol	Temporal trends in IBD characteristics and treatment patterns
27688654	2016	Review	World J Gastroenterol	IBD in India — past, present and future, including thiopurine treatment context

Germany Market Information

No marketing authorizations are on record for this drug in the current dataset. Market status is reported as Not Marketed, with 0 total licenses.

Safety Considerations

Please refer to the package insert for safety information.

Note: This evidence pack flags a Blocking data gap (DG001) — TFDA/BfArM label warnings and contraindications are unavailable. This prevents a formal S1 safety pre-assessment for azathioprine, independent of the efficacy evidence summarized above.

Conclusion and Next Steps

Decision: Hold

Rationale:

The efficacy evidence for azathioprine in IBD is strong (L1: multiple RCTs and Cochrane systematic reviews spanning decades), and the mechanistic rationale is sound — but this reflects an already well-established use rather than a novel repurposing opportunity.
A Blocking-severity data gap (missing label warnings/contraindications) prevents safety pre-assessment (S1), and the drug currently has no market authorization in this jurisdiction (0 licenses, "Not Marketed"), so a "Proceed with Guardrails" call cannot yet be responsibly made.
Eight of the ten TxGNN-predicted indications in this pack (rare congenital/genetic syndromes) have no clinical or literature support and should not be pursued.

To proceed, the following is needed:

Retrieve TFDA/BfArM package insert (warnings, contraindications, DDI) to complete S1 safety pre-assessment
Confirm original/current approved indications and MOA via DrugBank or regulatory source
Clarify regulatory pathway for market authorization given current "Not Marketed" status
If proceeding, implement TPMT/NUDT15 genotype-guided dosing and routine CBC/liver monitoring per the pharmacogenetic literature identified above
Disclaimer

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