Tofacitinib
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Tofacitinib: From Rheumatoid Arthritis to Plasma Cell Myeloma
One-Sentence Summary
Tofacitinib is an oral JAK inhibitor originally used to treat rheumatoid arthritis. The TxGNN model's top-ranked prediction is colobomatous microphthalmia-rhizomelic dysplasia syndrome, but that prediction has no supporting evidence. The best-supported candidate is plasma cell myeloma (rank 4), with 0 clinical trials and 3 publications, of which only 1 is preclinical efficacy work.
Note on the choice of indication: The top three predictions (rank 1 to 3) have no clinical trials or literature, or only a theoretical link. This report therefore presents the top-ranked indication (rank 1) in the overview for transparency, and focuses its evidence review on plasma cell myeloma, the highest-ranked indication with published evidence.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Rheumatoid arthritis (the Singapore licence record contains no approved indication text) |
| Predicted New Indication | Top-ranked: colobomatous microphthalmia-rhizomelic dysplasia syndrome; best-supported: plasma cell myeloma |
| TxGNN Prediction Score | 98.96% (rank 1 prediction); 96.09% (plasma cell myeloma) |
| Evidence Level | L5 (rank 1 prediction); L4 (plasma cell myeloma) |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 1 |
| Recommended Decision | Hold (rank 1 prediction); plasma cell myeloma is a research question and should be treated as Hold until further evidence is available |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not currently available in the data compiled for this report. Based on known pharmacology, tofacitinib is a JAK inhibitor (mainly JAK1/JAK3) that blocks cytokine signalling through the JAK/STAT pathway. Its efficacy in rheumatoid arthritis comes from dampening inflammatory cytokine signalling.
Plasma cell myeloma: The link is mechanistically plausible. IL-6/JAK/STAT3 signalling supports myeloma cell growth and survival, especially within the bone marrow microenvironment. A 2018 preclinical study (PMID 29622655) reported that tofacitinib reversed the growth-promoting effects of bone marrow stromal cells on myeloma cells. This is laboratory evidence, not proof of clinical benefit.
Indolent plasma cell myeloma (rank 3) is plausible by analogy, but no specific studies were found.
Top-ranked prediction and rare syndromes: For colobomatous microphthalmia-rhizomelic dysplasia syndrome and brachydactyly-syndactyly syndrome (ranks 1 and 2), no mechanistic link is supported by the data. These are congenital developmental disorders, and the high scores are graph-based predictions only. A high TxGNN score does not by itself indicate clinical plausibility.
Myeloid leukaemia (rank 5) has JAK/STAT biology behind it, but the evidence is preclinical, indirect, or anecdotal, and the direction of effect is mixed (see below).
Clinical Trial Evidence
Currently no related clinical trials registered for plasma cell myeloma or for any of the other top 10 predicted indications.
Literature Evidence
Plasma cell myeloma
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 29622655 | 2018 | Preclinical | Haematologica | Repurposing screen identified tofacitinib as able to reverse the tumour-promoting effects of bone marrow stromal cells on myeloma cells; JAK/STAT activation implicated |
| 39819734 | 2025 | Cohort | BMC Rheumatology | Study of DMARD use and myeloma incidence in US veterans with rheumatoid arthritis; a risk-association study, not efficacy evidence |
| 38071595 | 2024 | Cohort/pharmacovigilance | J Eur Acad Dermatol Venereol | FDA adverse event database analysis linking immunosuppression and myeloma to sebaceous carcinoma; a risk signal, not efficacy evidence |
Myeloid leukaemia (rank 5, selected papers)
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 29458040 | 2018 | Preclinical | Eur J Pharmacol | JAK3 inhibition enhanced imatinib antitumour activity in CML cells |
| 26300391 | 2015 | Preclinical | Eur J Pharmacol | JAK inhibitors altered gene expression and cell cycle in AML cell lines |
| 34693224 | 2021 | Preclinical | iScience | JAK inhibitors including tofacitinib reduced SLFN11 expression in leukaemia cells with JAK pathway mutations |
| 31263618 | 2019 | Case report | Case Rep Rheumatol | CML arising in a patient receiving tofacitinib; a safety signal, not evidence of benefit |
| 38992456 | 2024 | Preclinical | Arch Biochem Biophys | Tofacitinib and ponatinib modulate aryl hydrocarbon receptor activity |
Three further papers for this indication are a review of kinase inhibitors in rheumatoid arthritis (PMID 22777068), a co-culture screening methods study (PMID 37352275), and an LC-MS/MS assay method (PMID 31816725). They do not bear directly on efficacy.
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN14664P | XELJANZ TABLET 5MG (Pfizer Manufacturing Deutschland GmbH) | Film-coated tablet (oral) | Not stated in the licence record |
Safety Considerations
- Drug Interactions: The interaction screen returned 100 interacting drugs in total. Those listed include:
- Major: corticosteroids (hydrocortisone, triamcinolone including ophthalmic, dexamethasone, betamethasone, budesonide, prednisone, prednisolone) and clarithromycin.
- Moderate: aprepitant, morphine (including liposomal), opium, acetylsalicylic acid, omeprazole, esomeprazole, lansoprazole and miconazole.
- Minor: zinc sulfate and zinc acetate.
- Malignancy signals in the literature: A case report describes CML arising during tofacitinib therapy (PMID 31263618), and a pharmacovigilance study links immunosuppressive medications with sebaceous carcinoma (PMID 38071595). These are signals and not established causal findings, but they deserve attention in any oncology repurposing.
- Immunosuppression: Because tofacitinib is immunosuppressive, it could worsen existing T-cell deficiency (relevant to the rank 9 prediction, vertebral anomalies and variable endocrine and T-cell dysfunction).
Please refer to the package insert for full warnings and contraindications.
Conclusion and Next Steps
Decision: Hold
Rationale:
- The top-ranked predictions (ranks 1, 2, 6, 7, 8, 10) rest on model scores alone, with no trials, literature, or mechanistic link. Plasma cell myeloma has plausible biology and one preclinical study, but no clinical trials, and the available epidemiological papers raise malignancy-risk questions rather than showing benefit. The evidence is not yet enough to support clinical development.
To proceed, the following is needed:
- The Singapore package insert warnings and contraindications (currently missing and blocking safety screening)
- Detailed mechanism of action data
- Further preclinical validation of tofacitinib in myeloma models, including in vivo work and combination studies
- Assessment of malignancy risk in patients with plasma cell disorders
- Clarification of the approved indication wording on the Singapore licence
- Route compatibility assessment (oral tablet only is currently available)
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.