Bosentan
| Evidence Level: L4 | Predicted Indications: 10 |
Table of Contents
Bosentan: From Pulmonary Arterial Hypertension to Rheumatoid Arthritis
One-Sentence Summary
Bosentan is an endothelin receptor antagonist originally used to treat pulmonary arterial hypertension and systemic sclerosis (scleroderma). The TxGNN model predicts it may be effective for rheumatoid arthritis, but there are currently no registered clinical trials and only animal-model studies supporting this direction (15 publications retrieved, most of which concern connective-tissue-disease-associated PAH rather than rheumatoid arthritis itself). The evidence is limited to model prediction and preclinical work.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Pulmonary arterial hypertension, systemic sclerosis (scleroderma). No approved indication text is recorded in the Singapore licences. |
| Predicted New Indication | Rheumatoid arthritis |
| TxGNN Prediction Score | 99.80% |
| Evidence Level | L4 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 2 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Based on known information, bosentan is a dual endothelin receptor (ETA/ETB) antagonist. Its efficacy in pulmonary arterial hypertension has been established, and mechanistically it may be applicable to inflammatory joint disease.
Endothelin-1 contributes to synovial inflammation, vascular dysfunction and the release of inflammatory mediators such as TNF and LTB4. Two preclinical studies support this link: bosentan ameliorated collagen-induced arthritis in mice (PMID 22249931), and endothelin receptor blockade modulated inflammation in zymosan-induced arthritis (PMID 18515326).
The link to the original indications is indirect. Rheumatoid arthritis and systemic sclerosis are both connective tissue diseases with vascular involvement. However, much of the retrieved literature describes bosentan in connective-tissue-disease-associated PAH, which is the approved use and not evidence of benefit in rheumatoid arthritis. No human trials in rheumatoid arthritis were found.
Clinical Trial Evidence
Currently no related clinical trials registered.
Literature Evidence
Only studies relevant to rheumatoid arthritis are listed; the remaining retrieved items concern CTD-associated PAH or are unrelated.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 22249931 | 2012 | Preclinical (animal model) | Inflamm Res | Bosentan ameliorated collagen-induced arthritis in mice; TNF-α is involved in inducing endothelin system genes |
| 18515326 | 2008 | Preclinical (animal model) | J Leukoc Biol | Endothelins modulate inflammation in zymosan-induced arthritis via LTB4, TNF-α and CXCL-1 |
| 16766656 | 2006 | Preclinical (not bosentan-specific) | Proc Natl Acad Sci U S A | IL-15-induced hypernociception was inhibited by dual ETA/ETB receptor blockade |
| 20054770 | 2009 | Case report | Kardiol Pol | Child with Eisenmenger syndrome on bosentan who was later diagnosed with juvenile rheumatoid arthritis; bosentan was given for the heart condition, not arthritis |
| 24268012 | 2014 | Review | Rheum Dis Clin North Am | Review of PAH related to connective tissue disease; not RA efficacy |
| 16218473 | 2005 | Review | Lupus | PAH in connective tissue diseases, including rheumatoid arthritis to a lesser extent |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN15132P | PROART FILM COATED TABLETS 125MG | Tablet, film coated | Not recorded |
| SIN15133P | PROART FILM COATED TABLETS 62.5MG | Tablet, film coated | Not recorded |
Both products are single-ingredient, valid licences held by Sun Pharmaceutical Industries Limited, for oral use.
Safety Considerations
- Contraindications suggested by the knowledge graph (not label text): liver failure, liver disease, drug-induced liver injury, hyperbilirubinemia (including hereditary forms and Gilbert syndrome), gallbladder disease, thrombocytopenia, anemia (including macrocytic anemia), congestive heart failure, pulmonary edema and pulmonary veno-occlusive disease.
- Drug Interactions: 100 interactions were identified; the 20 reviewed are all Moderate severity. Main ones include:
- Corticosteroids: hydrocortisone, dexamethasone, betamethasone, triamcinolone
- Antidiabetic drugs: pioglitazone, acetohexamide, chlorpropamide, and the SGLT2 inhibitors canagliflozin, dapagliflozin, empagliflozin, ertugliflozin
- Anti-infectives and CYP-related agents: clarithromycin, metronidazole, clotrimazole, cimetidine, aprepitant
- Others: cisapride, dronabinol, eliglustat, eluxadoline
Package insert warnings and contraindications were not available in the data compiled for this report. Please refer to the package insert for full safety information.
Conclusion and Next Steps
Decision: Hold
Rationale: The prediction score is high, but there are no clinical trials and no human data in rheumatoid arthritis. The supporting evidence is limited to mouse models, so the evidence level is L4. The knowledge-graph liver, haematological and cardiac contraindication signals also call for caution.
To proceed, the following is needed:
- Package insert warnings and contraindications from HSA (currently a blocking gap for safety screening)
- Mechanism of action data from DrugBank
- Human studies (at least a well-designed Phase 2 trial) of bosentan in rheumatoid arthritis
- A benefit-risk assessment addressing hepatotoxicity, anaemia and fluid retention in an RA population, who commonly take corticosteroids and other interacting drugs
Other predictions of note:
- Limited systemic sclerosis (score 99.65%, L4) is largely an extension of existing use, since systemic sclerosis is already an original indication. Evidence includes a 2023 systematic review and meta-analysis on digital ulcers (PMID 36974107), a 2025 randomised trial of bosentan versus nifedipine for scleroderma vasculopathy (PMID 36278776), and in vitro work on endothelial-to-mesenchymal transition (PMID 27716320). The underlying pivotal digital-ulcer RCTs are not in the compiled data and should be verified before upgrading the evidence level. This is the most promising direction for follow-up.
- Gout and the other eight predictions (rare developmental and skin syndromes, hypertrichosis, and so on) have no supporting clinical evidence and should be held.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.