Sulfasalazine
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
- Sulfasalazine
- Sulfasalazine: From Rheumatoid Arthritis and Inflammatory Bowel Disease to Brachydactyly-Syndactyly Syndrome
Sulfasalazine: From Rheumatoid Arthritis and Inflammatory Bowel Disease to Brachydactyly-Syndactyly Syndrome
One-Sentence Summary
Sulfasalazine was originally used to treat rheumatoid arthritis, ulcerative colitis and other inflammatory bowel and joint conditions. The TxGNN model's top-ranked prediction is brachydactyly-syndactyly syndrome, a rare congenital limb malformation, but there are 0 clinical trials and 0 publications supporting it, so this is a model prediction only. Among the ten predictions, osteoarthritis has the most supporting material (preclinical studies only, no clinical trials), and it is discussed below as the most credible direction.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Rheumatoid arthritis, ulcerative colitis, inflammatory bowel disease, juvenile idiopathic arthritis, spondyloarthropathy (the Singapore licence record contains no approved indication text) |
| Predicted New Indication | Brachydactyly-syndactyly syndrome (top-ranked); osteoarthritis is the most evidence-supported alternative |
| TxGNN Prediction Score | 99.94% (osteoarthritis: 99.64%) |
| Evidence Level | L5 (osteoarthritis: L4) |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 1 |
| Recommended Decision | Hold (osteoarthritis: research question only) |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Based on known information, sulfasalazine is an anti-inflammatory drug whose activity is generally attributed to NF-kB modulation and, in preclinical work, inhibition of the cystine/glutamate antiporter (system xc-). Its efficacy in rheumatoid arthritis and inflammatory bowel disease is established.
Brachydactyly-syndactyly syndrome (top prediction): No mechanistic link is supported. This is a rare congenital limb malformation, and an anti-inflammatory drug has no evident relevance to a developmental skeletal disorder. The high score of 0.999 reflects model inference only. The same applies to most other top-ranked predictions: colobomatous microphthalmia-rhizomelic dysplasia syndrome, congenital hypotrichosis with juvenile macular dystrophy, acromesomelic dysplasia (Hunter-Thompson type), brachyolmia-amelogenesis imperfecta syndrome and myosclerosis. WHIM syndrome is also unsupported, as it is driven by CXCR4 gain-of-function mutations and sulfasalazine has no known CXCR4 activity.
Osteoarthritis (most plausible direction): Preclinical studies suggest a credible link. Sulfasalazine reduced cytokine-induced proteoglycan and collagen release from cartilage (PMID 19690126), attenuated cartilage destruction in an ACL transection/meniscectomy model (PMID 26466556), and altered the chondrocyte protein profile (PMID 24329131). A sulfasalazine-hyaluronic acid formulation also reduced inflammation and cartilage degradation in a rat model (PMID 29548914). All of this evidence is preclinical or indirect.
Spondyloarthropathy susceptibility: Sulfasalazine is already an established therapy for spondyloarthropathy, mainly for peripheral arthritis, so this is not a true repurposing candidate.
Osteoarthritis susceptibility is a genetic-risk label rather than a treatable clinical condition.
Clinical Trial Evidence
Currently no related clinical trials registered for any of the top-ten predicted indications, including brachydactyly-syndactyly syndrome and osteoarthritis.
Literature Evidence
No literature was found for the top-ranked prediction (brachydactyly-syndactyly syndrome). The table below covers the most relevant publications for osteoarthritis (rank 5), the best-supported prediction. Studies are preclinical or reviews, and none is a randomised trial.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 19690126 | 2009 | Preclinical (cartilage explant) | Rheumatology (Oxford) | Sulfasalazine blocked release of proteoglycan and collagen from cytokine-stimulated cartilage and down-regulated metalloproteinases |
| 26466556 | 2016 | Preclinical (animal model) | J Orthop Res | Attenuated cartilage destruction after ACL transection and meniscectomy, via inhibition of the cystine/glutamate antiporter |
| 29548914 | 2018 | Preclinical (in vitro/in vivo) | Int J Biol Macromol | Sulfasalazine-hyaluronic acid system gave sustained release up to 60 days and reduced inflammation and cartilage degradation in a rat OA model |
| 24329131 | 2014 | Preclinical (chondrocyte proteomics) | Mod Rheumatol | Examined effects of sulfasalazine and tofacitinib on the protein profile of articular chondrocytes |
| 1673814 | 1991 | Preclinical (in vitro) | Wien Klin Wochenschr | Sulfasalazine and its metabolites altered prostaglandin and leukotriene release from human synovial tissue (including OA patients) |
| 35958605 | 2022 | Review | Front Immunol | Review of ferroptosis in inflammatory arthritis, including osteoarthritis |
| 9567207 | 1998 | Review | Curr Opin Rheumatol | Update on clinical trials in rheumatic diseases including osteoarthritis |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN06512P | PMS-SULFASALAZINE E.C. TABLET 500 mg | Enteric coated tablet | Indication text not recorded in the licence data |
The only available route is oral. The product is a valid single-ingredient licence.
Safety Considerations
Package insert warnings and contraindications were not available in the data compiled for this report. Please refer to the package insert for safety information.
Contraindication-related conditions (from the knowledge graph, not label text): porphyria (including inherited porphyria and porphyrin metabolism disease), kidney disease, liver disease, gallbladder disease, asthma (including intrinsic and allergic asthma), neutropenia, agranulocytosis, aplastic anaemia (including idiopathic), slow acetylator status, G6PD deficiency, glycogen storage disease, cystinuria, galactosemia, urinary tract obstruction and pyoureter. These should be verified against the official label.
Drug Interactions: 100 interactions were recorded. The first 20 listed include:
- Major: methenamine, human immunoglobulin G (intravenous), prilocaine (topical)
- Moderate: NSAIDs (ketorolac, ibuprofen, celecoxib), azathioprine, aminoglycoside and polypeptide antibiotics (amikacin, bacitracin), amphotericin B (including lipid complex), acyclovir, oestrogens (ethinylestradiol, estradiol), alpelisib, apalutamide, asparaginase (E. coli and Erwinia), aminolevulinic acid (topical)
- Minor: folic acid
Conclusion and Next Steps
Decision: Hold
Rationale: The top-ranked prediction, brachydactyly-syndactyly syndrome, rests on a model score alone, with no trials, no literature and no plausible mechanism (Evidence Level L5). Osteoarthritis is the only prediction with a credible mechanistic rationale, but its evidence is entirely preclinical (L4), so it should be treated as a research question rather than a development candidate.
To proceed, the following is needed:
- Package insert warnings and contraindications from the HSA (currently missing and blocking safety screening)
- Mechanism of action data from DrugBank
- For osteoarthritis: well-designed clinical studies, ideally starting with a small proof-of-concept trial, and consideration of local delivery (such as the sulfasalazine-hyaluronic acid system) given systemic safety concerns
- Confirmation of the approved indications on the Singapore licence, which are blank in the current record
- Review of the knowledge-graph contraindications (notably blood disorders, G6PD deficiency, porphyria and asthma) against the official label
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.