Sulfasalazine
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Sulfasalazine: From Rheumatoid Arthritis and Ulcerative Colitis to Osteoarthritis
One-Sentence Summary
Sulfasalazine was originally used to treat rheumatoid arthritis, ulcerative colitis and other inflammatory bowel and joint diseases. The TxGNN model’s top-ranked predictions are mostly rare congenital syndromes with no supporting evidence. The only prediction with a plausible, evidence-backed link is Osteoarthritis, where there are 0 clinical trials and about 20 publications, mostly general rheumatology reviews plus a few preclinical studies on sulfasalazine and cartilage.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Rheumatoid arthritis, ulcerative colitis, inflammatory bowel disease, juvenile idiopathic arthritis, spondyloarthropathy |
| Predicted New Indication | Osteoarthritis (the most credible among the top 10 predictions; the rank 1 prediction is brachydactyly-syndactyly syndrome) |
| TxGNN Prediction Score | 99.64% for osteoarthritis (99.94% for the rank 1 prediction, brachydactyly-syndactyly syndrome) |
| Evidence Level | L4 (preclinical only) for osteoarthritis |
| US Market Status | Cancelled only (no currently valid licenses) |
| Number of NDAs | 6 (all cancelled) |
| Recommended Decision | Hold |
Note: The top-ranked prediction, brachydactyly-syndactyly syndrome, has only model-based support (L5). The osteoarthritis entry is highlighted here because it is the only one with a plausible link and some preclinical data.
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available for this drug in the data compiled for this report. Based on known information, sulfasalazine is an anti-inflammatory agent whose efficacy in rheumatoid arthritis and inflammatory bowel disease is established. It is commonly described as an NF-kB inhibitor and an inhibitor of the cystine/glutamate antiporter (system xc-).
The link to osteoarthritis is indirect but plausible. Osteoarthritis involves inflammatory mediators and cartilage breakdown, and several preclinical studies are consistent with an effect on these processes:
- Sulfasalazine blocked the release of proteoglycan and collagen from cytokine-stimulated cartilage and down-regulated metalloproteinases (PMID 19690126).
- It reduced cartilage destruction in a rat model of ACL transection and meniscectomy, possibly through system xc- inhibition (PMID 26466556).
- A sulfasalazine-containing hyaluronic acid formulation reduced inflammation and cartilage degradation in a rat osteoarthritis model (PMID 29548914).
All of this evidence is from in vitro or animal work. A clinical benefit in human osteoarthritis is unproven, and the intra-articular formulation is investigational.
For the other nine top predictions, no supporting mechanism was found:
- Most are rare congenital developmental or skeletal syndromes, such as brachydactyly-syndactyly syndrome, acromesomelic dysplasia and brachyolmia-amelogenesis imperfecta syndrome, with no evident pharmacological relevance to sulfasalazine.
- WHIM syndrome, a CXCR4 gain-of-function immunodeficiency, has no supported mechanistic connection either.
- “Spondyloarthropathy, susceptibility to” is already an original indication, so it is not a true repurposing candidate.
Clinical Trial Evidence
Currently no related clinical trials registered.
Literature Evidence
The table shows the most relevant publications for osteoarthritis, with sulfasalazine-specific studies first.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 26466556 | 2016 | Animal model | J Orthop Res | Sulfasalazine attenuated cartilage destruction after ACL transection and meniscectomy by inhibiting the cystine/glutamate antiporter |
| 29548914 | 2018 | Animal model / formulation | Int J Biol Macromol | Sulfasalazine-containing hyaluronic acid gave sustained release for up to 60 days and reduced inflammation and cartilage degradation in a rat osteoarthritis model |
| 19690126 | 2009 | In vitro / ex vivo | Rheumatology (Oxford) | Sulfasalazine blocked proteoglycan and collagen release from cytokine-stimulated cartilage and down-regulated metalloproteinases |
| 24329131 | 2014 | In vitro | Mod Rheumatol | Sulfasalazine and tofacitinib altered the protein profile of articular chondrocytes |
| 1673814 | 1991 | In vitro | Wien Klin Wochenschr | Sulfasalazine and its metabolites affected prostaglandin and leukotriene release from human synovial tissue (including osteoarthritis patients) |
| 35958605 | 2022 | Review | Front Immunol | Review of ferroptosis in inflammatory arthritis, including osteoarthritis |
| 24231065 | 2014 | Systematic review | Semin Arthritis Rheum | DMARD- and biologic-associated interstitial lung disease in rheumatoid arthritis (not osteoarthritis-specific) |
| 9567207 | 1998 | Review | Curr Opin Rheumatol | Update on clinical trials in rheumatic diseases (general) |
For the “spondyloarthropathy, susceptibility to” entry, the retrieved literature consists mainly of reviews that describe sulfasalazine as established therapy. One genetic association study (PMID 25413361, 2014, BMC Pharmacol Toxicol) examined NAT polymorphisms in Han Chinese ankylosing spondylitis patients and their link to sulfasalazine adverse reactions.
US Market Information
All six US authorizations are cancelled, so the drug has no currently valid US license in the data compiled for this report. Approved indication text was not available for any of them.
| Authorization Number | Product Name | Dosage Form | Status |
|---|---|---|---|
| NDA007073 | Sulfasalazine (A-S Medication Solutions) | Tablet | Cancelled |
| ANDA075339 | Sulfasalazine (Sunrise Pharmaceutical) | Tablet, delayed release | Cancelled |
| ANDA085828 | Sulfasalazine (Teva Pharmaceuticals USA) | Tablet | Cancelled |
| ANDA040349 | Sulfasalazine (Sunrise Pharmaceutical) | Tablet | Cancelled |
| ANDA219046 | Sulfasalazine (Rising Pharma Holdings) | Tablet | Cancelled |
Safety Considerations
- Disease associations from the knowledge graph (not label text): The knowledge graph links sulfasalazine to contraindication relationships with the following conditions:
- Porphyria (including inherited porphyria and porphyrin metabolism disease)
- Kidney disease, pyoureter and urinary tract obstruction
- Liver disease and gallbladder disease
- Asthma (including intrinsic and allergic asthma)
- Neutropenia, agranulocytosis, and idiopathic aplastic anemia and aplastic anemia
- G6PD deficiency and slow acetylation
- Glycogen storage disease, cystinuria and galactosemia
- Drug Interactions: 100 interactions were recorded. The main ones are:
- Major: prilocaine (topical), human immunoglobulin G (intravenous), methenamine
- Moderate (examples): NSAIDs (ketorolac, ibuprofen, celecoxib), azathioprine, estrogens (ethinylestradiol, estradiol), nephrotoxic agents (amphotericin B, amikacin, bacitracin), acyclovir, alpelisib, apalutamide, asparaginase products
- Minor: folic acid
Please refer to the package insert for formal warnings and contraindications, which were not available in the data compiled for this report.
Conclusion and Next Steps
Decision: Hold
Rationale: The high TxGNN scores are model predictions only. Eight of the ten top predictions have no clinical or literature support, and one is an existing indication. Osteoarthritis has only preclinical support, no registered trials, and an investigational intra-articular formulation. In addition, all US licenses are cancelled, and the package insert safety data and mechanism of action data were not available.
To proceed, the following is needed:
- Package insert warnings and contraindications (blocking for safety screening)
- Detailed mechanism of action data
- Further preclinical validation and, if warranted, early-phase trials of sulfasalazine, for example an intra-articular formulation, in osteoarthritis
- Review of the knowledge-graph disease associations in the context of the target osteoarthritis population (for example, liver, kidney and blood disorders)
- Clarification of the US regulatory and supply situation, since no valid licenses are currently listed
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.