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Sulfasalazine and its metabolites inhibit platelet function in patients with inflammatory arthritis

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Abstract

The purpose of this study is to assess the effect of sulfasalazine and its metabolites on platelet function in patients with inflammatory arthritis (IA). One hundred thirty-five consecutive patients with an established diagnosis of IA were screened. Those with a history of cardiovascular disease (CVD), taking anti-platelet agents or non-steroidal anti-inflammatory drugs (NSAIDs) were excluded. A total of 32 patients were investigated, 15 taking sulfasalazine and 17 taking other disease-modifying anti-rheumatic drugs (DMARDs) and no sulfasalazine. These two cohorts were compared to 15 patients with stable CVD on long-term aspirin. The effect of sulfasalazine and its metabolites on arachidonic acid (AA)-induced platelet aggregation was also tested in vitro in samples from healthy donors (n = 18). Demographics, CVD risk factors and disease activity indices were similar in the sulfasalazine and other DMARD groups. AA-induced platelet aggregation was significantly inhibited in the sulfasalazine group (9 ± 7 %) and comparable to that in the aspirin group (10 ± 6 %). In contrast, there was no effect on AA-induced platelet aggregation in the other DMARDs group (77 ± 12 %) (p < 0.001). Furthermore, sulfasalazine therapy had no effect on platelet aggregation in response to multiple other agonists. Sulfasalazine and its metabolites (5-aminosalicylic acid and sulfapyridine) exerted an additive and dose-dependent inhibitory effect on AA-induced platelet aggregation in vitro (p < 0.001). The inhibition of AA-induced platelet aggregation by sulfasalazine is comparable to that achieved by aspirin and is dependent on both sulfasalazine and its metabolites. This represents a potential mechanism that may contribute to the known cardioprotective effect of sulfasalazine in patients with IA.

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Acknowledgments

The authors would like to acknowledge Dr. Conor McCarthy and Dr. Suzanne Donnelly of the Mater Hospital’s Rheumatology Department for their assistance in recruiting participants for this study.

Authors’ contributions

Paul MacMullan was involved in all aspects of this research, including study design, data collection, analyses and manuscript preparation. Anne Madigan’s main contribution centred around patient recruitment, disease activity assessment, data collection and write-up. Nevin Paul performed the experiments for the in vitro work and subsequent data collection and analysis. Aaron Peace was involved in study design, adaptation of the appropriate platelet function testing procedures, data analysis and write-up. Ahmed Alagha helped to design the in vitro experiments, prepared the agents to be tested and collected data. Kevin Nolan oversaw the in vitro work and contributed to the write-up. As the senior authors, both Geraldine McCarthy and Dermot Kenny were involved in all aspects of this work, including study design, data analyses and preparation of final submission.

Authors’ information

The first author, Dr. Paul MacMullan, is a graduate of the Irish SpR Program in Rheumatology and has recently taken up an appointment as Clinical Assistant Professor at the University of Calgary in Alberta, Canada. His main areas of research interest include mechanisms of cardiovascular disease and platelet function in the inflammatory arthritis, crystal arthritis and the potential pathogenic role of basic calcium phosphate crystals in osteoarthritis. He has several publications in international peer-reviewed journals and is completing a higher degree in research.

As one of the two senior authors, Professor Geraldine McCarthy is a world-renowned rheumatologist with an international research reputation. She has published widely in many different areas and is a sought-after speaker with a particular expertise in gout.

Prof. Dermot Kenny is a cardiologist and clinician scientist based at the RCSI in Dublin. He is an international expert and authority on platelet function and is a member of the International Society for Thrombosis and Haemostasis (ISTH) committee for recommendations and guidelines surrounding platelet function testing.

Conflict of interest

All authors have completed the Unified Competing Interest form and declare no financial relationships with any organisations that might have an interest in the submitted work and no other relationships or activities that could appear to have influenced the submitted work.

Grant support

This work was not funded by any formal grant, but was partially supported by indirect funding from the Health Research Board (Ireland) and by unrestricted training allowances from Abbott Laboratories (Ireland) Ltd. and Pfizer (Ireland) Ltd.

Author information

Authors and Affiliations

  1. Rheumatology Department, Mater Hospital, Dublin, Ireland

    Anne M. Madigan & Geraldine M. McCarthy

  2. Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St Stephen’s Green, Dublin 2, Ireland

    Nevin Paul, Aaron J. Peace & Dermot Kenny

  3. Department of Biochemistry, RCSI, Dublin, Ireland

    Ahmed Alagha & Kevin B. Nolan

  4. Division of Rheumatology, University of Calgary, Calgary, Canada

    Paul A. MacMullan

Authors
  1. Paul A. MacMullan
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  2. Anne M. Madigan
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  3. Nevin Paul
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  4. Aaron J. Peace
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  5. Ahmed Alagha
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  6. Kevin B. Nolan
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  7. Geraldine M. McCarthy
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  8. Dermot Kenny
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Corresponding author

Correspondence to Paul A. MacMullan.

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MacMullan, P.A., Madigan, A.M., Paul, N. et al. Sulfasalazine and its metabolites inhibit platelet function in patients with inflammatory arthritis. Clin Rheumatol 35, 447–455 (2016). https://doi.org/10.1007/s10067-014-2769-x

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  • DOI: https://doi.org/10.1007/s10067-014-2769-x

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