Salazosulphapyridine-related Stevens-Johnson Syndrome Caused by Sulphapyridine and Confirmed by Enzyme-linked Immunospot Assay

Salazosulphapyridine-related Stevens-Johnson Syndrome Caused by Sulphapyridine and Confirmed by... Salazosulphapyridine[SASP], a drug developed in the 1930s, is commonly prescribed for inflammatory bowel disease [IBD]. SASP consists of sulphapyridine and 5-amino salicylic acid[5-ASA] joined by an azo-bond, which is broken by intestinal bacteria in the colon.1 5-ASA is normally supposed to be the active constituent responsible for the therapeutic efficacy in IBD, but further researches found that SASP was more effective than stand-alone 5-ASAs in the management of IBD, due to the antibacterial properties of its sulphapyridine moiety.2 Minor adverse effects, such as nausea, vomiting, skin rash, and joint pain are commonly recognised in patients treated with SASP. Nevertheless, SASP-induced Stevens-Johnson syndrome[SJS] has been rarely reported. We herein reported a case of SJS due to the administration of SASP and confirmed by interferon-gamma [IFN-γ] enzyme-linked immunospot [ELISPOT] assay. Furthermore, we verified that SASP-related SJS was caused by SASP’s hydrolysate sulphapyridine. A 61-year-old woman was diagnosed with ulcerative colitis and treated with SASP. Twelve days after the administration of SASP, the patient developed a widespread maculo-papular rash and scattered erythema multiforme lesions over the trunk and extremities, accompanied by oral mucosa erosion and dysphagia. SASP-induced SJS was suspected and an IFN-γ ELISPOT assay was performed. IFN-γ ELISPOT assay is a sensitive method for identifying the culprit drug in SJS cases, by recognising drug-specific T cells among thousands of peripheral blood mononuclear cells[PBMCs].3 In this case, significant numbers of IFN-γ spot-forming cells were demonstrated [300 spots/106 PBMCs] upon incubation with sulphapyridine, and a few cells [90 spots/106 PBMCs] were detected with SASP. No IFN-γ–secreting cells were demonstrated in a negative control or upon stimulation with 5-ASA and an irrelevant drug, carbamazepine [Figure 1]. The results suggested that drug-specific T cells were induced by sulphapyridine, not by 5-ASA. The few cells detected in the SASP reaction might be attributed to the sulphapyridine produced by partial hydrolysis of SASP. Figure 1. View largeDownload slide Drug-specifc interferon-γ responses as demonstrated by enzyme-linked immunospot assay. Figure 1. View largeDownload slide Drug-specifc interferon-γ responses as demonstrated by enzyme-linked immunospot assay. SJS is a life-threatening mucocutaneous reaction, predominantly drug induced. It is characterised by blisters, large skin detachment, confluent erythema, atypical target lesions, and sometimes internal organ involvement. Mortality in SJS is over 10%, so the determination of the culprit drug is significant for physicians and patients. To date, more than 100 compounds have been identified as the most likely triggers of individual SJS/ toxic epidermal necrolysis [TEN] cases. The most frequently incriminated drugs are anticonvulsants, allopurinol, antibiotics, and non-steroidal anti-inflammatory drugs.4 SASP-induced SJS/TEN is rarely reported. Here we confirmed that this case was a SASP-related SJS by IFN-γ ELISPOT assay. We also found that the reaction was caused by sulphapyridine. Tremblay5 previously reported two cases of SJS associated with the use of SASP in two ulcerative colitis patients tolerant to mesalamine, which supported our finding. Our findings suggest that SASP-intolerant patients may switch to stand-alone 5-ASAs for the treatment of IBD. Funding This work was supported by the National Natural Science Foundation of China [grant 81472873]. Conflict of Interest The authors declare that they have no conflict of interest. Author Contributions All authors have contributed equally to writing the manuscript. References 1. Das KM, Eastwood MA, Macmanus JP, Sircus W. Salazopyrin metabolism in ulcerative colitis. Gut  1972; 13: 840. Google Scholar PubMed  2. Nikfar S, Rahimi R, Rezaie A, Abdollahi M. A meta-analysis of the efficacy of sulfasalazine in comparison with 5-aminosalicylates in the induction of improvement and maintenance of remission in patients with ulcerative colitis. Dig Dis Sci  2009; 54: 1157– 70. Google Scholar CrossRef Search ADS PubMed  3. Porebski G, Pecaric-Petkovic T, Groux-Keller M, Bosak M, Kawabata TT, Pichler WJ. In vitro drug causality assessment in Stevens-Johnson syndrome - alternatives for lymphocyte transformation test. Clin Exp Allergy  2013; 43: 1027– 37. Google Scholar CrossRef Search ADS PubMed  4. Chung WH, Wang CW, Dao RL. Severe cutaneous adverse drug reactions. J Dermatol  2016; 43: 758– 66. Google Scholar CrossRef Search ADS PubMed  5. Tremblay L, Pineton de Chambrun G, De Vroey Bet al.   Stevens-Johnson syndrome with sulphasalazine treatment: report of two cases. J Crohns Colitis  2011; 5: 457– 60. Google Scholar CrossRef Search ADS PubMed  Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Crohn's and Colitis Oxford University Press

Salazosulphapyridine-related Stevens-Johnson Syndrome Caused by Sulphapyridine and Confirmed by Enzyme-linked Immunospot Assay

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Publisher
Elsevier Science
Copyright
Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
ISSN
1873-9946
eISSN
1876-4479
D.O.I.
10.1093/ecco-jcc/jjx148
Publisher site
See Article on Publisher Site

Abstract

Salazosulphapyridine[SASP], a drug developed in the 1930s, is commonly prescribed for inflammatory bowel disease [IBD]. SASP consists of sulphapyridine and 5-amino salicylic acid[5-ASA] joined by an azo-bond, which is broken by intestinal bacteria in the colon.1 5-ASA is normally supposed to be the active constituent responsible for the therapeutic efficacy in IBD, but further researches found that SASP was more effective than stand-alone 5-ASAs in the management of IBD, due to the antibacterial properties of its sulphapyridine moiety.2 Minor adverse effects, such as nausea, vomiting, skin rash, and joint pain are commonly recognised in patients treated with SASP. Nevertheless, SASP-induced Stevens-Johnson syndrome[SJS] has been rarely reported. We herein reported a case of SJS due to the administration of SASP and confirmed by interferon-gamma [IFN-γ] enzyme-linked immunospot [ELISPOT] assay. Furthermore, we verified that SASP-related SJS was caused by SASP’s hydrolysate sulphapyridine. A 61-year-old woman was diagnosed with ulcerative colitis and treated with SASP. Twelve days after the administration of SASP, the patient developed a widespread maculo-papular rash and scattered erythema multiforme lesions over the trunk and extremities, accompanied by oral mucosa erosion and dysphagia. SASP-induced SJS was suspected and an IFN-γ ELISPOT assay was performed. IFN-γ ELISPOT assay is a sensitive method for identifying the culprit drug in SJS cases, by recognising drug-specific T cells among thousands of peripheral blood mononuclear cells[PBMCs].3 In this case, significant numbers of IFN-γ spot-forming cells were demonstrated [300 spots/106 PBMCs] upon incubation with sulphapyridine, and a few cells [90 spots/106 PBMCs] were detected with SASP. No IFN-γ–secreting cells were demonstrated in a negative control or upon stimulation with 5-ASA and an irrelevant drug, carbamazepine [Figure 1]. The results suggested that drug-specific T cells were induced by sulphapyridine, not by 5-ASA. The few cells detected in the SASP reaction might be attributed to the sulphapyridine produced by partial hydrolysis of SASP. Figure 1. View largeDownload slide Drug-specifc interferon-γ responses as demonstrated by enzyme-linked immunospot assay. Figure 1. View largeDownload slide Drug-specifc interferon-γ responses as demonstrated by enzyme-linked immunospot assay. SJS is a life-threatening mucocutaneous reaction, predominantly drug induced. It is characterised by blisters, large skin detachment, confluent erythema, atypical target lesions, and sometimes internal organ involvement. Mortality in SJS is over 10%, so the determination of the culprit drug is significant for physicians and patients. To date, more than 100 compounds have been identified as the most likely triggers of individual SJS/ toxic epidermal necrolysis [TEN] cases. The most frequently incriminated drugs are anticonvulsants, allopurinol, antibiotics, and non-steroidal anti-inflammatory drugs.4 SASP-induced SJS/TEN is rarely reported. Here we confirmed that this case was a SASP-related SJS by IFN-γ ELISPOT assay. We also found that the reaction was caused by sulphapyridine. Tremblay5 previously reported two cases of SJS associated with the use of SASP in two ulcerative colitis patients tolerant to mesalamine, which supported our finding. Our findings suggest that SASP-intolerant patients may switch to stand-alone 5-ASAs for the treatment of IBD. Funding This work was supported by the National Natural Science Foundation of China [grant 81472873]. Conflict of Interest The authors declare that they have no conflict of interest. Author Contributions All authors have contributed equally to writing the manuscript. References 1. Das KM, Eastwood MA, Macmanus JP, Sircus W. Salazopyrin metabolism in ulcerative colitis. Gut  1972; 13: 840. Google Scholar PubMed  2. Nikfar S, Rahimi R, Rezaie A, Abdollahi M. A meta-analysis of the efficacy of sulfasalazine in comparison with 5-aminosalicylates in the induction of improvement and maintenance of remission in patients with ulcerative colitis. Dig Dis Sci  2009; 54: 1157– 70. Google Scholar CrossRef Search ADS PubMed  3. Porebski G, Pecaric-Petkovic T, Groux-Keller M, Bosak M, Kawabata TT, Pichler WJ. In vitro drug causality assessment in Stevens-Johnson syndrome - alternatives for lymphocyte transformation test. Clin Exp Allergy  2013; 43: 1027– 37. Google Scholar CrossRef Search ADS PubMed  4. Chung WH, Wang CW, Dao RL. Severe cutaneous adverse drug reactions. J Dermatol  2016; 43: 758– 66. Google Scholar CrossRef Search ADS PubMed  5. Tremblay L, Pineton de Chambrun G, De Vroey Bet al.   Stevens-Johnson syndrome with sulphasalazine treatment: report of two cases. J Crohns Colitis  2011; 5: 457– 60. Google Scholar CrossRef Search ADS PubMed  Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com

Journal

Journal of Crohn's and ColitisOxford University Press

Published: Mar 1, 2018

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