Stevens-Johnson syndrome pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anila Hussain, MD [2]
Overview
SJS, like toxic epidermal necrolysis and erythema multiforme, are characterized by confluent epidermal necrosis with minimal associated inflammation. The acuity is apparent from the (normal) basket weave-like pattern of the stratum corneum. The exact pathogenesis of SJS/TEN is not completely understood. However, It is believed that SJS/TEN is immune-mediated and the result of an MHC Class-I restricted T-cell mediated cytotoxic reaction to drug antigens in keratinocytes leading to apoptosis[1]. Drug antigens bind to MHC-I and T cell Receptors (TCR) leading to the clonal proliferation of the drug-specific cytotoxic T cells. On the activation of these T cells, various cytotoxic signals, including Fas/Fas ligand, perforin/granzyme B, and granulysin, are known to be responsible for mediating the damages in skin lesions and the subsequent worsening of the disease.
Pathophysiology
Pathogenesis
- The exact pathogenesis of SJS/TEN is not completely understood
- However, It is believed that SJS/TEN is immune mediated and the result of a MHC Class-I restricted T-cell mediated cytotoxic reaction to drug antigens in keratinocytes leading to apoptosis[1]
- Drug antigens bind to MHC-I and T cell Receptors (TCR) leading to the clonal proliferation of the drug specific cytotoxic T cells
- On the activation of these T cells, various cytotoxic signals, including Fas/Fas ligand , perforin/granzyme B , and granulysin, are known to be responsible for mediating the damages in skin lesions and the subsequent worsening of the disease as explained below.
- T lymphocytes found in bisters were CD8+, HLA-DR+, CLA+ (cutaneous lymphocyte antigen), CD56+ and were shown to be strongly immunoreactive for granzyme B suggesting perforin/granzyme mediated cytotoxicity[2]
- There is also beleived to be some involvement of the soluble FasL (sFasL) in keratinocyte apoptosis in SJS and TEN. sFasL is secreted by peripheral bood mononuclear cells (PBMC's) and interacts with the Fas that is expressed on keratinocyte leading to apoptosis. Higher serum levels of sFasL may be seen in patients with suspicion of SJS/TEN[3]
- Recent studies suggest that the Granulysin, which is a cytotoxic protein released from cytotoxic T cells or natural killer (NK) cells, is a key mediator for disseminated keratinocyte apoptosis in SJS/TEN[4] and is identified by gene expression profiling as the highly cytotoxic molecule and confirmed by PCR and immunohistochemistry. Granulysin concentrations in blister fluid were found to be 2x to 4x more than the Perforin/Granzyme B/sFasL thus making it the most important cytotoxic molecule in SJS/TEN pathogenesis[5]
- Other cytokines that may be associated with trafficking, activation and proliferation of cytotoxic T cells and other immune cells include IFN-Y(gamma), TNF-aplha, IL-2, IL-5, IL-6, IL-10, IL-13. IL-15 was one of the cytokines that was seen in the highest amount and also correlated with disease severity and mortality. Studies also suggest that IL-15 is important in mentaining long-lasting cytotoxic T lymphocyte responses as well as generating and mentaining Nk cells. It is also responsible for enhancing MHC-I antigen presentation thus has an important contribution in SJS/TEN pathogenesis[6]
Genetics
- Some people have genetic predisposition which increases their risk of developing SJS in response to certain trigger medications. The most common genetic variation contributing to the predisposition is seen in the HLA-B gene. Examples include
- People with HLA-B 1502 gene have 10 percent risk of developing SJS on exposure to anti-epileptic drugs like Phenytoin, Carbamazepine, Phenobarbital, Lamotrigine[7]
- People with HLA-B 5801 have high risk of developing SJS on exposure to Allupurinol[8]
- Certain studies have identified HLA-B 3101 as a genetic risk factor for carbamazepine induced skin reactions including SJS[9]
- HLA-B 1511, HLA-B 2402 are also considered to increase SJS risk in certain populations
- Genetic Polymorphism in CYP2C gene variants may lead to an increased risk of SJS/TEN on exposure to certain anti-seizure medications in some populations[10]
Associated Conditions
Some conditions that are associated with an increased risk of SJS/TEN include HIV, immunodeficiency, active cancers (mostly hematological) and some genetic factors.
Gross Pathology
- On gross examination in SJS/TEN, blisters/erosions/bullae and vesicles are seen along with Confluent redness and skin sloughing. Nikolsky Sign may be positive which is the detachment of superficial epidermis on gentle pressure or rubbing of skin
Microscopic Pathology
On microscopic histopathological analysis,full-thickness extensive keratinocyte necrosis that develop into subepidermal bullae is seen in established SJS/TEN[11]. Satellite cell necrosis may also be seen[12]
References
- ↑ 1.0 1.1 Correia O, Delgado L, Ramos JP, Resende C, Torrinha JA (1993). "Cutaneous T-cell recruitment in toxic epidermal necrolysis. Further evidence of CD8+ lymphocyte involvement". Arch Dermatol. 129 (4): 466–8. PMID 8466217.
- ↑ Nassif A, Bensussan A, Boumsell L, Deniaud A, Moslehi H, Wolkenstein P; et al. (2004). "Toxic epidermal necrolysis: effector cells are drug-specific cytotoxic T cells". J Allergy Clin Immunol. 114 (5): 1209–15. doi:10.1016/j.jaci.2004.07.047. PMID 15536433.
- ↑ Abe R, Shimizu T, Shibaki A, Nakamura H, Watanabe H, Shimizu H (2003). "Toxic epidermal necrolysis and Stevens-Johnson syndrome are induced by soluble Fas ligand". Am J Pathol. 162 (5): 1515–20. doi:10.1016/S0002-9440(10)64284-8. PMC 1851208. PMID 12707034.
- ↑ Chung WH, Hung SI (2012). "Recent advances in the genetics and immunology of Stevens-Johnson syndrome and toxic epidermal necrosis". J Dermatol Sci. 66 (3): 190–6. doi:10.1016/j.jdermsci.2012.04.002. PMID 22541332.
- ↑ Chung WH, Hung SI, Yang JY, Su SC, Huang SP, Wei CY; et al. (2008). "Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis". Nat Med. 14 (12): 1343–50. doi:10.1038/nm.1884. PMID 19029983.
- ↑ Su SC, Mockenhaupt M, Wolkenstein P, Dunant A, Le Gouvello S, Chen CB; et al. (2017). "Interleukin-15 Is Associated with Severity and Mortality in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis". J Invest Dermatol. 137 (5): 1065–1073. doi:10.1016/j.jid.2016.11.034. PMID 28011147.
- ↑ Li X, Yu K, Mei S, Huo J, Wang J, Zhu Y; et al. (2015). "HLA-B*1502 increases the risk of phenytoin or lamotrigine induced Stevens-Johnson Syndrome/toxic epidermal necrolysis: evidence from a meta-analysis of nine case-control studies". Drug Res (Stuttg). 65 (2): 107–11. doi:10.1055/s-0034-1375684. PMID 24871931.
- ↑ Somkrua R, Eickman EE, Saokaew S, Lohitnavy M, Chaiyakunapruk N (2011). "Association of HLA-B*5801 allele and allopurinol-induced Stevens Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis". BMC Med Genet. 12: 118. doi:10.1186/1471-2350-12-118. PMC 3189112. PMID 21906289.
- ↑ McCormack M, Alfirevic A, Bourgeois S, Farrell JJ, Kasperavičiūtė D, Carrington M; et al. (2011). "HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans". N Engl J Med. 364 (12): 1134–43. doi:10.1056/NEJMoa1013297. PMC 3113609. PMID 21428769.
- ↑ Manuyakorn W, Siripool K, Kamchaisatian W, Pakakasama S, Visudtibhan A, Vilaiyuk S; et al. (2013). "Phenobarbital-induced severe cutaneous adverse drug reactions are associated with CYP2C19*2 in Thai children". Pediatr Allergy Immunol. 24 (3): 299–303. doi:10.1111/pai.12058. PMID 23551241.
- ↑ Orime M (2017). "Immunohistopathological Findings of Severe Cutaneous Adverse Drug Reactions". J Immunol Res. 2017: 6928363. doi:10.1155/2017/6928363. PMC 5684554. PMID 29226159.
- ↑ Hosaka H, Ohtoshi S, Nakada T, Iijima M (2010). "Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis: frozen-section diagnosis". J Dermatol. 37 (5): 407–12. doi:10.1111/j.1346-8138.2009.00746.x. PMID 20536645.