Case Report Toxic Epidermal Necrolysis and SJS : Case Reports & Brief Review Deepali P. Mohite*, Satyajitraje Tekade*, Amol Gadbail*, M. S. Chaudhary** Abstract : Toxic epidermal necrolysis (TEN) and Stevens Johnson Syndrome (SJS) are considered part of a spectrum of adverse cutaneous drug reactions showing severe skin detachment. Both are morphologically characterised by active apoptotic keratinocyte cell death that results in the separation of epidermis from the dermis. Almost all cases appear to be caused by an idiosyncratic drug reaction. We report two cases- one TEN and other SJS and the current opinion in the probable pathophysiologic mechanisms and management. Keywords: Toxic epidermal necrolysis, Stevens Johnson Syndrome. Introduction : Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare cutaneous diseases marked by substantial epidermal denudation and are often complicated by sepsis and multiple organ failure(1). Early description of toxic epidermal necrolysis (TEN) dates back to 1956 by Alan Lyell when he described toxic epidermal necrolysis as "an eruption resembling scalding of the skin (2). Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are grave disorders with mortality rates ranging from 20 to 30%. The incidence of SJS is 1 to 6 cases per million person-years, and the incidence of TEN is 0.4 to 1.2 cases per million personyears.the classification of these disorders is based on the degree of involvement of skin and other organs - SJS is an acute mucocutaneous disease defined as a rapidly expanding macular eruption affecting less than 10% of body surface area (BSA) and involving more than one mucosal surface (oral, conjunctival, or anogenital). The overlapping entity of SJS-TEN is described as a disorder with 10 to 30% epidermal involvement. A diagnosis of TEN requires involvement of greater than 30% of BSA. (1, 3) Case Reports : Two cases one with Steven's Johnson syndrome and other Toxic Epidermal Necrolysis are described below: Case 1 A 14-year-old female patient reported with the complaint of lesions all over the body since 6 days. She took antipyretics for fever and chills and was afforded no relief. Then her drug profile was changed to include antipyretics and antihistaminic; following which red lesions appeared all over the body and on the 2nd day the Fig 1 : Picture showing extensive desquamation of skin of face & lips (SJS) Senior Lecturer * Prof and Head** Dept. of Oral Pathology and Microbiology Sharad Pawar Dental College, DMIMS(DU), Sawangi (Meghe), Wardha, Maharashtra, India. Fig 2 : Extensive exfoliation of skin (SJS) 136
fig 3 : Multiple large bullae over the skin (SJS) lesions turned black. There was edema of both hands and feet and itching over the lesions. She did not give history of allergy to any drug. Examination revealed well to ill-defined hyperpigmented plaques, macules, bullae and some vesicles all over the body, face and neck with epidermal detachment and sloughing. The hair was normal, there was discharge from the eyes and crusting was seen over lips and ears along with serous discharge. Intra-oral findings included variably sized erosions and ulcerations over the buccal mucosa, tongue and vermillion border of the lips. The erosions over the buccal mucosa demonstrated varying degrees of erythema from pale pink to fiery red. The mucosa over the hard palate and gingiva showed ulcerations and few Petechial spots. Movement of tongue was restricted and speech was difficult due to extreme pain associated with the lesions. The dorsal surface of the tongue was erythematous. Few hemorrhagic areas were also noticed. Teeth were not affected & nontender; though complain of sensitivity was associated. Further intraoral examination was not possible due to extreme pain associated with mouth opening (Fig : 1-3). Case 2 : A 22-year-old female reported with history of fever, cough and cold, itching, burning sensation in mouth and black lesions over the face since 8 days which spread to other areas 3 days later. She gave history of drug consumption, though she could not specify which drug. She also complains of crusting over lips and discharge from eyes. Examination revealed multiple hyperpigmented macules, papules and vesicles all over the body. There were erosions, crusting and serous discharge from the ears, eyes and lips. Intraoral examination revealed extensive erosions over the buccal mucosa on both right & left sides. These erosions were irregular in outline and at the level of the occlusal plane showed hypertrophic margins. Many large Fig 4 : Erosions, crusting and serous discharge from the ears, eyes and lips (TEN). Fig 5 : Erosions, crusting and serous discharge from the ears, eyes and lips (TEN). Fig 6 : multiple hyperpigmented macules, papules and vesicles (TEN). & small irregular hyperpigmented spots were noted in few areas of the buccal mucosa. The hard palate and gingiva were relatively spared with few hyperpigmented macules over the gingival part of hard palate. Pain was associated with these lesions and increased during mastication and speech. (Fig 4-6) Discussion : Toxic epidermal necrolysis is a potentially lifethreatening skin disorder that most commonly is drug induced. However, other etiologies, including infection, malignancy, and vaccinations may exist. Toxic epidermal necrolysis is idiosyncratic and its occurrence is not predicted easily. Some authors believe Stevens-Johnson syndrome (SJS) is a manifestation of the same process, 137
with the former representing more extensive necrotic epidermal detachment (1,2). The mucocutaneous reaction is characterized by widespread erythema, necrosis and bullous detachment of the epidermis and mucous membranes resulting in exfoliation, sepsis and death. Mucous membrane involvement can result in gastrointestinal hemorrhage, respiratory failure and ocular and genitourinary complications (3). Erythema multiforme major (EMM), once thought to be a mild variant of this disease spectrum, differs from SJS/TEN in its distribution, lesion morphology, and etiology. Acrally distributed, raised target lesions characterize EMM. The skin lesions of SJS and TEN are predominately central, consist of blisters that arise on erythematous or purpuric macules and involve two or more mucosal surfaces. A classification system based largely on the extent of epidermal detachment and morphology of the skin lesions helps in differentiating the disease entities (3). Bullous Erythema Multiforme (EM) - Typical round targets with 3 different zones and well-defined borders, prominent on the extremities characterize bullous EM. Confluence of the lesions and epidermal detachment is limited to less than 10% of the body surface area (3). SJS - Widespread, irregularly shaped erythematous or purpuric macules with blistering that occur on all or part of the macule characterize SJS. Confluence of individual lesions and epidermal detachment is limited, involving less than 10% of the body surface area (3). Overlap SJS-TEN - Widespread, irregularly shaped erythematous or purpuric macules with blistering that occurs on all or part of the macule characterize overlap SJS-TEN. Blisters become confluent and result in detachment of the epidermis and erosions on 10-29% of the body surface area (3). TEN "with spots" - Widespread, irregularly shaped erythematous or purpuric macules with blistering that occurs on all or part of the macule characterize TEN with spots. Blisters become more confluent and result in detachment of the epidermis and erosions on greater than 30% of the body surface area (3). TEN "without spots" - Widespread, large erythematous areas with no discrete lesion characterizes TEN without spots (3). The pathophysiology has not been fully elucidated; however, multiple pathophysiologic mechanisms for the development of TEN have been proposed. Current opinion suggests that epidermolysis is the result of keratinocyte cell apoptosis an organized series of biochemical reactions leading to cell changes and cell death. Cytotoxic T-cell lymphocytes, found in the blister fluid of patients with TEN, is believed to induce a cascade of intracellular enzymes that results in a rapid, triggered cell death(2,3,4). Role of humoral immunity (auto antibodies) which was believed to be the main culprit in the past has completely fallen into disfavour. Several lines of evidence support the Cytotoxic T-cell lymphocytes (CTL) mediated pathogensis of TEN. These include (1) Link to some specific HLA haplotypes to increased susceptibility to TEN, (2) Characteristic lag between the exposure and disease onset (1 to 45 days, mean 14 days), (3) Increased inflammatory CD8+ T cells in the epidermis, and (4) Increased apoptosis of the keratinocytes in TEN patients (5). Although a specific link between the drug metabolite and the immunologic hypothesis is still lacking, drug-reactive T cells have been shown in the skin and blood of patients with various types of adverse cutaneous drug reaction demonstrating that a CTLmediated immune response against drugs occurs. Recent studies indicate that TEN, like some other cutaneous drug eruptions, is an HLA class I-restricted, specific drug sensitivity, resulting in clonal expansion of CD8+ CTLs. Cytotoxicity is mediated by CTL granzyme and possibly death receptor (DR) ligand (DR-L), probably Fas ligand (FasL). Particular to TEN, there is then an amplification sequence involving further DR-L expression. FasL is likely to be particularly important but tumour necrosis factor (TNF) may well contribute, via the TNF receptor 1 (TNF-R1) death pathway. Alternatively, the possibility of upregulation of an antiapoptotic TNF- R1 nuclear factor κb pathway, which would proscribe treatments which downregulate this pathway(6). Tumor necrosis factor - α (TNF-α) and IL-6 have also been involved in the pathogensis of TEN as increased amount of these cytokines are found in the blister fluids in TEN patients. These inflammatory cytokines may play their damaging roles by recruiting the cytotoxic T cells to the epidermis. They may also cause damages directly as cytokines such as TNF - α are known to cause increased apoptosis(7,8). French and co-workers have found that epidermal keratinocytes in TEN patients express large amount of lytically active Fas ligand (CD95L) and interactions between these CD95L and Fas (CD 95) on the effector cells are directly involved in the epidermal necrolysis (7,8,9). The current trend in the management of such cases involves the use of naturally occurring anti-fas 138
immunoglobulins (in the plasma) which is concentrated in human intravenous immunoglobulin (IVIG) to quickly reverse the disease progression in TEN patients (8-13). Many proinflammatory cytokines have been shown to upregulate Fas ligand expression and cause enhanced apoptosis. It is tempting to speculate that increased production of inflammatory cytokines e.g. TNF-α in TEN patients may also indirectly cause necrolysis by upregulating expression of Fas ligand (14,15,16). In that scenario, resolution of TEN may also be achieved by treating patients with specific anti -cytokine antibodies. The difficulty towards understanding the molecular changes in the T cells or keratinocytes in TEN patients is also due to the lack of a suitable system to study human T cells at a clonal level in vitro. Using immortalized human T cell clones with a strain of Herpes virus saimiri (HVS), to understand the specific pathogenesis has been proposed. To summarize the management protocol (Clinical significance):- 1) Basic laboratory tests may be helpful in planning symptomatic or supportive therapy. 2) Diffuse skin involvement may cause significant fluid loss and electrolyte abnormalities. 3) Renal failure can result from hypovolemic shock or sepsis. Surveillance cultures of blood, skin, and urine should be obtained. 4) No specific imaging studies are indicated. 5) Chest radiography should be performed in the setting of respiratory distress because tracheobronchial inflammation may predispose to diffuse interstitial pulmonary disease or pneumonia. 6) TEN is diagnosed by histopathologic analysis. Skin biopsy, harvested at the earliest possible stage, is important in establishing an accurate diagnosis and directing specific therapeutic modalities. Therefore, early involvement of a dermatologist and dermatopathologist is recommended. Currently a multifaceted regimen for management of TEN & SJS appears indicated, targeting various likely intermediary mechanisms, including elimination of residual drug, immunosuppression, inhibition of DR pathways, general antiapoptotic strategies, and aggressive supportive care. Particular attention has been directed at avoiding potential conflicts between different treatments and avoiding agents that theoretically might have a net proapoptotic rather than antiapoptotic effect. The primary objective for a favourable outcome depends on rapid and aggressive supportive care until the skin regenerates itself in this self- limiting acute skin condition. Sterile handling of the patients is a must and cannot be over emphasized to minimize nosocomial infection. References: 1. Heng-Leong Chan, Robert S. Stern, Kenneth A. Arndt et al. The Incidence of Erythema Multiforme, Stevens - Johnson syndrome and Toxic Epidermal Necrolysis. Arch Dermatol, 126:43-47, 1990. 2. A case report and a proposed algorithm for the transfer of patients with Stevens - Johnson syndrome and toxic epidermal necrolysis to a burn center. Military Medicine, 2002. 3. Toxic Epidermal Necrolysis, 2006. 4. Uchenna R Ofoma, Edward K Chapnick. Fluconazole induced toxic epidermal necrolysis: a case report. Cases Journal ; 2: 9071, 2009. 5. Toxic Epidermal Necrolysis, 2007. 6. Amal Nassif, Homayoun Moslehi, Sabine Le Gouvello et al. Evaluation of the Potential Role of Cytokines in Toxic Epidermal Necrolysis. Journal of Investigative Dermatology; 123: 850 855, 2004. 7. Chave T.A, Mortimer N.J, Sladden M.J et al. Toxic epidermal necrolysis: current evidence, practical management and future directions. British Journal of Dermatology. ; Vol 153 Issue 2: 241 253, 2005. 8. Isabelle Viard, Philippe Wehrli, Roberto Bullani et al. Inhibition of Toxic Epidermal Necrolysis by Blockade of CD95 with Human Intravenous Immunoglobulin. Science : Vol. 282; No. 5388: 490 493, 1998. 9. Sidney Hurwitz. Erythema Multiforme: A Review of Its Characteristics, Diagnostic Criteria, and Management. Pediatr. Rev. ; 11: 217-222, 1990. 10. Sylvie Bastuji-Garin, Berthold Rzany, Robert S. Stern et al. Clinical Classification of Cases of Toxic Epidermal Necrolysis, Stevens - Johnson syndrome, and Erythema Multiforme. Arch Dermatol.; 129(1):92-96, 1993. 11. Benoît Côté, Janine Wechsler, Sylvie Bastuji-Garin, et al. Clinicopathologic Correlation in Erythema Multiforme and Stevens - Johnson syndrome. Arch Dermatol. ; 131(11):1268-1272, 1995. 12. Karan K. Sra, Michelle Babb-Tarbox, Sina Aboutalebi et al. Molecular Diagnosis of Cutaneous Diseases. Arch Dermatol.; 141:225-241, 2005. 13.. Soluble Interleukin 2 Receptor and Interleukin 1 in Toxic Epidermal Necrolysis: A Comparative Analysis of Serum and Blister Fluid Samples. Arch Dermatol. 2002; 138:29-32. 14. Ueta M., Sotozono C., Inatomi T., Hamuro J. et al. Gene Expression Analysis of Monocytes Derived From the Patients of Stevens-johnson Syndrome With Ocular Complications. Invest Ophthalmol Vis Sci. ; 48: 386, 2007. 139
Toxic Epidermal Necrolysis & SJS 15. Aurelian, L, Ono, F, and J Burnett. Herpes simplex virus (HSV)-associated erythema multiforme (HAEM): A viral disease with an autoimmune component. Dermatology Online Journal 9 (1): 1, 2003. 16. Junko Murata1 and Riichiro Abe. Soluble Fas Ligand: Is It a Critical Mediator of Toxic Epidermal Necrolysis and Stevens Johnson Syndrome? Journal of Investigative Dermatology. ; 127: 744 745, 2007. Financial Support : Declared None Conflict of Interest : Declared None Month of Receipt : January 2012 Month of Acceptance : June 2012 E-mail of Author : deepalipmohite@rediffmail.com Manuscript no. : 2012 / D - 2 140