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E-IJD® - BASIC RESEARCH
Year : 2022  |  Volume : 67  |  Issue : 4  |  Page : 479
Clinical, biochemical, genetic, and therapeutic profile of patients with epidermal necrolysis: A descriptive study


1 From the Department of Anatomy, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
2 Department of Dermat ology and Venereology, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
3 Cornea, Cataract and Refractive Surgery Services, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
4 Royal Victorian Eye and Ear Hospital, Melbourne, University of Melbourne, Vision Eye Institute, Melbourne, Australia

Date of Web Publication2-Nov-2022

Correspondence Address:
Arundhati Sharma
Laboratory of Cyto-Molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijd.ijd_1089_20

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   Abstract 


Background: Epidermal necrolysis (SJS/TEN) is a rare but acute severe drug reaction associated with high morbidity and mortality rates. Aims: To describe the clinical, molecular, biochemical, and therapeutic profile of these patients. Methods: A total of 24 acute SJS/TEN patients were recruited during their hospital stay and detailed clinical history and treatment course recorded. Blood samples collected were subjected to DNA and serum separation for molecular and biochemical analysis. Results: Of 24 patients, 18 (75%) were females and six (25%) were males with six SJS, six SJS–TEN overlap, and 12 TEN cases. The inciting drugs were non-steroidal anti-inflammatory (87.50%; n = 21) followed by antibiotics (66.67%; n = 16), antiepileptics (37.50%; n = 9), and others (37.50%; n = 9). Seventeen patients (77.2%) showed skin eruptions within 7 days after drug intake. Different co-morbidities were observed in 22 (91.6%) and 20 (83.3%) patients showed ocular manifestations. Length of hospital stay ranged from 8 to 55 days, 20 (83.3%) patients were treated with corticosteroids, and four (16.6%) received antimicrobial therapy. Interleukin polymorphisms revealed significantly low frequency of IL-4 in the patients, HLA-A locus typing revealed higher frequency of HLA-A*3301 (20.8%), HLA-A*02 (25%), HLA-A*2402 (14.6%), and sera showed raised levels of granulysin and sFas L in the patients compared to controls. Conclusions: The preliminary study illustrates the clinical, molecular, and biochemical features of acute SJS/TEN and provides a better understanding that helps to improve patient care at an earlier stage. It also highlights the use of corticosteroids and antimicrobial therapy for effective treatment of patients.


Keywords: Corticosteroids, epidermal necrolysis, granulysin, HLA, interleukins, polymorphisms


How to cite this article:
Sangwan SK, Khanna N, Sharma N, Agarwal T, Sharma A, Vajpayee RB. Clinical, biochemical, genetic, and therapeutic profile of patients with epidermal necrolysis: A descriptive study. Indian J Dermatol 2022;67:479

How to cite this URL:
Sangwan SK, Khanna N, Sharma N, Agarwal T, Sharma A, Vajpayee RB. Clinical, biochemical, genetic, and therapeutic profile of patients with epidermal necrolysis: A descriptive study. Indian J Dermatol [serial online] 2022 [cited 2022 Dec 10];67:479. Available from: https://www.e-ijd.org/text.asp?2022/67/4/479/360297





   Introduction Top


Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) described together as epidermal necrolysis (EN)[1] are rare adverse skin reactions associated with substantial morbidity and mortality (10-34%).[2] It is classified into SJS (<10%), SJS/TEN overlap (10–30%), and TEN (>30%) on the basis of epidermal sloughing[3] and mainly caused by medicines and rarely by infections.[4]

The prognosis parameters are assessed and scored within the first 3 days of hospitalization [Table 1]a through specific scoring system called as SCORe of Toxic Epidermal Necrolysis (SCORTEN).[5] Higher score signifies poor prognosis and higher risk of death and is also associated with major metabolic abnormalities, sepsis, multiorgan failure, etc.[6]
Table 1:

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Although the pathogenesis of SJS/TEN is unknown, there is T-cell activation that leads to keratinocyte apoptosis mediated by biochemical markers. Previous studies also associated its susceptibility to interleukin (IL) and human leukocyte antigen (HLA) genes but such associations vary with different drugs and population under study and thereby suggest specific risks among different populations and ethnicities.

The early diagnosis, prompt withdrawal of suspected drug and supportive and specific therapy can reduce the mortality.[7],[8] So, in spite of controversies over usage and dosage of steroids, risk of infection, and other long-term side effects, studies highlighted the effective and beneficial role of steroids in treatment of SJS/TEN.[9],[10]

The aim of this study was to describe the clinical, molecular, biochemical, and therapeutic profile in acute SJS/TEN patients.


   Materials and Methods Top


The study complied with the Declaration of Helsinki and was approved by the Ethics Committee of the institute. The patients hospitalised between July 2011 and December 2013 in the Department of Dermatology and Venerology, and having a history of acute onset of high fever, serious muco-cutaneous illness with skin eruptions and epidermal necrosis were recruited. Prospective review and analysis of SJS/TEN patients was performed to include basic characteristics, such as gender, age, patient and family history, diagnosis, time from drug intake to onset of disease, suspected drugs/infection before disease onset, any pre-existing conditions and co- morbidities, complications, degree of skin and mucosal involvement, treatment, and outcome. The patients were classified into three groups, namely, SJS, SJS/TEN overlap, and TEN on the basis of percentage of body surface area involved. SCORTEN values were calculated to predict mortality rates [Table 1]b in patients based on a numerical score of prognostic factors. The course of treatment during hospital stay was immediate cessation of suspected drugs, provision of active support, cleaning of eroded surfaces, and systemic therapy with corticosteroids and antimicrobial drugs.

Peripheral blood samples were collected for DNA and serum from the enrolled patients. Blister fluid was collected from the patients wherever possible. DNA samples were used for PCR amplification of interleukins polymorphisms and HLA screening and serum was used for quantitative estimation of apoptotic markers granulysin and sFas L. Control data for HLA-A alleles were obtained from IMGT/HLA database.

Genomic DNA was isolated using standard protocol and subjected to PCR amplification of interleukins (IL-4, IL-13 promoter region and IL-4R, and IL-13 coding regions) using 100–120 ng DNA, 1.5 mM MgCl2, 0.2 mM of each of the dNTPs (Invitrogen, USA), 0.5 μM of each primer, and 0.5 units of Taq polymerase (Invitrogen, USA) in 25 μl volume mixture using thermocycler ABI 9700 (Applied Biosystems, USA). The products were sequenced directly with BigDye Terminator Mix Version 3.1 (Applied Biosystems, Foster City, CA, USA) according to the manufacturer's instructions and were then analyzed on an ABI-3100 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA). Nucleotide sequences were compared with the published cDNA sequences of IL-4 gene (GeneBank accession number ENSG00000113520), IL-4R (GeneBank accession number ENSG00000077238), and IL-13 gene (GeneBank accession number ENSG00000169194).

HLA typing of 'A' locus alleles was done using LABType SSO A Locus typing kits (One Lambda Inc, CA, USA). The analysis and interpretation of data was done by One Lambda HLA Fusion Software v 3.5 following the manufacturer's instructions.

The levels of biochemical markers Granulysin and sFas L were quantified using sandwich ELISA kits (USCN Life Science Inc., Hubei, PRC) as per manufacturer's protocol.

Statistical analyses were carried out with Stata IC/11.2 software. Qualitative data are presented as frequency (percentages) and compared between groups using Chi-square. Quantitative data are presented either as mean ± standard deviation (SD) or median (IQR) depending on the distribution pattern and compared using non-parametric Mann-Whitney test. The level of significance was set at 5%.


   Results Top


The study included 24 SJS/TEN patients who were hospitalised and treated between July 2011 and December 2013. Of these, 18 (75%) were females and 6 (25%) were males with a median age of 25.5 (15, 45.5) years: median (IQR) at onset of symptoms. The youngest patient was a 6-year-old child and the oldest was an 85-year-old male. Among the enrolled patients, six (25%) were diagnosed with SJS, six (25%) with SJS–TEN overlap, and 12 (50%) with TEN. Two patients died, one with TEN died of cardiac arrest and another with SJS–TEN overlap died of septic shock.

The drugs associated with causation of this condition were documented to be nonsteroidal anti-inflammatory drugs (NSAIDs), including antipyretics (87.50%; n = 21), antibiotics (66.67%; n = 16), anti-epileptics (37.50%; n = 9), and others (37.50%; n = 9). In majority of cases, the main suspect drug was paracetamol (n = 12) followed by cephalosporin (n = 7), phenytoin (n = 6), and allopurinol (n = 3). In the cases with suspicion of multiple drugs usage, negative provocation tests for drugs were conducted and a safe drug list was provided on discharge.

Clinical profile

The duration of medication intake prior to skin eruption ranged from 1 to 15 days and this duration was divided into two categories, viz., 1) ≤7 days and 2) >7 days. It was noted that 17 (77.2%) patients showed skin eruptions within the first 7 days after intake of the inciting drug.

Different types of co-morbidities were observed in 22 SJS/TEN patients that included anemia, hypertension, diabetes, deep vein thrombosis, kidney, hepatic and electrolyte dysfunction, sepsis, atrial flutter, seizure disorder, cancer, pneumonia, meningitis, systemic lupus erythematosus, etc. Anemia, hypertension, diabetes, seizures, sepsis, and kidney dysfunction were the most common complications.

Ocular manifestations of mild to severe form were observed in 20 (83.3%) patients. The complications of conjunctival congestion, discharge, photophobia, erythema, dryness, epithelial defect, corneal, and eyelid edema were common in acute cases of SJS/TEN. To prevent the chronic ocular sequelae, amniotic membrane graft was performed in 12.5% (n = 3) patients. The treatment regimen consisted of antibiotic and steroid eye drops and lubricants.

The SCORTEN scoring system [Table 2] was used to grade the severity of the disease. The majority of the patients had a score of 2 (38%) followed by score 0 or 1 (23.8%), score 4 (19%), and score 3 (14.2%). Only one 65-year-old female TEN patient had a score of 5, but responded well to the treatment therapy. Three patients were excluded because of inadequate information.
Table 2: Clinical features, molecular, biochemical findings, culprit drugs, and treatment modalities in acute SJS/TEN patients

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Molecular profile

Molecular screening of interleukins (IL-4 and IL-13 promoter regions and IL-4R and IL-13 coding regions) was done. IL-4 screening revealed reported C/T change (rs2243250) in 12.5%; 40.4%, IL-4R screening A/G polymorphism (rs1801275) in 45.8%; 48.1%, IL-13 coding region revealed G/A polymorphism (rs20541) in 33.4%; 31.3% and IL-13 promoter region showed reported changes in 37.5%; 29% in patients and controls, respectively.

HLA-A locus typing in SJS/TEN cases revealed HLA-A*3301 (20.8%; 0.5%), HLA-A*02 (25%; 5.8%), and HLA-A*2402 (14.6%; 1.7%) alleles in patients and controls, respectively.

Biochemical profile

Granulysin levels represented as median (IQR) differed significantly between patients (5.48; 3.8, 7.6) and controls (1.75; 0.23, 2.68). Similarly, sFas L levels also showed significant difference between patients (26.93; 12.19, 57.96) and controls (7.71; 6.19, 10.76).

Blister fluid samples that were available in three cases (1 female and 2 males) also showed raised levels of granulysin and sFas L.

Therapeutic profile

Of the 24 patients, 20 (83.3%) were treated with corticosteroids with intravenous dexamethasone being the most common steroid. It was given in tapering doses for a short period in patients with an early active disease. One patient was also given dexamethasone pulse therapy on the advice of the ophthalmologist. Remaining four patients (16.6%) were given antimicrobial therapy that mainly included antibiotics. None of the patients received intravenous immunoglobulin except for one who had received it in a private hospital. The length of hospital stay of patients ranged from 8 to 55 days.

Two patients succumbed to death. The mortality was because of septicemia followed by septic shock in a 6-year-old child (Scorten score: 2) and cardiac arrest in an 85-year-old male (Scorten score: 4).


   Discussion Top


EN (SJS, SJS/TEN overlap, and TEN) is rare but severe blistering disorder characterised by widespread epidermal necrosis of the skin and mucosa. Early stage recognition is important, as it is associated with substantial morbidity and mortality.[11] This study observed preponderance of females that is similar to another Indian study where more women were affected (61–64%) for unspecified reasons and other studies.[7],[12],[13] The age range of patients was similar to that reported in earlier studies.[14]

It is interesting to note that SJS/TEN often triggered by specific medications[15] and the most common precipitating drugs were NSAIDs including antipyretics. The non-steroidal antipyretic analgesics were mostly purchased by the patients over the counter without consulting a doctor for symptoms of fever and headache. Paracetamol (NSAIDs) and phenytoin (anticonvulsant) were the most common drugs found in this study that is supported by findings of previous studies on Indian and other populations.[14],[16],[17],[18],[19],[20],[21],[22] Higher reporting of paracetamol may be because of its common prescription and availability as an over-the-counter drug.[14] In contrast, a recent study reported antibiotics to be the most implicated in the onset of acute SJS/TEN.[19],[23]

In spite of drug-induced causation, multiple studies demonstrated the role of several genetic markers, especially cytokines (IL-13 and IL-4) in SJS/TEN.[24] This study screened polymorphisms of IL-13, IL-4, and IL-4R in patients and controls and found significant difference between the two groups for IL-4 promoter region (C/T) change, which needs validation on larger sample size.

Various studies suggested the role of HLA in inducing severe adverse drug reactions. Furthermore, the allelic variants of HLA genes can influence an individual's response to medication.[25] In this study, higher frequencies of alleles HLA-A*3301 (20.8%), HLA-A*02 (25%), and HLA-A*2402 (14.6%) in patients were noted in comparison to controls.

This study found HLA-A*3301 allele in a higher percentage in SJS/TEN individuals that is in concordance with previous studies, suggesting it to be a risk allele because of positive association with SJS/TEN with severe ocular complications (SOCs).[26] Ramanujam et al.[27] noted HLA-A*3301 allele to be higher among maculopapular exanthema (MPE) cases compared to levetiracetam-tolerant controls, although the association was not significant. In this study, the frequency of HLA-A*02 alleles is high in patients in comparison to controls. HLA-A*0206, very common among the Japanese, rare in Caucasians, and less frequent in Southern Han Chinese,[28] was seen in 4.2% of the patients in this study. Lucena et al.[29] report on 201 patients identified two novel HLA alleles, HLA-A*0201 and HLA-B*1801, as risk factors for drug amoxicillin-clavulanate-induced liver injury. Shi and coworkers[30] suggested HLA-A*2402 to be a potential shared risk factor for carbamazepine (CBZ)-, lamotrigine (LTG)-, and phenytoin (PHT)-induced SJS/TEN and recommended its pretreatment screening. The same group also identified HLA-A*2402 as another genetic factor that might contribute to CBZ-induced SJS/TEN in addition to HLA-B*1502.[30] A study of 21 Korean patients showed significant association of HLA-A*2402 with LTG-induced maculopapular exanthema. These studies together suggested that HLA-A*2402 is an independent risk factor for severe SJS/TEN as well as for milder MPE. Furthermore, allele HLA-A*2402 is prevalent in most of the populations (http://www.allelefrequencies.net). This study also showed presence of allele HLA-A*2402 in 14.6% of SJS/TEN cases that is quite high compared to controls.

Granulysin a key mediator of keratinocyte apoptosis in SJS/TEN is most highly expressed cytotoxic molecule in early stages, being two to four orders of magnitude higher in concentrations than that of perforin/granzyme B or sFas L.[31] This study also found higher concentration of granulysin in both blister fluid and sera samples of patients compared to controls. During acute phase of the disease, the blister fluid cells express high levels of granulysin mRNA leading to higher concentration of the protein thereby resulting in higher cytotoxicity. A study on mice showed that its removal reduced the cytotoxicity of blister fluid and when injected into mouse skin resulted in changes that mimicked SJS/TEN.[31]

Viard et al.[32] for the first time showed increased soluble (sFas L) concentrations in the sera of patients with TEN in contrast to normal levels found in other drug-induced eruptions. Other studies also demonstrated elevated levels of soluble Fas ligand (sFas L) on drug stimulation by peripheral blood mononuclear cells (PBMCs) obtained from SJS/TEN patients. This study also reported significantly elevated levels of sFas L in SJS/TEN patients in comparison to controls. Chang and colleagues[33] measured serum sFas L levels over a period of time and found raised levels within 24–48 hours after the onset of significant skin damage in a patient with acute TEN.

Despite the controversy on usage of systemic corticosteroids in the management of patients, number of studies concluded that early treatment with steroids reduces morbidity, improves survival,[9],[12] and results in 99% recovery of patients. On similar lines, 83.3% patients of this study were treated with intravenous dexamethasone (corticosteroids) and showed good outcome except for an 85-year-old patient who died of cardiac arrest. The findings of this study with regard to corticosteroid treatment are similar to that of previous studies[34] that suggested the beneficial use of corticosteroids in patients with SJS/TEN. In contrast, a recent study also documented high risk of bacterial infections/sepsis associated with corticosteroids in comparison to supportive care treatment.[18]

In context of high dose associated with higher risk of infections, Liu et al.[10] emphasised on the determination of appropriate dosage of corticosteroids. On similar grounds, this study emphasises use of antimicrobial therapy to be considered concurrently with corticosteroids for treatment of SJS/TEN patients. This study also recorded a lower mortality rate in comparison to previous reports.[35] This could be attributed to early diagnosis, immediate elimination of suspected drug, supportive care, and specific immunosuppressive treatment.

To summarise, the study documented preponderance of females among affected patients, common triggering drugs to be NSAIDs (including antipyretics), involvement of polymorphisms of IL-13 and IL-4, higher frequencies of specific HLA-A alleles (HLA-A*3301, HLA-A*02, and HLA-A*2402), and raised levels of apoptotic markers (granulysin and sFas L). The study also highlighted that corticosteroids and antimicrobial therapy are effective treatment modalities for patients with systemic manifestations. A larger study with more number of patients should be able to elaborate extensively on different aspects of SJS/TEN.

To conclude, this preliminary descriptive study on SJS/TEN patients provides a better understanding of the clinical characteristics and associated risk factors, despite the limitation of a small sample size. As patients have reported usage of multiple drugs before onset, it is difficult to conclude whether a single drug or class of drugs are responsible for disease manifestation. Molecular and biochemical markers after validation on a larger sample size may help to improve patient care at an earlier stage. In addition, with early diagnosis and selective treatment, the morbidity and mortality of this debilitating disease could be minimised.

Financial support and sponsorship

Funded by extramural grant from the Indian Council of Medical Research (ICMR), New Delhi, India, Project Code No. I-723. Sushil K. Sangwan was supported by the Council of Scientific and Industrial Research (CSIR), New Delhi, India.

Conflicts of interest

There are no conflicts of interest.



 
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Patel TK, Barvaliya MJ, Sharma D, Tripathi C. A systematic review of the drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Indian population. Indian J Dermatol Venereol Leprol 2013;79:389-98.  Back to cited text no. 14
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