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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 6  |  Issue : 2  |  Page : 140-143

Pharmacovigilance of Severe Cutaneous Adverse Drug Reactions


Department of Dermatology, B. J. Medical College and Civil Hospital, Ahmedabad, Gujarat, India

Date of Submission01-May-2021
Date of Decision02-Oct-2021
Date of Acceptance31-Dec-2021
Date of Web Publication26-Aug-2022

Correspondence Address:
Amita Sutaria
A 304, Sahjanand Residency, Near Helmet Circle, Memnagar, Ahmedabad - 52, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cdr.cdr_34_21

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  Abstract 


Background: Severe cutaneous adverse drug reactions (SCARs) are idiosyncratic reactions comprising 2% of all drug-induced skin reactions. These include Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis. These dermatologic emergencies lead to increased morbidity, mortality, and economic burden and may be a cause of litigation. Objectives: The aim was to study the clinicoepidemiological profile of SCARs and establish causal association. Materials and Methods: Patients presenting with SCARs over a period of 2 years were included in this observational, cohort, hospital-based study conducted in a tertiary care center in western India. The patterns of drug reactions were analyzed, and the drug causality was established. Results: A total of 62 patients were included in this study. SJS was the most common pattern of drug reaction observed. Aromatic anticonvulsants (phenytoin and carbamazepine), antimicrobials (co-trimoxazole and amoxicillin), and nonsteroidal anti-inflammatory drugs were the most common drugs implicated. Drug reactions in people living with HIV/AIDS on antiretroviral therapy were noteworthy. Conclusion: SCARs represent the most challenging dermatoses in terms of survival, sequelae, and quality of life. Prompt withdrawal of the offending drug and strict pharmacovigilance can improve the prognosis of SCARs. There is a need for exploration of newer genetic associations which may be the only tool to predict these severe reactions.

Keywords: Adverse drug reactions, pharmacovigilance, Stevens–Johnson syndrome, toxic epidermal necrolysis


How to cite this article:
Saini K, Sutaria A, Shah B. Pharmacovigilance of Severe Cutaneous Adverse Drug Reactions. Clin Dermatol Rev 2022;6:140-3

How to cite this URL:
Saini K, Sutaria A, Shah B. Pharmacovigilance of Severe Cutaneous Adverse Drug Reactions. Clin Dermatol Rev [serial online] 2022 [cited 2022 Sep 26];6:140-3. Available from: https://www.cdriadvlkn.org/text.asp?2022/6/2/140/354752




  Introduction Top


Severe cutaneous adverse drug reactions (SCARs) comprise around 2% of all drug-induced skin reactions.[1] The spectrum of illness includes acute generalized exanthematous pustulosis (AGEP), drug-induced exfoliative dermatitis, drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens–Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Apart from the skin rash, systemic involvements such as liver, and less commonly renal, lung, intestinal, cardiac, thyroid, and pancreatic, as seen in DRESS are associated with long-term morbidity. SJS-TEN are associated with a high degree of morbidity and mortality, with mortality due to TEN approaching 30%.[2] SCARs represent a potentially life-threatening form of delayed T-cell-mediated reaction pattern. Pharmacovigilance of SCARs is important as they represent one of the most challenging and difficult-to-treat dermatoses.[3]


  Materials and Methods Top


An observational, cohort, hospital-based study was conducted in the department of dermatology of a tertiary care center in western India over a period of 2 years from September 2016 to August 2018. Ethical clearance was obtained from the institutional ethics committee (IEC/Certi/92/17). Patients presenting with SCARs-SJS, TEN, DRESS, drug-induced exfoliative dermatitis, or AGEP following intake of allopathic medicines were included in the study. Patients who developed cutaneous adverse drug reaction (CADR) following intake of alternative medicine such as homeopathic, ayurvedic, indigenous, or unknown medicines were excluded from the study. Written informed consent was taken in all cases. A preset pro forma was used to collect demographic and clinical details, comorbidities (if any), and detailed drug history including generic or brand names of each medicine consumed, the duration and indication for which they were taken, and alternative forms of medicine (if any) used. Details regarding past or family history of any drug allergies were also recorded. All patients were hospitalized for intensive care and management, including care of skin and mucosa, optimal fluid, and electrolyte management. General and systemic examination, along with complete mucocutaneous examination, noting any special morphology was done in all patients. Routine blood investigations such as complete blood counts, liver and renal function test, blood glucose estimation, and screening for viral markers along with routine urine examination were obtained for all patients. CD4+ count, chest radiography, and ultrasonography of the abdomen were done in relevant cases. SCORTEN was calculated in all patients of SJS-TEN at the time of admission and after 72 h.[4] RegiSCAR criteria were used for diagnosis of DRESS.[5] Rechallenge was avoided due to ethical reasons. Final decision of causality was made according to the Naranjo Adverse Drug Reaction Probability Scale.[6] The decision of administering systemic corticosteroids and their dose and duration was individualized for each patient after careful clinical assessment. Patients were given a list of all the offending, probable, and cross-reacting drugs to be avoided in future.


  Results Top


A total of 62 patients were included in the study. The average age was 35 years (range: 2–72 years) with a male preponderance in all types of drug reactions (M:F – 1.17:1). The most common drug reaction pattern observed was SJS-TEN (n = 42). Aromatic anticonvulsants were the most common cause of SCARSs, seen in 50% of the patients (n = 21). None of the patients had any documented evidence of history of drug reaction in the past or in a close family member. Various SCARs observed in the study are summarized in [Table 1].
Table 1: Various severe cutaneous adverse drug reactions observed in the study

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The most common causative drugs for SJS-TEN were phenytoin (n = 15), followed by antiretrovirals (n = 10) and carbamazepine (n = 5) [Figure 1]. Causality assessment by Naranjo's algorithm was “probable” in all cases. The average duration of the hospital stay was 12 days. All the causative and suspected drugs were immediately stopped, and a short course of steroids was given in all patients leading to drastic improvement. However, seven patients of TEN succumbed to the disease, septicemia being the most common cause of death.
Figure 1: Stevens–Johnson syndrome-toxic epidermal necrolysis induced by phenytoin

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Ten patients of DRESS were reported during the study period [Figure 2]. The youngest patient was aged 16 years and the oldest 65 years. The mean interval between the drug intake and the development of rash was 35.1 days (range: 6–87 days). All the patients had systemic involvement in the form of deranged liver function tests, and two patients in addition had deranged renal function tests. Phenytoin was the causative agent in five patients, followed by carbamazepine and oxcarbazepine in four patients. Six patients developed AGEP, of which two were on terbinafine, two on amoxicillin, and one patient on levofloxacin and chloroquine each [Figure 3]. Four patients developed generalized exfoliative dermatitis after drug administration. Isoniazid was the offending drug in two patients, while phenytoin and diclofenac were the causative drugs in one patient each. The causative drugs for various SCARs are summarized in [Table 2].{Table 1}
Figure 2: Drug reaction with eosinophilia and systemic symptoms induced by phenytoin

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Figure 3: Acute generalized exanthematous pustulosis induced by terbinafine

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Twelve people living with HIV/AIDS (PLHIV) were included in the study, all of them presenting in SJS-TEN. On analysis of their antiretroviral medications (ARTs), eight patients were on zidovudine, lamivudine, and nevirapine (AZT + 3TC + NVP) regimen and four patients were on tenofovir, lamivudine, and efavirenz (TDF + 3TC + EFV) regimen. Four patients were on co-trimoxazole prophylaxis along with ART and two patients were on category 1 antitubercular treatment concurrently with ART.


  Discussion Top


SCARs are T-cell immune responses to antigenic drug–host tissue complex. They are a significant cause of morbidity and mortality in the dermatology practice. Three pathomechanisms of the formation of antigenic complex have been described, namely covalent binding of the drug to a cellular peptide (hapten/pro-hapten concept); noncovalent, direct interaction of the drug with a specific major histocompatibility complex (MHC) I allotype (p-i concept); and presentation of an altered self repertoire by direct drug–MHC I interaction (altered peptide concept).[7] Phenytoin was the most common anti-epileptic drug incriminated in our study, similar to a study by Sharma et al.[1] SJS-TEN was the most common reaction pattern observed followed by DRESS, and aromatic anticonvulsants were the most common causes, similar to other studies.[1],[8] Anti-epileptic drugs such as phenytoin, carbamazepine, and lamotrigine elicit severe drug reactions by p-i mechanism of T-cell stimulation. It involves noncovalent and labile interaction between the drug, human leukocyte antigen (HLA) complex, and T-cell receptor.[8] For sulfonamide group of drugs, the nitroso metabolites cause direct cytotoxicity or bind to T-cells, leading to an immune response resulting in severe reactions such as SJS/TEN.[9] Some drugs are more likely to induce certain reaction patterns – aromatic anticonvulsants, antitubercular drugs, penicillins, cephalosporins, sulfa drugs, allopurinol, and NSAIDs are more likely to produce SJS-TEN spectrum of illness, while aromatic anticonvulsants, lamotrigine, minocycline, and dapsone are common causes of DRESS.[10] Exfoliative dermatitis is known to be induced by antibiotics, NSAIDs, dapsone, anticonvulsants, etc., AGEP is mediated by drug-specific CD4+ and CD8+ T-cells with high levels of CXCL-8, interleukin (IL)-17, and IL-36 production.[7] Macrolide antibiotics, hydroxychloroquine, and diltiazem are well known to induce AGEP.[11] Terbinafine, an important drug in the era of fungal recrudescence, has been reported as an important cause of AGEP.[1],[12] Two patients developed AGEP after starting terbinafine in this study.

Association of drug-induced adverse reactions with particular HLA alleles is increasingly being studied. Associations of carbamazepine-induced SJS-TEN with HLA-B 15:02, allopurinol-induced SCARs with HLA-B 58:01, and abacavir-induced hypersensitivity with HLA-B 57:01 are well recognized.[10] Recently, many other HLA associations in SCARs have been reported. SCARs due to phenytoin have been reported with CYP2C9*3 and HLA-B 51:01, oxicam induced SCARs in HLA-B*73:01, HLA-Cw8 reported in nevirapine hypersensitivity, HLA-B 13:01 associated with dapsone hypersensitivity etc.[10],[13],[14] Genetic predisposition also appears to play a role in AGEP as HLA-B51, DR11, and DQ3 were found to be more frequently associated in these patients than the general population.[7]

Factors such as polypharmacy, higher stage of HIV, low CD4 counts, pharmaco-genomic variations, nutritional deficiencies, increasing age and comorbidities may contribute to the increased incidence of SCARs in PLHIV than the general population. Although TDF + 3TC + EFV is now the first-line antiretroviral drug, nevirapine still remains an important cause of SJS-TEN patients on AZT + 3TC + NVP regimen.[14],[15],[16]


  Conclusion Top


SCARs are idiosyncratic reactions which affect a minority of patients and many a times have a genetic predisposition. Aromatic anticonvulsants continue to remain the most important cause of these reactions. SCARs are an important cause of mortality in PLHIV. Genomic HLA marker studies are available but only at select large centers, stressing the need for further exploration of genetic associations which may be the only tool to predict these severe drug reactions. Early diagnosis, prompt withdrawal of the causative drugs, and proper inpatient management can decrease the morbidity and mortality of patients presenting with SCARs.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Sharma R, Dogra N, Dogra D. A clinical study of severe cutaneous adverse drug reactions and role of corticosteroids in their management. Indian J Drugs Dermatol 2017;3:20-3.  Back to cited text no. 1
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2.
Dodiuk-Gad RP, Chung WH, Valeyrie-Allanore L, Shear NH. Stevens-Johnson syndrome and toxic epidermal necrolysis: An update. Am J Clin Dermatol 2015;16:475-93.  Back to cited text no. 2
    
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Mustafa SS, Ostrov D, Yerly D. Severe cutaneous adverse drug reactions: Presentation, risk factors, and management. Curr Allergy Asthma Rep 2018;18:26.  Back to cited text no. 3
    
4.
Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein P. SCORTEN: A severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol 2000;115:149-53.  Back to cited text no. 4
    
5.
Kardaun SH, Sidoroff A, Valeyrie-Allanore L, Halevy S, Davidovici BB, Mockenhaupte M, et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: Does a DRESS syndrome really exist? Br J Dermatol 2007;156:609-11.  Back to cited text no. 5
    
6.
Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.  Back to cited text no. 6
    
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Hoetzenecker W, Nägeli M, Mehra ET, Jensen AN, Saulite I, Schmid-Grendelmeier P, et al. Adverse cutaneous drug eruptions: Current understanding. Semin Immunopathol 2016;38:75-86.  Back to cited text no. 7
    
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Mullan KA, Anderson A, Illing PT, Kwan P, Purcell AW, Mifsud NA. HLA-associated antiepileptic drug-induced cutaneous adverse reactions. HLA 2019;93:417-35.  Back to cited text no. 8
    
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Khan DA, Knowles SR, Shear NH. Sulfonamide hypersensitivity: Fact and fiction. J Allergy Clin Immunol Pract 2019;7:2116-23.  Back to cited text no. 9
    
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Nguyen DV, Vidal C, Chu HC, van Nunen S. Human leukocyte antigen-associated severe cutaneous adverse drug reactions: From bedside to bench and beyond. Asia Pac Allergy 2019;9:e20.  Back to cited text no. 10
    
11.
Sasidharanpillai S, Riyaz N, Khader A, Rajan U, Binitha MP, Sureshan DN. Severe cutaneous adverse drug reactions: A clinicoepidemiological study. Indian J Dermatol 2015;60:102.  Back to cited text no. 11
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12.
Rubegni P, Mandato F, Sbano P, Fimiani M. Terbinafine-induced acute generalized exanthematous pustulosis. G Ital Dermatol Venereol 2008;143:151-5.  Back to cited text no. 12
    
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John S, Balakrishnan K, Sukasem C, Anand TC, Canyuk B, Pattharachayakul S. Association of HLA-B*51:01, HLA-B*55:01, CYP2C9*3, and phenytoin-induced cutaneous adverse drug reactions in the South Indian Tamil population. J Pers Med 2021;11:737.  Back to cited text no. 13
    
14.
Li Y, Deshpande P, Hertzman RJ, Palubinsky AM, Gibson A, Phillips EJ. Genomic risk factors driving immune-mediated delayed drug hypersensitivity reactions. Front Genet 2021;12:641905.  Back to cited text no. 14
    
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Kouotou EA, Nansseu JR, Ngono VN, Tatah SA, Zoung-Kanyi Bissek AC, Ndjitoyap Ndam EC. Prevalence and clinical profile of drug eruptions among antiretroviral therapy-exposed HIV infected people in Yaoundé, Cameroon. Dermatol Res Pract 2017;2017:6216193.  Back to cited text no. 15
    
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Todd G. Adverse cutaneous drug eruptions and HIV: A clinician's global perspective. Dermatol Clin 2006;24:459-72, vi.  Back to cited text no. 16
    


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