Insights into Severe Cutaneous Adverse Drug Reactions: A 5-Year Retrospective Analysis of Stevens- Johnson Syndrome- Toxic Epidermal Necrolysis and Drug Rash with Eosinophilia and Systemic Symptoms

Abstract

Background:

With limited data on the clinic-demographic profile of severe cutaneous adverse drug reactions (SCARs), this study aimed to analyze the clinical parameters, laboratory findings, mortality, and outcomes of SCARs in the Indian population.

Patients and Methods:

A retrospective review was conducted for patients diagnosed with SCARs—Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS)—from January 2019 to June 2024. Clinical and investigational data of outpatient and hospitalized cases were obtained from medical records.

Results:

Forty-nine cases of SJS-TEN and 115 cases of DRESS were analyzed. The mean age was 38.1 ± 18.3 years (range 8–73) for SJS-TEN and 44.1 ± 17.0 years (range 7–82) for DRESS. Antiepileptics were the most commonly implicated drugs in both groups (SJS-TEN: 51%; DRESS: 33%). Mortality was seen in 1/115 in DRESS (hepatic involvement) and 10/49 (20.4%) in SJS-TEN, with refractory septic shock being the most common cause in SJS-TEN. Key predictors of mortality in SJS-TEN included higher body surface area involvement, SCORe of toxic epidermal necrosis (SCORTEN) ≥2, systemic involvement, nasal mucosal involvement, and delayed presentation.

Limitations:

This retrospective study had limitations, including polypharmacy in some patients, which limited the accuracy of causality assessment. Rechallenge was not performed due to ethical reasons, which may have affected drug identification.

Conclusion:

SCARs contribute significantly to morbidity and mortality. Early diagnosis, prompt withdrawal of the culprit drug, and interdisciplinary management are essential. Patients should be educated about early warning signs, particularly when prescribed antiepileptics and nonsteroidal anti-inflammatory drugs.

Introduction

An adverse drug reaction (ADR) is ‘a response to a drug that is noxious and unintended and occurs at doses used in humans for prophylaxis, diagnosis or therapy of a disease or for modification of physiological function’.[1] The incidence of cutaneous ADRs (cADRs) in developing countries like India varies from 2% to 5%.[2,3,4,5]

Drug-related skin eruptions can be broadly categorized into benign cADRs and severe cutaneous adverse reactions (SCARs). SCARs include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). These reactions often present as dermatological emergencies and can have life-threatening consequences. According to data from Western literature, SJS alone has mortality rate of around 10%, while mortality in TEN is much higher at 30%.[6]

Indian population data show antimicrobials, antiepileptics, and nonsteroidal anti-inflammatory drugs (NSAIDs) as the most common causative agents for cADRs.[7] There is still a lack of comprehensive studies on SCARs from India, evaluating clinicodemographic parameters with the investigative workup, as well as mortality and recovery rates. We attempted to fill these lacunae in current Indian literature as well as globally.

Patients and Methods

This was a retrospective record review of all patients enrolled in the drug reaction clinic or inpatient dermatology care between January 2019 and June 2024 at the Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India, catering to a large population of five surrounding states. The clinical and investigational details of the outpatient department and inpatient cases were recorded from their clinic files. The European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) criteria was used to diagnose DRESS.[8] SJS-TEN cases were diagnosed based on thorough clinical history and examination. Involvement of at least two mucosal surfaces with dusky red erythematous macules, atypical target lesions, and bullae and erosions with epidermal detachment were classified as SJS, SJS-TEN overlap, and TEN based on the classification by Bastuji-Garin et al.[9] Epidermal detachment of less than 10% of total body surface area (TBSA) was regarded as SJS, 10–30% as SJS-TEN overlap, and more than 30% as TEN. The disease severity in cases of SJS-TEN was assessed based on SCORe of toxic epidermal necrosis (SCORTEN). DRESS patients were categorized as definite (score > 5), probable (score 4–5), and possible (score 2–3) DRESS based on the RegiSCAR score.[8,10] The algorithm of drug causality for epidermal necrolysis (ALDEN) score was used to assess drug causality.[11]

Patients were treated as per the standard management protocol of our clinic. All SJS/TEN patients, after initial evaluation of factors such as the day of presentation, renal involvement, and sepsis, were offered oral cyclosporine, intravenous immunoglobulin (IVIG), or a combination therapy, along with supportive care (antibiotics, intravenous fluids, and paraffin gauze dressings). DRESS patients received antihistamines, systemic corticosteroids, or cyclosporine based on initial evaluation and comorbidities. Quality of life (QoL) was assessed using the Dermatology Life Quality Index (DLQI) score at baseline and at a 6-week follow-up (telephonically) in a subset. Data were entered into a structured proforma, capturing demographics, diagnosis, implicated drug, reaction latency, clinical/systemic features, investigations, severity scoring, treatment, and QoL outcome. Analysis was done using Microsoft Excel and IBM SPSS Statistics 22.0 (SPSS, Chicago, IL, USA). As this was a retrospective study, ethical approval was not required as per institutional policy.

Results

As per hospital records, 49 cases of SJS-TEN and 115 cases of DRESS were registered in the clinic during the study period.

SJS-TEN

Among SJS-TEN patients, females were predominantly affected (male/female ratio 1:1.33). The mean age was 38.1 ± 18.3 years (range 8–73) [Table 1]. The median time from initiation of drug to presentation was 7 days (range 2–60). Of the 49 patients, 7 had prior hospitalization and were referrals; all had TBSA >10%. SJS was seen in 11 (22.4%), SJS-TEN in 12 (24.4%), and TEN in 26 (53.1%) cases. Mucosal involvement included oral (46; 93.9%), ocular (36; 73.4%), genital (14; 28.5%), and nasal (11; 22.4%) mucosae. Mean SCORTEN at presentation was 1.71 ± 1.47 (range 0–6). Antiepileptics were the most commonly implicated drugs per ALDEN score (25; 51%), followed by NSAIDs (5; 10.2%). Phenytoin and carbamazepine were the most frequent antiepileptics, while nimesulide, aceclofenac, and etoricoxib were the common NSAIDs.

Table 1.

Clinicodemographic and laboratory features of SJS-TEN (n=49) and DRESS patients (n=160)

Parameter	Values
SJS-TEN
Male: Female ratio	0.75:1
Mean age	38.1.1±18.3 years
Median latency period	7 days (range 2-60 days)
SJS [<10% TBSA]	11 (22.4%)
SJS-TEN [10-30% TBSA]	12 (24.4%)
TEN [>30% TBSA]	26 (53.1%)
AST > 100 IU/L	9/49 (18.4%)
ALT>100 IU/L	9/49 (18.4%)
Serum creatinine >1.5 (from baseline)	8/49 (16%)
DRESS
Male: Female ratio	1:1.3
Mean age	44.1±17 years
Mean latency period	24.32±15.61 days
Outpatient department cases	70 (62.6%)
Emergency presentations	14 (12.2%)
Referral cases from other departments	29 (25.2%)
AST >100 IU/L	28/115 (24.3%)
ALT >100 IU/L	26/115 (22.6%)
Serum creatinine >1.5 (from baseline)	16/115 (14%)

ALT: Alanine transaminase; AST: Aspartate transaminase; DRESS: Drug reaction with eosinophilia and systemic symptoms; SJS: Stevens-Johnson syndrome; TBSA: Total body surface area; TEN: Toxic epidermal necrolysis

Systemic involvement was seen in 29 (59.1%) cases, with prerenal acute kidney injury (AKI) and transaminitis in 17 (34.6%) each. Transaminitis was mild, with only 9 (18.4%) cases showing levels more than twice the upper limit of normal. Abnormal creatinine level (greater than 1.5 times baseline) was seen in 8 patients (16%). These cases were excluded from a diagnosis of DRESS due to the absence of eosinophilia, facial edema, and a RegiSCAR score <2. Other systems involved included the respiratory system (3; 6.1%), genitourinary system (2; 4%), and lymphadenopathy (4; 8.1%).

Cyclosporine was the most commonly used drug for treatment (37; 75.5%), administered at 3–5 mg/kg for 7–10 days. IVIG was used in 4 (8.1%) cases at 400 mg/kg/day for 5 days. Mortality occurred in 10 (20.4%) cases, with refractory septic shock as the leading cause (6/10, 60%). Five deceased patients were referred with an extended illness duration. Most infections were hospital-acquired, with methicillin-resistant Staphylococcus aureus (MRSA), Klebsiella, Pseudomonas, and Acetinobacter being the most commonly isolated pathogens. Among deaths, six cases received cyclosporine, one received cyclosporine plus IVIG, and one received only IVIG. Mortality was significantly associated with IVIG-cyclosporine combination (P = 0.04), though only one patient received it.

Significant predictors for mortality included TBSA >70% (Odd’s Ratio, OR 6.78, P = 0.009), SCORTEN ≥2 (OR 8.4, P = 0.004), systemic involvement (OR 12, P < 0.001), nasal mucosa involvement (OR 6.4, P = 0.01), and delayed presentation >5 days (OR 6.18, P = 0.013). Drug class was not significantly associated with mortality, though antiepileptics accounted for six deaths. Bivariate regression showed no significant association between mortality and age (P = 0.8) or prior hospitalization (P = 0.11).

DRESS

Analysis of 115 DRESS patients showed female predominance with a male: female ratio of 1:1.3. The mean age was 44.10 ± 17.0 years (range 7–82) [Table 1]. The mean latency from drug intake to rash onset was 24.32 ± 15.61 days. Seventy (62.6%) cases were from the outpatient department, 14 (12.2%) presented to the emergency, and 29 (25.2%) were referrals. Based on RegiSCAR criteria, 53 (46%) were probable DRESS, 50 (43.5%) were possible DRESS, and 12 were (10.4%) definite DRESS.

Pruritus was the predominant symptom in 102 (88.7%) patients, followed by facial swelling in 80 (69.6%), oral mucosal involvement in 56 (48.7%), fever in 85 (74%), and lymphadenopathy in 43 (37.4%) cases. All had maculopapular rash; erythroderma was seen in 22 (19%), erythema multiforme (EM)-like lesions in 25 (21.7%), purpuric macules in 18 (15.7%), vesicular lesions in 8 (7%), eczematous rash in 6 (5.2%), pustules in 3 (2.6%), and urticaria in 2 (1.7%) cases.

Antiepileptics were the most common drugs implicated (38; 33%), followed by anti-tubercular therapy (ATT, 19; 16.5%), allopurinol (9; 7.8%), unknown/herbal medications (8; 6.9%), vancomycin (6; 5.2%), and beta-lactams (5; 4.3%) [Figure 1]. Others included NSAIDs, sulfa drugs, allylamines, fluoroquinolones, azoles, and tyrosine kinase inhibitors. Mean TBSA involvement was 73.4 ± 21%.

Figure 1.

Composite bar chart showing drug groups and individual drug contributions in SJS-TEN and DRESS. The chart illustrates the distribution of drugs implicated in SJS-TEN (left bars) and DRESS (right bars) across major therapeutic categories. For SJS-TEN, individual antiepileptics [phenytoin, most common agent (n = 14) (peach), followed by carbamazepine (n = 4) (grey), lamotrigine (n = 2) (light red), and phenobarbitone (n = 1) (red)] and NSAIDs (nimesulide, aceclofenac, etoricoxib) are distinctly represented. In DRESS, antiepileptics and anti-tubercular therapy are the most common. The visual highlights the predominant role of antiepileptics in both conditions. *ATT: Anti-tubercular therapy; DRESS: Drug reaction with eosinophilia and systemic symptoms; NSAIDs: Nonsteroidal anti-inflammatory drugs; SJS: Stevens Johnson syndrome; TEN: Toxic epidermal necrolysis

Chest radiography showed bronchovascular markings in 16 (14%), consolidation in 8 (7%), and pleural effusion or calcific foci in 1 (0.9%) case each. In TB patients, radiographic findings were interpreted in conjunction with eosinophilia and a drug history to establish the lung involvement due to DRESS. Internal organ involvement included the liver in 32 (27.8%) and the kidney in 6 (5.2%) cases. Logistic regression analysis showed a higher odds ratio of liver involvement with EM-like lesions (OR 6.2 [1.6–23]).

Systemic corticosteroids (1 mg/kg/day) were used in 85 (74%) patients, cyclosporine in 6 (5.2%), and antihistamines alone in 24 (20.9%). Herbal/unknown drug history was noted in 8 cases, mostly belonging to the possible RegiSCAR group without organ involvement. All patients received supportive care, drug withdrawal, and a drug alert card.

Mortality was noted in one patient due to hepatic involvement. Two patients relapsed due to rapid steroid tapering and drug reintake. Supportive care included room temperature control, fluid–electrolyte management, and nutrition. At 3 weeks, most patients had improved pruritus and partial rash resolution, with complete clearance at 6 weeks. Post-DRESS sequelae included persistent scaling in two patients and alopecia areata in one patient.

DLQI was assessed at baseline. Among 60 patients (45 DRESS, 15 SJS-TEN) available for 6-week telephonic follow-up, the mean DLQI improved from 18.2 ± 3.1 to 4.6 ± 2.4. In DRESS patients, 37/45 (82.2%) resumed daily activities; 10/15 (66.7%) SJS-TEN survivors did so. Symptomatic relief was reported for pruritus in 55 (91.7%), sleep in 47 (78.3%), and emotional distress in 37 (61.7%), reflecting overall improvement with timely treatment.

Discussion

As noted in a few previous studies,[12,13,14,15,16,17] a female preponderance was observed by us in both SJS-TEN (57.1%) and DRESS (56.5%), which has been hypothesized to be due to polypharmacy and a higher elderly female population. Maximum patients belonged to the 30–50 years age group; a slightly higher age group preponderance (41–50 years) was observed among the DRESS cohort. Most available literature studies suggest an increased incidence of cADRs with age.[8,18]

Among SJS-TEN cases, more than half were TEN, which may reflect selection bias at our tertiary care center. Most DRESS patients were managed on an outpatient basis (70/115), with only 14/115 presenting to the emergency department. In contrast, all 49 SJS-TEN patients required inpatient care. All SJS-TEN cases had mucosal involvement, most commonly oral (90%), followed by ocular (73.4%). Nasal mucosal involvement was significantly associated with mortality, likely due to severe mucosal damage and extensive epithelial destruction. Such involvement often leads to complications like respiratory distress and secondary infections, underscoring its importance in prognosis, risk stratification, and the need for intensive care. However, we found no existing studies identifying nasal mucosal involvement as an independent predictor of mortality. In DRESS, it was noted that 48.7% of cases had erosions and cheilitis, findings similar to the existing literature.[8] Other pertinent findings included palatal erosions, geographic tongue, and conjunctival hyperemia in a few DRESS patients.

The most common presenting feature of the DRESS cohort was pruritic rash, followed by fever and facial swelling. Facial edema, along with fever and rash, thus constitutes a warning signal and shifts the diagnosis toward DRESS, as other cADRs rarely cause facial swelling.[19,20] Among cutaneous features, maculopapular rash was seen in all DRESS patients, followed by EM-like lesions and erythroderma. Other morphologies noted were purpuric lesions, urticaria, pustules, and eczematous lesions, similar to observations by Ang et al.[21]

The most frequent findings detected in laboratory investigations of SJS-TEN patients were elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) values. ESR and CRP are acute-phase reactants that are often found elevated in patients with SCARs and can be used to monitor the acute phase of the disease.[22] AKI and liver involvement, in the form of transaminitis, were the most common systemic complications in SJS-TEN. However, only 18.4% of patients demonstrated significantly raised aspartate transaminase (AST) and alanine transaminase (ALT) levels (>twice the upper limit of normal). Serum urea levels more than 60 mg/dL have been associated with a poor prognosis, and this parameter has been included in the SCORTEN scale for the prognostication of SJS-TEN. Eleven cases had urea levels more than 60 mg/dL, and mortality was observed in approximately half of these cases. These findings mirror a study by Thakur et al.[23] where elevated blood urea nitrogen levels had a significant association with mortality in SJS-TEN cases. In addition, we also noted involvement of the respiratory and genitourinary systems along with generalized lymphadenopathy in a few cases, which highlights the potential for systemic involvement and severe complications in SJS-TEN, requiring multidisciplinary management.

Among the DRESS cohort, liver was the most common organ involved, followed by the kidney and pulmonary system, findings similar to existing literature.[8] Transaminitis and hepatomegaly constituted the most common features. The presence of EM-like lesions was associated with greater odds of liver involvement in DRESS patients. Thus, EM-like lesions may serve as an important prognostic marker for timely identification of patients at risk. These findings are consistent with the postulations made in previous studies.

The drug causality for DRESS was determined by drug charting and assessment of temporality. Among patients with DRESS, antiepileptics constituted 33% (n = 38), followed by fixed-dose ATT drugs (n = 19, 16.5%) and allopurinol (n = 9, 7.8%). Among ATT-associated DRESS syndrome cases that have been reported from Asia, ethambutol has been commonly implicated.[24,25,26,27] However, we could not determine the individual agent responsible, as ours was a retrospective study and drug rechallenge was not conducted. There was a history of intake of herbal medicine/unidentifiable drug in 8 cases.

ALDEN score was used to determine the most probable cause of SJS-TEN. Aromatic antiepileptics are the most implicated drug group leading to SCARs in India.[7,28] Our study showed similar findings, with 51% (n = 25) of SJS-TEN cases being caused by antiepileptics. Contrary to most Asian studies, which report carbamazepine as the most common antiepileptic involved in SJS-TEN,[29,30,31] we found phenytoin to be the most common agent (n = 14), followed by carbamazepine (n = 4), lamotrigine (n = 2), and phenobarbitone (n = 1). Despite the S3 guidelines for diagnosis and management of SJS-TEN, the treatment remains a challenge, especially in resource-poor settings like ours. Systemic steroids, IVIG, cyclosporine, and plasmapheresis have been tried in various studies.[32,33,34] Cyclosporine has been shown to produce near-complete re-epithelialization in patients with SJS-TEN by 12 days.[35] A meta-analysis by Singh et al. showed that cyclosporine usage in patients with SJS-TEN reduced the mortality rates.[36] Chen et al.[37] also showed that the mean hospital stay was reduced when a 10-day course of cyclosporine was used. Miyamoto and colleagues have mentioned the advantages of using IVIG in SJS-TEN.[32] However, we were able to administer IVIG in only four patients due to financial constraints.

The majority of the SJS-TEN cases (n = 41, 83.6%) were managed with cyclosporine (oral and/or intravenous). Of these, 37 patients (75.5%) received cyclosporine as monotherapy at a dose of 3–5 mg/kg/day in divided doses for 10 days; with a mortality rate of 18.9% (n = 7). However, this could be attributed to a delay in initiating treatment in a few cases due to late presentation to our center. Among patients who received cyclosporine monotherapy, five cases developed sepsis (13.5%), out of which only one patient survived. The remaining patients had a favorable outcome with re-epithelialization and eventual recovery within 10–12 days.

We observed that early administration of cyclosporine in individuals with no renal impairment resulted in a favorable outcome. IVIG was administered in 4 cases (8.1%), and mortality was reported in only one case due to pneumonia. The combination of IVIG and cyclosporine was used in one case; however, the patient succumbed to her illness. The plausible explanation for mortality in the latter case was a delay in starting treatment due to late presentation, increased detachable TBSA at presentation (>50%), and prolonged hospital stay (>14 days). Among SJS-TEN cases reported in our study, the mortality rate was observed to be 20.4% (n = 10). The average baseline SCORTEN was 1.71, and the predicted mortality rate was around 3–12%. However, the observed mortality rate was much higher. Among 10 deaths that were reported, seven were due to sepsis, while the remaining were due to pneumonia (n = 1) and AKI (n = 2).

The majority of DRESS patients were effectively managed by administration of systemic corticosteroids at a starting dose of 1 mg/kg/day. Cyclosporine was administered to six patients in whom steroids were less beneficial owing to comorbidities. The remaining patients were managed on a symptomatic basis with antihistaminics and emollients. We had only a single mortality among the DRESS cohort, which was due to hepatic failure. This is in contrast with previously reported data that state a mortality rate close to 10%.[38]

An often overlooked yet clinically significant outcome in SCARs is the improvement in QoL following appropriate management. Our study found that timely withdrawal of the culprit drug and institution of immunomodulatory therapy not only led to clinical resolution but also yielded substantial functional and psychological recovery. The observed reduction in DLQI scores from severe to mild impairment by the 6-week follow-up reflects this improvement. Restoration of sleep, alleviation of distress from pruritus, and return to daily activities were frequently reported by patients. These findings are consistent with prior literature, which highlights the long-term psychosocial burden of SCARs, including anxiety, post-inflammatory dyschromia, and fear of drug rechallenge. Incorporating QoL assessment tools in routine follow-up can provide valuable insight into patient recovery and aid in the holistic management of these reactions. In resource-limited settings, where extended hospitalization and follow-up may be constrained, these measures can help prioritize early interventions with high impact on patient-centered outcomes.

Limitations

This was a retrospective study. A few patients had a history of polypharmacy intake, which reduces the accuracy of causality assessment. A rechallenge test was not performed in any patient due to ethical considerations. Hence, the possibility of misidentification of causative drugs cannot be ruled out entirely.

Conclusion

SCARs are a significant problem in the Indian healthcare system. Injudicious and unmonitored use of antibiotics, rampant usage of over-the-counter prescriptions, and medicines prescribed by quacks are widely prevalent. Clinicians of all specialities must be aware of the possibility of such reactions while prescribing medications. Patients must be adequately counselled to look out for warning signs. The possibility of SCARs occurring while prescribing common medications like NSAIDs must not be overlooked.

Data availability statement

Data are available from the corresponding author on reasonable request.

Conflicts of interest

One of the authors is an editor of the journal and the article was subject to the journal’s standard procedures, with peer review handled independently of this editor and their research groups.

Use of artificial intelligence (AI)

The preparation of this manuscript was carried out entirely by the authors without the use of artificial intelligence technologies.

Funding Statement

Nil.