Pramudita A, et al.
A rare case of symmetrical drug-related.
A rare case of symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) Ardisa Pramudita*.
Inges Prawita Sari.
Saraswati Anindhita Kusumaningrum.
Sri Awalia Febriana.
Fajar Waskito.
Dyah Ayu Mira Oktarina.
Niken Indrastuti Department of Dermatology and Venereology.
Faculty of Medicine.
Public Health and Nursing Universitas Gadjah Mada/ Sardjito General Hospital.
Yogyakarta.
Indonesia https://doi.
org/10.
22146/inajbcs.
ABSTRACT
Submitted: 2026-01-13 Accepted : 2026-03-27 Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is a rare maculopapular drug eruption mediated by type IV hypersensitivity reaction and characterized by symmetrical erythematous involvement of flexural and intertriginous areas without systemic symptoms.
This case report describes a rare presentation of SDRIFE and emphasizes the importance of early recognition and prompt withdrawal of the offending drugs.
A 27-year-old woman presented with well-demarcated erythematous patches involving the axillae, inframammary region, antecubital fossae, inguinal, popliteal, and gluteal areas following exposure to multiple systemic medications, including cefadroxil, mefenamic acid, amoxicillin, oral dexamethasone, paracetamol, and loratadine.
No mucosal involvement or systemic manifestations were observed.
Histopathological examination revealed non-specific findings of cutaneous drug eruption.
The clinical presentation met the established diagnostic criteria for SDRIFE, and drug causality assessment using the Naranjo Scale identified several medications as probable triggers.
Management consisted of discontinuation of the suspected drugs, patient education to avoid re-exposure, and treatment with systemic and topical corticosteroids, resulting in marked clinical improvement within approximately two weeks.
Differential diagnoses, including drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and fixed drug eruption (FDE), were considered and excluded based on clinical features and laboratory findings.
Histopathological findings in SDRIFE are known to be variable and non-specific.
Although drug patch testing is recommended to identify the causative agent, it has not yet been performed in this case.
In conclusion, this report highlights the diagnostic value of clinical criteria and the Naranjo Scale in SDRIFE.
It also highlights the importance of early diagnosis and prompt drug withdrawal, particularly in patients exposed to multiple ABSTRACT Keywords:
Cutaneous adverse drug Naranjo scale.
Symmetrical drugrelated intertriginous and flexural exanthema Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) merupakan erupsi obat makulopapular yang jarang terjadi, dimediasi oleh reaksi hipersensitivitas tipe IV, dan ditandai dengan patch eritematosa pada area fleksural dan intertriginosa yang simetris tanpa disertai gejala sistemik.
Laporan kasus ini bertujuan untuk mendeskripsikan manifestasi SDRIFE yang jarang serta menekankan pentingnya deteksi dini dan penghentian segera obat penyebab.
Seorang perempuan berusia 27 tahun datang dengan keluhan bercak kemerahan batas tegas yang melibatkan aksila, regio inframammae, fossa antekubiti, inguinal, poplitea, dan glutea setelah terpapar beberapa obat sistemik, yang meliputi sefadroksil, asam mefenamat, amoksisilin, deksametason oral, parasetamol, dan loratadin.
Tidak ditemukan keterlibatan mukosa maupun manifestasi sistemik.
Pemeriksaan histopatologi menunjukkan gambaran tidak spesifik untuk erupsi obat pada kulit.
Gambaran klinis memenuhi kriteria diagnostik SDRIFE, dan penilaian kausalitas obat menggunakan Skala Naranjo mengidentifikasi beberapa obat pemicu yang bersifat probable.
Tata laksana meliputi penghentian obat-obatan yang dicurigai, edukasi pasien untuk menghindari pajanan ulang, serta pemberian kortikosteroid sistemik dan topikal, yang menghasilkan perbaikan klinis bermakna dalam waktu sekitar dua minggu.
Diagnosis banding pada kasus meliputi drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), dan fixed drug eruption (FDE) dipertimbangkan dan disingkirkan berdasarkan gambaran klinis dan temuan laboratorium.
Temuan histopatologis pada SDRIFE diketahui bervariasi dan Meskipun uji tempel obat direkomendasikan untuk mengidentifikasi agen penyebab, pemeriksaan tersebut belum dilakukan pada kasus ini.
Laporan ini menegaskan nilai diagnostik kriteria klinis dan Skala Naranjo dalam menegakkan diagnosis SDRIFE serta pentingnya diagnosis dini dan penghentian segera obat penyebab, terutama pada pasien yang terpapar banyak obat.
*corresponding author: pramudita.
ardisa51@gmail.
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INTRODUCTION
Cutaneous adverse drug reactions (CADR.
are skin changes that develop following the systemic use of medications.
These reactions are immune-mediated, unpredictable, and affect more than 7% of the global population.
2 According to the International Consensus on Drug Allergies (ICON), cutaneous drug hypersensitivity reactions are classified into immediate and delayed Immediate-type hypersensitivity reactions typically appear within 1-6 hours after drug exposure, presenting as angioedema, urticaria, or In contrast, delayed-type hypersensitivity reactions arise several days to weeks after drug administration and range from mild eruptions such as maculopapular exanthema and fixed drug eruption (FDE), to severe conditions including drug reaction with eosinophilia and systemic symptoms (DRESS).
Stevens-Johnson syndrome/ toxic epidermal necrolysis (SJS/TEN), and acute generalized exanthematous pustulosis (AGEP).
Symmetrical drug-related intertriginous and flexural exanthema
(SDRIFE)
maculopapular drug eruption erythema affecting at least one manifestations, mediated by type IV hypersensitivity reactions or delayedtype reactions.
3-5 Over the 25 years since its initial recognition, approximately 100 cases have been documented in the literature, with amoxicillin and other -lactamantibiotics remaining However.
SDRIFE has also been associated with immunoglobulin therapy, chemotherapeutic drugs, and biologic agents.
3 The present case is important because the rash appeared after the patient was exposed to several systemic medications, making it difficult to identify the causative agent.
This case report aims to describe a rare case of SDRIFE following multi-drug exposure lessons, including the importance of constructing a clear chronological drug timeline, applying diagnostic criteria systematically, and the importance of timely identification of CADR and withdrawal of the offending drugs.
CASE
A 27-year-old woman presented with progressively worsening erythematous patches predominantly involving the flexural areas, including the axillae, antecubital fossae, inguinal folds, popliteal fossae, and bilateral gluteal Five weeks prior to admission, the patient received a 14-day course of cefadroxil and mefenamic acid without adverse reactions.
One week before admission, she was re-exposed to the oral cefadroxil and mefenamic acid.
On five days before admission, she developed erythematous patches over both antecubital fossae, which gradually extended to the inframammary region and back, accompanied by mild pruritus.
She had no other complaints of fever, odynophagia, or dyspnea.
Four days before admission, the medications were subsequently replaced with oral amoxicillin and oral dexamethasone.
however, the eruption continued to Two days before admission, she received parenteral dexamethasone and diphenhydramine, followed by oral paracetamol and loratadine.
the rash continued to spread, she was referred to Sardjito General Hospital for further evaluation.
There was no mucosal involvement, systemic symptoms, or evidence of vesiculation or She had no significant past medical history, including no previous drug eruptions or food allergies.
Family history was notable for a paternal seafood allergy, with no known drug allergies.
Pramudita A, et al.
A rare case of symmetrical drug-related.
Dermatological examination revealed multiple erythematous macules, patches, and plaques of varying sizes, some coalescing, symmetrically distributed over the inframammary region, axillae, antecubital fossae, abdomen, posterior trunk, inguinal folds, gluteal region, and bilateral popliteal fossae (FIGURE .
The main differential diagnoses considered were SDRIFE.
DRESS.
AGEP, and FDE.
Laboratory investigations demonstrated leukocytosis .
8 y 10A/ AAL) with neutrophilia .
3 y 10A/AAL), mild eosinophilia .
61 y 10A/AAL), and elevated liver transaminases (AST 38 U/L.
ALT 118 U/L), with normal renal function.
Skin biopsy was performed on the second day of hospitalization, histopathological examination demonstrated orthohyperkeratosis with a basket-weave pattern, hyperpigmentation, and mild patchy perivascular lymphocytic infiltration in the dermis, findings that were non-specific for cutaneous drug eruption (FIGURE The non-specific histopathological findings may be related to the biopsy performed on the second day corticosteroid therapy had already been initiated, which may have influenced the observed histological features.
The distribution, absence of mucosal and systemic involvement, and supportive findings supported the diagnosis of SDRIFE.
Given the exposure to multiple medications within a short period of time, structured causality assessment was performed using the Naranjo Scale for each suspected drug separately.
Cefadroxil, mefenamic acid, amoxicillin, paracetamol, and dexamethasone were classified as probable offending drugs, while loratadine was considered as possible trigger.
Management included discontinuation of the suspected drugs, patient education to avoid these drugs in the future, and treatment with systemic and topical corticosteroids, resulting in clinical improvement within approximately two weeks.
A drug patch test was planned.
however, the patient was lost to follow-up.
FIGURE 1.
Symmetrical erythematous macules, patches, and plaques involving the axillae .
, antecubital fossae .
, inframammary region .
, inguinal folds .
, gluteal region .
, and bilateral popliteal fossae .
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5 weeks 7 days Got cefadroxil No skin rash 5 days Re- exposure 4 days 3 days Erythematous A Drug switched: Oral patches on amoxicillin and A Erythematous patches progress to region and back Day of Day Ae 1 A All suspected A Previous hospital Dexamethasone IV Systemic diphenhydramine IV A Oral paracetamol and loratadine A Erythematous patches progress to other flexural area Skin biopsy FIGURE 2.
Timeline of drug exposure, skin lesion, and biopsy timing FIGURE
(A)
Low-magnification .
(B) High-magnification view .
showing moderate spongiosis and basal layer hyperpigmentation.
TABLE 1.
Naranjo Adverse Drug Reaction Probability Assessment for Each Suspected Drug Naranjo Item Cefadroxil Amoxicillin Mefenamic Paracetamol Dexamethasone Loratadine Previous reports of this reaction 2 Event appeared after drug was Reaction improved after drug Reaction on re-administration Alternative causes present Reaction with placebo Toxic drug level detected DoseAeresponse relationship Similar reaction previously Objective evidence Total score Interpretation Probable Probable Probable Probable Probable Possible Pramudita A, et al.
A rare case of symmetrical drug-related.
DISCUSSION
The diagnosis of SDRIFE in this case was established based on the fulfillment of all five diagnostic criteria proposed by Hausermann et al.
(TABLE
6 Cutaneous eruptions associated with SDRIFE typically occur within 2Ae3 days after drug exposure in previously sensitized patients and within 9Ae10 days to more than two weeks in non-sensitized 7 Previous reports indicate that the inguinal folds and axillae are the most commonly affected sites, with characteristic lesions presenting as erythematous plaques and/or papules, occasionally accompanied by scaling.
This observation supports the presence of prior sensitization in our case, where the eruption happened on the second day following re-exposure to cefadroxil and mefenamic acid.
Although several systemic drugs were administered in this case, causality was assessed using the Naranjo Scale as a pragmatic pharmacovigilance However, its performance may be limited in routine clinical practice due to confounding factors, and it is primarily designed as a screening tool rather than for definitive causality In comparative studies, both the Naranjo and Liverpool tools demonstrate low specificity, supporting the need for confirmatory testing when 8 Although the Naranjo Scale is not a diagnostic tool, it remains one of the most commonly used screening instruments for evaluating the causal relationship between a suspected drug and an adverse drug reaction when interpreted alongside clinical findings, with a reported sensitivity of 8 Based on the available literature, -lactam antibiotics are most often implicated in SDRIFE and are therefore the most likely culprits in this case.
Other medications, including mefenamic acid, should be considered possible contributors pending confirmation through tests such as patch testing.
Caution is warranted when labeling multiple drugs as definite allergens without confirmation, as this may result in unnecessary restriction of future treatment options.
SDRIFE is typically associated with a single identifiable trigger, with -lactam antibioticsAiparticularly amoxicillinAi accounting for approximately 45Ae50% of reported cases.
Other recognized causes include iodinated contrast media and antihypertensive agents.
9 In contrast, this case involved exposure to multiple systemic drugs, creating a more complex causality scenario.
Reports of SDRIFE in the setting of polypharmacy remain limited, and attributing the reaction to a single agent becomes challenging when multiple potential triggers are present.
This highlights the importance of careful reconstruction of the drug exposure timeline, a structured approach to causality assessment, and underscores the need for systematic pharmacovigilance in clinical practice.
Histopathological in the present case spongiosis with basal layer hyperpigmentation and mild perivascular lymphocytic infiltration.
Although these findings are nonspecific for SDRIFE, they may have been influenced by treatment administered prior to biopsy.
According to the literature, the histopathological features of SDRIFE are variable, with the most commonly reported findings including superficial perivascular lymphocytic infiltration, dermal eosinophils, and epidermal spongiosis.
5 Therefore, the histopathological features observed in this case remain supportive of the diagnosis of SDRIFE when correlated with the characteristic clinical presentation.
Histopathological particularly recommended in atypical presentations of SDRIFE, such as the presence of pustular or bullous lesions without systemic symptoms, to rule out alternative diagnoses.
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The pathomechanism underlying the predilection for flexural involvement in SDRIFE remains unclear.
10 One proposed mechanism suggests accumulation of the causative drug or its metabolites in apocrine glands located in flexural areas, leading to local toxicity and subsequent keratinocyte injury.
This process may be further exacerbated by occlusion, friction, and sweating, which can increase drug concentration on the skin surface and further amplify the local inflammatory response.
In addition, the pharmacological interaction with immune receptors concept .
-i concep.
has been proposed, that certain drugs can bind to T-cell receptors directly and non-covalently without requiring (MHC) molecules to process or present 11 These mechanisms may explain the characteristic distribution of lesions observed in SDRIFE.
The proposed pathophysiological pathway of SDRIFE is summarized in FIGURE 4.
TABLE 2.
Diagnostic Checklist for SDRIFE Based on Hausermann Criteria Diagnostic criteria (Hausermann et al.
,)6
Finding in this case Fulfillment Exposure to a systemically administered History of exposure drug .
nitial or repeat dosin.
systemic drugs Oo Sharply demarcated erythema in gluteal Well-demarcated and/or inguinal regions lesions in gluteal and inguinal regions Oo Involvement of at least one additional Axillae, antecubital fossae, popliteal flexural area Symmetrical distribution of lesions Bilateral and symmetrical involvement of flexural areas Oo Absence of systemic symptoms No fever, lymphadenopathy, or organ Systemic Drug Exposure Drug Ae protein complex Local factors (Occlusion, sweating and friction in flexural are.
Drug Binds T-cell receptor -i concep.
T-cell mediated immune response (Type IV hypersensitivit.
Direct keratinocyte toxicity Cytokine release & Inflamation Symmetric intertriginous erythema
(SDRIFE)
FIGURE 4.
Proposed pathophysiological mechanism of symmetrical drug-related intertriginous and flexural exanthema (SDRIFE).
Pramudita A, et al.
A rare case of symmetrical drug-related.
TABLE 3.
Comparison of SDRIFE with other drug-induced cutaneous adverse reactions Case
Drug
Onset
SDRIFE5,6
First or repeated doses of systemic drug exposure DRESS12
Delayed onset
after drug
Ae8 AGEP13
FDE14
Clinical manifestations Systemic Symptoms Mucosal Involvement Histopathology Well-defined gluteal/ perianal erythema and/ or V-shaped inguinal of Ou1 additional flexural Absent Absent Non-specific findings.
superficial perivascular lymphocytic infiltrate A mild spongiosis Polymorphic eruption .
orbilliform, urticarial, pustular, bullou.
and limbs Present .
Possible Variable.
dermatitis and dermal infiltrates.
pathognomonic features Acute onset, usually 24Ae48 hours after drug intake Edematous, erythematous skin with multiple small, nonfollicular sterile pustules.
frequently begins in intertriginous areas Present .
Mild Subcorneal or intraepidermal pustules with neutrophilic Re-exposure to offending Well-demarcated erythematous to violaceous patch or plaque with dusky often lips or Absent Common Vacuolar interface and deep perivascular lymphocytes and SDRIFE: Symmetrical drug-related intertriginous and flexural exanthema.
DRESS: drug reaction with eosinophilia and systemic symptoms.
AGEP: acute generalized exanthematous pustulosis.
FDE: Fixed drug eruption.
The differential diagnoses of SDRIFE include DREESS.
AGEP, and FDE.
In the present case.
DRESS was considered because of eosinophilia and elevation of transaminase, but the absence of fever, lymphadenopathy, mucosal involvement, and systemic organ dysfunction made DRESS unlikely according to RegiSCAR AGEP was ruled out due to the absence of sterile pustular lesions, fever, and characteristic histopathological findings such as subcorneal or intraepidermal pustules.
Fixed drug eruption was considered unlikely because no recurrent lesions occurred at the same anatomical sites following reexposure to the suspected medications.
Collectively, these findings support the diagnosis of SDRIFE in this patient.
The suspected causative drugs were discontinued in this present case, and initiation of systemic and topical corticosteroid therapy leading to clinical improvement within approximately two In line with previous reports, the principal management of SDRIFE is the identification and discontinuation of the offending drugs.
Skin lesions are typically self-limiting.
Supportive treatment with topical corticosteroids and emollients can reduce erythema generally occurs within approximately three weeks.
3,10,15 Administration of shorten the disease duration.
Previous reports have described rapid clinical intramuscular and oral antihistamines, and topical corticosteroids, with nearcomplete resolution of skin lesions within eight days.
Prognosis is generally excellent, and lesions resolve after drug withdrawal, but recurrence on re-exposure has been InaJBCS.
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therefore, clear documentation and patient counseling are essential to prevent avoidable re-challenge.
5,6 For suspected -lactam-associated SDRIFE, consideration of class avoidance and structured allergy evaluation .
ncluding delayed skin testin.
can help address potential cross-reactivity and preserve future treatment options.
11 Management of SDRIFE is centered on prompt identification and discontinuation of the offending drug.
, as the eruption is typically benign and self-limited once exposure stops.
9 In our patient, short-course systemic corticosteroids were used to reduce inflammation, emollients supported barrier recovery.
Although many SDRIFE cases resolve with supportive care alone, systemic corticosteroids may be considered for extensive involvement or significant symptoms, recognizing the limited evidence base and the need to balance benefits against adverse effects.
Resolution generally occurs within days to a few weeks after withdrawal, consistent with the approximately twoweek improvement observed here.
In this case, a drug patch test was planned to identify the suspected causative drugs.
however, the patient had not returned for further evaluation at the time of manuscript preparation, which limits causality certainty.
The patient was also counseled to avoid medications classified as probable or possible triggers.
Drug patch testing is a safe and well-tolerated diagnostic tool used in the evaluation of delayed drug hypersensitivity reactions.
Although its overall sensitivity is relatively low, patch testing remains particularly useful in SDRIFE, with reported positivity rates of approximately 52Ae82%.
11,16 A positive result on patch test can help identify the cause, especially in cases of exposure to multiple drugs.
6,17
symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), the diagnosis was established based on clinical history, physical examination.
This case demonstrates that eruptions confined to flexural and intertriginous areas should be recognized as a distinct manifestation of an adverse drug reaction, particularly SDRIFE.
patients with multiple drug exposure, clinicians should systematically review the medication history and reconstruct a clear chronological drug timeline.
Causality assessment tools such as the Naranjo scale can assist in causality assessment, but should be interpreted cautiously to avoid misattribution of multiple agents as the cause.
Early recognition and withdrawal of the most likely offending drug remain essential to optimize patient outcomes.
Patch testing should be considered, when feasible, to help identify the definite causative agent.
CONCLUSION
ACKNOWLEDGMENT