Drug-Induced Erythema Multiforme

Erythema multiforme (EM) is an acute inflammatory, mucocutaneous, psychosomatic, and vesiculobullous condition that varies from minor to major forms. The acral distribution of target lesions is a characteristic of this condition. The aetiology of erythema multiforme is multifactorial. 90% of the cases are triggered by a herpes infection, whereas 10% occur secondary to drug intake. The offending drugs include nonsteroidal anti-inflammatory drugs, antibiotics, and anticonvulsants. The present case series discusses four cases of drug-induced erythema multiforme and their management.


Introduction
Erythema multiforme (EM) is an acute infammatory, mucocutaneous, psychosomatic, and vesiculobullous condition that varies from minor to major forms [1].Te name "multiforme" denotes its multiple clinical presentations varying from macules, papules, and vesicles to ulcers.Te classical feature of this disease is the acral distribution of target lesions, characterized by concentric rings surrounding a darker centre.Tese lesions can be typical (three concentric rings) or atypical (two concentric rings) [1,2].Based on mucous membrane involvement, EM can be classifed as EM minor (no mucosal involvement) and EM major (with mucosal involvement).Te most commonly afected mucosal sites are the lips, tongue, and oral mucosa.Ocular and genital mucous membrane involvement has also been reported [1,3].Previously, EM was considered a part of the spectrum that involved Stevens-Johnson syndrome and toxic epidermal necrolysis; however, studies have revealed that these disorders are signifcantly distinct and should not be clubbed together [4].
EM has a multifactorial aetiology; however, most EM (90%) cases report infection, especially herpes (HSV-1/2), as the triggering agent.Drug-induced EM accounts for <10% of all cases [5].In the present case series, we describe four cases of drug-induced EM and their management.

Case 1
A 23-year-old male presented with painful bleeding ulcers in the mouth and difculty swallowing for two days.Tree days before the presentation, he had self-medicated with paracetamol 500 mg for fever.On the second day of medication, he suddenly developed ulcers on the lips and in the mouth.His personal and family histories were noncontributory.On general physical examination, he was febrile (99.5 °F) and had minor erosive areas on both thighs.Extraoral examination of the lesion revealed difused erosive areas on the lips and corners of the mouth with bleeding and crustation.Erythematous areas were also observed in the lower conjunctiva and lower palpebral fssures.On intraoral examination, illdefned erosive areas were noted in the oral cavity, including the tongue, upper/lower labial mucosa, bilateral buccal mucosa, hard and soft palates, and the anterior pharyngeal wall.Active bleeding was observed in these lesions (Figure 1).
Based on the patient's history and clinical examination fndings, he was diagnosed with drug-induced EM.Te diferential diagnoses included thrombocytopenic purpura and mucous membrane pemphigoid.He received 2 ml of dexamethasone intravenously, followed by prednisolone 40 mg for ten days, tapered over two weeks.Tree days later, he reported moderate ulcer relief.However, he developed fuid-flled vesicles in the right corner of his mouth the following day.Serology tests confrmed that he was positive for HSV, and there was an increase in the antibody titer; thus, acyclovir 400 mg, fve times a day, was added to the regimen.A one-month follow-up revealed complete remission (Figures 2 and 3).

Case 2
A 49-year-old male presented with ulceration of the gums and rashes all over the body for two days.Two days before the presentation, he was diagnosed with trigeminal neuralgia and was prescribed carbamazepine 100 mg three times a day.Soon after taking the medication, he developed rashes, which worsened after the next dose.He had no clinical history of such lesions.His personal and family histories were noncontributory.Extraoral examination revealed multiple erythematous rashes on the face and palms.Multiple targetoid lesions were noted on the chest, waist, and the back region (Figure 4).Erythematous areas were observed in the lower conjunctiva and lower palpebral fssures.Intraoral examination revealed multiple erosive areas on the bilateral vestibules, gingiva of both arch, and the palate (Figure 5).Nikolsky's sign was negative.On palpation, the ulcers were highly tender with profuse bleeding.Serological tests were negative for HSV.He was diagnosed with druginduced EM and managed with prednisolone 40 mg once daily for 10 days, which was subsequently tapered (30 mg, 20 mg, 10 mg, 5 mg, and 2.5 mg) over four weeks.Fluconazole tablets (150 mg for 3 days) were also advised to avoid superadded candidal infection.A one-month follow-up revealed complete remission (Figures 6 and 7).

Case 3
A 63-year-old female presented with ulcerations in the mouth, pain, and inability to eat for one week.She had a past history of diarrhoea and abdominal pain for two weeks, for which she was administered cefxime 200 mg and diclofenac sodium 50 mg.Within 12 hours, she developed multiple ulcerations of the lips and mouth.She had visited a local dentist, where she was prescribed a local anaesthetic gel and amoxicillin 500 mg, which did not provide any relief.Typical target lesions were evident on the palms, legs, and feet (Figure 8).Multiple ulcerations with crustation and bleeding points were evident on both the upper and lower lips.Erythematous areas were also observed in the conjunctiva and lower palpebral fssures.Te intraoral examination revealed extensive irregular ulcerations with sloughing of the entire oral mucosa (Figure 9).Nikolsky's sign was negative.Serological tests were negative for HSV.She was also administeredprednisolone 40 mg once daily for 10 days and tapered over the next 28 days (30 mg, 20 mg, 10 mg, 5 mg, and 2.5 mg).A one-month follow-up revealed complete remission (Figures 10 and 11).

Case 4
A 27-year-old male presented with a complaint of painful ulcerations in the mouth for one week.He had a history of headaches, for which he took paracetamol 500 mg from a local drug dealer.Within 24 hours, he developed multiple ulcerations on the lips and mouth.Multiple ulcerations with crustations were evident on the upper and lower lips.Erythematous areas were observed in the conjunctiva and lower palpebral fssures.Te intraoral examination revealed extensive irregular ulcerations with sloughing of the entire oral mucosa (Figure 12).Nikolsky's sign and serological tests for HSV were negative.He was managed with methylprednisolone 16 mg once daily for 10 days, which was tapered over the next 21 days (8 mg, 4 mg, and 2 mg).He was also advised to apply a topical 0.1% triamcinolone acetonide ointment, and fuconazole tablets (150 mg tablet for three days) were administered to avoid candida superinfection.He informed about complete remission in three weeks by telephone communication (follow-up images could not be taken due to the COVID-19 pandemic).

Discussion
EM was frst reported in 1,846 by Bateman and Bulky, followed by Hebra in 1866 [6].Pathogenetically, the aetiologies of Herpes-associated EM and drug-induced EM are diferent.Herpes-associated EM (HAEM) is a hypersensitivity reaction in which CD4+T1 cells produce IFN-c (interferon-gamma).IFN-c initiates an infammatory cascade that includes expression of IFN-c induced genes, increased sequestration of circulating leukocytes, monocytes and natural killer (NK) cells, and the recruitment of autoreactive T-cells.Te cytotoxic T-cells, NK cells, and chemokines ultimately result in keratinocytes damage [7].In contrast, in drug-induced EM (DIEM), the destruction is mediated by the tumor necrosis factor alpha (TNF-α) [7].In addition, in patients with DIEM, there is abnormal metabolism of the ofending drug, which increases the production of toxic metabolites via the cytochrome-P450 pathway [8].Te most common ofending drugs reported are nonsteroidal anti-infammatory drugs (NSAIDs), antibiotics, and anticonvulsants [9].In this study, we are reporting paracetamol, carbamazepine, cefxime, and diclofenac as the ofending drugs.
Clinically, HAEM and DIEM are indistinguishable.Both entities present extensive, ill-defned, erosive areas involving 2 Case Reports in Dermatological Medicine the skin and mucous membranes, along with target lesions.However, in HAEM, the viral culture tests positive (ELISA or PCR for HSV-1/2).Te pathognomonic feature of DIEM is the temporal relationship between drug intake and the appearance of lesions.Clinicians should diferentiate DIEM from other adverse reactions, especially fxed-drug reaction (FDR).FDR tends to occur at the same site even after repeated insults, whereas DIEM can spread to involve multiple sites.In addition, FDR does not include target lesions.Soares and Sokumbi suggested that the ofending drug must be discontinued, as a primary treatment of DIEM [2].In patients with mild mucosal involvement and mild   Case Reports in Dermatological Medicine discomfort, topical steroids along with antiseptics and antihistamines are recommended.In patients with moderate mucosal involvement, systemic steroids should be initiated at a starting dose of 40-60 mg tapered over 2 weeks [4,10].Antiseptics and antihistamines should also be included.
Patients with ocular involvement require an ophthalmic consultation (antibiotic/steroid eye drops) to avoid future complications.In severe cases, hospitalization is recommended for electrolyte repletion and intravenous steroid administration [4].Cases that are nonresponsive to steroids can be managed successfully with azathioprine, apremilast, cyclosporine, mycophenolate mofetil, thalidomide, adalimumab, hydroxychloroquine, levamisole, and dapsone [10,11].

Case Reports in Dermatological Medicine
Pre-treatment Post-treatment

Case Reports in Dermatological Medicine
In this report, all patients had moderate mucosal and ocular involvement.Tus, systemic steroids (prednisolone 40 mg), antihistamines (benzydamine hydrochloride 0.15%), and an antiseptic mouthwash (betadine) were administered.An ophthalmic consultation was also conducted when betamethasone eyedrops were prescribed.In case 1, acyclovir was initiated because of superimposed herpes infection.All three patients responded well to systemic steroids, which were later tapered over 2 weeks.
Because of the temporal relationship between drug intake and the development of the lesions, none of our case was investigated for the presence of Mycoplasma.
Historically, dermatologic/mucosal manifestation of mycoplasma and other infectious organisms was considered as the spectrum of erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).However, recent literatures suggested it as separate clinical entity and classifed under broad category of reactive infectious mucocutaneous eruption (RIME) [12].
Reactive infectious mucocutaneous eruption describes an eruption of prominent mucositis with/without cutaneous involvement triggered by Mycoplasma pneumoniae (MP) and other infectious organism [13].Mycoplasma pneumoniae infection is associated with mucocutaneous eruptions  6.1.Limitations.All of our cases were diagnosed solely based on the temporal relationship between drug intake and the development of the lesions.Te cases were not tested for the presence of mycoplasma/other associated viruses and in vivo or in vitro drug testing to confrm drug causality.We also did not perform a biopsy or immunofuorescence test to rule out other causes of mucositis such as mucous membrane pemphigoid.Tus, the authors suggest strongly performing these investigations to give the diagnosis of drug-induced erythema multiforme.

Conclusion
DIEM is a less commonly reported variant of EM, and the ofending drugs are mostly NSAIDs, antibiotics, and anticonvulsants.Te oral mucosa is most commonly involved, especially the lips, tongue, and buccal mucosa.A temporal relationship exists between recent drug intake and the appearance of symptoms in EM.For the management of EM, the ofending drug should be immediately discontinued and steroids should be initiated depending on the extent and severity of the involvement.

Figure 1 :
Figure 1: Case 1: multiple bleeding erosive areas involving buccal mucosa, labial mucosa, ventral surface of the tongue, palate, and lateral border of the tongue (a-e).(f ) Erythematous areas were also seen on the lower conjunctiva and lower palpebral fssures.

Figure 5 :
Figure 5: Case 2: multiple bleeding erosive areas involving buccal mucosa, labial mucosa, ventral surface of the tongue, palate, and lateral border of the tongue (a-e).(f ) Erythematous areas were also seen on the lower conjunctiva and lower palpebral fssures.

Figure 9 :
Figure 9: Case 3: multiple bleeding erosive areas involving buccal mucosa, labial mucosa, ventral surface of the tongue, palate, and lateral border of the tongue.(a-e).(f ) Erythematous areas were also seen on the lower conjunctiva and lower palpebral fssures.