erythema multiforme ( em ) is an acute , self - limited , type iv hypersensitivity reaction associated with certain infections ( herpes simplex and mycoplasma ) , medications , and other triggers such as cold , sunlight , collagen vascular diseases , non - hodgkin 's lymphoma , and multiple myeloma . common medications causing em are reportedly sulfa drugs , anticonvulsants , antibiotics ( penicillin , ampicillin , tetracyclines , amoxicillin , cefotaxime , cefaclor , cephalexin , ciprofloxacin , erythromycin , minocycline , sulfonamides , trimethoprim - sulfamethoxazole , and vancomycin ) , anti - tuberculosis drugs ( rifampicin , isoniazid , thiacetazone , and pyrazinamide ) , analgesics ( aspirin , phenylbutazone , oxyphenbutazone , and phenazone ) . however , em due to arsenic trioxide ( ato ) is yet to be reported . a pubmed search with keywords  erythema multiforme , arsenic trioxide  showed no results . here , we are reporting a case of em caused due to ato in a patient of acute promyelocytic leukemia ( apl ) . a 41-year - old female presented with a history of fatigue and intermittent fever of 2 weeks duration , together with easy bruising and menorrhagia . her hemogram showed pancytopenia ( hemoglobin 8.6 g / dl , white blood cell count 1.8  10/l , and platelet count 30  10/l ) . examination of peripheral blood smear revealed the presence of abnormal promyelocytes , comprising 28% of total leukocytes . bone marrow aspiration showed hypercellular marrow with trilineage suppression , with abnormal promyelocytes constituting more than 90% of bone marrow nucleated cells . immunophenotyping showed these cells to be positive for myeloperoxidase , cd13 and cd33 , weakly positive for cd15 and cd64 , and negative for human leukocyte antigen - diabetic retinopathy , cd34 , and cd117 . real - time polymerase chain reaction for promyelocytic leukemia - retinoic acid receptor alfa ( pml - rara ) was positive for the variant form of the fusion protein . the patient received induction therapy with the combination of all - trans - retinoic acid ( atra ) at 45 mg / m / day p.o . in two divided doses and ato 0.15 mg / kg / day intravenous infusion over 2 h. the patient also received vancomycin to tide over the crisis of febrile neutropenia as an empiric antibiotic therapy as per hospital protocol . the induction therapy of atra and ato was started on day 1 and was planned to be continued until bone marrow remission . on day 27 of induction therapy , she developed a few erythematous macular lesions on her upper chest [ figure 1 ] . naranjo 's causality assessment was done , and the scale showed a score of 5 for vancomycin ( probable adverse drug reaction [ adr ] ) and three for the atra - ato combination ( possible adr ) . world health organization - uppsala monitoring centre ( who - umc ) causality categories fared similarly for either of the two drugs . thus , the em lesions were attributed to vancomycin used for febrile neutropenia during induction phase . erythematous macular lesions on upper chest subsequently , she was planned to receive two cycles of ato consolidation ( 0.15 mg / kg / day for 5 days a week for 5 consecutive weeks ) . on day 15 of the first cycle ato consolidation , she again developed a painless , mildly pruritic , erythematous plaque , and a few was having necrotic center or dusky erythema on the trunk and face . palms and soles developed nonblanchable erythematous macule [ figure 2 ] though oral and genital mucosa was spared . the rash responded to levocetirizine 10 mg and topical betamethasone dipropionate 0.05% w / v twice daily over affected part and subsided within 7 days . ato was continued due to the favorable benefit : risk ratio and since only two cycles were planned . nonblanchable erythematous macule on soles the adverse event report was submitted to pharmacovigilance program of india and bears the worldwide unique number of 2015 - 11618 . the recurrence of the rash in spite of nonusage of vancomycin was a cue that some other drug used in the course of therapy might be responsible . the causality assessment of the incidence of em with use of ato was done using the naranjo adr probability scale and who - umc criteria . the naranjo scale showed a score of 7 , which places the reaction in the  probable  category . according to the who - umc criteria , the case qualifies as  probable  causality category . severity assessment by the hartwig 's severity assessment scale showed that the severity was  moderate prophylactic steroids ( prednisolone 0.5 mg / kg / day ) were used with the subsequent cycle of ato consolidation . the patient had mild em skin lesions briefly in second consolidation cycle . at present , she has achieved complete molecular remission after consolidation therapy and was receiving maintenance therapy with atra , 6-mercaptopurine , and methotrexate . em - induced by drug hypersensitivity involves abnormal or altered metabolism of the responsible drug . thus , the major metabolism of the drug is carried out by an alternative route , i.e. , oxidation by p450 enzymes . affected individuals have a defect in detoxifying these reactive metabolites , which then act as hapten by binding to the proteins on epithelial cells covalently . ato is metabolized by methylation to methylarsonic acid ( maa ) and di - maa . there are pharmacogenetic variations in the activities of enzymes that catalyze s - methylation , o - methylation , n - methylation . these inherited variations are responsible for interindividual differences in the metabolism , effect , and toxicity of drugs that undergo methylation . . there might be a possibility that the genetic variation of methyl conjugation in the individual had triggered the response , and the altered metabolic byproducts acted as a hapten in the subsequent keratinocyte necrosis . we should bear in mind that early institution of treatment is necessary to prevent the feared steven furthermore , one should be cautious in patients who have suffered such an episode earlier as em tends to recur .
erythema multiforme ( em ) is an acute , self - limited , type iv hypersensitivity reactions associated with infections and drugs . in this case of 
 acute promyelocytic leukemia , em diagnosed during the induction phase was mistakenly attributed to vancomycin used to treat febrile neutropenia during that period . 
 however , the occurrence of the lesions of em again during the consolidation phase with arsenic trioxide ( ato ) lead to a re - evaluation of the patient and both the naranjo and world health organization - uppsala monitoring centre scale showed the causality association as  probable .  the rash responded to topical corticosteroids and antihistamines . 
 this rare event of em being caused by ato may be attributed to the genetic variation of methyl conjugation in the individual which had triggered the response , and the altered metabolic byproducts acted as a hapten in the subsequent keratinocyte necrosis .