Case Report

Stevens-Johnson Syndrome Induced by

Methotrexate, An Uncommon Adverse Drug
Reaction: A Case Report
Vishakha Gupta1,*, Afroz Abidi1
1
Department of Pharmacology, Era's Lucknow Medical College, Lucknow

Abstract
Adverse drug reactions (ADRs) can lead to severe consequences and increased mortality rates. This case report focuses
on a 41-year-old woman, who developed methotrexate-induced Stevens-Johnson syndrome (SJS), emphasizing the
importance of recognizing and managing such a patient. The patient exhibited recurrent vomiting, maculopapular rashes,
erosions and ulcers in multiple locations, consistent with SJS. These symptoms highlight the severity of the adverse drug
reaction. Treatment involved was the discontinuation of medications, oral ointments, gargles, prophylactic antibiotics, and
blood transfusion. Significant improvement was observed after 15 days of treatment. This case report underscores the life-
threatening nature of methotrexate-induced SJS. Early recognition, discontinuation of offending medications, and prompt
intervention are crucial to mitigate harm. Raising awareness about ADRs and their management is vital for enhancing
patient safety and outcomes.
Keywords
Methotrexate; Stevens-Johnson syndrome; Pharmacovigilance; Adverse drug reactions; Causality Assessment

Introduction Commission), in collaboration with

Adverse drug reactions (ADRs) are WHO, is working to ensure the
an important contributor to a signifi- safety of prescribed medicines and
cant number of morbidity and medical products. Pharmaco
mortality in the healthcare industry, vigilance is done by gathering
which manifests as harmful and information regarding ADRs from
undesired responses to the drug at healthcare providers, pharmaceu-
prescribed doses. According to the tical companies, and consumers
World Health Organization (WHO), and making drug safety and medical
adverse drug reactions (ADRs) are product information available to
defined as "Any response to a drug healthcare professionals, regulatory
that is noxious and unintended, and authorities, pharmaceutical compa-
that occurs at doses typically used in nies, and the general public 2 .
humans for the prophylaxis, diagno- Standardized assessment tools,
sis, or therapy of disease or the known as the causality assessment
modification of physiological system, are used to identify ADRs
function1. and determine their relationship with
a drug. The most recommended and
WHO Programme for International popularly used ones are the
Drug Monitoring (PIDM) focuses on Uppsala Monitoring Centre (WHO-
Pharmacovigilance and is vital in UMC) assessment scale and
advancing drug safety worldwide. It
Corresponding Author aims to provide reliable and
balanced information to assist public How to cite:
Dr. Vishakha Gupta health programs in evaluating the Gupta V., Abidi A., Volume I, Issue I,
Junior Resident, Department of Stevens-Johnson syndrome induced by
risk-benefit profile of different
Pharmacology, Era's Lucknow Methotrexate, an uncommon adverse
Medical College, Lucknow, medications1. In India, NCC-PvPI- drug reaction: A case report. Future
Uttar Pradesh IPC (National Coordination Centre- Health 2023; 1(1):104-107
Email Pharmacovigilance Programme of Submitted: 27 May 2023
drvishakhagupta22@gmail.com India- Indian Pharmacopoeia Accepted: 01 September 2023

© 2023 Future Health | AIIMS Bhopal | www.aiimsbhopal.edu.in

 Gupta & Abidi, Stevens-Johnson syndrome induced by methotrexate

Naranjo Probability Scale3. Methotrexate is an anti- esophagitis and antral gastritis. Blood Investigations
folate drug that is used to treat inflammatory disorders revealed Hb-6.7 gm%; TLC- 2600/cub.mm.; Platelets-
and certain neoplastic conditions. However, 50 thousand; Blood Urea-90 mg/dl; S creatinine-5.8
methotrexate can also cause serious adverse reactions mg/dl, S. uric acid-11.3 mg/dl. Viral markers were non-
or toxicities, such as bone marrow suppression, reactive. The patient was evaluated and was diag-
increased risks of infections, hepatotoxicity and lung nosed with Stevens- Johnson syndrome. All the
problems4. There are also very few studies reporting previous medications were discontinued. She was
methotrexate-induced Stevens-Johnson syndrome treated with injectable steroids and antihistaminic
(SJS), as it is an uncommon entity5. Here we are drugs, prophylactic injectable antibiotics, oral oint-
presenting Methotrexate (MTX)-induced Stevens- ments and paints, gargles/mouth wash. She also
Johnson syndrome (SJS), a rare but life-threatening underwent a blood transfusion as her Hb and platelets
cutaneous reaction. were low. The lesions started to heal after 15 days of
Case Report hospitalization.
A 41-Year-old female presented to the emergency We used WHO-UMC and Naranjo scale to determine
department of our teaching hospital with chief the causality of this case and categorized it under
complaints of recurrent vomiting for three months, probable/likely (score = 5). This adverse drug reaction
maculopapular rashes, multiple erosions, and ulcers in was reported in the vigiflow for further analysis by
the mouth, throat, vaginal mucosa, and buttocks for one National Coordination Center (NCC) under the
week. Pharmacovigilance programme of India (PvPI), Indian
Pharmacopoeia Commission (IPC) Ghaziabad.
She could not take an oral diet and had become weak
over time. She experienced 15-20 episodes of vomiting
per day, aggravated by food intake and not getting
relieved by any medication. Initially, the vomitus was
watery, whitish, and not blood-tinged. But later, she had
an episode of blood-mixed vomitus. She had a mild
fever associated with painful ulcers in her mouth and
throat, which had a sudden onset and progressed over
time; however, no aggravating or relieving factors could
be identified. On examination, there were multiple
hemorrhagic erosion and ulcers with crusting over lips,
buccal mucosa [Fig 1], and vaginal mucosa [Fig.2.].
The ulcers were discrete, oval-shaped, reddish to
black, but no pus-filled lesions were observed. She also
had multiple erosions over her buttocks, legs, and hand Figure 1: Multiple erosions and ulcers at mouth
[Fig.3.].
Concerning her medical history, she has been suffering
from rheumatoid arthritis for almost ten years with
irregular medication and was on tablet methotrexate.
She used to have severe pain in her joints while waking
up. The pain was in both small and large joints of the
hands and feet. There was no history of other illnesses
or addictions. Her appetite was good earlier but
decreased for three months, and she started having
dysphagia for a solid diet.On arrival at the emergency,
her general appearance was sick, and her vitals were
as follows: Blood pressure-110/70 mm Hg, heart rate-
90 beats per minute, respiratory rate-19/min, and body
temperature-101 0F. She could not speak, eat or drink
due to pain in ulcers and vomiting. Her bone marrow
aspiration showed pancytopenia. Endoscopy showed

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 Gupta & Abidi, Stevens-Johnson syndrome induced by methotrexate

tion, cytokine production, intercellular adhesion

molecules, and IL-1β receptor binding. Methotrexate
has multiple therapeutic uses in conditions such as
Crohn's disease, severe psoriasis, psoriatic arthritis,
rheumatoid arthritis, and certain malignancies,
including childhood acute lymphoblastic leukemia,
lymphoproliferative disorders, choriocarcinoma, and
various tumors. Certain drugs like (NSAIDs),
phenytoin, ciprofloxacin, penicillin-type drugs,
probenecid, amiodarone, and proton pump inhibitors
inhibit the renal excretion of Methotrexate (MTX) and
can increase the risk of MTX-related toxicity. There is a
long list of contraindications or risk factors for using
Figure 2: Erosions and ulcer at vaginal mucosa methotrexate as it is a potent drug that can affect many
Figure 3: Multiple erosion and ulcers at thigh, legs and organs and systems in the body such as chronic liver
buttock disease, liver cirrhosis, chronic alcoholism, during
pregnancy or lactation, blood disorders etc. In general,
Methotrexate is well tolerated at therapeutic doses of
Discussion rheumatoid arthritis. In case of toxicity, it typically
Stevens-Johnson syndrome (SJS) and toxic epidermal presents with nausea, loose stools, stomatitis, punctate
necrolysis (TEN) are severe cutaneous adverse drug cutaneous eruption, central nervous system (CNS)
reactions6. SJS/TEN is rare but is fatal. Extensive manifestations like headache, fatigue, impaired
epidermal necrosis, associated with mucous concentration, alopecia, fever (either drug-related or
membranes, and progressive severe skin detachment due to infection), and hematologic abnormalities,
characterize SJS and TEN, with SJS involving less than particularly macrocytosis8,9.
10% of body surface area and having a mortality rate of To mitigate the toxic effects of methotrexate,
1-5%. In comparison, TEN involves more than 30% leucovorin, a fully reduced folate coenzyme, can be
skin detachment and has a mortality rate of 25-30%. administered. Leucovorin replenishes the intracellular
The disease initiates with influenza-like symptoms with pool of FH4 cofactors, helping terminate the toxic
a prodromal phase lasting 1 to 14 days. Patients may effects of methotrexate7.
experience fever, sore throat, headache, malaise, and
chills. Eventually, mucocutaneous lesions appear
Conclusion
rapidly. Initially, rashes appear as macules and
progress into papules, vesicles, bullae, or confluent Stevens Johnson syndrome is a rare but fatal adverse
erythema6. These lesions are primarily flat, irregular, drug reaction associated with drugs like NSAIDs,
and atypical target-shaped or widespread purpuric paracetamol, penicillin, cephalosporin, anti-
macules. The disease can progress to involve oral, convulsants9 and levofloxacin10. There are sparse
nasal, ocular, vaginal, urethral, gastrointestinal, and reports of SJS induced by methotrexate5. We present
lower respiratory tract mucous membranes. There is this case to raise awareness and educate clinicians
also a risk of necrosis developing in the gastrointestinal about the need for caution when using methotrexate.
and respiratory systems in severe cases. Many Even in patients with a previous history of SJS, it is
patients affected by this condition also experience essential to avoid using drugs known to have the
ocular involvement7. potential to cause SJS.11
Early identification of this adverse drug reaction is Declaration of patient consent
crucial. It is essential to discontinue the use of all The authors certify that they have obtained all appro-
potentially causative medications, especially those priate patient consent forms. The patient understand
administered within one month before the onset of the that their names and initials will not be published, and
reaction. The diagnosis of SJS or TEN is primarily due efforts will be made to conceal their identity, but
made based on clinical assessment, but it is crucial to anonymity cannot be guaranteed.
confirm the diagnosis through histopathological
examination7.
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