JCDR 10 FC01
JCDR 10 FC01
JCDR 10 FC01
DOI: 10.7860/JCDR/2016/16430.7047
Original Article
ABSTRACT
Aim: The study sought to identify the magnitude and
characteristic of severe cutaneous adverse reactions (SCARs)
like StevenJohnson syndrome (SJS) and Toxic Epidermal
Necrolysis (TEN).
Materials and Methods: A prospective study was conducted
by the Department of Pharmacology in association with
Department of Dermatology in SMHS hospital. The study was
carried out from June 2013-June 2015 on hospitalized cases
of cutaneous adverse drug reaction reporting in hospital. The
SCARs were reported in a structured questionnaire based on
adverse drug reaction (ADR) reporting form provided by the
Central Drug Standard Control Organization (CDSCO) Ministry
of Health and Family welfare, Government of India. The SCARs
were analysed for their characteristics, causality, severity and
prognosis. Causality assessment was done by using a validated
ADR probability scale of Naranjo as well as WHO Uppsala
Monitoring Center (WHO-UMC) system for standardized case
causality assessment. The management protocol were analysed
for their clinical outcome through a proper follow up period.
Introduction
Adverse drug reactions (ADRs) are the inevitable consequence of
pharmacotherapy. Cutaneous manifestations are among the most
frequent adverse reaction to drugs [1]. Several multicentric trails
have established that acute cutaneous reaction to drugs affected
3% of hospital inpatients. Reactions usually occur a few days to
4 weeks after initiation of therapy [2]. SJS and TEN are two rare
acute life threatening SCARs characterized by mucocutaneous
tenderness, erythema, and extensive exfoliation and detachment of
epidermis. SJS is characterized by <10% of body surface area of
epidermal detachment, SJS-TEN overlap by 10-30% and TEN by
>30%. SJS and TEN have an annual incidence of 1.2-6 and 0.4-1.2
per million peoples respectively. Both effect women more frequently
than men with a ratio of 1.5:1 and the incidence increases with
age [3-6]. The average mortality rate is 1-5% for SJS and 25-35%
for TEN. Elderly, immunocomprised and those on radiotherapy are
at higher risk. Around 100 drugs have been identified as causal
agents of SJS/TEN [3,4,7-12]. Most frequently implicated drugs
are sulphonamides, antibiotics, oxicam NSAIDs, quinolones, AEDs
and allopurinol [13].
In view of the above facts a prospective study was undertaken with
an objective to estimate risk of SJS and TEN associated with use
of specific drugs in patients of North Indian ethnic background.
Journal of Clinical and Diagnostic Research. 2016 Jan, Vol-10(1): FC01-FC04
Samina Farhat et al., Antecedent Drug Exposure and Management in SJS and TEN
RESULTS
A total of 52 patients were identified as CADRs of which 15 cases
(28%) were SCARs of these 9 (17%) cases were diagnosed as SJS
and 6 (12%) cases as TEN. SJS was seen in 2 (22%) males and 7
(78%) females while as TEN was diagnosed in females only.
The study revealed that these events were associated more
commonly with short term therapy with agents like lamotrigine,
carbamazepine, valproic acid and phenytoin. The other drugs
associated were levofloxacin, oxicam NSAIDs and Ibuprofen. The
study revealed that almost all cases of SJS/TEN develop within
two months of use of aromatic anticonvulsant and within 3 week of
Prognostic factors
Points
Glycaemia >14mmol/L
SCORTEN
1
Probability of death(%)
0-1
12
35
58
90
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Discussion
The results in [Table/Fig-2] suggest that in a series of cases short
term use of AEDs act as a culprit in 56% of SJS/TEN patients
followed by NSAIDs use. The study revealed a mean age of 37
years in SJS/TEN patients. Aromatic anticonvulsants, lamotrigine,
NSAIDs, sulfasalazine and quinolones are among the high risk
medications most frequently associated with SJS/TEN [5,11,18,19].
Lamotrigine a phenyltriazine is a new anticonvulsant and has shown
its efficacy for prophylaxis of depression in bipolar disorders.
Our study reveals 2 cases of SJS and 2 cases of TEN which are
associated with LTG use and reaction occurs within 3 weeks after
the initiation of therapy. This is in conformity with other studies where
LTG has strong association with SJS/TEN. In two cases of our
study valproate is a concomitant drug with LTG. Its concomitant use
with LTG significantly increases the risk for development of adverse
cutaneous reaction. [20]. Valproate increases plasma levels of LTG
by inhibiting its metabolism [21,22]. Moreover, there have been
several case reports on the short term use of LTG in association of
SJS and TEN [23-28].
Other drugs including aromatic AEDs show an onset of reaction
within 1-2 months. The results are obviously showing predilection
for female gender. Despite, no evidence based medicine standards
of acceptance; present study reveals that all the patients responded
well to short-term administration of systemic corticosteroids without
any mortality. In patients, where AED therapy were offending agents
the drugs were withdrawn immediately as a measure for prevention
of drug reaction and were switched to Levetiracetam and Clobazam
to maintain seizure free remission.
Since the uncertainty persists regarding the well defined treatment
modalities of SJS/TEN other treatment protocols besides system
corticosteroids are high dose immunoglobulins (IVIG) [29-31],
thalidomide [32], cyclosporine [33,34], TNF-antagonists [35],
plasmapheresis/plasma exchange [36] and cyclophosphamide
[37].
In view of the pharmacogenetic influences underlying great number
of drug reactions like HLA-B 1502 being associated with SJS/TEN
induced by CBZ, PHT, and LTG [38]. HLA-B 5801 with allopurinol
induced SCARs [39] and HLA-B 5701 with abacavir hypersensitivity
[40]. It is also suggested that ethnicity has a role to play in difference of
the individual genetic susceptibility [41]. A pharmacogenomic study
done on CBZ has shown a strong association of HLA-A-3101 and
CBZ- hypersensitivity in Caucasian patients [42]. This association
encompasses all forms of cutaneous eruptions besides SJS/TEN.
This is in contrary to association of HLA-B 1502 which is specific
for SJS/TEN in Chinese patients. The association with HLA-A 3101
and CBZ hypersensitivity has been replicated in Japanase [43],
South Korean [44] and Canadian populations [45].
More recently, drug labels of various drugs have been altered by
the US Food and Drug Administration (FDA) and by the European
Journal of Clinical and Diagnostic Research. 2016 Jan, Vol-10(1): FC01-FC04
www.jcdr.net
S.No
Samina Farhat et al., Antecedent Drug Exposure and Management in SJS and TEN
Age/Sex
Drug Therapy
35/F
Lamotrigine (LTG)
Dose
12.5mg/day Initially
Followed by 25mg/day,
Then 50mg/day
Concomitant drugs
Cutaneous
manifestation
Indications
Days to onset
Seizures with
BPAD
20
Quetiapine SR 200mg
Sodium valproate (600mg/day)
Etizolam (1mg/day)
Propanolol (40mg/day)
SJS
BPAD
15
Metoprolol SR 100mg/day
Clonidipine 10mg/day
Olmesartan 20mg/day
Rosuvastatin 5mg/day
Quetiapine 25mg/day
Clopidogril 75mg/day Aspirin 75mg/
day
SJS
58/F
LTG
30/F
LTG
25mg/day,
BPAD with
depression
15
Paroxetine
Clonezepam 12.5mg/day
TEN
30/F
CBZ
200mg/day,
Trigeminal
Neuralgia
10
Naproxen -500mg/day
TEN
300mg/day
OLE
post traumatic
epilepsy
10
Gabapentin 400mg/day
Nortryptiline 10mg/day
Citicoline 500mg/day
Piracetam 400mg/day
Vit B complex
SJS
Ankylosing
spondylitis
15
Thiocholchicoside 8mg/day
SJS
60/M
PHT
26/M
NSAID
50/F
Levofloxacin
750mg/day
UTI
10
None
TEN
60/F
Piroxicam
LBA
None
SJS
27/F
Ibuprofen
1200mg/day
For 2-3days
Osteoarthritis
Paracetamol 1000mg/day
SJS
10
24/F
Levofloxacin
RTI
None
TEN
11
50/F
Piroxicam
LBA
None
SJS
12
35/F
Sulfasalazine
(delayed release
form)
Aceclofenac 100mg/day
Thiocholchicoside 4mg/day
SJS
13
54/F
LTG
Valproate 1200mg/day
Levothroxine 50mcg/day
TEN
14
20/F
CBZ
15
16
17/F
22/F
CBZ/PHT
PHT
NA
Rheumatoid
arthiritis
1
month
GTCS
28
GTCS
2 months
None
TEN
GTCS
2 months
None
TEN
PHT 300mg/day
Focal epilepsy
1 month
AKT-4
R-450/mg /day
Z-1500mg/day
E 800mg/day
H-300mg/day
SJS
Medicine agency (EMA), which requires testing for HLA prior to the
prescription of drug concerned.
Realizing the importance of these genetic susceptibilities it is highly
recommended that genotyping be undertaken as a screening
measure for these HLA-B alleles in North Indian ethnic population
prior to prescription of these respective drugs.
CONCLUSION
The present study illustrates that inspite of rare occurrence of
SJS/TEN North Indian ethnic population has great predisposition
of SCARs due to aromatic AEDs, LTG, oxicam NSAIDs and
quinolones. These reactions need to be reported at an earliest as
it has an instrumental role and forms an important component of
pharmacovigilance programmes. Patients should be educated
to avoid re-exposure to suspect drug (s) to yield outcome based
results.
Journal of Clinical and Diagnostic Research. 2016 Jan, Vol-10(1): FC01-FC04
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PARTICULARS OF CONTRIBUTORS:
1.
2.
3.
Associate Professor and Head, Department of Pharmacology, Government Medical College (GMC), Srinagar, India.
Lecturer, Department of Pharmacology, Government Medical College (GMC), Srinagar, India.
Professor and Head, Department of Dermatology, Government Medical College (GMC), Srinagar, India.