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 Table of Contents  
CASE REPORT
Year : 2021  |  Volume : 7  |  Issue : 2  |  Page : 91-94

Single dose etanercept monotherapy for treating Stevens–Johnson syndrome


1 Department of Dermatology, Command Hospital, Pune, Maharashtra, India
2 Department of Dermatology, Armed Forces Medical College, Pune, Maharashtra, India
3 Department of Pathology, Command Hospital, Pune, Maharashtra, India
4 Department of Community Medicine, AFMC, Pune, Maharashtra, India

Date of Submission28-Jun-2020
Date of Decision03-Jun-2021
Date of Acceptance01-Sep-2021
Date of Web Publication14-Dec-2021

Correspondence Address:
Vikas Pathania
Department of Dermatology, Command Hospital (SC), Pune, Maharashtra 411040.
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdd.ijdd_37_20

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  Abstract 

Stevens–Johnson syndrome (SJS) is a delayed type hypersensitivity reaction to drugs and less commonly infections. The entity represents one end of the spectrum of SJS-TEN (Toxic Epidermal Necrolysis) complex. Together, both conditions contribute to the majority of Severe Cutaneous Drug Reactions (SCARs) with high mortality and morbidity. Clinically, it presents with widespread painful erythematous macules, targetoid lesions, full-thickness or focal epidermal necrosis while mucosal involvement involves oral, genital, and ocular mucous membranes along with preceding prodromal flu like symptoms. While there is no consensus on the treatment of choice, systemic steroids, intravenous immunoglobulin and cyclosporin are most often employed for specific management of SJS-TEN. We report a case of SJS managed with a single dose of etanercept monotherapy.

Keywords: Etanercept, SJS, Stevens-Johnson syndrome, TNF-alpha


How to cite this article:
Pathania V, Kothari R, Tripathy DM, Sengupta P, Vashisht D, Shankar P. Single dose etanercept monotherapy for treating Stevens–Johnson syndrome. Indian J Drugs Dermatol 2021;7:91-4

How to cite this URL:
Pathania V, Kothari R, Tripathy DM, Sengupta P, Vashisht D, Shankar P. Single dose etanercept monotherapy for treating Stevens–Johnson syndrome. Indian J Drugs Dermatol [serial online] 2021 [cited 2022 Jan 25];7:91-4. Available from: https://www.ijdd.in/text.asp?2021/7/2/91/332422




  Introduction Top


Stevens–Johnson syndrome (SJS) is one of the severe cutaneous adverse drug reactions (SCARs) which lies within the continuum between erythema multiforme major (EMM) and toxic epidermal necrolysis (TEN). The condition was first reported in 1922 by Stevens and Johnson as “new eruptive fever with stomatitis and ophthalmia” in two children.[1],[2]Commonly implicated triggers include drugs, infectious agents such as Mycoplasma pneumoniae, re-activation of cytomegalovirus, herpes virus, and dengue virus, and mumps measles rubella vaccination and contrast agents have also been reported as potential causes.[3] Currently, systemic glucocorticoids, cyclosporine, and intravenous immunoglobulin are the most prevalent options available for specific management.[4],[5],[6] We report a case of SJS managed with a single dose of etanercept monotherapy.


  Case History Top


A 42-year-old male, an old case of right middle cerebral artery territory infarct diagnosed 2 years back on tab aspirin and atorvastatin, presented with complaints of fever with multiple red raised painful lesions over the body and multiple painful oral erosions following introduction of tab oxcarbazepine 11 days back for sensory neuropathy of right upper limb. The oral lesions and fever which were of moderate grade and not associated with chills or rigors preceded the skin lesions by 24 h which presented as painful dusky red lesions over the face predominantly, over the cheeks initially that coalesced over the next 48 h and simultaneously developed similar but smaller lesions over rest of the body which were painful and were not associated with any itching. Over the next 48 h, vesicles developed over some of the lesions rupturing to form hemorrhagic crusted erosions. Fever subsided with antipyretics and did not occur after the first day. There was no history of any other novel drug intake, vaccination, history suggestive of other mucosae being involved or any systemic symptoms. There was no history of photosensitivity, joint pains, or similar episodes in the past.

On examination, he was febrile with a temperature of 100.9°F with tachycardia of 126/min, which was regular in rhythm. Dermatological examination revealed involvement of around 10% body surface area (BSA) in the form of multiple discrete well-defined purpuric lesions with central hemorrhagic blisters and crusting showing targetoid morphology distributed over the face (predominantly the malar prominences, bridge of nose with relative sparing of the nasolabial folds), neck, trunk, upper extremities, and both thighs [Figure 1]b. Nikolsky’s sign was positive over the lesions. Multiple confluent erosions were noted over labial and buccal mucosae with hemorrhagic crusting and purulent discharge covering the entire lips [Figure 1]a. Other mucosae were spared and rest of the dermatological examination was normal.
Figure 1: (A): Multiple erosions over labial mucosa with haemorrhagic crusting and purulent discharge over the lips. (B): Multiple erythematous targetoid papules and plaques with central haemorrhagic blisters and crusting

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On evaluation, all hematological, biochemical, and radiological investigations were normal except serum bicarbonate levels which were reduced to 19 mEq/L. Antinuclear antibody (ANA) by indirect immunofluorescence (IIF) was negative. Blood and urine cultures were sterile. An interferon gamma release assay was done for the patient which was negative. A skin biopsy performed on the day of admission revealed subepidermal bulla with necrotic keratinocytes with sparse perivascular lymphocytic infiltrate in the dermis [Figure 2]. SJS and TEN such as acute cutaneous lupus and bullous pemphigoid were kept as probable differential diagnosis. Direct immunofluorescence performed on the skin biopsy was negative ruling out bullous pemphigoid, and a negative ANA excluded acute cutaneous lupus. Based on history, temporal drug profile, clinical presentation, and histopathology, he was diagnosed as a case of SJS/TEN with a SCORTEN of 3 at presentation with a Naranjo probability score of 9 for oxcarbazepine as the implicated drug.
Figure 2: Section from a representative lesion showing pan-epidermal necrosis, dermo-epidermal split, and extravasated RBCs with sparse perivascular lymphocytic infiltrate in dermis (H & E stain, 100x)

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The patient was managed in intensive care setting with immediate withdrawal of the offending drug, burns dressings for the skin lesions, Condy’s lotion, and 2% mupirocin ointment for oral mucosa and lips and a meticulous fluid and dietary management. As the patient’s comorbidities (stroke in young) precluded the use of oral steroids and cyclosporine due to their associated adverse effects such as hypertension and with no contraindication to tumor necrosis factor (TNF)-α inhibitors for which he was adequately worked up, a single dose of inj. etanercept 50 mg subcutaneously was therefore administered. In the absence of any evidence of sepsis on investigations, systemic antibiotics were withheld. He responded well to the treatment in the form of no new lesions after the injection and the existing lesions started crusting and re-epithelialization had begun after day 5 of the injection over body lesions [Figure 3]b and after day 10 of the injection over lips and face associated with post-inflammatory hyperpigmentation [Figure 3]a. The oral mucosal lesions took around 2 weeks to heal. All the lesions healed completely leaving behind post-inflammatory hyperpigmentation in 3 weeks.
Figure 3: (A): Well-healed lip erosions and facial lesions with post-inflammatory hyperpigmentation at day 9 following inj. etanercept. (B): Initial lesions showing crusting and re-epithelization at day 5 following inj. etanercept

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  Discussion Top


SJS-TEN represents a spectrum of SCARs where there is extensive involvement of skin and mucosae leading to epidermal separation and life-threatening complications. The SJS end of spectrum is defined as involvement of two or more mucosal sites and a relatively smaller percentage of BSA (<10%) when compared with TEN. Immunopathologically, it is essentially a delayed type hypersensitivity response to a drug-peptide complex in HLA-mediated genetically susceptible individuals. The pathogenesis centers around CD8+ and natural killer (NK) lymphocytes. Keratinocyte apoptosis is mediated through fas-fas ligand, granulysin–perforin pathway, and TNF-α.[3],[6] Drugs are the most common causative agents high of SJS/TEN, and aromatic anti-epileptics (phenytoin, carbamazepine, and lamotrigine) are very commonly implicated. Other commonly implicated drugs include allopurinol, nevirapine, sulfonamides, and oxicam non-steroidal anti-inflammatory drugs.[3] In our patient, tab oxcarbazepine, a congener of carbamazepine, was identified as the definite implicated drug with a Naranjo probability score of 9.[7]

Management of SJS-TEN is a multi-disciplinary procedure including ophthalmology, otorhinolaryngology, intensivist, and urologist. A patient of SJS-TEN has to be managed in an ICU setting/burns unit with prompt general and specific measures. After immediate withdrawal of the offending drug, general measures include strict reverse barrier nursing at 30–32°C, meticulous fluid, and electrolyte management. Local wound care is extremely important to maintain the skin barrier and to prevent infection. No specific agent has been proven to be mainstay for the management of SJS-TEN. However, systemic corticosteroids, cyclosporine, intravenous immunoglobulin, and plasmapheresis have been used successfully in the past. Corticosteroids delay epithelialization, whereas cyclosporine can lead to life-threatening hypertension and nephrotoxicity, especially in at-risk patients.[4],[6] There is a growing body of evidence in recent literature establishing anti-TNF-α agents as novel alternatives for the management of these cases. Infliximab and etanercept have been shown to be highly effective in arresting the disease process.[8],[9] Administration of single dose of etanercept provides the treating dermatologist a simpler and effective option which requires just one time administration curbing additional investigations for monitoring adverse effects of drugs such as corticosteroids and cyclosporine. Our patient was worked up for etanercept and had no contraindications and therefore was managed with single inj. etanercept 50 mg monotherapy with clinical response within 5 days and complete recovery over 20 days.

In a large case series of TEN cases treated with a single dose of 50 mg of etanercept subcutaneously by Paradisi et al.,[10] the median time to re-epithelization without complications or side effects to the drug was 8.5 days which was less compared with other existing therapies. In another randomized controlled trial by Wang et al.,[11] etanercept decreased the SCORTEN-based predicted mortality rate (predicted and observed rates, 17.7% and 8.3%, respectively) and significantly reduced the median skin-healing time in moderate-to-severe SJS-TEN patients when compared with corticosteroids (14 and 19 days for etanercept and corticosteroids, respectively). However, given the fact that TNF-α agents are essentially immunosuppressants, their judicious use is conditional to the nature of comorbid conditions, enhanced susceptibility to infection, and the fact that by themselves TNF-α agents have been implicated in causation of SJS-TEN. The case highlights the increasing role of monotherapy with single dose etanercept in successful and safe management of SJS-TEN.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Stevens AM, Johnson FC. A new eruptive fever associated with stomatitis and ophthalmia. Am J Dis Child 1922;24:526.  Back to cited text no. 1
    
2.
Lyell A. Toxic epidermal necrolysis: An eruption resembling scalding of the skin. Br J Dermatol 1956;68:355-61.  Back to cited text no. 2
    
3.
Schwartz RA, McDonough PH, Lee BW. Toxic epidermal necrolysis. J Am Acad Dermatol 2013;69:173.e1-13.  Back to cited text no. 3
    
4.
Kumar R, Das A, Das S. Management of Stevens–Johnson syndrome-toxic epidermal necrolysis: Looking beyond guidelines! Indian J Dermatol 2018;63:117-24.  Back to cited text no. 4
    
5.
Zimmermann S, Sekula P, Venhoff M, Motschall E, Knaus J, Schumacher M, et al. Systemic immunomodulating therapies for Stevens–Johnson syndrome and toxic epidermal necrolysis. JAMA Dermatol 2017;153:514.  Back to cited text no. 5
    
6.
Schneider JA, Cohen PR. Stevens–Johnson syndrome and toxic epidermal necrolysis: A concise review with a comprehensive summary of therapeutic interventions emphasizing supportive measures. Adv Ther 2017;34:1235-44.  Back to cited text no. 6
    
7.
Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.  Back to cited text no. 7
    
8.
Woolridge KF, Boler PL, Lee BD. Tumor necrosis factor α inhibitors in the treatment of toxic epidermal necrolysis. Cutis 2018;101:E15-21.  Back to cited text no. 8
    
9.
Zhang S, Tang S, Li S, Pan Y, Ding Y. Biologic TNF-alpha inhibitors in the treatment of Stevens–Johnson syndrome and toxic epidermal necrolysis: A systemic review. J Dermatol Treat 2020;31:66-73.  Back to cited text no. 9
    
10.
Paradisi A, Abeni D, Bergamo F, Ricci F, Didona D, Didona B. Etanercept therapy for toxic epidermal necrolysis. J Am Acad Dermatol 2014;71:278-83.  Back to cited text no. 10
    
11.
Wang C-W, Yang L-Y, Chen C-B, Ho H-C, Hung S-I, Yang C-H, et al. Randomized, controlled trial of TNF-α antagonist in CTL-mediated severe cutaneous adverse reactions. J Clin Invest 2018;128:985-96.  Back to cited text no. 11
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

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