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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 14  |  Issue : 5  |  Page : 67-75

Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum for the rheumatologist


1 Department of Immunology and Rheumatology, IMS and SUM Hospital, Bhubaneswar, Odisha, India
2 Department of Rheumatology, S. C. B. Medical College and Hospital, Cuttack, Odisha, India

Date of Web Publication2-Dec-2019

Correspondence Address:
Dr. Saumya Ranjan Tripathy
Department of Rheumatology, S. C. B. Medical College and Hospital, Cuttack - 753 007, Odisha
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-3698.272155

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  Abstract 


Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) represent a spectrum of mucocutaneous manifestations characterized by widespread epidermal and/or mucosal detachment from dermis. It occurs due to Type IV hypersensitivity leading to keratinocyte apoptosis. Many extrinsic and intrinsic defects in the apoptotic pathway have been postulated to result in its dysregulation. The characteristic skin lesions of SJS/TEN include ill-defined, coalescing, red macules with necrotic centers followed by extensive epidermal detachment. Mucosa is involved in up to 90% of cases causing erosions and crusts that may precede or follow skin lesions. Supportive care is the mainstay of treatment and if not started promptly may result in high mortality and morbidity. Although many immunosuppressive drugs have been tried in treatment, no treatment has proven beneficial except cyclosporine which has been shown to retard the progression of SJS/TEN. A patient with SJS/TEN as a presenting feature poses two-fold challenge to a rheumatologist as it could be a manifestation of lupus or side effects of a myriad of drugs used by the rheumatologist.

Keywords: Adverse effects, drug induced, Stevens-Johnson syndrome, toxic epidermal necrolysis


How to cite this article:
Parida JR, Tripathy SR. Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum for the rheumatologist. Indian J Rheumatol 2019;14, Suppl S1:67-75

How to cite this URL:
Parida JR, Tripathy SR. Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum for the rheumatologist. Indian J Rheumatol [serial online] 2019 [cited 2019 Dec 7];14, Suppl S1:67-75. Available from: http://www.indianjrheumatol.com/text.asp?2019/14/5/67/272155




  Introduction Top


 Stevens-Johnson syndrome More Details/toxic epidermal necrolysis (SJS/TEN) spectrum of manifestations represent a potentially life-threatening constellation of mucocutaneous reactions.[1] They are characterized morphologically by widespread epidermal and/or mucosal detachment from the underlying tissue secondary to keratinocyte apoptosis.[2]


  History Top


Stevens and Johnsons in 1922 described two children with skin exanthema and eruptions distinct from erythema multiforme (EM), fever, stomatitis, and conjunctivitis, which laid the cornerstone for the recognition of severe cutaneous adverse reactions (SCARs).[3] A more aggressive form of scalding skin reaction was described in a series of four patients by Lyell, who coined the term TEN in recognition of the disease being limited to epidermal detachment and exclusion of dermis.[4] Bastuji-Garin et al. gave the first classification system of the severe adverse cutaneous reactions, describing a spectrum of five different types of skin reactions: (a) bullous EM - detachment <10% of body surface area (BSA) plus localized typical targets or raised atypical targets; (b) SJS - detachment <10% BSA plus widespread macules or flat atypical targets; (c) overlap SJS-TEN - detachment between 10% and 30% of BSA plus widespread macules or flat atypical targets; (d) TEN with spots with or without blisters - detachment >30% BSA plus widespread macules or flat atypical targets; and (e) TEN without spots - detachment >10% BSA with large epidermal sheets and without any macules or targets.[5] Subsequently, differences between EM and SJS/TEN spectrum both in terms of severity and demography were recognized. EM was more commonly found in young males, with milder mucosal involvement; lesser degree of systemic symptoms; and lack of association with HIV, malignancies, and connective tissue disorders.[6] As per the definitions of the World Allergy Organization (2014), SCARs include SJS/TEN spectrum, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis.[1],[7]


  Why Should a Rheumatologist Know About Stevens-johnson Syndrome/toxic Epidermal Necrolysis? Top


From a rheumatologist's perspective, SJS/TEN spectrum of manifestations are important because of two main reasons. First, rheumatologists deal with drugs which have the potential to cause SJS/TEN syndrome. Second, SJS/TEN spectrum may be the manifestation of some connective tissue disorders, especially lupus which must be differentiated from drug/infection-induced SJS/TEN spectrum. The current review will attempt to highlight the immunologic basis of the pathogenesis of SJS/TEN, potential risk of SJS/TEN spectrum with antirheumatic drugs, clinical features of SJS/TEN as well as special features of systemic lupus erythematosus (SLE)-associated SJS/TEN, and finally the management and prognosis of patients suffering from SJS/TEN.


  Epidemiology Top


SJS/TEN spectrum of manifestations is rare and thus there are few epidemiologic studies. Worldwide, the incidence of SJS and TEN is estimated to be between 1-6 and 1-2 per million/year.[2] In a recent study from USA, the mean estimated annual incidence rates of SJS, SJS/TEN overlap, and TEN were 9.2, 1.6, and 1.9 per million adults, respectively.[8] The mortality rates of SJS, SJS/TEN overlap, and TEN in the study were 4.8%, 19.4%, and 14.8%, respectively. The rate of SJS/TEN spectrum was higher (2-3-fold increased risk) in Africans and Asians compared to Caucasians.[8],[9] The limited data from India reveal that the incidence rate of SJS and TEN varies from 1.2 to 6/million patient-years and 0.4 to 1.2/million patient-years, respectively.[10] The mortality rate in TEN is estimated to be three times higher than SJS. Although both sexes can be affected by SJS/TEN spectrum, females were found to be affected slightly more commonly than males.[8],[9]

Data on the prevalence of SJS/TEN in rheumatologic diseases are scarce. In a multicentric Brazilian study, 0.6% of 852 female patients with childhood-onset SLE were detected to have SJS/TEN.[11] In a study from UK, patients with SLE had increased risk of developing SJS/TEN (odds ratio [OR] =16, 95% confidence interval [CI] = 1.79-143.15).[9] Apart from SLE, the only other rheumatologic disease found to have a high risk of SJS/TEN was gout, with the introduction of allopurinol (OR = 20.48, 95% CI = 2.39-175.19).[9]


  Pathophysiology Top


The exact pathophysiology of SJS/TEN is unclear. Classically, it is considered to be a Type IV hypersensitivity reaction in which the final result is keratinocyte apoptosis leading to epidermal detachment from underlying dermis.[12] Necroptosis is another form of programmed cell death, which is postulated to cause SJS/TEN. It can be induced by annexin A1, secreted by monocytes reacting with formyl peptide receptor 1.[13] Inhibition of necroptosis prevented occurrence of SJS/TEN in mouse models.[14]

The apoptotic pathway may be activated intrinsically or extrinsically. The intrinsic pathway is usually activated in SJS/TEN by electrophilic drug metabolites and/or via reactive oxygen species.[15] The extrinsic pathway is usually activated by the Fas/FasL pathway. Fas is usually membrane-bound on keratinocytes and is activated by FasL, expressed by activated cytotoxic T-lymphocytes (CTL) and natural killer (NK) cells. Viard et al. demonstrated Fas-mediated increased cell death in frozen skin sections from TEN patients compared with skin sections from healthy or from non-SJS/TEN maculopapular rashes.[14] In contrast, Nassif et al. found lack of FasL on blister lymphocytes and inability of anti-Fas monoclonal antibodies to inhibit cytotoxicity of blister CTLs.[16] A second mechanism of Fas-activation by soluble FasL (sFasL) has been proposed. Serum sFasL is increased in early stages of TEN. It is secreted by keratinocytes and peripheral blood mononuclear cells.[17] However, sFasL is not specific for SJS/TEN and is found in other drug reactions. Furthermore, the cytotoxicity of sFasL is 1000 times less compared to membrane-bound FasL.[18]

CTLs also mediate cell death in keratinocytes via cytotoxic proteins: perforin-granzyme and granulysin. Attenuation of blister fluid lymphocytes by inhibition of the perforin-granzyme pathway supports the role of this pathway in SJS/TEN.[18] Granulysins disrupt the charge on cell membranes and trigger mitochondrial dysfunction and apoptosis. High serum granulysin is found 2-4 days before the onset of SJS/TEN. In mouse models, TEN-like lesions can be induced by intracutaneous injection of granulysin.[19] However, granulysin is not specific to SJS/TEN.[16]

Two novel pathways have been proposed in SJS/TEN. Micro-RNAs (miRs) are short nucleotide chains with regulatory function. Serum miR-18a-5p correlates with severity of SJS/TEN. Transfection into keratinocytes inhibits anti-apoptotic BCL2L10 and increases caspase-9 activation and apoptosis.[20] The second pathway is the interaction between HLA-E expressed on keratinocytes and HLA-E receptor (NKG2C/CD94) expressed by peripheral blood T-cells and NK-cells, thereby triggering T-cell receptor (TCR)-independent cytotoxicity in T- and NK-cells leading to SJS/TEN.[21]

Other cells

T-reg cells are reduced in number and function and are unable to inhibit CTLs. Th17-cells, especially those expressing skin-homing molecules (CLA + CCR4+), are increased and help recruit neutrophils and other inflammatory cells contributing to skin damage.[22] Monocytes expressing costimulatory molecules CD137 and CD80/86 activate and increase cytotoxicity of CTLs by binding with CD137 L and CD28, respectively.[18]

Cytokines and Chemokines

The various cytokines that are implicated include tumor necrosis factor (TNF)-α; interferon (IFN)-γ; TRAIL; TWEAK; interleukin (IL)-2, 5, 6, 10, 12, 13, 15, and 18; CCR3; CXCR3; CXC4; CXCR10; and CCL27.[18] TNFα and IFN-γ increase inducible nitric oxide synthase and expression of FasL.[23] TNF, TWEAK, and TRAIL can induce apoptosis by the Fas-pathway. The other cytokines help in trafficking, activation, regulation, and proliferation of inflammatory cells.

Now after understanding the mechanisms by which cell death is triggered and the central role played by CTLs, it is also important to understand how these T-cells are stimulated by drugs in the first place. Currently, there are four theories which attempt to explain activation of CTLs by drugs: [18]

  1. Hapten-prohapten theory: The inciting drugs are themselves inert but produce active metabolites called haptens that bind inert carrier proteins to form neoantigens and trigger T-cells through antigen presenting cells
  2. Pharmacological interaction (p-i) theory: Drugs can directly bind to TCRs and/or HLA molecules to trigger specific T-cells
  3. Altered peptide theory: The drug binds to the pocket of a specific HLA but not to other closely related HLA. The drug-HLA complex structure is altered before the HLA gets loaded with the peptide to be presented. Thus, even when self-peptides are presented, the T-cells recognize them as neoantigens and become reactive
  4. Altered TCR theory: The drug binds TCR instead of HLA and alters the structure leading to the same malfunction of transmitting a signal of neopeptide as in altered peptide theory.


Apart from the hapten theory, the other three theories tend to support the idea of HLA association with drug sensitivity and predisposition to SJS/TEN.


  Genetic Predisposition Top


SJS/TEN spectrum is not an inherited condition. However, strong association between certain genes and predisposition to drug-induced SJS/TEN has been detected. Genetic association of some drugs which a rheumatologist may often use is described in [Table 1].
Table 1: Drugs implicated in Stevens-Johnson syndrome/toxic epidermal necrolysis with HLA predisposition and ethnicity where the predisposition is detected1

Click here to view



  Drugs Used by Rheumatologists Associated With Stevens-johnson Syndrome/toxic Epidermal Necrolysis Top


There is a long list of drugs implicated to be associated with SJS/TEN. A rheumatologist deals with medicines used in general by any internist (such as antibiotics, antihypertensives, antidiabetics, and antiepileptics) as well as special molecules for rheumatologic diseases such as nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, disease-modifying antirheumatic drugs (DMARDs) (conventional synthetic, biologics and biosimilars, and targeted synthetic small molecules), urate-lowering therapy (allopurinol and febuxostat), and others. Most data available on drugs causing SJS/TEN are based on case reports or small case series. However, the RegiSCAR/EuroSCAR registry has enabled us to understand and classify the more commonly used drugs associated with SJS/TEN as high risk, moderate risk, or low risk[24] [Table 2].
Table 2: Drugs commonly associated with Stevens-Johnson syndrome/toxic epidermal necrolysis25

Click here to view


On the other hand, many new drugs have come up since the publication of these data especially biologics and targeted synthetic DMARDs such as the Janus kinase inhibitors (tofacitinib and baricitinib). [Table 3] enlists the special drugs used by a rheumatologist for which anecdotal reports of SJS are available.
Table 3: Drugs used by rheumatologists associated with Stevens-Johnson syndrome/toxic epidermal necrolysis

Click here to view


Allopurinol is the most common drug implicated for SJS/TEN in the RegiSCAR data. At doses ≥200 mg/day, the risk of SJS/TEN is increased (adjusted OR = 36; 95% CI = 17-76) than lower doses (adjusted OR = 3.0, 95% CI = 1.1-8.4). A systematic review of Indian data implicated antimicrobials (37.27%), antiepileptic (35.73%), and NSAIDs (15.93%) as the most common drugs causing SJS/TEN. Carbamazepine (18.25%), phenytoin (13.37%), fluoroquinolones (8.48%), and paracetamol (6.17%) were the most commonly implicated drugs.[34] However, it is also important to note that even for the drugs having the highest relative risk of SJS, the actual incidence/absolute risk still remains very low (1/1000-1/100,000).[24]


  Other Etiologies Top


SJS/TEN can also be triggered by various infections such as viruses (herpes simplex virus, HIV, Epstein-Barr virus, enteroviruses, and others), bacteria (mycoplasma, mycobacteria, Group-A beta-hemolytic streptococcus, and others), fungi (paracoccidioidomycosis and histoplasmosis), and protozoa (malaria). Malignancies such as carcinomas and lymphomas have also been associated. Still, SJS/TEN remains idiopathic in 25%-50% of cases.[35]


  Clinical Features Top


The mucocutaneous manifestations of SJS/TEN may be preceded by a prodrome of 1-3 days characterized by high-grade fever (<38°C), malaise, myalgia, arthralgia, photophobia, conjunctival itching, or difficulty in swallowing. Exanthematous eruptions may be seen in some patients at this phase.

Skin lesions

The characteristic skin lesions of SJS/TEN include ill-defined, coalescing, red macules with purpuric/necrotic centers.[36] These lesions may be associated with intense pain and erythema. Typically, they start on the face and thorax, followed by other areas and are often symmetrical.[37] They usually spare scalp, palms, and soles.[38] With disease progression, vesicles and bullae form and the skin begins to slough within days [Figure 1]. Two important clinical signs of SJS/TEN are the Nikolsky sign (dislodgement of intact superficial epidermis by a gentle lateral pressure, indicating a plane of cleavage at the dermoepidermal junction) and the bulla spread sign (lateral spread of bullae on application of pressure).
Figure 1: young male having toxic epidermal necrolysis (TEN) showing the presence of multiple vesicles and bullae over the face, upper limbs, and torso with desquamation over the lower lip, right pinna, and extensive areas over the right shoulder, trunk, and back

Click here to view


Mucosal lesions

SJS/TEN involve mucosa in up to 90% of patients causing erosions and crusts that may precede or follow skin lesions.[39] It typically involves oral mucosa and vermilion border with painful hemorrhagic erosions with grayish white membrane. Difficulty in opening mouth leads to undernutrition and dehydration. Eye involvement occurs in 80% of cases and manifest as purulent conjunctivitis, corneal ulcers, anterior uveitis, or panophthalmitis. The eye manifestations usually regress completely. However, more than half of these patients may develop late sequelae. Urogenital lesions are common in females with vaginal ulcers and erosions, vulval bullae, or vaginal synechiae.

The acute phase of fever, epidermal sloughing and large areas of denuded skin, mucosal erosions, and ulcers lasts for 8-12 days, which is usually followed by the phase of reepithelialization and healing.[40]

Clinically, it is very difficult to differentiate between drug-induced SJS/TEN and SLE-SJS/TEN, but a definitive history of drug exposure and associated clinical features with serological profile helps in differentiating between both. Histopathology with immunofluorescence also aids in distinguishing between the two [Table 4].
Table 4: Difference between systemic lupus erythematosus-Stevens-Johnson syndrome/toxic epidermal necrolysis and drug-induced Stevens-Johnson syndrome/toxic epidermal necrolysis

Click here to view


Acute complications

Because of severe skin loss, it can lead to massive fluid loss, electrolyte imbalance, hypovolemic shock, acute kidney injury, and multiorgan failure. Patients with SJS/TEN are at high risk of developing infections mainly by Staphylococcus aureus, Pseudomonasaeruginosa, and Enterobacteriaceae, which if not treated may lead to septic shock and death.[41] The risk is higher in patients more than 40 years, >30% BSA involvement, and leukocytosis. Other complications include acute respiratory distress syndrome (ARDS); necrosis of gastrointestinal tract including esophagus, small bowel, and colon; and bowel perforation.

Long-term sequelae

As the survival has increased in patients with SJS/TEN, many long-term sequelae have been reported in these patients as follows:[42],[43]

  • Skin - Hypo/hyperpigmentation, scarring, dystrophy of nails, alopecia, chronic pruritus, etc.
  • Eye - Xerophthalmia, visual abnormalities, trichiasis, corneal neovascularization and scarring, symblepharon, etc.
  • Oral - Xerostomia, gingival synechiae, caries, and periodontal diseases
  • Urogenital - Vaginal dryness and stenosis, dyspareunia, urinary retention and recurrent cystitis, hematocolpos, etc.
  • Pulmonary - Chronic bronchitis/bronchiolitis with obstructive changes, bronchiectasis, etc.


Laboratory tests

Anemia and lymphopenia are frequent.[37] Neutropenia, if present, usually carries a worse prognosis.[44] Neutrophilic leukocytosis usually suggests secondary bacterial infection. Eosinophilia is unusual.

Reduced serum albumin, raised liver enzymes, urea, and creatinine must warn treating physicians about impending multiorgan failure. Metabolic abnormalities such as dyselectrolytemia and raised blood glucose are also seen commonly.

Blood cultures and wound cultures should always be sent for ruling out secondary infections.

Skin biopsy

Skin biopsy from early stages of SJS/TEN show apoptotic keratinocytes scattered in stratum basale with perivascular lymphocytic infiltrates in papillary dermis.[45] The role of skin biopsy is to exclude other mimickers, rather than establish diagnosis of SJS/TEN. Direct immunofluorescence can demonstrate deposits of immunoglobulins, complements, and immune complexes in SLE-SJS/TEN and help differentiate from drug-induced SJS/TEN.

Serum markers

Soluble FasL, soluble CD40 L, HMGB-1, granulysin, IL-15, and others have been evaluated in small studies,[19],[46] but they require validation in larger studies for establishing utility in diagnosis and management of SJS/TEN.


  Diagnosis Top


In the absence of any specific diagnostic criteria or histopathology, a provisional diagnosis of SJS/TEN should be made in the following clinical settings:[47]

  1. History of drug exposure (usually 1-4 weeks for 1st exposure but <2 days in subsequent exposures)
  2. A prodrome of acute onset febrile illness
  3. A painful rash that progresses rapidly
  4. Red macules or target lesions progressing to vesicle and bullae
  5. Positive Nikolsky sign or bullae spread sign
  6. Oral/ocular mucosal involvement.



  Treatment Top


Treatment of SJS/TEN poses many challenges due to associated morbidity and mortality. In a setting of connective tissue disease, it could be because of disease activity itself (SLE) or various drugs used for the treatment of such patients. If it is due to disease activity, it usually responds to immunosuppressive drugs whereas drug-induced SJS/TEN requires immediate withdrawal of culprit drug. The prognosis of drug-induced SJS/TEN may vary from patient-to-patient and is predicted by score for toxic epidermal necrosis (SCORTEN) score.[48] This score is determined by seven individual prognostic factors (age, associated malignancy, involved BSA, tachycardia, serum urea, glucose, and bicarbonate), which can be easily measured bedside. Patients with skin involvement >30% or SCORTEN score ≥2 should be managed in intensive care unit or burn unit.[49]

The management of drug-associated SJS/TEN can be discussed in the following headings:

  1. Prompt withdrawal of causative drug
  2. Supportive management
  3. Skin care
  4. Eye care
  5. Role of systemic adjunctive therapy.


Prompt withdrawal of causative drug

Prompt recognition and withdrawal of offending drugs is the cornerstone of drug-induced SJS/TEN and reduces the mortality risk by 30% for each day before development of blisters or erosion.[50]

Supportive treatment

Fluid replacement is crucial in early part of management because of incipient fluid loss from the denuded dermis. Initial fluid (crystalloid) requirement is usually 2 ml/kg multiplied by % BSA of detached epidermis in the first 24-h, which is sufficient to ensure adequate urine output.[51] Room temperature should be maintained at 30°C-32°C. Ryle's tube feeding should be considered in case of oropharyngeal lesions producing odynophagia. Pain should be adequately managed with opioid or nonopioid analgesics.

Skin care

There are two approaches to deal with the denuded skin: (a) surgical debridement to remove necrotic skin or (b) to leave the detached skin intact as a layer of biological dressing. The outcome of both the approaches is similar and the optimal approach is yet to be validated. Empirical antibiotics covering Gram-negative rods and Pseudomonasaeruginosa should be promptly started if secondary infection is suspected.[52]

Eye care

Immediate detection of eye involvement and its treatment is required to prevent permanent ocular complications. In patients without eye involvement (Grade 0), saline rinse or artificial tear drops should be used. In patients having conjunctival hyperemia (Grade 1), topical corticosteroid with broad-spectrum antibiotics may be used. In case of ocular surface epithelial defect and/or pseudomembrane formation (Grade 2 and 3), early amniotic membrane transplant may be considered (within 7-10 days) to prevent loss of vision.[53] Systemic corticosteroids or intravenous immunoglobulin (IVIG) has no role in improving visual acuity or preventing complications.


  Role of Systemic Adjunctive Therapies Top


Although many systemic therapies, such as corticosteroids, IVIG, cyclosporine, anti-TNF antibodies, and plasmapheresis, have been tried in the treatment of SJS/TEN, most of them are based on clinical experience and small nonrandomized trials. Most drugs have failed to show any consistent benefit compared to supportive therapy alone, although some recent case series have demonstrated beneficial role of cyclosporine in retarding the progression of SJS/TEN.

Corticosteroids

Role of corticosteroid has been debatable in the management of SJS/TEN. A recent meta-analysis of 1209 individual patient data showed decreased risk of death (OR = 0.67, 95% CI = 0.46-0.97) with systemic corticosteroids and supportive therapies in comparison to supportive therapy alone, but failed to achieve significance in stratified model analysis as well as meta-analysis of 11 studies comparing steroids versus supportive therapy.[54] However, different studies have used different steroid regimens (intravenous pulse methylprednisolone vs. oral high-dose steroid), timing of steroid introduction in treatment, duration, and coprescription of other drugs such as cyclosporine; hence, it is difficult at present to recommend any definite protocol of steroid administration. In addition, there is a fear of increased risk of sepsis and delayed reepithelialization, making its use in patients with extensive skin involvement controversial.

Intravenous immunoglobulin

In SJS/TEN, early use of IVIG was thought to be beneficial by antagonizing FasL-mediated apoptosis. Both low dose (1-1.5 g/kg in a single infusion) and high dose (2-4 g/kg) have been tried, but have failed to show any survival benefit in a recent meta-analysis in 2017.[54] Further risk of major complications such as renal, hematologic, neurological, and thrombotic complications makes it unsuitable for use in these patients. There are many small cohort studies where IVIG in combination with corticosteroids has found to decrease death rate compared to IVIG or corticosteroid alone, but the data are insufficient to advocate its use at present.

Cyclosporine

CTLs are accepted as the main mediator of apoptosis in SJS/TEN patients. Cyclosporine, which targets CTLs, has been tried. Multiple case-series and meta-analysis have found that early use of cyclosporine (3-5 mg/kg/day) may reduce the mortality rate by 70% (pooled standardized mortality ratio = 0.32, 95% CI = 0.12-0.52).[55]

Antitumor necrosis factor

TNF plays a crucial role in the pathogenesis of SJS/TEN and both infliximab and etanercept have been found to halt the progression of skin detachment[56] and induce rapid reepithelialization in case reports and small nonrandomized trials. However, further studies are required to decide usefulness, optimum dose, and duration of anti-TNF therapy. Thalidomide, which has anti-TNF properties, was tried in a randomized trial, but the trial was prematurely terminated due to increased mortality rate among thalidomide users.[57]

Plasmapheresis

Plasmapheresis helps in the removal of toxins, drug metabolites, and other disease mediators, but failed to show clear advantage in terms of mortality benefits.[58]


  Treatment of Systemic Lupus Erythematosus-Associated Stevens-johnson Syndrome/toxic Epidermal Necrolysis Top


Because of rarity of the condition, there is no randomized controlled trial regarding management of SLE-associated SJS/TEN and most treatment suggestions are based on case reports and expert opinions. Usually, this is associated with SLE flare and other extracutaneous manifestations of SLE, and treatment regimen is decided accordingly. It responds well to high-dose corticosteroids (with or without pulse therapy depending on severity and extracutaneous major organ involvement). In a recent literature review, steroid alone helped in resolution in 52% of patients and at least 32% of patients were resistant to steroids alone.[59] Steroid-sparing immunosuppressive drugs such as mycophenolate, cyclophosphamide, and azathioprine have been started simultaneously and found to be effective. In steroid-resistant cases, IVIG has been successfully used in 75% of cases and plasmapheresis has been reported to be effective in at least two cases.[59] Although anti-TNF drugs have been reported to be effective in SJS/TEN without SLE,[60] it is better avoided for the fear of aggravation of lupus flare. Once treated successfully, recurrence of SLE-associated SJS/TEN is rare.[59]


  Prognosis Top


With improvement in supportive care, the mortality rate in SJS/TEN patients has improved in recent years (approximately 10% in SJS but 30% in TEN).[61] Sepsis, multiorgan failure, and ARDS remain the most common causes of death. In patients who survive, long-term sequelae such as cutaneous, mucosal, ocular, and pulmonary complications increase morbidity in patients.

Recurrence of SJS/TEN is related to reexposure of offending drugs. Sometimes, structurally unrelated drugs and infectious agents may cause recurrence.[62] The risk of recurrence is higher in children. As carbamazepine-, phenytoin-, and allopurinol-related SJS/TEN are HLA related; the family members of these patients should be advised to avoid such medications.

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.



 
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