Ocular involvement in Steven-Johnson syndrome/toxic epidermal necrolysis: recent insights into pathophysiology, biomarkers, and therapeutic strategies.

PURPOSE OF REVIEW: To review the pathophysiology, recent biomarkers related to the ocular aspects of Steven-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), and to highlight notable evidence published in recent years. RECENT FINDINGS: Several studies reveal the relationship between tear cytokines and the pathological components in eyes of SJS/TEN patients. Specific clinical features and associated risk factors in the acute stage have shown significant correlations with chronic ocular sequelae. Recent treatment protocols, including early pulse systemic and topical steroids, as well as tumor necrosis factor-α inhibitors, have demonstrated positive effects on ocular outcomes. In addition to conventional surgical treatment, a new surgical technique, simple oral mucosal epithelial transplantation (SOMET), has been introduced as a simple ocular surface reconstruction for patient with SJS. SUMMARY: Advancements in knowledge and management strategies have notably enhanced ocular outcomes for SJS/TEN eyes. A deeper understanding of the biomarker changes in these eyes could facilitate the development of future targeted treatment options.

The outcomes of corneal sight rehabilitating surgery in Stevens-Johnson syndrome: case series.

PURPOSE: To summarize the outcomes of corneal sight rehabilitating surgery in Stevens-Johnson syndrome (SJS). METHODS: This is a retrospective analysis of a consecutive case series. Twenty-four eyes of 18 SJS patients were included in this study. The ocular parameters, surgical procedures, postoperative complications, and additional treatments of the cases were reviewed. RESULTS: A total of 29 corneal sight rehabilitating surgeries, which consists of 9 keratoplasties, 8 Keratolimbal allograft (KLAL) and 12 combined surgeries (keratoplasty and KLAL simultaneously) were performed on the 24 eyes. All patients were treated with glucocorticoid eyedrops and tacrolimus eyedrops for anti-rejection treatment without combining systemic immunosuppression, except two patients who were prescribed prednisone tablets for the management of systemic conditions. The mean follow-up period was 50.6 ± 28.1 months. The optimal visual acuity (VA) (0.74 ± 0.60 logarithm of the minimum angle of resolution [logMAR]) and endpoint VA (1.06 ± 0.82 logMAR) were both significantly better than the preoperative VA (1.96 ± 0.43 logMAR) (95% CI, p = 0.000). 57.1% patients (8/14) were no longer in the low vision spectrum, and 88.9% patients (8/9) were no longer blind. The mean epithelialization time was 7.1 ± 7.6 weeks. The success rate was 86.7%. Additional treatments for improving epithelialization included administration of serum eyedrops (n = 10), contact lens (n = 15), amniotic membrane transplantation (n = 6), and tarsorrhaphy (n = 8). Complications included delayed epithelialization (n = 4, over 12 weeks), glaucoma (n = 11), and severe allograft opacity (n = 4). Only one graft rejection was observed. CONCLUSIONS: Keratoplasty and KLAL can remarkably enhance VA and improve low vision or even eliminate blindness for ocular complications of SJS. The outcome of the surgeries was correlated with the preoperative ocular situation and choice of operative methods.

Severe cutaneous adverse reactions.

Severe cutaneous adverse reactions (SCARs), which include Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (also known as drug-induced hypersensitivity syndrome), acute generalized exanthematous pustulosis, and generalized bullous fixed drug eruption, are life-threatening conditions. The pathogenesis of SCARs involves T cell receptors recognizing drug antigens presented by human leukocyte antigens, triggering the activation of distinct T cell subsets. These cells interact with keratinocytes and various immune cells, orchestrating cutaneous lesions and systemic manifestations. Genetic predisposition, impaired drug metabolism, viral reactivation or infections, and heterologous immunity influence SCAR development and clinical presentation. Specific genetic associations with distinct SCAR phenotypes have been identified, leading to the implementation of genetic screening before prescription in various countries to prevent SCARs. Whilst systemic corticosteroids and conventional immunomodulators have been the primary therapeutic agents, evolving strategies, including biologics and small molecules targeting tumour necrosis factor, different cytokines, or Janus kinase signalling pathways, signify a shift towards a precision management paradigm that considers individual clinical presentations.

Genotyping HLA alleles to predict the development of Severe cutaneous adverse drug reactions (SCARs): state-of-the-art.

Introduction: Pharmacogenomics has great potential in reducing drug-induced severe cutaneous adverse drug reactions (SCARs). Pharmacogenomic studies have revealed an association between HLA genes and SCARs including acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).Areas covered: Pharmacogenomics-guided therapy could prevent severe drug hypersensitivity reactions. The US Food and Drug Administration (FDA), Clinical Pharmacogenetics Implementation Consortium (CPIC), and Dutch Pharmacogenetics Working Group (DPWG) provided guidelines in the translation of clinically relevant and evidence-based SCARs pharmacogenomics research into clinical practice. In this review, we intended to summarize the significant HLA alleles associated with SCARs induced by different drugs in different populations. We also summarize the SCARs associated with genetic and non-genetic factors and the cost-effectiveness of screening tests.Expert opinion: The effectiveness of HLA screening on a wider scale in clinical practice requires significant resources, including state-of-the-art laboratory; multidisciplinary team approach and health care provider education and engagement; clinical decision support alert system via electronic medical record (EMR); laboratory standards and quality assurance; evidence of cost-effectiveness; and cost of pharmacogenomics tests and reimbursement.

Oral Mucosal Epithelial Transplantation and Limbal-Rigid Contact Lens: A Therapeutic Modality for the Treatment of Severe Ocular Surface Disorders.

Stevens-Johnson syndrome, ocular cicatricial pemphigoid, and severe thermal or chemical injury are considered severe ocular surface disorders (OSDs) because they affect the entire ocular surface, including corneal and conjunctival epithelial stem cells. In patients with severe OSDs, the long-term prognosis for limbal transplantation is poor, and the related corneal opacity and cicatrization lead to devastating visual impairment. To date, there is no standardized treatment to improve vision in cases with severe OSD. Investigating novel treatment methods for severe OSDs, our group began cultivated oral mucosal epithelial transplantation in 2002 and developed a limbal-supported rigid-type contact lens that can be applied as a nonsurgical treatment. When used in combination, these treatment methods make it possible to successfully restore vision in cases with severe OSDs.

Acute generalized exanthematous pustulosis and Stevens-Johnson syndrome overlap due to hydroxychloroquine: a case report.

BACKGROUND: Since the World Health Organization declared a global pandemic due to the novel coronavirus disease2019, there have been targeted efforts to establish management modalities. Hydroxychloroquine has been suggested as a possible treatment; however, it is associated with multiple adverse reactions. We report a rare case of a patient with acute generalized exanthematous pustulosis with Stevens-Johnson syndrome due to hydroxychloroquine. Acute generalized exanthematous pustulosis is characterized by acute onset of a generalized rash that is pustular and erosive in nature, affecting limbs; trunk; face; and, less often, mucosal membranes. Although rare, it is important to be mindful of this side effect because the diagnosis is often delayed, and the disease has the potential to be life-threatening. CASE PRESENTATION: A 68-year-old American woman presented to our hospital with a painful, rapidly spreading rash. Its morphologic features included erythema multiforme-like lesions with extensive skin sloughing in various regions of the head, neck, and trunk and mucosal involvement. Her Nikolsky sign was negative, and she had no evidence of lesions on areas of skin trauma. Four weeks prior, she had been initiated on hydroxychloroquine for a presumed diagnosis of cutaneous sarcoidosis. Three punch biopsies of the head and neck area revealed subcorneal pustules consistent with acute generalized exanthematous pustulosis. Treatment began with high doses of methylprednisolone, leading to only minimal improvement of existing areas and ongoing spread to new areas. Treatment with intravenous immunoglobulin was initiated, at which point disease stability was achieved. The patient's rash ultimately resolved, as did her cutaneous pain and pruritus. CONCLUSIONS: Among many potential adverse reactions involving hydroxychloroquine, cutaneous side effects are varied and can lead to significant morbidity or even death. The drug is currently being investigated in a multitude of trials for coronavirus disease2019 treatment, prevention, and prophylaxis after exposure to severe acute respiratory syndrome coronavirus 2. Acute generalized exanthematous pustulosis is a rare side effect of hydroxychloroquine, and even fewer cases demonstrate histologic evidence of acute generalized exanthematous pustulosis while clinically presenting with Stevens-Johnson syndrome. Patients who develop Stevens-Johnson syndrome/toxic epidermal necrolysis require best supportive care with aggressive fluid and electrolyte replacement and prevention of further breakdown of the skin barrier. With the potential of widespread hydroxychloroquine use, it is important that providers be aware of its potential severe adverse drug reactions.

Fatal pediatric Stevens-Johnson syndrome/toxic epidermal necrolysis: Three case reports.

RATIONALE: Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are extremely rare but potentially life-threatening disorders. We presented 3 fatal pediatric SJS/TEN cases. PATIENT CONCERNS: Our patients had some severe complications such as septic shock, respiratory failure and obliterans bronchiolitis (BO) etc. DIAGNOSIS:: Three patients diagnosed SJS/TEN with clinical symptoms that were triggered by antibiotics, nonsteroidal anti-inflammatory drugs, previous infection, or neoplasms. INTERVENTIONS: All of them accepted mechanical ventilation, intravenous immunoglobulin (IVIG), blood transfusion, glucocorticoid, and multi-anti-infectious therapy. OUTCOMES: They all died because of out-of-control severe infections. In Patient 1, he died 6 days after being admitted to the PICU on the 28th day from onset. In Patient 2, he died on the 211th day from the onset of illness during the third time of PICU admission. In Patient 3, she died 12 days after PICU admission on the 87th day from onset. LESSONS: We should be aware that mucosal damage occurs on the skin and within the mucosa of visceral organs, leading to the occurrence of bronchiectasia, BO, enterocolitis, acute renal failure, and severe secondary infections. Establish a clinically predictive score that includes severe infection for pediatric patients to evaluate the risk of mortality in children in order to improve poor outcomes.

Development and Validation of a Risk Prediction Model for In-Hospital Mortality Among Patients With Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis-ABCD-10.

Importance: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a spectrum of severe mucocutaneous drug reaction associated with significant morbidity and mortality. A previously developed SJS/TEN-specific severity-of-illness model (Score of Toxic Epidermal Necrolysis [SCORTEN]) has been reported to overestimate and underestimate SJS/TEN-related in-hospital mortality in various populations. Objective: To derive a risk prediction model for in-hospital mortality among patients with SJS/TEN and to compare prognostic accuracy with the SCORTEN model in a multi-institutional cohort of patients in the United States. Design, Setting, and Participants: Data from a multicenter cohort of patients 18 years and older treated for SJS/TEN between January 1, 2000, and June 1, 2015, were obtained from inpatient consult databases and electronic medical record systems at 18 medical centers in the United States as part of the Society for Dermatology Hospitalists. A risk model was derived based on data from 370 of these patients. Model discrimination (calculated as area under the receiver operating characteristic curve [AUC]) and calibration (calculated as predicted vs observed mortality, and examined using the Hosmer-Lemeshow goodness-of-fit statistic) were assessed, and the predictive accuracy was compared with that of SCORTEN. All analysis took place between December 2016 and April 2018. Main Outcomes and Measures: In-hospital mortality. Results: Among 370 patients (mean [SD] age 49.0 [19.1] years; 195 [52.7%] women), 54 (15.14%) did not survive to hospital discharge. Five covariates, measured at the time of admission, were independent predictors of in-hospital mortality: age in years (odds ratio [OR], 1.05; 95% CI, 1.02-1.07), body surface area (BSA) in percentage of epidermal detachment (OR, 1.02; 95% CI, 1.01-1.04), serum bicarbonate level below 20 mmol/L (OR, 2.90; 95% CI, 1.43-5.88), active cancer (OR, 4.40; 95% CI, 1.82-10.61), and dialysis prior to admission (OR, 15.94; 95% CI, 3.38-66.30). A severity-of-illness score was calculated by taking the sum of 1 point each for age 50 years or older, epidermal detachment greater than 10% of BSA, and serum bicarbonate level below 20 mmol/L; 2 points for the presence of active cancer; and 3 points for dialysis prior to admission. The score was named ABCD-10 (age, bicarbonate, cancer, dialysis, 10% BSA). The ABCD-10 model showed good discrimination (AUC, 0.816; 95% CI, 0.759-0.872) and calibration (Hosmer-Lemeshow goodness of fit test, P = .30). For SCORTEN, on admission, the AUC was 0.827 (95% CI, 0.774-0.879) and was not significantly different from that of the ABCD-10 model (P = .72). Conclusions and Relevance: In this cohort of patients with SJS/TEN, ABCD-10 accurately predicted in-hospital mortality, with discrimination that was not significantly different from SCORTEN. Additional research is needed to validate ABCD-10 in other populations. Future use of a new mortality prediction model may provide improved prognostic information for contemporary patients, including those enrolled in observational studies and therapeutic trials.

Sutureless Amniotic Membrane Transplantation in a Pediatric Patient with Acute Toxic Epidermal Necrolysis

The purpose of this case report is to describe a new surgical method for sutureless placement of the amniotic membrane with a symblepharon ring in a pediatric patient with acute toxic epidermal necrolysis (TEN). A 1-year-old girl developed severe ocular surface inflammation with large corneal and conjunctival epithelial defects secondary to TEN. She was treated by applying a large (4 cm x 4 cm) amniotic membrane graft and non-sterile symblepharon ring under sedoanalgesia at bedside in the intensive care unit. The ocular surface was completely epithelized by post-treatment week 6 in the right and week 8 in the left eye. Two years after amniotic membrane transplantation, both eyes were quiet with no symblepharon, scar formation, or limbal stem cell deficiency. Performing bilateral amniotic membrane transplantation under a symblepharon ring at bedside provided sufficient acute coverage of the ocular surface and led to excellent clinical outcomes by reducing inflammation and protecting the ocular surface.

Tumor necrosis factor alpha inhibitors in the treatment of toxic epidermal necrolysis.

Toxic epidermal necrolysis (TEN) is a rare, life-threatening adverse drug reaction for which there is no standardized or consistently effective treatment. Due to a greater understanding of disease pathogenesis and the identification of tumor necrosis factor (TNF) α as a mediator of keratinocyte death, TNF-α antagonists have been used in the treatment of TEN. Specifically, infliximab and etanercept have been shown to be effective at halting disease progression. The objective of this study is to review published case reports and case series using anti-TNF-α medications in the treatment of TEN. Results of many of the articles reviewed support the use of TNF-α inhibitors in TEN in both adult and pediatric populations; however, the risks caused by these potent immunosuppressants must be weighed, and if administered, patients must be closely monitored for infections. Additional studies are needed to further characterize the role of TNF-α inhibition in the treatment of TEN.

Necrolisis epidérmica tóxica: un paradigma de enfermedad crítica / Toxic epidermal necrolysis: a paradigm of critical illness

RESUMEN La necrolisis epidérmica tóxica es una reacción cutánea adversa de tipo inmunológico secundaria en la mayor parte de los casos a la administración de un fármaco. La necrolisis epidérmica tóxica, el síndrome de Steven Johnson y el eritema exudativo multiforme forman parte del mismo espectro de enfermedad. La mortalidad de la necrolisis epidérmica tóxica es alrededor del 30%. La fisiopatología de la necrolisis epidérmica tóxica es semejante en muchos aspectos a la de las quemaduras dérmicas superficiales. La afectación mucosa del epitelio ocular y genital se asocia con secuelas graves si no se trata de forma temprana. Se acepta en general que los pacientes con necrolisis epidérmica tóxica son tratados mejor en unidades de grandes quemados, donde existe experiencia en el manejo de enfermos con pérdida cutánea extensa. El tratamiento es de soporte, eliminación y cobertura con derivados biosintéticos de la piel de las zonas afectadas, tratamiento de la afectación mucosa, y tratamiento inmunosupresor específico. De los tratamientos ensayados sólo se usa actualmente en la mayor parte de los centros la inmunoglobulina G y la ciclosporina A, aun cuando no existe evidencia sólida para recomendar ningún tratamiento específico. Entre los aspectos particulares del tratamiento de esta enfermedad se encuentra la prevención de secuelas relacionadas con la formación de sinequias, los cuidados oculares para prevenir secuelas graves que pueden conducir a la ceguera, y el tratamiento específico inmunosupresor. Un mejor conocimiento de los principios del manejo de la necrolisis epidérmica tóxica llevará a un mejor manejo de la enfermedad, a una mayor supervivencia y una menor prevalencia de las secuelas.

ABSTRACT Toxic epidermal necrolysis is an adverse immunological skin reaction secondary in most cases to the administration of a drug. Toxic epidermal necrolysis, Stevens-Johnson syndrome, and multiform exudative erythema are part of the same disease spectrum. The mortality rate from toxic epidermal necrolysis is approximately 30%. The pathophysiology of toxic epidermal necrolysis is similar in many respects to that of superficial skin burns. Mucosal involvement of the ocular and genital epithelium is associated with serious sequelae if the condition is not treated early. It is generally accepted that patients with toxic epidermal necrolysis are better treated in burn units, which are experienced in the management of patients with extensive skin loss. Treatment includes support, elimination, and coverage with biosynthetic derivatives of the skin in affected areas, treatment of mucosal involvement, and specific immunosuppressive treatment. Of the treatments tested, only immunoglobulin G and cyclosporin A are currently used in most centers, even though there is no solid evidence to recommend any specific treatment. The particular aspects of the treatment of this disease include the prevention of sequelae related to the formation of synechiae, eye care to prevent serious sequelae that can lead to blindness, and specific immunosuppressive treatment. Better knowledge of the management principles of toxic epidermal necrolysis will lead to better disease management, higher survival rates, and lower prevalence of sequelae.

Acute Generalized Erythrodermic Pustular Psoriasis Associated with Bupropion/Naltrexone (Contrave®).

BACKGROUND: We report a case of erythrodermic pustular psoriasis associated with initiation of bupropion/naltrexone (Contrave®; Orexigen Therapeutics, La Jolla, CA) in a patient with no history of psoriasis. CASE REPORT: A 55-year-old woman was transferred to our tertiary medical center from a community hospital for possible Stevens-Johnson syndrome 3 weeks after initiation of bupropion/naltrexone. The patient was admitted to the burn unit for wound treatment and hydration. She received intravenous cyclosporine during the admission that resulted in acute kidney injury and the therapy was discontinued. The skin biopsy ruled out Stevens-Johnson syndrome and was more consistent with generalized pustular psoriasis. After discharge, the patient followed up with her dermatologist. She was diagnosed with acute generalized and erythrodermic psoriasis and the patient was restarted on cyclosporine 100 mg twice a day. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Few case reports of bupropion-induced generalized pustular psoriasis and erythrodermic psoriasis in patients with a history of psoriasis have been reported. To our knowledge, acute generalized erythrodermic pustular psoriasis associated with bupropion/naltrexone has not been reported in a patient without history of psoriasis. Due to increases in obesity and increases in prescribing of bupropion/naltrexone SR, health care providers should be aware of this possible severe adverse reaction.

Russian Keratoprosthesis in Stevens-Johnson Syndrome.

PURPOSE: To evaluate the efficacy and safety of Moscow Eye Microsurgery Complex in Russia (MICOF) keratoprosthesis (KPro) implantation in patients with Stevens-Johnson syndrome (SJS). METHODS: This was a retrospective case series. Fourteen eyes of 13 patients with SJS underwent KPro implantation at the Chinese People's Liberation Army General Hospital between April 1, 2000, and December 24, 2014. The visual outcome, KPro retention rate, and incidence of postoperative complications and their management were recorded and investigated. RESULTS: The mean age and follow-up duration were 61.5 ± 17.3 years (range: 27-87 yrs) and 62 ± 39.1 months (range: 13-144 mo). Thirteen eyes (92.9%) achieved a best-corrected visual acuity of 20/200 or better, and 8 eyes (57.1%) achieved a best-corrected visual acuity of 20/40 or better after surgery. However, 71.4% (10/14) experienced visual decline because of different postoperative complications. Common complications included corneal melting, glaucoma, vitritis, superficial tissue overgrowth, and retroprosthetic membrane, and the incidence of these complications was 71.4%, 28.6%, 35.7%, 14.3%, and 28.6%, respectively. After repair and autoauricular cartilage reinforcement, all cases had stable anatomical retention at the last visit. CONCLUSIONS: The MICOF KPro improved vision of patients with SJS, but lifelong surveillance is necessitated because of a high rate of postoperative complications. Corneal melting was the main reason for KPro failure. Infectious endophthalmitis and glaucoma were the main risk factors for visual loss.

Interleukin-15 Is Associated with Severity and Mortality in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis.

Early diagnosis and prognosis monitoring for Stevens-Johnson syndrome/toxic epidermal necrolysis (TEN) still remain a challenge. This study aims to explore any cytokine/chemokine with prognostic potential in Stevens-Johnson syndrome/TEN. Through screening a panel of 28 serological factors, IL-6, IL-8, IL-15, tumor necrosis factor-α, and granulysin were upregulated in patients with Stevens-Johnson syndrome/TEN and selected for the further validation in total 155 patients with Stevens-Johnson syndrome/TEN, including 77 from Taiwan and 78 from the Registry of Severe Cutaneous Adverse Reactions. Among these factors evaluated, the levels of IL-15 (r = 0.401; P < 0.001) and granulysin (r = 0.223; P = 0.026) were significantly correlated with the disease severity in 112 samples after excluding patients with insufficient data to calculate the score of TEN. In addition, IL-15 was also associated with mortality (P = 0.002; odds ratio, 1.09; 95% confidence interval, 1.03-1.14; P = 0.001; adjusted odds ratio, 1.10; 95% confidence interval, 1.04-1.16). Consistent results were obtained after the exclusion of Taiwanese patients with sepsis to rule out possible confounders. Moreover, IL-15 was shown to enhance cytotoxicity of cultured natural killer cells and blister cells from patients with TEN. Our findings highlight a usefulness of IL-15 in prognosis monitoring and therapeutic intervention of this devastating condition.

Minor salivary glands function is decreased in hyposalivation-related diseases.

OBJECTIVES: The aim of this cross-sectional study was to investigate the relationship between minor salivary gland (MSG) flow rates and oral dryness degrees in patients with xerostomia induced by primary Sjögren's syndrome (pSS), IgG4-related sialadenitis (IgG4-RS), radiation therapy-induced dry mouth (RTDM), or Steven-Johnson syndrome (SJS). DESIGN: 160 patients with pSS, IgG4-RS, RTDM, or SJS and their age- and sex-matched healthy control subjects were enrolled. The whole saliva flow rates and MSG flow rates were measured in four locations, including the upper labial, lower labial, buccal, and palatal mucosae. The degree of oral dryness was assessed in patient groups using the summated xerostomia inventory (SXI). RESULTS: The flow rates of whole saliva and most MSGs in patient groups were significantly lower than the flow rates in healthy control groups (P<0.05). The mean relative percentage of decrease in saliva flow rates was smaller in MSGs than in whole saliva in patient groups (P<0.05), indicating that these disorders have less impact on MSGs. Among the four MSG locations (the upper labial, lower labial, buccal, and palatal), buccal glands showed the highest flow rates in patient groups (P<0.05). SXI scores were significantly higher in pSS and RTDM patients than in IgG4-RS and SJS patients (P<0.05). The degree of xerostomia varied among different patient groups (P<0.05) and there was no clear correlation between MSG flow rates and SXI scores (P>0.05). CONCLUSIONS: MSG function is significantly reduced in pSS, RTDM, IgG4-RS, and SJS patients, but this reduction is more pronounced in the major salivary glands.