Predictive Factors Associated With Acute Ocular Involvement in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis




Purpose


To suggest an objective score for grading the acute ocular severity of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), and to determine predictive factors for severe acute ocular involvement such as ocular surface epithelial defect and/or pseudomembrane formation.


Design


Retrospective cohort study.


Methods


The medical records of SJS (n = 87) and TEN (n = 48) patients between 2005 and 2007 were reviewed. An acute ocular severity score was determined on a scale from 0 to 3 (none, mild, severe, and very severe) according to the existence of hyperemia, corneal or conjunctival epithelial defect, and pseudomembrane formation. The associations between the severe acute ocular involvement and factors such as patient age, exposed drugs, systemic severity, and the prevalence of ocular sequelae were examined.


Results


The number of cases with score grade 0, 1, 2, and 3 was 19 (21.8%), 31 (35.6%), 22 (25.3%), and 15 (17.2%) in 87 SJS cases and 12 (25.0%), 11 (22.9%), 17 (35.4%), and 8 (16.7%) in 48 TEN cases. Multivariate logistic regression analysis revealed that patient age (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.96–0.99; P = .007) and nonsteroidal anti-inflammatory drugs NSAIDs or cold remedies (OR, 2.58; 95% CI, 1.26–5.29; P = .010) were predictive factors for severe acute ocular involvement. The prevalence of visual disturbance and eye dryness increased according to the increase of acute ocular severity ( P = .001 and P = .007 in SJS; P = .007 and P = .014 in TEN, respectively).


Conclusions


At the onset of SJS/TEN, strict attention should be paid to ocular involvement in young patients and in patients exposed to NSAIDs or cold remedies.


Stevens-Johnson syndrome (SJS) and its more severe variant, toxic epidermal necrolysis (TEN), are acute inflammatory disorders of the skin and mucous membranes that predispose patients to life-threatening complications such as sepsis, respiratory dysfunction, and multiple organ failure. Both diseases are rare, yet can affect anyone, regardless of age, and usually as a consequence of adverse drug reactions. A variety of drugs including antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), and antiepileptic medications (ie, many if not most of the popularly used over-the-counter drugs) have been reported to cause severe drug reactions and induce SJS or TEN. Ocular surface inflammation develops rapidly at the acute stage of the disease, and acute conjunctivitis occur prior to, or simultaneously with, skin eruptions. Extensive inflammation of the ocular surface is often accompanied by corneal and/or conjunctival epithelial defects. Common signs after the acute stage include persistent epithelial defects, ulceration, and perforation, ultimately developing into corneal, conjunctival, and eyelid cicatricial changes such as neovascularization, opacification, keratinization, and symblepharon. Visual impairment and severe dryness of the eye continue lifelong as ocular sequelae. Although we previously reported both surgical and nonsurgical therapeutic methods to treat chronic-stage SJS/TEN, it remains impossible to restore the ocular surface to its normal healthy state (ie, that of before disease onset).


In a previous report from Power and associates, the authors categorized acute ocular severity into the grades of mild, severe, or very severe. In that grading system, mild involvement was defined as mild conjunctival injection, lid edema, and/or chemosis; moderate involvement consisted of membrane formation, corneal epithelial loss of more than 30%, corneal ulceration, and/or corneal infiltrates; and severe involvement consisted of fornix shortening, symblepharon formation, and/or visual loss. Considering the fact that SJS and TEN are characterized by epidermal necrosis with detachment and erosion of the mucous membranes, corneal or conjunctival epithelial defects are prominent disease-related factors at the onset. In addition, it is reported that extreme inflammation develops on the ocular surface accompanying pseudomembrane formation at the acute stage. Thus, we hypothesized that a simple grading system based on the presence of conjunctivitis, corneal or conjunctival epithelial defect, and pseudomembrane formation might be appropriate to evaluate acute ocular severity of SJS/TEN.


Owing to the high mortality rate of patients with SJS and TEN (1%∼5% and 20%∼30%, respectively), investigations of these diseases have been intensively focused on systemic severity and general treatment. Unfortunately, even in the large-scale survey of the severe adverse drug reactions conducted in Europe, the ocular involvement was not explored. Moreover, the predictive features of ocular involvement at the acute stage of SJS/TEN remain unclear.


The aim of this study was to construct a simpler and more practical score for grading the acute ocular severity of SJS and TEN, as well as to determine predictive factors having severe or very severe (as opposed to none or mild) acute ocular involvement in SJS/TEN patients based on a Japanese nationwide retrospective study of SJS and TEN patients in which both dermatologists and ophthalmologists participated. Furthermore, correlation between the severe acute ocular involvement and the prevalence of ocular sequelae (visual disturbance and dryness of the eye) was examined.


Methods


This study was approved by the Ethics Committee and Institutional Review Board of Kyoto Prefectural University of Medicine, Kyoto, Japan (RBMR-E-215), and was carried out in accordance with the tenets set forth in the Declaration of Helsinki.


Patients


In order to investigate ocular involvement in SJS/TEN patients as a first step, we retrospectively reviewed SJS and TEN patients who were diagnosed in the period from January 2005 to December 2007, with the medical records of those patients being obtained from dermatologists.


Data Collection


To identify SJS and TEN patients, a questionnaire was first sent to dermatologists at 607 medical institutions, and dermatologists from 212 medical institutions responded. Secondly, case report forms (CRFs) were sent to dermatologists. Based on the medical records in each institution, patients matching the diagnostic criteria for SJS and TEN, which was made by the Japanese Ministry of Health, Labour and Welfare in 2005 ( Table 1 ) (diagnostic criteria and systemic severity index score for Stevens-Johnson syndrome available at www.nanbyou.or.jp/entry/3680 , accessed April 21, 2015), were determined. The CRF was structured as follows: (1) diagnostic criteria, (2) patient information (ie, sex, age, past medical history and accompanying systemic diseases), (3) exposed drugs, (4) clinical symptoms, (5) systemic findings (ie, existence of a high fever and/or respiratory problem, the quality and location of a rash, and involvement of the lips, mouth, or other mucous membrane), (6) laboratory findings, and (7) a histopathologic examination of a skin biopsy. The results by this study for systemic and dermatologic findings had already been reported.



Table 1

Diagnostic Criteria for Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis by Japanese Ministry of Health, Labour and Welfare (2005)















































Diagnostic Criteria
Stevens-Johnson syndrome
Clinical entity A severe mucocutaneous disorder characterized by erythema, epidermal detachment, and enanthema accompanied by high fever
Essential criteria (required) 1. Severe hyperemic and/or hemorrhagic mucocutaneous lesions
2. Epidermal detachment involving <10% of the total body surface area
3. High-grade fever (≥38.0 °C) in the absence of antipyretic therapy
Supportive findings 1. Flat, atypical target lesions
2. Bilateral acute keratoconjunctivitis accompanied by ocular surface epithelial defect and/or pseudomembrane formation
3. Histologic evidence of epidermal necrosis
Toxic epidermal necrolysis
Clinical entity A severe mucocutaneous disorder characterized by extensive erythema, epidermal detachment (including blisters and erosions), and enanthema accompanied by high fever. The extent of epidermal detachment is ≥10% of the total body surface area
Essential criteria (required) 1. Epidermal detachment involving >10% of the total body surface area
2. Exclusion of staphylococcal scalded skin syndrome
3. High-grade fever (≥38.0 °C) in the absence of antipyretic therapy
Supportive findings 1. Generalized macular or diffuse erythema
2. Enanthema including bilateral acute keratoconjunctivitis accompanied by ocular surface epithelial defect and/or pseudomembrane formation
3. Histologic evidence of marked epidermal necrosis


Then, for registration of this survey, CRFs for investigating ocular involvement were sent to ophthalmologists, to whom patients were referred by dermatologists, and the patients who were treated by ophthalmologists were selected as this study population. This ophthalmologic CRF consisted of (1) ocular surface findings at first appearance, at the day of worst severity, and at last appearance, with the sketches of epithelial defect and pseudomembrane formation being included; (2) pre-existing ocular diseases; (3) ocular sequelae at the chronic stage (ie, visual disturbance and eye dryness); and (4) exposed drug and therapeutic drugs. Ocular surface findings at the acute stage were graded as an acute ocular severity score, as described below ( Table 2 ). Ocular findings at last appearance (at the chronic stage) were graded as per the previously described methods. Exposed drugs were categorized to NSAIDs, cold remedies, antibiotics, anticonvulsants, and others. The records of steroid pulse therapy, high-dose steroids, intravenous immunoglobulin, plasmapheresis as systemic therapy, and topical antibiotics and steroids were collected.



Table 2

Grading Scores for Acute Ocular Severity of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis



















Acute Ocular Manifestations Grade
No ocular involvement 0 (none)
Conjunctival hyperemia 1 (mild)
Either ocular surface epithelial defect or pseudomembrane formation 2 (severe)
Both ocular surface epithelial defect and pseudomembrane formation 3 (very severe)


Acute Ocular Severity Score, Definition and Measurement


In this study, ocular surface findings at the acute stage were graded as an acute ocular severity score ranging from grade 0 to 3, which were termed as “none,” “mild,” “severe,” and “very severe” ( Table 2 ). We considered that ocular surface inflammation and epithelial necrosis or apoptosis might be the initial ocular pathologic processes of SJS/TEN. Conjunctival hyperemia, which indicates ocular surface inflammation, was assessed as grade 1. Eyes with accompanying pseudomembrane formation or ocular surface epithelial defect were assessed as grade 2. Eyes with both pseudomembrane formation and ocular surface epithelial defect were assessed as grade 3. In addition, we checked all of the sketches of ocular surface appearances contained within the ophthalmologic CRF.


The acute stage was defined as the first 2 months from onset, because both SJS and TEN are self-limited until 6–8 weeks after onset. In addition, the acute ocular severity scores at the day of worst severity during the acute stage were documented, because ocular severity at the acute stage often worsens, even during medical treatment. In cases where the acute ocular severity differed between both eyes, the more severe eye was chosen as the eye to be evaluated.


The systemic severity index score is a summed score, shown in the Supplemental Table (available at AJO.com ), with the maximum score being 14. Moreover, the systemic severity index subscore is defined as a summed score that includes the score for surface area of skin lesions on the body, except for the score for ocular lesion, with the maximum score being 11.


Statistical Analysis


Acute ocular severity at the day of worst severity was compared to various factors such as the patient’s age, sex, exposed drugs, and the systemic severity index subscore ( Supplemental Table ). In addition, predictive factors at diagnosis associated with acute ocular severity were examined. Finally, correlation between the acute ocular severity score and the prevalence of ocular sequelae (visual disturbance and eye dryness) was examined.


To summarize the data, the mean (standard deviation [SD]) for continuous variables and frequencies (%) for categorical variables were used. To examine whether or not the increase of acute ocular severity affected the linear trend for each factor, the Jonckheere-Terpstra test of trend for continuous variables and the Cochran-Armitage test of trend for categorical variables were used. In addition, the logistic regression model was used to determine predictive factors for categories of the acute ocular severity score, which included the cases with no or mild ocular involvement (acute ocular severity score grades 0 and 1, as reference) and the cases with severe or very severe ocular involvement (acute ocular severity score grades 2 and 3). The candidate predictive factors were selected with a P value of <.05 for the Wald test in univariate analysis, and the predictive factors were selected from those factors by using the reverse method with a P value of <.05 for each factor in multivariate analysis. The odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) based on the Wald test were then estimated. All analyses were performed by SAS version 9.3 (SAS Institute, Cary, North Carolina, USA).




Results


Patient Characteristics and Therapy


In the current study, 87 SJS patients and 48 TEN patients were identified from institutions throughout Japan. Of those patients, 36 SJS patients (41.4%) and 23 TEN patients (47.9%) were men. In addition, the mean age (SD) for SJS and TEN patients was 51.6 (19.4) and 53.9 (20.8), respectively. Systemic steroid pulse therapy was administered in 40 SJS cases (46.0%) and in 28 TEN cases (58.3%). Intravenous immunoglobulin was administered in 8 SJS cases (9.2%) and in 21 TEN cases (43.3%). Plasmapheresis was performed in 3 SJS cases (3.4%) and in 10 TEN cases (20.8%). Of the 104 cases with ocular involvement, antibiotics and steroids were administered in 74 cases (71.2%) and 85 cases (81.7%), respectively. Topical steroids were administered in all 23 cases with acute ocular severity score grade 3 (very severe).


Acute Ocular Severity Score


Of the 87 SJS cases, the acute ocular severity score was grade 0 in 19 cases (21.8%), grade 1 in 31 cases (35.6%), grade 2 in 22 cases (25.3%), and grade 3 in 15 cases (17.2%) ( Table 3 ). Of the 48 TEN cases, the score was grade 0 in 12 cases (25.0%), grade 1 in 11 cases (22.9%), grade 2 in 17 cases (35.4%), and grade 3 in 8 cases (16.7%) ( Table 3 ). The typical findings observed in such cases are shown in Figure 1 .



Table 3

Relationship Between Factors and Acute Ocular Severity Score in the Patients With Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis























































































































































































































































































Variable Acute Ocular Severity Score P Value
0 (None) 1 (Mild) 2 (Severe) 3 (Very Severe)
Stevens-Johnson syndrome (N = 87) N = 19 N = 31 N = 22 N = 15
Demographic variables
Sex, n (%)
Male 7 (36.8%) 16 (51.6%) 8 (36.4%) 5 (33.3%) .567
Age at onset
Mean ± SD, y 57.1 ± 18.2 52.3 ± 18.7 54.4 ± 19.1 39.2 ± 19.2 .050
<50, n (%) 7 (36.8%) 11 (35.5%) 8 (36.4%) 11 (73.3%) .054
Systemic severity index subscore
Mean ± SD 4.5 ± 1.6 3.9 ± 1.8 4.0 ± 1.6 4.8 ± 1.4 .579
Median (range) 5.0 (1–7) 4.0 (1–8) 4.0 (1–7) 5.0 (2–7)
Exposed drug, n (%)
NSAIDs
Yes 9 (47.4%) 10 (32.3%) 9 (40.9%) 9 (60.0%) .394
Cold remedies
Yes 1 (5.3%) 3 (9.7%) 3 (13.6%) 4 (26.7%) .062
Antibiotics
Yes 4 (21.1%) 6 (19.4%) 3 (13.6%) 1 (6.7%) .212
Anticonvulsants
Yes 4 (21.1%) 14 (45.2%) 6 (27.3%) 2 (13.3%) .370
Toxic epidermal necrolysis (N = 48) N = 12 N = 11 N = 17 N = 8
Demographic variables
Sex, n (%)
Male 5 (41.7%) 6 (54.5%) 8 (47.1%) 4 (50.0%) .794
Age at onset
Mean ± SD, y 62.0 ± 14.5 64.6 ± 25.5 47.9 ± 19.0 39.6 ± 14.6 .062
<50, n (%) 2 (16.7%) 2 (18.2%) 9 (52.9%) 6 (75.0%) .002
Systemic severity index subscore
Mean ± SD 7.1 ± 1.7 8.3 ± 2.2 8.0 ± 1.5 8.0 ±1.3 .335
Median (range) 7.5 (4–9) 9.0 (3–11) 9.0 (4–10) 8.5 (6–9)
Exposed drug, n (%)
NSAIDs
Yes 3 (25.0%) 2 (18.2%) 9 (52.9%) 4 (50.0%) .079
Cold remedies
Yes 0 (0.0%) 0 (0.0%) 6 (35.3%) 2 (25.0%) .015
Antibiotics
Yes 0 (0.0%) 5 (45.5%) 4 (23.5%) 1 (12.5%) .578
Anticonvulsants
Yes 2 (16.7%) 1 (9.1%) 4 (23.5%) 2 (25.0%) .463

NSAIDs = nonsteroidal anti-inflammatory drugs.

The Jonckheere-Terpstra test of trend for continuous variables and the Cochran-Armitage test of trend for categorical variables were used.



Figure 1


Representative slit-lamp appearances of Stevens-Johnson syndrome (SJS)- and toxic epidermal necrolysis (TEN)-associated ocular involvement at the acute stage. Bilateral conjunctivitis with hyperemia (Top left) is the most frequently associated ocular finding. Pseudomembrane formation (Top right) is seen in cases accompanying extensive ocular surface inflammation. Ocular surface corneal (Middle left) or conjunctival (Bottom left) epithelial defects can easily be seen by fluorescein staining (Middle right and Bottom right).


Association Between Characteristics at Diagnosis and Acute Ocular Severity Score


The acute ocular severity scores in male subjects were similar to those in female subjects in both SJS ( P = .603) and TEN ( P = .940). Patient age at disease onset tended to be younger in the group with severe or very severe ocular involvement than in the group with no or mild ocular involvement in both disease categories (SJS: P = .050; TEN: P = .062) ( Figure 2 and Table 3 ). In addition, the systemic severity index subscores did not differ among the 4 groups according to the acute ocular severity score in both SJS and TEN (SJS: P = .579; TEN: P = .335) ( Table 3 ).




Figure 2


Relationship between the acute ocular severity score and patient age in the Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) cases. The horizontal line within each shaded box represents the median value, and the bottom and top lines of each box represent the 25th and 75th percentiles, respectively. The vertical lines extending from the top and bottom of each box represent the lowest and highest values, respectively (or are located 1.5 times the interquartile range away from the box). The Jonckheere-Terpstra test was used to determine whether or not patient age was related to the severity scores.


NSAIDs were the exposed drugs in more than 40.0% of the SJS and TEN cases with an acute ocular severity score grade 2 and 3; however, the use of NSAIDs was found to not be associated with the acute ocular severity (SJS: P = .394; TEN: P = .079) ( Table 3 ). In addition, the use of cold remedies (as the exposed drugs) was found to be increased according to the worsening of acute ocular severity in TEN patients ( P = .015), but not in SJS patients ( P = .062) ( Table 3 ). The use of antibiotics was found to not be associated with the acute ocular severity (SJS: P = .212; TEN: P = .578) ( Table 3 ). Furthermore, the use of anticonvulsants was found to not be associated with the acute ocular severity (SJS: P = .370; TEN: P = .463) ( Table 3 ).


Predictive Factors at Diagnosis Associated With Acute Ocular Severity


A total of 135 patients were analyzed. Univariate logistic regression analysis revealed that disease (TEN or SJS) was not associated with acute ocular severity (grade 2 and 3 vs grade 0 and 1, OR: 1.47, 95% CI: 0.72–2.98, P = .287). In contrast, patient age (OR: 0.97, 95% CI: 0.96–0.99, P = .004) and NSAIDs (OR: 2.04, 95% CI: 1.02–4.10, P = .045), cold remedies (OR: 5.51, 95% CI: 1.72–17.6, P = .004), and NSAIDs or cold remedies (OR: 2.68, 95% CI: 1.33–5.38, P = .006) were associated with acute ocular severity (grade 2 and 3 vs grade 0 and 1) as the candidate predictive factors ( Table 4 ). Further, in multivariate logistic regression analysis, patient age (OR: 0.98, 95% CI: 0.96–0.99, P = .007) and NSAIDs or cold remedies (OR: 2.58, 95% CI: 1.26–5.29, P = .010) were identified as predictive factors for acute ocular severity (grade 2 and 3 vs grade 0 and 1).



Table 4

Logistic Regression Analysis of the Association Between Variables at Onset and Acute Ocular Severity in Patients With Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis























































































Variable at Onset N = 135 Univariate Logistic Regression Multivariate Logistic Regression
OR 95% CI P Value OR 95% CI P Value
Disease: TEN (vs SJS) 1.47 0.72–2.98 .287
Sex: male (vs female) 0.78 0.39–1.54 .466
Age at onset (y) 0.97 0.96–0.99 .004 0.98 0.96–0.99 .007
Age at onset (y): >50 (vs 50≤) 0.36 0.18–0.72 .004
NSAIDs 2.04 1.02–4.1 .045
Cold remedies 5.51 1.72–17.62 .004
NSAIDs or cold remedies 2.68 1.33–5.38 .006 2.58 1.26–5.29 .010
Antibiotics 0.66 0.27–1.63 .363
Anticonvulsants 0.72 0.33–1.58 .415

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Jan 7, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on Predictive Factors Associated With Acute Ocular Involvement in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
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