Development and Validation of a Novel Score to Predict Mortality in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: CRISTEN.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening, severe mucocutaneous adverse reactions. Severity prediction at early onset is urgently required for treatment. However, previous prediction scores have been based on data of blood tests. OBJECTIVE: This study aimed to present a novel score that predicts mortality in patients with SJS/TEN in the early stages based on only clinical information. METHODS: We retrospectively evaluated 382 patients with SJS/TEN in a development study. A clinical risk score for TEN (CRISTEN) was created according to the association of potential risk factors with death. We calculated the sum of these risk factors using CRISTEN, and this was validated in a multinational survey of 416 patients and was compared with previous scoring systems. RESULTS: The significant risk factors for death in SJS/TEN comprised 10 items, including patients' age of ≥65 years, ≥10% body surface area involvement, the use of antibiotics as culprit drugs, the use of systemic corticosteroid therapy before the onset, and mucosal damage affecting the ocular, buccal, and genital mucosa. Renal impairment, diabetes, cardiovascular disease, malignant neoplasm, and bacterial infection were included as underlying diseases. The CRISTEN model showed good discrimination (area under the curve [AUC] = 0.884) and calibration. In the validation study, the AUC was 0.827, which was statistically comparable to those of previous systems. CONCLUSION: A scoring system based on only clinical information was developed to predict mortality in SJS/TEN and was validated in an independent multinational study. CRISTEN may predict individual survival probabilities and direct the management and therapy of patients with SJS/TEN.

Topical Betamethasone Treatment of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis with Ocular Involvement in the Acute Phase.

PURPOSE: To clarify the importance of administering topical steroids for the treatment of Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN) with ocular involvement in the acute phase. DESIGN: Retrospective case series. METHODS: Using the medical records of acute SJS/TEN patients treated at the Kyoto Prefectural University of Medicine Hospital, Kyoto, Japan, between July 2006 and July 2017, the ocular findings, topical steroid dosage, systemic steroid dosage, and ocular sequelae were retrospectively examined. The level of cytokines in tear fluid and serum samples was also analyzed. RESULTS: This study involved 13 cases. In 10 cases in whom the clinical courses were recorded before the start of steroid therapy, the mean acute ocular severity score (AOSS: 3 = very severe; 2 = severe; 1 = mild; 0 = none) was 2.8 ± 0.4 points in the severest phase. The mean systemic steroid dose after steroid pulse therapy was 694 ± 386 mg and the mean topical steroid (0.1% betamethasone eye drop and ointment) dose was 13.4 ± 3.3 times daily in the severest phase. Analysis of cytokine levels of 4 cases showed that a cytokine storm occurred in the tear fluid after the steroid pulse therapy. At final follow-up, 16 eyes of 8 patients had a logMAR visual acuity of ≤0, and no serious ocular sequelae were observed. CONCLUSIONS: In patients with SJS/TEN, ocular surface inflammation remains strong even after systemic inflammation has improved post steroid pulse therapy, thus suggesting that both systemic and topical steroid therapy should be administered appropriately.

Risk factors for sepsis and effects of pretreatment with systemic steroid therapy for underlying condition in SJS/TEN patients: Results of a nationwide cross-sectional survey in 489 Japanese patients.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse reactions (SCARs). Sepsis has been shown to be the main cause of death in SJS/TEN. The European SCAR study reported that 14.8 % of SJS/TEN patients were receiving systemic steroid therapy for their underlying condition prior to onset. However, it remained unclear whether this factor affected the mortality rate. OBJECTIVE: This study was performed to identify risk factors for sepsis in SJS/TEN patients. In addition, we compared patients who had and had not received systemic steroid therapy for their underlying condition. METHODS: A primary survey regarding the numbers of SJS/TEN patients between 2016 and 2018 was sent to 1205 institutions in Japan. A secondary survey seeking more detailed information was sent to institutions reporting SJS/TEN patients. We analyzed 315 SJS patients and 174 TEN patients using a logistic regression model, Wilcoxon's rank-sum test, χ2 test, and Fisher's exact test. RESULTS: Significant risk factors for sepsis included TEN, diabetes, and intensive care unit (ICU) admission. The mortality rate was significantly higher among patients with sepsis. Patients who had received systemic steroid therapy had a lower incidence of fever, and showed a higher mortality rate. CONCLUSION: Based on a nationwide epidemiological survey of SJS/TEN in Japan, we identified risk factors for sepsis and found that patients who had received steroid therapy for their underlying condition had a lower incidence of fever and a higher mortality rate.

Multi-state model for predicting ocular progression in acute Stevens-Johnson syndrome/toxic epidermal necrolysis.

This study aimed to clarify the etiologic factors predicting acute ocular progression in SJS/TEN, and identify patients who require immediate and intensive ophthalmological treatment. We previously conducted two Japanese Surveys of SJS/TEN (i.e., cases arising between 2005-2007 and between 2008-2010), and obtained the medical records, including detailed dermatological and ophthalmological findings, of 230 patients. Acute ocular severity was evaluated as none, mild, severe, and very severe. A multi-state model assuming the Markov process based on the Cox proportional hazards model was used to elucidate the specific factors affecting the acute ocular progression. Our findings revealed that of the total 230 patients, 23 (24%) of 97 cases that were mild at initial presentation worsened to severe/very severe. Acute ocular progression developed within 3 weeks from disease onset. Exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) and younger patient age were found to be statistically significant for the progression of ocular severity from mild to severe/very severe [hazard ratio (HR) 3.83; 95% confidence interval (CI) 1.48 to 9.91] and none to severe/very severe [HR 0.98; 95% CI 0.97 to 0.99], respectively. The acute ocular severity score at worst-condition was found to be significantly correlated with ocular sequelae. Thus, our detailed findings on acute ocular progression revealed that in 24% of SJS/TEN cases with ocular involvement, ocular severity progresses even after initiating intensive treatment, and that in younger-age patients with a history of exposure to NSAIDs, very strict attention must be given to their ophthalmological appearances.

Accuracy of the Barrett Universal II formula integrated into a commercially available optical biometer when using a preloaded single-piece intraocular lens.

PURPOSE: To compare the commonly used formulas for intraocular lens (IOL) selection using IOLMaster®700 (Carl Zeiss Meditec) and to evaluate the Barrett Universal II (BU-II) formula accuracy when using the Vivinex™ iSert® XY1 IOL (Hoya Corporation Medical Division). METHODS: A retrospective chart review was performed that included patients who underwent uneventful cataract surgery with in-the-bag insertion of Vivinex™ iSert® XY1 IOL. Prediction errors at 3 months postoperative of IOLMaster® 700 with Haigis, Holladay 1, SRK/T, and BU-II formulas were compared. As a subgroup analysis, we focused on the axial length (AL) and IOL power. AL subgroup analysis was based on the following AL subgroups: short (<22.5 mm), medium (22.5-25.5 mm), and long (>25.5 mm). IOL power subgroup analysis was based on the following IOL power subgroups: low (≤18.0 diopters [D]), medium (18.5-24.0 D), and high (≥24.5 D). RESULTS: This study included 590 eyes of 590 patients. Overall, the four IOL calculation formulas appeared to be similarly accurate. In the long AL subgroup, the BU-II formula had a significantly lower absolute error (AE) than the Holladay 1 formula. In the low-power subgroup, the BU-II formula had a significantly lower AE than the Holladay 1 and SRK/T formulas. On the other hand, in the high-power subgroup, the BU-Ⅱ formula was significantly less accurate than the SRK/T formula and also appeared to be worse than the Holladay 1 formula (P = 0.052). CONCLUSION: The BU-II formula might be less accurate when using a Vivinex™ iSert® XY1 IOL of 24.5 D or greater.

Corticosteroid Pulse Therapy for Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Patients With Acute Ocular Involvement.

PURPOSE: To investigate the long-term effects of corticosteroid pulse therapy (CPT) for the treatment of acute-stage Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) patients with severe ocular involvement. DESIGN: Retrospective, comparative case series. METHODS: This study retrospectively reviewed the medical records of 116 SJS/TEN patients who developed the disease between 2002 and 2018. Patients with severe ocular disorders (ie, ocular surface epithelial defect, pseudomembranous formation, or both) at the acute stage and who were followed for >1 year post SJS/TEN onset were enrolled. In those patients, the treatments administered for acute-stage SJS/TEN and associated ocular sequelae were examined, including the best-corrected visual acuity (BCVA) in the patient's worse eye and the incidence of the ocular complications at the final follow-up examination. RESULTS: A total of 85 patients were enrolled. Of those, 36 received CPT within 4 days post disease onset (group A) and 49 patients did not receive CPT within 4 days post disease onset (group B). The percentage of eyes with a BCVA in the worse eye of ≥ 1.0 were 52.8% in group A and 14.3% in group B. Severe ocular sequelae (ie, a worsening of BCVA and corneal and conjunctival complications) were significantly less in group A than in group B. CONCLUSIONS: In SJS/TEN patients with acute ocular involvement, CPT initiated within 4 days from disease onset may help reduce severe ocular sequelae.

The nationwide epidemiological survey of Stevens-Johnson syndrome and toxic epidermal necrolysis in Japan, 2016-2018.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse reactions (SCARs). The first national epidemiological survey of SJS/TEN was carried out in 2008. We conducted a new survey to identify changes from the previous survey. OBJECTIVE: The present survey aimed to estimate the number of SJS/TEN patients in Japan between 2016 and 2018 (primary survey) and to clarify clinical epidemiological profiles (secondary survey). METHODS: A primary survey asking for numbers of SJS/TEN patients during the study period was sent to 1205 institutions nationwide. A secondary survey was sent to institutions reporting SJS/TEN patients, seeking detailed information. RESULTS: Yearly prevalence per million was 2.5 for SJS and 1 for TEN. The secondary survey allowed analysis of 315 SJS cases and 174 TEN cases from 160 institutions. Mean age was 53.9 years in SJS, and 61.8 years in TEN. Mortality rate was 4.1 % for SJS and 29.9 % for TEN. In TEN, mean age and mortality rates had increased from the previous survey. The ratio of expected to observed mortality calculated by SCORTEN score was lowest with high-dose steroid therapy (0.40), followed by steroid pulse therapy (0.52). CONCLUSION: The present findings suggest that the mortality rate of TEN has increased because of increases in mean ages of patients and patients with malignant neoplasm as underlying disease. When comparing the ratio of expected mortality to actual mortality, high-dose steroid therapy achieved the greatest reduction in mortality.

Prospective Clinical Trial of Intravitreal Aflibercept Treat-and-extend Regimen for Diabetic Macular Edema: 1-Year Outcomes.

PURPOSE: To investigate the efficacy of aflibercept for the treatment of diabetic macular edema via a treat-and-extend regimen. METHODS: This prospective, single-center, open-label, interventional study involved 30 patients with a best-corrected visual acuity (BCVA) ≤0.6 and a central retinal thickness (CRT) ≥300 µm. The enrolled eyes each received a monthly intravitreal aflibercept injection until the CRT decreased below 300 µm, upon which the administration interval was extended for 1 month until the CRT once again increased to ≥300 µm. Main outcome measures were median BCVA and CRT at 6 and 12 months after initiation of treatment via last observation carried forward analysis, the median number of injections over the 12 months, and the effects on the diabetic retinopathy severity scale (DRSS) score of the patients who completed the 12-month follow-up period. RESULTS: Of the 30 enrolled patients, 29 and 25 respectively completed the 6- and 12-month follow-up examinations. From baseline to 6 and 12 months after treatment initiation, the median BCVA (logarithm of the minimum angle of resolution) significantly improved from 0.52 to 0.30 and 0.35, respectively, and the median CRT significantly decreased from 439.5 to 268.5 and 249.0 µm, respectively. The median number of injections over the 12-month follow-up period was 6.0. Compared to baseline, the DRSS score at 12 months was improved by 2 steps in 16% of patients; in no cases did the DRSS score worsen or improve by three steps or more. CONCLUSIONS: When administered in a treat-and-extend regimen, aflibercept is an effective treatment option for diabetic macular edema.

Evaluation of pre- and post-surgery reading ability in patients with epiretinal membrane: a prospective observational study.

BACKGROUND: This study aimed to investigate the pre- and post-surgery reading ability in patients with idiopathic epiretinal membrane (ERM) to evaluate whether measurement of reading performance is a helpful test in addition to visual acuity (VA) as an assessment measure. METHODS: This prospective observational study involved 42 eyes of 40 patients with idiopathic ERM. Best-corrected visual acuity (BCVA), reading ability, and metamorphopsia score were evaluated at baseline and at 3, 6, and 12 months post-surgery. As the outcome measure, the reading ability of each patient (i.e., overall performance) was examined with MNREAD-J, the Japanese version of the MNREAD reading acuity (RA) charts, to determine RA, critical print size (CPS), and maximum reading speed (MRS). Generally, a difference of 0.2 logMAR or more is considered a significant change in BCVA. Thus, as a subgroup analysis, we additionally evaluated the BCVA and reading ability of the patients with a BCVA difference of 0.1 logMAR or less between at baseline and at 12 months post-surgery. RESULTS: Relative to their values at baseline, the subjects exhibited significantly improved BCVA, RA, and CPS throughout the post-surgery examination period (P < 0.001) and significantly improved MRS at 12 months post-surgery (P = 0.04). No significant change in the vertical metamorphopsia score was observed throughout the post-surgery follow-up period. However, and compared to the value at baseline, significant improvements in the horizontal metamorphopsia score were observed at 3, 6 (P < 0.05), and 12 months (P < 0.001) post-surgery. In the subgroup analysis of the 23 eyes that exhibited a BCVA improvement of 0.1 logMAR or less, the median BCVA did not change, but the median RA and CPS improved by 0.2 logMAR. CONCLUSIONS: Our findings showed that the surgical removal of ERM improves reading ability, even when the BCVA score does not improve. The measurement of reading performance appears to be a helpful test in addition to VA as a measure for assessing the surgical removal of ERM.

Expression of prostaglandin E2 receptor 3 in the eyelid epidermis of patients with Stevens-Johnson syndrome/toxic epidermal necrolysis.

BACKGROUND/AIMS: In a previous genome-wide association study of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) patients we reported the association between SJS/TEN and the prostaglandin E receptor 3 (PTGER3) gene, and that its protein PGE2 receptor 3 (EP3) was markedly downregulated in the conjunctival epithelium of SJS/TEN patients. Here we examined EP3 expression of the eyelid epidermis in SJS/TEN patients with severe ocular complications and investigated the function of EP3. METHODS: For the immunohistochemical study, we obtained eyelid samples from five SJS/TEN patients and five patients without SJS/TEN (control subjects) who were undergoing surgery to treat trichiasis, and investigated the expression of EP3 protein in the epidermis of those samples. To investigate the EP3 function in the human epidermal keratinocytes, we performed ELISA and quantitative reverse transcription polymerase chain reaction, since it is reported that PGE2 suppresses cytokine production via EP3 in human conjunctival epithelium. RESULTS: The results of the immunohistochemical study revealed that EP3 expression in the eyelid epidermis of the SJS/TEN patients was the same as that in the controls. PGE2 and a selective EP3 agonist suppressed cytokine production and expression induced by polyinosine-polycytidylic acid stimulation, such as chemokine ligand 5 and chemokine motif ligand 10. CONCLUSION: Our findings revealed that in chronic-phase SJS/TEN, EP3 protein was expressed in the eyelid epidermis and was not downregulated, unlike in conjunctival epithelium, and that PGE2 could suppress cytokine production via EP3 in human epidermal keratinocytes. Thus, EP3 expression in the epidermis might contribute to a silencing of skin inflammation in chronic-phase SJS/TEN.

pH balance and lactic acid increase in the vitreous body of diabetes mellitus patients.

Although there have been no previous reports on the pH of the human vitreous body, it has been highly theorized that it changes in patients with diabetes mellitus (DM). In humans, it is necessary to measure the vitreous pH in vitro, which is an important point that presents a major problem, as vitreous pH immediately changes when exposed to air. The purpose of this present study was to report our recent development of an in vitro method for measuring vitreous pH via the combination of 27-gauge (G) vitreous surgery and a blood gas analyzer, as well as our investigative findings on whether or not there is a difference of pH depending on the presence of diabetes mellitus (DM). This cross-sectional study involved 30 subjects [18 subjects without DM (DM-) and 12 subjects with DM (DM+)] with no previous history of ophthalmologic surgery. The DM+ group included 6 cases of proliferative diabetic retinopathy (PDR) and 6 cases of non-PDR (NPDR). The DM- Group was comprised of patients with a macular hole or idiopathic epiretinal membrane. The DM+ Group included patients not only with macular hole or idiopathic epiretinal membrane but also diabetic macular edema, however, patients with obvious vitreous hemorrhage were excluded. In all patients, a vitreous specimen was anaerobically obtained at the start of 27G pars plana vitrectomy, with a venous blood sample being collected immediately prior to surgery. Between the DM- and DM+ subjects, pH, partial pressure of carbon dioxide (pCO2), partial pressure of oxygen (pO2), K+, Na+, Ca2+, Cl-, lactate, and glucose were compared. In the items in which a significant difference was found between DM- and DM+, the values between the PDR and NPDR cases were also compared. Our findings showed no significant difference in vitreous and venous-blood pH between the DM- and DM+ subjects. The vitreous biochemical data revealed that Ca2+ significantly reduced and lactate and glucose significantly increased in DM+ compared to DM-. Thus, we compared Ca2+, lactate, and glucose between the PDR and NPDR cases. Although glucose did not significantly change, Ca2+ significantly decreased and lactate significantly increased in the PDR cases. The venous biochemical data revealed that only glucose significantly increased in DM+. The data in all investigated items was found to be significantly different between the vitreous and venous samples. Our findings revealed that lactate increases and Ca2+ decreases in the vitreous body of DM patients, especially those with PDR, probably due to the increased production of lactic acid. However, although the production of lactic acid increased, the pH remained at a nearly constant value, thus suggesting that the human vitreous body has a high buffering capacity.

The Efficacy of Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors for the treatment of chronic diabetic macular oedema in vitrectomised eyes: a retrospective study.

OBJECTIVE: To investigate the change of chronic diabetic macular oedema (DMO) in vitrectomised eyes when the administration of sodium-glucose cotransporter 2 (SGLT2) inhibitors is initiated as a systemic medical treatment. METHODS AND ANALYSIS: This study involved 10 eyes of five patients with chronic DMO lasting more than 6 months who had previously undergone vitrectomy and whose systemic medical treatments were newly changed to SGLT2 inhibitors. In this study, chronic DMO was defined as persistent diffuse macular oedema despite ophthalmic treatment in patients with diabetes. Patients who received antivascular endothelial growth factor therapy or steroids administration, or change of eye-drop medication from at 3 months before and after the initiation of SGLT2 inhibitors, were excluded. In this study, visual acuity (VA) and central retinal thickness (CRT, µm) prior to and at 3, 6 and 12 months after the initiation of SGLT2 inhibitors were retrospectively compared. The Wilcoxon signed-rank test was used for statistical analysis. RESULTS: In the 10 treated eyes, from at baseline to at 3, 6 and 12 months after the initiation of SGLT2 inhibitor, median VA (logMAR) improved from 0.35 to 0.15 (p=0.038), 0.2 (p=0.157) and 0.2 (p=0.096), respectively, and median CRT significantly reduced from 500.5 µm to 410 µm (p<0.01), 378 µm (p<0.01) and 339 µm (p<0.01), respectively. CONCLUSION: Although this study involved only five patients, our findings indicate that SGLT2 inhibitors might have structural efficacy for chronic DMO in vitrectomised eyes.