Management of Adult Patients With Drug Reaction With Eosinophilia and Systemic Symptoms: A Delphi-Based International Consensus.

Importance: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but potentially fatal drug hypersensitivity reaction. To our knowledge, there is no international consensus on its severity assessment and treatment. Objective: To reach an international, Delphi-based multinational expert consensus on the diagnostic workup, severity assessment, and treatment of patients with DRESS. Design, Setting, and Participants: The Delphi method was used to assess 100 statements related to baseline workup, evaluation of severity, acute phase, and postacute management of DRESS. Fifty-seven international experts in DRESS were invited, and 54 participated in the survey, which took place from July to September 2022. Main Outcomes/Measures: The degree of agreement was calculated with the RAND-UCLA Appropriateness Method. Consensus was defined as a statement with a median appropriateness value of 7 or higher (appropriate) and a disagreement index of lower than 1. Results: In the first Delphi round, consensus was reached on 82 statements. Thirteen statements were revised and assessed in a second round. A consensus was reached for 93 statements overall. The experts agreed on a set of basic diagnostic workup procedures as well as severity- and organ-specific further investigations. They reached a consensus on severity assessment (mild, moderate, and severe) based on the extent of liver, kidney, and blood involvement and the damage of other organs. The panel agreed on the main lines of DRESS management according to these severity grades. General recommendations were generated on the postacute phase follow-up of patients with DRESS and the allergological workup. Conclusions and Relevance: This Delphi exercise represents, to our knowledge, the first international expert consensus on diagnostic workup, severity assessment, and management of DRESS. This should support clinicians in the diagnosis and management of DRESS and constitute the basis for development of future guidelines.

Allopurinol non-covalently facilitates binding of unconventional peptides to HLA-B*58:01.

Allopurinol, widely used in gout treatment, is the most common cause of severe cutaneous adverse drug reactions. The risk of developing such life-threatening reactions is increased particularly for HLA-B*58:01 positive individuals. However the mechanism of action between allopurinol and HLA remains unknown. We demonstrate here that a Lamin A/C peptide KAGQVVTI which is unable to bind HLA-B*58:01 on its own, is enabled to form a stable peptide-HLA complex only in the presence of allopurinol. Crystal structure analysis reveal that allopurinol non-covalently facilitated KAGQVVTI to adopt an unusual binding conformation, whereby the C-terminal isoleucine does not engage as a PΩ that typically fit deeply in the binding F-pocket. A similar observation, though to a lesser degree was seen with oxypurinol. Presentation of unconventional peptides by HLA-B*58:01 aided by allopurinol contributes to our fundamental understanding of drug-HLA interactions. The binding of peptides from endogenously available proteins such as self-protein lamin A/C and viral protein EBNA3B suggest that aberrant loading of unconventional peptides in the presence of allopurinol or oxypurinol may be able to trigger anti-self reactions that can lead to Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).

Perceptions of teledermatology in the COVID-19 era: are patients ready for it?

Introduction: The COVID-19 pandemic has changed care provision models, with a rapid increase in the adoption of telemedicine to reduce in-person visits. Although there are many benefits to teledermatology, there are also factors that hinder its widespread adoption. We aimed to examine patients' perceptions of teledermatology to identify the barriers to its adoption. Methods: A prospective study was conducted from 15 June to 14 August 2020. Patients were invited to complete a questionnaire in an outpatient dermatology clinic via direct approach by clinical staff or posters posted at the door of consultation rooms. Results: Out of 2,276 clinic attendances, 997 survey responses (43.8%) were collected over a 3-month period. When asked if they would change their subsequent visit to teledermatology, 294 (29.5%) patients were keen, 166 (16.6%) were unsure and 537 (53.9%) declined. Significant factors for declining teledermatology were lack of prior exposure to videoconferencing (P < 0.01) and lower educational level (P = 0.019). Patients also raised concerns regarding the ability of teledermatology to address medical concerns (32.1%) and indicated a preference for face-to-face consultation (29.7%). Conclusion: Factors that influence patients' decision to adopt teledermatology, such as concerns about its ability to address medical issues, lack of IT literacy or experience in teleconferencing, are modifiable. Targeted strategies such as careful patient selection, a dedicated teleconsultation workflow, and the use of a novel 'teledermatology patient journey' (including a clinic walkthrough at the first visit) and an intuitive audio-enabled user interface, may improve patient perceptions and adoption of teleconsultation service.

Systemic Versus Topical Corticosteroids in the Treatment of DRESS: A Retrospective Cohort Study Followed by a Meta-Analysis.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe systemic drug hypersensitivity syndrome with significant risks of mortality and long-term sequelae. Management is challenging; whilst systemic corticosteroids are generally regarded as standard of care, there is a suggestion that topical corticosteroids may be a safe alternative. OBJECTIVE: We aimed to compare the clinical outcomes of patients with DRESS treated with systemic corticosteroids and topical corticosteroids in an academic medical center. METHODS: The medical records of patients diagnosed with DRESS at the Singapore General Hospital between 2009 and 2017 were retrospectively reviewed. A secondary systematic review and meta-analysis were performed to further clarify the outcomes. RESULTS: Out of 94 patients with DRESS, 41 (44%) were treated with topical corticosteroids and 53 (56%) were treated with systemic corticosteroids. Patients receiving systemic corticosteroids were more likely to develop infective complications (32.1 vs 12.2%, p = 0.02). One-month and 12-month mortality, length of hospital stay, flares of DRESS, and viral reactivation were similar between the two groups. In our meta-analysis (six studies, n = 292), there were no significant differences in mortality or length of stay between patients treated with systemic or topical corticosteroids. LIMITATIONS: This study was a non-controlled retrospective cohort study and the allocation of treatment may have been influenced by the severity of disease. Results of the secondary meta-analysis are limited by the quality of included studies. CONCLUSIONS: Topical corticosteroids may be a safe and efficacious alternative to systemic corticosteroids in the treatment of mild-to-moderate DRESS. CLINICAL TRIAL REGISTRATION: PROSPERO registration CRD42021285691.

Incidence of cutaneous graft-versus-host disease in a Singapore academic medical centre - A retrospective cohort study.

BACKGROUND: Cutaneous graft-versus-host disease (GVHD) is common in allogeneic haematopoietic stem cell transplantation. HLA mismatch is the most significant determinant of GVHD. Our study aimed to compare the incidence of cutaneous GVHD haploidentical (Haplo) and matched donors in an Asian population. METHODS: Retrospective cohort study of the 2015-2019 bone marrow transplant registry was conducted in a transplant centre. We compared the incidence of cutaneous GVHD in Haplo with allogeneic matched unrelated donor (MUD) and matched-sibling donor (MSD) transplant recipients. Secondary objectives include acute and chronic GVHD incidence, dermatology referrals, and histological findings. RESULTS: One hundred and seventy-nine out of 203 cases were reviewed; 17 (9.5%) Haplo, 80 (44.7%) MUDs and 82 (45.8%) MSDs. The median follow-up for Haplo, MUD and MSD was 15.2, 34.2 and 35.7 months, respectively. Haplo had a higher cumulative incidence of cutaneous GVHD than MUD and MSD (p = 0.053). Chronic GVHD was only reported in MSD. The most common histology was vacuolar interface changes (13 [44.8%]) with a wide range of onset post-transplant (19-456 days). CONCLUSIONS: Haplo donors may have a higher GVHD incidence than MUD and MSD in our predominantly Asian cohort. This information may be helpful when counselling patients pre-transplant. Further prospective studies are required.

Rituximab in Subepidermal Blistering Diseases.

BACKGROUND: Although rituximab is known to be effective in the treatment of pemphigus, its role in subepidermal autoimmune blistering diseases is unclear and currently limited to off-label use. SUMMARY: This is a meta-analysis of case reports, case series, and retrospective studies on the effectiveness and safety of rituximab in bullous pemphigoid, mucous membrane pemphigoid, ocular pemphigoid, and epidermolysis bullosa acquisita. We compared remission and relapse rates in patients who received rituximab with those who only received conventional medical therapy. Comparisons were also made among disease subgroups. KEY MESSAGE: The present analysis suggests that patients with subepidermal autoimmune blistering diseases treated with rituximab achieve a higher rate of complete remission and encounter their first relapse after a longer time interval. However, time to remission and total relapse rates were similar between groups. Adverse events and mortality rates were no more common in patients who received rituximab. This analysis was limited by the absence of randomized controlled trials and the observation that rituximab was used as a late rescue therapy in most reports. In conclusion, rituximab may be effective in subepidermal blistering disease, but randomized controlled studies are required for the validation of current observational data.

Improving drug allergy label accuracy by supervised safety- and protocol-driven evaluation.

INTRODUCTION: Drug allergies are often self-reported but of unknown accuracy. We carried out a prospective study to examine the utility and safety of formal allergology evaluation, and to identify factors associated with accurate drug allergy labels. METHOD: All patients who underwent drug allergy evaluation in our clinic during the study period were recruited. Baseline demographics, characteristics of index hypersensitivity reaction and outcomes of evaluation were recorded. RESULTS: A total of 331 patients from March 2019 to June 2021 completed drug allergy evaluation to index drugs of concern. There were 123 (37%) male patients, and the mean age was 49 years (standard deviation 17). There were 170 beta-lactam antibiotics, 53 peri-operative drugs, 43 others, 38 non steroidal anti-inflammatory drugs, and 27 non-beta-lactam antibiotic evaluations. Index reaction occurred within 5 years in 165 (50%) patients, with latency of less than 4 hours in 125 (38%) patients. The most common index reactions were rash, angioedema and urticaria. There were 57 (17%) evaluations stratified as low risk, 222 (67%) moderate risk, and 52 (16%) high risk based on multidisciplinary consensus. Allergy label was found to be false (negative drug evaluation) in 248 (75%) patients, while 16/237 (7%) skin tests, 44/331 (13%) in-clinic graded challenge, and 23/134 (17%) home prolonged challenges were positive (true drug allergy). The most common evaluation reactions were rash and urticaria. No cases of anaphylaxis were elicited. CONCLUSION: Seventy-five percent of drug allergy labels are inaccurate. Risk-stratified, protocolised allergy evaluation is safe. Prolonged drug challenge increases the sensitivity of drug allergy evaluation and should therefore be performed when indicated.

Patient and learner experience in a new set up of a multidisciplinary dermatology-rheumatology clinic care model for psoriatic arthritis.

OBJECTIVES: We described the set-up of a new multidisciplinary psoriatic arthritis-psoriasis (PsA-PsO) clinic incorporating service, education, and research between rheumatologists and dermatologists for PsA. We describe the patients' and learners' experience of this shared-care model. METHODS: A PsA-PsO clinic was newly set up in 2019. Each patient was first seen by a trainee, followed by both a dermatologist and a rheumatologist simultaneously in the same consultation room. We collected patients' and learners' experience through self-administered surveys. RESULTS: From May 2019 to January 2020, we collected data from 44 visits (55% new referrals, 45% follow up) from 30 patients: 22.7% were referred for diagnostic doubts, 77.3% were for therapeutic issues. Eight of the 10 patients referred for diagnosis had PsA confirmed. Medication changes occurred in 63.6% of visits; 63.6% of patients continued follow up in the PsA-PsO clinic, and 36.4% were discharged back to the original respective care. The median (interquartile range) rating of patient satisfaction of the care was 8 (7-8) out of 10; 96.1% of patients would "probably" or "definitely recommend" the care to others. From 20 learners, 95% reported the experience as "extremely" or "very" beneficial to training. The PsA-PsO clinic was suspended during the COVID-19 pandemic from February 2020 because of lack of available staff. The service was resumed gradually from May 2021. CONCLUSION: Despite challenges, we report the set-up of a new care model between dermatologists and rheumatologists for care of patients with psoriatic disease. The care model was well received by patients. Learners from various levels reported benefit from the learning experience.

Managing the ADR of Stevens-Johnson syndrome/toxic epidermal necrolysis.

INTRODUCTION: Stevens-Johnson syndrome and toxic epidermal necrolysis are severe, life-threatening adverse drug reactions that are collectively known as epidermal necrolysis. The abrupt detachment of the skin and mucositis results in systemic complications such as fluid and electrolyte disturbances, hypothermia, sepsis, organ failure, and death. Management is multidisciplinary and complex. AREAS COVERED: This present article reviews the principles and best practices in the care of patients with epidermal necrolysis. These include having prompt admissions to optimal care facilities, coordinated specialized care during the acute phase, as well as long-term follow-up to manage chronic sequelae. EXPERT OPINION: Patients with epidermal necrolysis should be managed in specialized/reference centers that are experienced with the management of the disease. Multi-disciplinary supportive care remains the cornerstone. Current evidence precludes definitive recommendation on any immunomodulatory agent as treatment. Long-term follow-up is required in order to diagnose and treat any chronic sequelae.

Mycoplasma-induced Stevens-Johnson syndrome/toxic epidermal necrolysis: Case-control analysis of a cohort managed in a specialized center.

BACKGROUND: Mycoplasma pneumoniae (MP) infection is associated with extrapulmonary complications such as Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). OBJECTIVE: We evaluated the differences in epidemiology, clinical characteristics, and disease outcomes between drug-induced and Mycoplasma-related SJS/TEN. METHODS: All patients with SJS/TEN admitted to our center between 2003 and 2016 inclusive were treated under a standardized protocol. Comparative analysis was made between patients who tested positive for MP versus a control group with negative MP serology in the presence of high-notoriety drugs defined by an algorithm for assessment of drug causality in epidermal necrolysis >5. RESULTS: Of 180 cases of SJS/TEN patients treated in our institution, 6 had positive MP serologies and were compared to a control group of 71 cases of drug-induced SJS/TEN with an algorithm for assessment of drug causality in epidermal necrolysis score of >5. There were no significant differences in baseline characteristics, disease classification, body surface area involved, and extent of mucosal involvement. We found significant differences in mortality rates between the Mycoplasma and control groups on discharge (0% vs 22.5%, P < .001) and at 1-year follow up (0% vs 32.4%, P = .002), respectively. LIMITATIONS: Retrospective design, small sample size. CONCLUSION: Although recent studies have shown that MP-induced SJS/TEN is morphologically different and deserves a separate classification system, this would need to be borne out in larger prospective studies.

Improvement of Mortality Prognostication in Patients With Epidermal Necrolysis: The Role of Novel Inflammatory Markers and Proposed Revision of SCORTEN (Re-SCORTEN).

IMPORTANCE: Epidermal necrolysis is a severe cutaneous adverse reaction in which severe systemic inflammation results in extensive epithelial keratinocyte necrosis. The most commonly used prognostic score in epidermal necrolysis, the Severity-of-Illness Score for Toxic Epidermal Necrolysis (SCORTEN), was recently found to overestimate mortality in contemporary cohorts. Identification of independent prognostic markers may help to stratify risk more accurately. OBJECTIVE: This study evaluates the association between novel inflammatory markers and in-hospital mortality in patients with epidermal necrolysis to study the incremental prognostic value of these markers in combination with SCORTEN. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted over a 17-year period from 2003 to 2019. Patients were enrolled from Singapore General Hospital, the national referral center for epidermal necrolysis. A total of 196 patients with epidermal necrolysis were recruited, 4 (2%) of whom were excluded owing to incomplete data. MAIN OUTCOMES AND MEASURES: The main outcome assessed was the in-hospital mortality rate. Discrimination and calibration of risk scores were assessed using the area under the receiver operating characteristic curve (AUC) and calibration plot, respectively. Evaluation of the incremental prognostic value of these markers was done by comparing the AUC between the old and new risk score, and the use of net reclassification improvement (NRI) and integrated discrimination improvement (IDI). RESULTS: Among 192 total patients (median [IQR] age 56 [42-70] years; 114 [59.4%] women), there were 43 (22.4%) who did not survive to discharge. Of the novel inflammatory markers, only red cell distribution width to hemoglobin ratio was significant in predicting in-hospital mortality (odds ratio [OR] 3.55; 95% CI, 1.76-7.16; P < .001) after adjusting for SCORTEN. The RDW/Hb as applied in 4 risk groups showed similar discrimination to SCORTEN (AUC [95% CI]: RDW/Hb in 4 groups, 0.76 [0.69-0.84], vs SCORTEN, 0.78 [0.70-0.85], P = .89). When RDW/Hb was added to SCORTEN, the composite score Re-SCORTEN showed significantly better discrimination than SCORTEN alone (AUC [95% CI]: Re-SCORTEN, 0.83 [0.77-0.89], vs SCORTEN, 0.78 [0.70-0.85], P = .02). The overall NRI was 0.94 (95% CI, 0.68-1.20), P < .001. The IDI was 0.06 (95% CI 0.03-0.08), P < .001. Re-SCORTEN showed good calibration based on the calibration plot. CONCLUSIONS AND RELEVANCE: In this cohort of patients, RDW/Hb, an inexpensive and readily available marker, showed similar predictive accuracy with SCORTEN. Furthermore, when used in combination with SCORTEN, it also helped augment prognostic ability.

Rapid Desensitization for Insulin Allergy in Type 1 Diabetes Using an Insulin Pump: A Case Report and Literature Review.

OBJECTIVE: Insulin allergy, although uncommon, poses a significant challenge in those with type 1 diabetes mellitus (T1D) as insulin replacement is a necessity. Our objective is to describe a patient in whom rapid desensitization to insulin aspart was achieved using an insulin pump. METHODS: A 40-year-old woman with newly diagnosed T1D developed pruritic wheals over the abdomen after being injected with insulin glargine U-300 (Toujeo) and insulin aspart. Type 1 insulin hypersensitivity was confirmed through intradermal testing and positive insulin-specific immunoglobulin E levels. RESULT: The patient underwent rapid desensitization with an insulin pump. Half the anticipated daily basal requirement was initially subcutaneously administered before initiating low-dose insulin via the pump (0.000025 units/h) and increasing the dose every 30 minutes to reach her basal requirements within 5 hours. Subsequent larger bolus insulin doses did not produce any local or anaphylactic reactions. No pretreatment with corticosteroids or antihistamines was provided. CONCLUSION: Previous protocols for insulin desensitization span over days and often involve routine premedication. The case we presented suggests that insulin desensitization can be achieved over several hours using an insulin pump. A subcutaneous basal insulin cover should be provided prior to desensitization to avoid hyperglycemia necessitating an insulin bolus. Routine premedication may not always be necessary depending on reaction severity.

The association of obstructive sleep apnea with melanoma incidence and mortality: a meta-analysis of 5,276,451 patients.

BACKGROUND: Melanoma is the most aggressive and lethal form of skin cancer. While emerging in-vivo evidence suggests that intermittent hypoxia, a hallmark feature of obstructive sleep apnea (OSA), may induce melanoma tumorigenesis, the epidemiological association between OSA and melanoma has been inconsistent. METHODS: We performed a literature search of PubMed, Embase, Scopus and Cochrane Library from inception until 6 June 2021. Two reviewers independently selected randomized trials or observational studies that reported the association of OSA with melanoma incidence or mortality in adults, in comparison to participants with no OSA. Two reviewers independently extracted relevant data and assessed the quality of evidence using the GRADE framework and the Newcastle-Ottawa Scale (NOS). We pooled data using an inverse variance-weighted meta-analysis and ran pre-specified subgrourp analyses. RESULTS: The meta-analysis included six studies out of 1897 records, comprising a combined cohort of 5,276,451 patients. All studies were adjusted for covariates, with majority of studies adjusting for age (N=5) and sex (N = 4). Compared to those without OSA, patients with OSA had 71% higher pooled hazards of melanoma (HR = 1.71; 95% CI: 1.08-2.69, I2 = 99%). Subgroup analyses for studies with (1) median follow-up duration of at least five years, (2) prospective study design, (3) adjustment for obesity yielded HRs of 1.88 (95%CI:1.32-2.67, N = 5), 1.11 (95%CI:0.77-1.60, N = 2) and 1.52 (95%CI:0.75-3.08, N = 3) respectively. One study investigating the relationship between OSA and melanoma mortality detected no association. There were insufficient studies to assess publication bias. CONCLUSIONS: Meta-analysis of mainly retrospective observational studies, with significant heterogeneity, suggests increased melanoma incidence in OSA patients. Future studies should prospectively explore the differential risk of melanoma for varying OSA severity, and whether timely OSA treatment may mitigate this risk.

Acute generalized exanthematous pustulosis: Epidemiology, clinical course, and treatment outcomes of patients treated in an Asian academic medical center.

BACKGROUND: Acute generalized exanthematous pustulosis (AGEP) is a rare severe cutaneous adverse drug reaction. Although acutely patients have significant morbidity and occasional systemic involvement, the clinical course is generally self-limited. To date, there has been no consensus on treatment. OBJECTIVE: The aim of our current study was to evaluate the clinical features, drug association, treatment, and outcomes in a cohort of patients treated in an academic medical center. METHODS: A retrospective review of electronic medical records over a period of 10 years from 2009 to 2018 in a single tertiary academic medical center in Singapore was performed. Forty-three medical records with probable/definite diagnosis of AGEP were identified and analyzed for statistical significance. RESULTS: Drug association was identified in 93% of cases. The most frequent drug class was antibiotics, including penicillins, cephalosporins, and vancomycin. Systemic involvement was reported in 13.9% of patients. All cases of AGEP resolved with cessation of the offending drug. There was no mortality attributed to AGEP. Treatment with systemic steroid was associated with a decreased length of hospital stay (P = .035) in patients with AGEP. CONCLUSION: AGEP was a self-limiting adverse drug reaction that was commonly caused by antibiotics. Although there was no difference in mortality, there was a significant reduction in the length of hospitalization with systemic corticosteroid treatment compared with that of topical corticosteroid treatment of AGEP.