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Cutaneous immune-related adverse events are common in cancer patients receiving immunotherapies but seldom studied in a comprehensive way of collecting all cancer types with comparisons between different immune-oncology drugs and correlation to patient survival. In this retrospective cohort study, we recruited 468 cancer patients receiving immunotherapies in a tertiary referral center in Taiwan and try to determine real-world incidence of cutaneous immune-related adverse events and their associations with the survival rates. Among them, 128 patients (27.4%) had cutaneous immune-related adverse events, with maculopapular eruption (10.6%) and pruritus (10.1%) most frequently identified in the monotherapy group. The incidence of these cutaneous immune-related adverse events was highest in patients receiving pembrolizumab (34.1%, P P P

BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) is a condition caused by a drug-induced immune response. Previous reports have found that CXCL10, also known as interferon-γ-induced protein (IP)-10, may participate in the pathogenesis of cutaneous adverse drug reactions. However, the exact role of IP-10 in DRESS and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) has remained unknown. OBJECTIVES This comparative prospective cohort study aimed to ascertain the roles of the IP-10/CXCR3 axis in DRESS and SJS/TEN. METHODS Plasma IP-10 levels were analysed, and univariate analyses were conducted to assess the relationship between IP-10, human herpesvirus (HHV)-6 reactivation and the development of long-term sequelae. We also performed immunohistochemical staining using skin specimens and flow cytometry to determine the expression of CXCR3 in peripheral blood mononuclear cells (PBMCs). RESULTS Significantly higher plasma IP-10 levels were observed in patients with DRESS with long-term sequelae (effect size 0·81) and also in those with HHV-6 reactivation (effect size 0·83). By immunohistochemistry, more abundant IP-10+ and CXCR3+ cells were demonstrated in the skin lesions of patients with DRESS with HHV-6 reactivation. The percentages of CLA+ CXCR3+ CD4+ cells and CLA+ CXCR3+ CD8+ cells were also higher in the PBMCs of HHV-6-reactivated patients with DRESS than in those of patients with SJS/TEN. CONCLUSIONS Higher plasma IP-10 levels are associated with the development of long-term sequelae in DRESS. Higher IP-10/CXCR3 expression in skin and more abundant CLA+ CXCR3+ CD4+ cells and CLA+ CXCR3+ CD8+ cells were observed in patients with DRESS with HHV-6 reactivation. The IP-10/CXCR3 axis is associated with HHV-6 reactivation and development of long-term sequelae in DRESS. What is already known about this topic? Elevated levels of interferon-γ-induced protein-10 (IP-10) have been observed in patients with drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Patients with DRESS tend to develop long-term autoimmune sequelae, including type 1 diabetes and autoimmune thyroiditis. IP-10 has been associated with these autoimmune diseases in previous studies. What does this study add? The patients with DRESS with HHV-6 reactivation exhibited higher levels of IP-10 in the plasma and skin than the patients with DRESS without HHV-6 reactivation and the patients with SJS/TEN. Patients with DRESS with higher plasma IP-10 levels tended to develop sequelae during long-term follow-up. What is the translational message? IP-10 is a useful biomarker to predict the development of long-term sequelae in patients with DRESS. Linked Comment: Belloon and Kardaun. Br J Dermatol 2020; 183:804-805.

Background/Objective There is a rising awareness of drug reaction with eosinophilia and systemic symptoms (DRESS) due to its possible morbidity and mortality. Early diagnosis of DRESS is crucial for administering timely treatment; however, prompt diagnosis based on its early presentation can be quite problematic due to its clinical resemblance to common maculopapular eruptions (MPE). Methods A retrospective cohort study of patient data from September 2010 to June 2016 was conducted to compare the clinical presentations of DRESS and MPE validated by the RegiSCAR scoring system. The demographic data, clinical presentations, and histopathological patterns were reviewed. Results Fifty-eight patients with DRESS and 29 patients with MPE were included. The mean age at diagnosis of DRESS was 47 years (range: 2–82 years), and female patients predominated by a ratio of 2.2:1. The three most common culprit medications for DRESS were allopurinol, sulfasalazine, and trimethoprim/sulfamethoxazole. The most significant differences between the DRESS and MPE groups were the presence of fever, peripheral blood eosinophilia and atypical lymphocytosis, characteristic skin lesions, abnormal liver functions, and prolonged resolution of skin lesions for more than 15 days in the DRESS patients. The most common histologic features in the DRESS patients were coexistent eczematous, interface dermatitis, and vascular damage patterns, or interface dermatitis alone. The concurrence of fever, peripheral blood eosinophilia, and abnormal liver function within three days of visiting a medical facility were more common in cases of DRESS than of MPE (24.1% vs. 0%, P = 0.004). Conclusion Although DRESS and MPE look similar, especially in the early stage of DRESS, the concurrence of fever, peripheral blood eosinophilia, and abnormal liver functions within three days of visiting a medical facility might aid in the early diagnosis of DRESS.

Background/Objectives Accumulating evidence has shown that omalizumab is an effective and safe treatment for chronic spontaneous urticaria (CSU), but there is little information regarding the use of omalizumab to treat CSU in Taiwan. Reports on clinical experiences with using omalizumab for CSU for more than 6 months are also lacking. Methods A retrospective review of medical records of consecutive CSU patients receiving omalizumab treatment in the Urticaria Special Clinic of one tertiary referral center in Taiwan was conducted. We analyzed clinical features of the patients, treatment efficacy and safety, and also long-term outcomes after omalizumab treatment. An Urticaria Activity Score over 7 days (UAS7) was recorded at each visit. Results A total of 17 CSU patients were identified (11 females and 6 males, age range: 21–83 years) with a baseline mean UAS7 of 29.8 ± 8.9 despite antihistamine treatment. All patients were treated with at least 3 doses of monthly subcutaneous injections of omalizumab. Fifteen patients achieved a UAS7 of 6 or less after 3 doses of monthly omalizumab injections. Seven of those 15 patients received an additional 1 to 3 doses and all ended up with a UAS7 of less than 2 at the 24-week follow-up. A sustained response to maintenance treatment after 24 weeks was observed in 5 patients with individual tailoring of treatment duration and dosing interval. Conclusion Omalizumab is an effective and safe treatment for antihistamine refractory CSU. Maintenance therapy with individual tailoring of the treatment duration and interval is possible.

Cutaneous adverse drug reactions (cADRs) encompass many types of clinical presentations, ranging from benign maculopapular eruption (MPE) to severe cutaneous adverse reactions (SCARs). The relationship between viral reactivation and drug eruptions has been widely observed and has provided a new direction for researchers to explore. In recent years, a number of studies have focused in particular on sequential human herpes virus (HHV) reactivation in drug reaction with eosinophilia and systemic symptoms (DRESS), and these studies have provided crucial evidence demonstrating that clinical presentations can be closely related to the dynamics of viral activity. The DRESS patients with long-term sequelae tended to present with viral activation, including sequential changes in serum cytokines, chemokines, and immune cells. Moreover, other cADRs might also be influenced by the reactivation of different viruses. In this study, we discuss recent progress in understanding the role of viral reactivation in cADRs and the possible pathomechanism underlying the drug-induced immune response.

Background: Plasmacytoid dendritic cells (pDCs) are implicated in the reactivation of human herpesvirus 6 (HHV-6) in drug reaction with eosinophilia and systemic symptoms (DRESS). Objectives: We aimed at identifying the alterations of circulating pDCs, basophils, and myeloid dendritic cells (mDCs) during the active stage of drug eruptions and the relationship between pDC alteration and HHV-6 reactivation in DRESS patients. Methods: Nine DRESS patients and twelve patients of other drug eruptions (ODE, including five cases of maculopapular eruptions (MPEs), five cases of Stevens–Johnson syndrome, and two cases of fixed drug eruption) were prospectively recruited. Blood samples were collected weekly for 2 consecutive weeks for flow cytometry of pDC, basophil, mDC, and detection of HHV-6 reactivation by serum anti-HHV-6 immunoglobulin G, or whole blood HHV-6 viral DNA by quantitative polymerase chain reaction. Results: The HHV-6 reactivation was exclusively seen in DRESS, and the pDC levels decreased in DRESS compared with ODE (P = 0.002) and (MPE, P = 0.021), with the timing of such decrease preceding HHV-6 reactivation. Conclusion: The decrease of pDC levels is significantly more common in DRESS patients and occurs before HHV-6 reactivation. The chronological sequence implies that the decrease of pDC may be crucial in the pathogenesis of viral reactivation.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse drug reactions characterized by different extents of epidermal necrosis and mucosal breakdown. A limited number of studies have reported the long-term patterns of SJS and TEN complications in patient populations over long follow-up periods. The aim of this retrospective study was to collect data on long-term sequelae in patients admitted for SJS, SJS/TEN overlap, or TEN between 1998 and 2012. Among all 102 patients eligible for analysis, the 2 most common sequelae were cutaneous and ocular problems, both with incidences of 44.1%. Visceral organ involvement was observed in 2 patients with irreversible deterioration of chronic kidney disease and in one patient with interstitial lung disease. Autoimmune disease was present in 6 patients: Sjögren's syndrome or Sjögren-like syndrome in 5 patients and concomitant systemic lupus erythematosus and Hashimoto thyroiditis in one patient.

Background Drug reaction with eosinophilia and systemic symptoms (DRESS) is a syndrome involving multiple systems. Liver injury is the most common visceral manifestation. Objective The purpose of this study was to investigate the types of liver injury and factors associated with DRESS. Methods A retrospective cohort study was conducted in Taiwan using a DRESS database compiled from December 2000 to March 2013. Results Seventy-two cases were included in this study. Among them, 62 (86.1%) cases involved liver injury, 6 of which (9.7%) were liver injury before skin presentation. The distribution of liver injury patterns at initial presentation was 23 cholestatic type (37.1%), 17 mixed type (27.4%), and 12 hepatocellular type (19.4%). Patients with hepatocellular-type injuries were younger, with a median age of 31.5 ( P = .044). Individuals with liver function results more than 10 times the upper limit were more likely to have fever ( P = .026), took more time to recover, and had fewer eosinophils in the dermis ( P = .002). Limitations The study was a retrospective cohort study with limited cases. Conclusions Liver injury is common in DRESS and frequently associated with atypical lymphocytosis. The cholestatic type is the most common type. Patients with cholestatic-type injuries were older and more frequently had interface changes in skin pathology.

Background Sequential human herpes virus (HHV) reactivation is well known in drug reaction with eosinophilia and systemic symptom (DRESS), but such a phenomenon has seldom studied in other types of cutaneous adverse drug reactions (cADRs). Moreover, the association between viral reactivations and cytokine or chemokine changes is largely unknown. We aimed to evaluate the viral reactivation rates of HHV-6, HHV-7, Epstein–Barr virus (EBV), and cytomegalovirus (CMV) in different cADRs and their impacts on clinical prognosis. Cytokine and chemokine changes with viral reactivations were also examined. Methods A prospective study was conducted to monitor the viral statuses of patients with different cADRs by polymerase chain reaction and serum-specific antibody titers. Changes in plasma cytokine and chemokine levels were also evaluated by sequential blood samples. Results Among the various cADRs, HHV-6 reactivation was only observed in DRESS, but EBV and CMV could be detected in other cADRs. Many proinflammatory cytokines and chemokines, including interleukin (IL)-1β, IL-2, IL-6, interferon-γ, tumor necrosis factor-α, were significantly lower in DRESS patients with HHV-6 reactivation when compared to those without HHV-6 reactivation. In addition, these mediators were significantly lower before and during HHV-6 reactivation, compared to cytokine levels after HHV-6 reactivation in the same patient. Conclusion HHV-6 reactivation was only observed in DRESS patients, not in any other cADR. In DRESS patients, some proinflammatory cytokines were significantly lower before or during HHV-6 reactivation.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe multiorgan hypersensitivity reaction mostly caused by a limited number of eliciting drugs in patients with a genetic predisposition. Patients with DRESS syndrome present with characteristic but variable clinical and pathological features. Reactivation of human herpesviruses (HHV), especially HHV-6, is the hallmark of the disease. Anti-viral immune responses intertwined with drug hypersensitivity make the disease more complicated and protracted. In recent years, emerging studies have outlined the disease more clearly, though several important questions remain unresolved. In this review, we provide an overview of DRESS syndrome, including clinical presentations, histopathological features, pathomechanisms, and treatments.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been widely used to treat non–small cell lung cancer. Four major skin toxic effects with different incidences have been reported from clinical studies, including acneiform eruption (60%-94%), pruritus (16%-60%), xerosis (4%-38%), and paronychia (6%-12%). 1,2 However, a direct comparison of the incidences and severities of the 4 types of skin toxic effects for 3 different EGFR-TKIs in the same patient cohort has been lacking to date. Methods | This retrospective study was approved by the research ethics committee of National Taiwan University Hospital. We recruited patients within a named patient program for compassionate use before registration who had ever received afatinib treatment for non–small cell lung cancer between November 1, 2007, and April 30, 2013. Most of the pa

Background Only few studies had investigated the histopathological presentations of drug reaction with eosinophilia with systemic symptoms (DRESS). The results of these studies were diverse and not conclusive. A characteristic histopathological feature is still lacking. Objective We tempted to identify characteristic histopathological features in DRESS and to correlate them with clinical presentations. Methods We retrospectively collected data from patients treated from 1998 through 2015. Available skin specimens from probable or definite cases according to the RegiSCAR criteria were analysed for histopathological patterns, which were then compared with the patients' clinical presentations. Chi-squared test was used for comparisons, while Bonferroni correction was applied if multiple comparison tests were encountered. Results Fifty-six patients with an average age of 52 years were identified, including 22 definite cases. The single most common histopathological pattern was interface dermatitis (75%). The co-existence of two or more patterns in a skin specimen was common (62.5%). In such cases, the co-existence of three patterns (the eczematous pattern, the interface dermatitis pattern and the vascular damage pattern) was most frequently encountered. It exhibited a significantly higher likelihood of being definite cases (P = 0.004) and was significantly associated with high grades of cutaneous abnormalities (P < 0.001). It showed a trend towards having higher grades of haematological abnormalities in patients with co-existence of three patterns (P = 0.04). In addition, patients with the co-existence of three patterns tended to have a higher rate of reactivation of human herpesvirus-6 than those with other patterns but not statistically significant (P = 0.052). Conclusion The co-existence of three histopathological patterns in a skin specimen is characteristic in DRESS and shows a significant association with clinical severity.

Importance Purpuric skin lesions have only rarely been reported in patients receiving epidermal growth factor receptor inhibitors. However, their clinical and histopathologic presentations have varied considerably. Objective To characterize purpuric skin eruptions caused by epidermal growth factor receptor inhibitors. Design, Setting, and Participants This prospective study enrolled 32 patients who presented to an integrated dermato-oncologic clinic in a tertiary referral medical center with purpuric skin lesions after using epidermal growth factor receptor inhibitors from January 1, 2013, through December 31, 2015. Exposures Epidermal growth factor receptor tyrosine kinase inhibitors, including gefitinib, erlotinib, and afatinib. Main Outcomes and Measures Clinical presentations, histopathologic features, laboratory examinations, and treatment outcomes of patients with purpuric drug eruptions. Results Thirty-two patients, 14 with purpuric drug eruptions without pustules (mean [SD] age, 60 [11] years; 12 female and 2 male) and 18 with purpuric drug eruptions with pustules (mean [SD] age, 64 [11] years; 12 female and 6 male), were identified. The median time to development of skin lesions was 3.5 months. The clinical presentations were characterized by purpuric macules, papules, and confluent plaques predominantly on the lower extremities. Pustules in various sizes could be found in 18 patients (56%). Eleven patients (34%) had skin lesions that covered places other than the lower extremities. Eczema craquele–like features developed in 13 patients (41%). Bacterial pathogens were frequently identified in these skin lesions. Among them,Staphylococcus aureuswas the most predominant and was found in 20 patients (63%), commonly in those with cutaneous pustules. Epidermal dysmaturation, neutrophil exocytosis, perivascular infiltration of lymphocytes and neutrophils, red blood cell extravasation, and plumping endothelium were the main histopathologic features. The expressions of filaggrin and human β-defensin 2 in lesional skin of these patients were markedly reduced. All patients improved after receiving at least 1 week of systemic antibiotic treatment; the doses of epidermal growth factor receptor inhibitors were also changed for 14 patients (44%). Conclusions and Relevance Purpuric drug eruptions caused by epidermal growth factor receptor inhibitors are uncommon and have characteristic clinical and histopathologic presentations. The role of bacterial pathogens in this reaction is important and requires further exploration.

Background Sequential human herpes virus (HHV) reactivation is wellknown in drug reaction with eosinophilia and systemic symptoms (DRESS), but a comparison study to investigate the association of HHV reactivation with other types of cutaneous adverse drug reactions (cADRs) is still lacking. Besides, the pathomechanisms or mediators of viral reactivations are largely unknown. In this study, we aimed to investigate the cytokine/chemokine profiles before or concurrent with HHV reactivations. Method We conducted a prospective study to evaluate HHV-6, Epstein–Barr virus (EBV) and cytomegalovirus (CMV) reactivation rates in various cADRs. Dynamic changes of cytokines and chemokines were also determined by sequential blood tests during acute stages. Interleukin-1 £] (IL-1£]), IL-1 receptor antagonist (IL-1Ra), IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, basic fibroblast growth factors, eotaxin, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon-£^ (IFN-£^), interferon £^-induced protein-10 (IP-10), monocyte chemoattractant protein-1, macrophage inflammatory protein-1£\ (MIP-1£\), MIP-1£], platelet-derived growth factor, chemokine (C-C motif) ligand 5 (CCL5), tumor necrosis factor-£\ (TNF-£\) and vascular endothelial growth factor were measured using the Bio-Plex Human Cytokine 27-Plex panel. Results A total of 62 patients were enrolled in this prospective study including 23 DRESS, 17 SJS/TEN, 13 MPE, 5 GBFDE and 4 EMM. HHV-6 reactivation was observed in ten DRESS patients (43.5%) but in none of the other cADR patients. In contrast, EBV reactivation was detected in 35 patients distributed in every cADR groups. EBV reactivation rates were 73.9% for DRESS (17 in 23 patients), 29.4% for SJS/TEN (5 in 17 patients), 53.8% for MPE (7 in 13 patients), 80% for GBFDE (4 in 5 patients), and 50% for EMM (2 in 4 patients). CMV reactivation rates were 43.5% in DRESS (10 in 23 patients) and 11.8% in SJS/TEN (2 in 17 patients) respectively, but none of the other cADRs. HHV-6 reactivation in DRESS patients was associated with decreased proinflammatory cytokines and chemokines (IL-1£], IL-1Ra, IL-2, TNF-£\, IFN-£^, and MIP-1£\) before viral reactivations. Only one chemokine, IP-10, was expressed higher in the HHV-6 reactivation group (P = 0.018).