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In recent years, the development of combination therapies with immune checkpoint inhibitors (ICIs) and cytotoxic anticancer drugs has radically changed the management of diverse malignancies and significantly improved patient outcomes. Several clinical trials have shown that skin rash caused by combination therapy with ICIs and cytotoxic drugs may be more frequent and severe than that developing after administration of ICIs alone or cytotoxic drug monotherapy. However, most reports provide little information on severity, treatment, post-diagnosis course, and recurrence of rashes on drug rechallenges. We aimed to describe the experience of skin rashes developing within 2 weeks from the first administration of combination therapy with ICIs and cytotoxic drugs in 11 patients visiting our dermatology department. This study included seven men and four women, and the patients' median age was 52 years. The primary disease was non-small-cell lung cancer in eight patients, cervical cancer in two patients, and esophageal cancer in one patient. Nine patients had a maculopapular rash and two patients developed erythema multiforme-like eruptions. The skin rash was often accompanied by extracutaneous symptoms, such as fever (n = 9), mucositis (n = 4), and liver dysfunction (n = 2). In all cases, the symptoms improved with topical steroid therapy alone, with no patients exhibiting severe symptoms requiring systemic steroids or immunosuppressive agents. In addition, when the causative drugs were re-administered after recovery from the rash, only two patients relapsed with accompanying systemic symptoms, and all patients except one were able to continue treatment using the same drug regimen. Although it was suggested that the rash caused by the combination therapy of ICIs and cytotoxic drugs may be more prominent than that caused by each agent alone, comprehensive judgment, including histopathological examination, may indicate the feasibility of continuing the treatment regimen for cancer., (© 2022 Japanese Dermatological Association.)

Purpose: To explore the effects of cyclosporine A (CsA) in the management of atopic keratoconjunctivitis (AKC)., Methods: Open single-group interventional consecutive cohort study (case series) at a single eye care facility in the UK. We reviewed the electronic patient records of 99 children and young people (CYP) aged 3.4-18 years with AKC treated with topical CsA 1 mg/ml. Main outcome measures were number of prescriptions and hospital clinic visits over 12 months before and after the start of CsA and the proportion of CYP affected by adverse effects., Results: The median number of inflammatory episodes requiring treatment with topical corticosteroids (tCS) fell from 3 (interquartile range IQR 1-4) during the 12 months prior to CsA to 1 (IQR 0-3) during the 12 months after, excluding tCS prescriptions with the first CsA prescription (Wilcoxon signed ranks test, 2 tailed, p < 0.01). In the 12-month period following initiation of CsA 1 mg/ml with concomitant prescription of tCS (n = 66), daily dosage of steroids was reduced in 62 CYP (93.9%), and they were discontinued in 43 (65.2%). The median number of hospital visits fell from 4 (IQR 3-6) to 3 (IQR 2-5; Wilcoxon p < 0.01). Adverse events leading to discontinuation of CsA were stinging (instillation site pain; 9/99, 9%) and a transient skin rash (1/99, 1%)., Conclusions: Off-label use of commercial preparations of CsA 1 mg/ml significantly reduces the need for concomitant topical corticosteroids and hospital clinic visits in CYP with AKC. Stinging and skin rash can lead to discontinuation., (© 2022 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: Cutaneous toxicities are common adverse effects following epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy. Zinc deficiency causes diverse diseases, including skin toxicities. Therefore, this study aimed to investigate the role of zinc deficiency in patients with EGFR-TKI-induced skin toxicities., Experimental Design: This retrospective study enrolled 269 patients with diverse skin disorders who visited our hospital between January 2016 and December 2017. The skin toxicity severities and plasma zinc levels of 101 EGFR-TKI-treated cancer patients were analysed and compared with those of 43 non-EGFR-TKI-treated cancer patients and 125 patients without cancer but presenting cutaneous manifestations. Additionally, the role of zinc in erlotinib-induced skin eruptions was established in a 14-day-murine model. Clinical features were further evaluated following systemic zinc supplementation in EGFR-TKI-treated cancer patients., Results: EGFR-TKI-treated patients demonstrated severe cutaneous manifestations and a significant decrease in plasma zinc levels than those of the control groups. The serum zinc level and Common Terminology Criteria for Adverse Events (CTCAE) 5.0 grading of EGFR-TKI-induced skin toxicities showed a significant negative correlation (r = -0.29; p < 0.0001). Moreover, erlotinib treatment decreased the plasma zinc levels and induced periorificial dermatitis in rats confirming zinc deficiency following EGFR-TKI treatment. Zinc supplementation to the EGFR-TKI-treated cancer patients showed a significant decrease in the CTCEA grading (p < 0.0005 for mucositis and p < 0.0.0001 for all other cases) after 8 weeks., Conclusions: Skin impairment following EGFR-TKI therapy could be ameliorated through zinc supplementation. Thus, zinc supplementation should be considered for cancer patients undergoing EGFR-TKI therapy., (© 2022 European Academy of Dermatology and Venereology.)

Rosacea is a kind of chronic inflammatory skin disease that usually occurs in the middle of the face. Diammonium glycyrrhizinate (DG), an effective monomer component extracted from licorice, has extensive anti-inflammatory, antioxidant, anti-allergic, and immunomodulatory effects. There is no research on its therapeutic effect on rosacea. In this study, we divided rosacea patients mainly characterized by papules and pustules randomly into three groups. Group A received clarithromycin 500 mg once a day, isotretinoin 10 mg once a day; Group B received DG 150 mg three times a day, other medicines were the same as Group A; Group C received clarithromycin 250 mg once a day, isotretinoin 10 mg once every 2 days, and DG 150 mg three times a day. All patients' symptom scores and laboratory tests were evaluated when followed up. We found that DG combined with clarithromycin and isotretinoin in the treatment of rosacea was more effective and quicker than clarithromycin and isotretinoin alone. Moreover, half common dosage of clarithromycin and isotretinoin combined with DG could achieve the same therapeutic effect as the conventional dose, and brought about lower incidences of adverse events (AEs). Therefore, it is recommended to use half common dosage of routine medication combined with DG for rosacea patients mainly characterized by papules and pustules., (© 2022 Wiley Periodicals LLC.)

Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), previously termed drug-related baboon syndrome, is an uncommon drug eruption. It is characterized by symmetrical erythema involving the gluteal and/or inguinal area in association with one other intertriginous area in the absence of systemic involvement. It typically develops a few hours to days after drug exposure. The diagnosis is based on clinical presentation and drug history. The treatment consists mainly of withdrawal of the causative agent; corticosteroids (topical or systemic) are prescribed to accelerate the resolution. We present three cases that appeared after proton-pump inhibitors (PPIs) intake., (© 2022 Australasian College of Dermatologists.)

On March 11, 2020, the World Health Organization (WHO) declared the novel coronavirus (COVID-19) a global pandemic. This has led to the rapid development and emergency approval of vaccines to overcome the alarming spread of the virus. Data on the cutaneous side effects related to the COVID-19 vaccine remains limited. In this prospective observational study, which was conducted from June 20 to September 20, 2021, we evaluated the incidence and various patterns of cutaneous side effects reported post COVID-19 vaccination in Al Buraimi Governorate in Oman. All vaccinated individuals aged 12 years and older, who had a skin reaction within 4 weeks following any dose of the COVID-19 vaccine, were enrolled in the study. The demographic data, medical history, vaccine-related information of all the patients were documented and the analysis was performed using the SPSS version 23 software. In total, 67 cutaneous reactions were reported by 55 patients accounting for 0.11% of all vaccinated individuals. The mean age of the patients was 33.3 years, 80.6% were females, 61.2% of the reactions were reported after the first vaccine dose, and 38.8% were reported after the second dose. We observed a wide range of cutaneous reactions and categorized them into three major patterns: local injection site reaction (2%), new onset rash (81.6%), and flare up of pre-existing dermatological conditions (16.4%). Notably, urticaria was the most common reaction overall, followed by generalized pruritus and maculopapular rash. In general, we reported a diversity of cutaneous side effects that healthcare workers should be aware of as some reactions may be overlooked and not linked to the COVID-19 vaccination., (© 2022 Wiley Periodicals LLC.)

The novel coronavirus disease 2019 (COVID-19) vaccination is now an essential strategy for controlling the COVID-19 epidemic. This study included 132 cases of adverse skin reactions after the injection of COVID-19 vaccination from January 2021 to January 2022. The rate of adverse skin reactions after the 1st, 2nd, and 3rd doses of the COVID-19 vaccine were 52%, 40%, and 8% of total adverse skin reactions, respectively. The Urticaria-like rash was the most common manifestation of all adverse skin reactions, accounting for 40.15% of all adverse reactions. The Eczema-like rash was 27.27%. The rates of adverse skin reactions after vaccination with the COVID-19 vaccine in patients with a previous skin disease was 12.12%. Other rare skin adverse reactions after COVID-19 vaccination included herpes zoster, pityriasis rosea, erythema multiforme, chickenpox, herpes simplex, psoriasis, erythrodermatitis, arthus reaction, lichen planus recurrence, measles-like rash, frostbite rash, seborrhea, and vitiligo. There were 23 cases of adverse skin reactions in the same individual after two doses of COVID-19 vaccine. There were three cases of adverse skin reactions in the same person after three doses of the vaccine. Treatment measures are mostly mild regimens, such as oral antihistamines, compounded glycopyrrolate and topical weak to moderately potent corticosteroid creams. The total duration of these skin adverse reactions ranged from 2 weeks to 1 month., (© 2022 Wiley Periodicals LLC.)

Therapeutic strategies that target novel pathways are urgently needed for patients with relapsed/refractory multiple myeloma (RRMM). Ibrutinib is an oral covalent inhibitor of Bruton tyrosine kinase, which is overexpressed in MM cells. This phase 1 dose-escalation study examined various doses of ibrutinib in combination with standard doses of lenalidomide (25 mg) and dexamethasone (40 mg) using a standard 3 + 3 design in RRMM patients. The primary objective was to determine the maximum tolerated dose (MTD) of ibrutinib in combination with lenalidomide and dexamethasone. Patients (n = 15) had received a median of 4 prior regimens, 53% were triple-class exposed, 33% were penta-exposed, and 54% were lenalidomide-refractory. The MTD of ibrutinib was 840 mg (n = 6) and only 1 dose-limiting toxicity; a grade 3 rash possibly related to ibrutinib was noted. The most common ≥ grade 3 adverse events were rash in 2 (13%), lymphopenia in 2 (13%), leukopenia, neutropenia, thrombocytopenia, and anemia all occurring in 3 (20%) patients each. One patient achieved a partial response for an overall response rate of 7%. The clinical benefit rate was 80%. The median time to progression was 3.8 months. Ibrutinib, lenalidomide and dexamethasone appears to be a safe and well-tolerated regimen with reasonable efficacy in heavily pretreated RRMM patients., (© 2022 John Wiley & Sons Ltd.)

Background: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe adverse drug reaction generally accompanied by skin manifestations as the first and most frequent symptoms. However, skin manifestations and associated clinical features of DRESS have not been fully explored and evaluated., Objectives: This study aimed to describe the skin manifestations of DRESS in detail and analyse their association with demographic characteristics and extra-cutaneous clinical features., Methods: We conducted this retrospective study on patients with DRESS diagnosed between September 2009 and August 2021 at three medical institutes and validated using the RegiSCAR score. Data regarding demographics, skin manifestations and clinical characteristics were retrieved through thorough chart reviews., Results: Among 182 potential cases of DRESS, the validated 125 cases were analysed. A widespread rash extending over more than 50% of the body surface area was observed in 122 patients (97.6%) and typical facial oedema was experienced by 67 patients (53.6%). Polymorphous maculopapules were the most common rash morphology (106, 84.8%): specifically, exfoliative (59, 47.2%), urticarial (57, 45.6%) and purpuric forms (39, 31.2%) were common. Mucosal involvement was observed in 41 patients (32.8%). Patients with carboxamide antiepileptics (carbamazepine and oxcarbazepine) experienced more oedema (P = 0.014) and typical facial oedema than those with allopurinol (P = 0.021). The RegiSCAR score was higher in patients with purpura (P < 0.01)., Conclusions: Skin manifestations of DRESS exhibit a wide range of skin lesions and can vary according to the culprit drugs. Early suspicion and prompt intervention are needed to improve prognosis., (© 2022 European Academy of Dermatology and Venereology.)

Aims: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare, drug-induced severe adverse reaction that usually occurs 3-6 weeks after initial exposure to certain drugs. It affects mainly adults and children to a lesser extent. Clinical features include fever, facial oedema, generalized skin rash, lymphadenopathy, haematological abnormalities and internal organ involvement. The objective was to investigate the clinical and laboratory features of patients with DRESS in our centre., Methods: We retrospectively describe and analyse 19 cases of DRESS whose diagnosis was based on the RegiSCAR criteria (≥6 points) that occurred from January 2009 to December 2019., Results: Patient age ranged from 4 to 76 years (4 children/15 adults); 10 were female (52.3%). The most common culprit drugs were antibiotics (74%) and anticonvulsants (21%). The most common comorbidities were epilepsy (26%) and hypertension (26%). All patients developed cutaneous manifestations and of those, 58% presented facial oedema. Liver function tests, urea/creatinine and troponin elevation were present in 74, 32 and 42%, respectively. The median time to develop the skin rash after the drug exposure was 3.7 weeks (interquartile range 2.4-4.2 wk). Eosinophilia (≥0.7 × 10 9 /L) was present in 95% of the patients and peaked around 10 days after the skin manifestations. Leucocytosis and reactive lymphocytes were reported in 84% and 26% of all patients respectively. Treatment with systemic steroids was reported in 16 patients. The mean recovery time was 2 weeks (interquartile range 2-3.5 wk) and mortality was 5%., Conclusion: DRESS is a serious condition with significant morbidity and mortality, which requires more research for a better understanding., (© 2022 British Pharmacological Society.)

Skin toxicity induced by gemcitabine, a chemotherapeutic agent, is not rare, but is usually mild. However, the occurrence of moderate to severe skin rash has been reported in patients treated with combinations of gemcitabine and other anticancer drugs. The aim of this study was to assess the characteristics of rash caused by gemcitabine-based chemotherapy. We analyzed 12 patients who developed maculopapular rash over more than 10% of their body surface following gemcitabine-based chemotherapy. Maculopapular rash appeared at 6.3 ± 1.3 days after the first administration in eight patients and the second administration in four patients. In two patients, the rash was localized on the lateral aspect of the trunk. The other 10 patients showed various degrees of rash on the chest and abdomen, in addition to the lateral aspect of the trunk. However, rash was absent on the upper and middle back in almost all patients. After the rash disappeared, gemcitabine was re-administrated in eight patients. They continued the therapy with no or only mild rash relapse. In conclusion, maculopapular rash caused by gemcitabine-based chemotherapy shows biased distribution to frontal and lateral sites of the trunk, which may be informative for consecutive chemotherapy., (© 2020 Japanese Dermatological Association.)

Coronavirus disease 2019 (COVID-19) emerged in Thailand in January 2020. Thailand was the first to report a confirmed case outside China. Cutaneous eruption in COVID-19 has been reported since the disease became pandemic but limited in tropical countries such as Thailand. The aim of this study was to observe the incidence, characteristics and relation of cutaneous eruption with COVID-19 at Bamrasnaradura Infectious Diseases Institute, a referral center of emerging infectious diseases in Thailand. An observational descriptive study observed the incidence and characteristics of cutaneous eruption in 204 COVID-19-infected patients at Bamrasnaradura Infectious Diseases Institute. We report five patients, who represented six incidences of skin eruption with four characteristics: maculopapular rash (50%), acute generalized exanthematous pustulosis (16.67%), Stevens-Johnson syndrome (16.67%) and urticarial vasculitis (16.67%). Incidences of cutaneous eruption in COVID-19 at Bamrasnaradura Infectious Diseases Institute were low. Most of the incidents were associated with medication used to treat COVID-19 infection, so drug allergy cannot be excluded as a cause of the rashes. Therefore, drug allergy should always be ruled out, and skin manifestation in COVID-19-infected patients should be further observed., (© 2020 Japanese Dermatological Association.)

Objectives: To evaluate cutaneous allergic reactions in clinical trials of adjunctive eslicarbazepine acetate (ESL) for focal seizures., Materials and Methods: Data were analyzed from three phase III randomized, double-blind, placebo-controlled studies of adjunctive ESL in adults (placebo, n = 426; ESL, n = 1021) and two randomized, double-blind, placebo-controlled studies (and open-label extensions [OLEs]) of adjunctive ESL in children aged 4-17 years (placebo, n = 160; ESL, n = 202; OLE, n = 337)., Results: Adult studies: Rash (ESL 1.9%, placebo 0.9%) and pruritus (ESL 1.2%, placebo 0.9%) were the most frequent rash-related treatment-emergent adverse events (TEAEs). Most rash-related TEAEs were mild or moderate in severity. Incidence of rash increased with increasing ESL dose, but was not higher for patients who initiated treatment with higher ESL doses. Pediatric studies: Allergic dermatitis (ESL 3.0%, placebo 0) and rash (controlled studies: ESL 1.0%, placebo 1.3%; OLE periods: ESL ≤1.2%) were the most frequent rash-related TEAEs. There was one case of DRESS in the ESL group. Most rash-related TEAEs were mild or moderate in severity and judged as not related to treatment with ESL., Conclusions: Serious skin rashes were rare during adult and pediatric clinical trials of ESL. Although the incidence of rash with ESL was low, it is important for patients/caregivers to be made aware of the potential signs and symptoms associated with serious skin rashes., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We conducted a retrospective investigation of the efficacy and safety of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation-positive advanced melanoma in real-world clinical practise. The study analyzed 50 patients who received dabrafenib and trametinib combination therapy for BRAF V600 mutation-positive advanced melanoma in our hospital (26 men and 24 women, aged 21-86 years, inclusive; median age, 53 years). The response rate was 72.3%, with complete response (CR) achieved in eight cases (17.0%), partial response in 26 (55.3%), stable disease in nine (19.1%) and progressive disease in four (8.5%). Median progression-free survival (PFS) was 12 months, and median overall survival (OS) was 23 months. Disease progression occurred in 29 of the 50 patients during the study period, and 25 patients died. Baseline lactate dehydrogenase and the number of organs with metastasis were important predictive factors for PFS and OS, and CR to combination therapy was a predictive factor for long-term remission. Adverse events occurred in 88% of cases; 16% were grade 3 or worse. The adverse events observed in 50% of more of patients were rash (56%) and pyrexia (52%). The efficacy of dabrafenib and trametinib combination therapy in Japanese patients was similar to that reported in global studies, and the same adverse events were generally reported; however, rash tended to occur more frequently in the patients in our study., (© 2019 Japanese Dermatological Association.)

The clinical classification of cutaneous adverse reactions by drugs should be clearly distinguished to avoid conceptual confusion and inconsistency. Although dermatologists appear to have established a roughly common consensus for cutaneous adverse reactions, some types are more rigorously defined than other, possibly misleading classifications. To assess the consensus on the clinical classifications, we investigated the concordance rate of diagnosis by Japanese experts through a snap visual inspection of various clinical pictures exhibiting erythema multiforme and maculopapular eruption types of cutaneous adverse reactions. The experts were shown images on a screen and were then asked to decide whether to classify cases as maculopapular eruption or erythema multiforme type, and the concordance rates were calculated. Overall, the mean concordance rate was 71.6% (standard deviation, 17.3%), and only 33.8% of cases had a 90% or more concordance rate. Our study shows that the determinations of erythema multiforme and maculopapular eruption types by the existing classification criteria were confusing even among experts, which prompted us to standardize the terminology. We propose clinically defining erythema multiforme type as generalized macules mainly of 1 cm or more with a tendency of elevation and coalescence, and maculopapular eruption type as generalized erythema other than erythema multiforme type. Currently, the clinical definitions of cutaneous adverse reactions are poorly described, which may be problematic upon analyzing large volumes of data. Our proposal for a new terminology will enhance the accuracy and consistency of information for the correct analysis of cutaneous adverse reactions., (© 2019 Japanese Dermatological Association.)

Background/objectives: Erosive oral lichen planus (LP) may be painful and debilitating. Symptomatic oral LP has been treated with a wide spectrum of topical and systemic therapies, but few have been evaluated in large series. Hydroxychloroquine is suggested to be effective in oral LP., Methods: Twenty-one consecutive patients with erosive, biopsy-confirmed oral LP were prescribed. hydroxychloroquine sulphate 400 mg/day. Symptomatic improvement was evaluated by means of a visual analogue scale into three groups: no change, moderate to marked improvement and complete remission., Results: Five (24%) patients obtained complete remission, 12 (57%) patients showed moderate to marked improvement, 3 (14%) patients did not improve at all and in one patient therapy was terminated after 1 month due to side effects. Response to therapy was observed after 2-4 months. Side effects which ultimately led to termination of therapy in three patients were elevated creatinine serum levels (after 1 month), visual field defects (after 8 months) and hyperpigmentation (after 24 months). Among six patients who responded to therapy, three flared on stopping., Conclusions: Hydroxychloroquine sulphate may be effective and relatively safe treatment for erosive oral LP., (© 2018 The Australasian College of Dermatologists.)

Duvelisib (IPI-145) is an oral dual inhibitor of phosphoinositide-3-kinase (PI3K)-δ and -γ in clinical development for the treatment of hematologic malignancies, including indolent non-Hodgkin lymphoma (iNHL). In a Phase 1, open-label study to determine the maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, clinical activity, and safety of duvelisib monotherapy in patients with advanced hematologic malignancies, duvelisib was administered at eight dose levels (8-100 mg BID) in a dose-escalation phase (n = 31 evaluable patients). Two dose-limiting toxicities (DLTs), Grade 3 transaminase elevations and Grade 3 rash, occurred at 100 mg BID, and the MTD was determined to be 75 mg BID. Across all doses, 58.1% of iNHL patients had a response (19.4% complete, 35.5% partial, and 3.2% minor); median time to response was 1.84 months and duration of response was 16.9 months. Median progression-free survival was 14.7 months, and the probability of overall survival at 24 months was 71.7%. Severe (Grade ≥ 3) adverse events included elevated liver enzymes (38.7%), diarrhea (25.8%), and neutropenia (29.0%). Three patients, all in the 75 mg BID cohort, experienced fatal AEs: E. coli sepsis, acute respiratory failure, and fungal pneumonia. No iNHL patients experienced Pneumocystis pneumonia. Duvelisib demonstrated favorable clinical activity and an acceptable safety profile in these high-risk, heavily pretreated, relapsed/refractory iNHL patients, with 25 mg BID selected for further clinical development., (© 2018 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.)

Over last fifty years, intravenous (iv) phenytoin (PHT) loading dose has been the treatment of choice for patients with benzodiazepine-resistant convulsive status epilepticus and several guidelines recommended this treatment regimen with simultaneous iv diazepam. Clinical studies have never shown a better efficacy of PHT over other antiepileptic drugs. In addition, iv PHT loading dose is a complex and time-consuming procedure which may expose patients to several risks, such as local cutaneous reactions (purple glove syndrome), severe hypotension and cardiac arrhythmias up to ventricular fibrillation and death, and increased risk of severe allergic reactions. A further disadvantage of PHT is that it is a strong enzymatic inducer and it may make ineffective several drugs that need to be used simultaneously with antiepileptic treatment. In patients with a benzodiazepine-resistant status epilepticus, we suggest iv administration of levetiracetam as soon as possible. If levetiracetam would be ineffective, a further antiepileptic drug among those currently available for iv use (valproate, lacosamide, or phenytoin) can be added before starting third line treatment., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The pathological mechanisms and immunological kinetics of drug-induced hypersensitivity syndrome (DIHS), including the relevance of interleukin (IL)-6, remain unclear. We report a case of drug adverse reaction that does not fulfill the diagnostic criteria of DIHS but mimics its characteristic features. Because the patient was under anti-IL-6 therapy at the onset, some symptoms typically seen in DIHS were absent, such as fever and leukocyte count abnormalities. However, the characteristic features of DIHS were clearly observed in the subsequent course, including the repeated recurrence of skin rash, prolonged liver dysfunction and reactivation of herpes viruses. This case suggested that IL-6 role at the onset is not a main factor to determine the subsequent pathomechanism of DIHS and attention should be paid to the preceding therapy for achieving accurate diagnosis., (© 2018 Japanese Dermatological Association.)

Ibrutinib is indicated in Europe for the treatment of several B-cell malignancies, including chronic lymphocytic leukaemia (CLL). However, despite the high efficacy and favourable toxicity profile of ibrutinib, recent data suggest that it is not always administered optimally in clinical practice, with an increased tendency for dose reduction and a higher frequency of discontinuation. An expert panel of European haematologists was convened to identify practical issues pertinent to physicians involved in the therapeutic management of ibrutinib-treated CLL patients and here we outline the findings. Practical management recommendations are given for treating patients with ibrutinib and clinical considerations for the management of adverse events (AEs) that can be associated with ibrutinib treatment are addressed. This article highlights that patients should be monitored for treatment emergent adverse events, most of which are mild, transient and generally occur early in therapy and that, even with more challenging AEs, patients can often be maintained on therapy with minimal disruption through careful management. The necessity to use the correct ibrutinib dose, along with increased awareness, vigilance, mitigation and management of AEs, are all recommended to maximise outcomes for CLL patients treated with ibrutinib., (© 2018 John Wiley & Sons Ltd.)

Fenretinide, a synthetic retinoid, induces apoptotic cell death in B-cell non-Hodgkin lymphoma (B-NHL) and acts synergistically with rituximab in preclinical models. We report results from a phase I-II study of fenretinide with rituximab for B-NHLs. Eligible diagnoses included indolent B-NHL or mantle cell lymphoma. The phase I design de-escalated from fenretinide at 900 mg/m 2 PO BID for days 1-5 of a 7-day cycle. The phase II portion added 375 mg/m 2 IV rituximab weekly on weeks 5-9 then every 3 months. Fenretinide was continued until progression or intolerance. Thirty-two patients were treated: 7 in phase I, and 25 in phase II of the trial. No dose-limiting toxicities were observed. The phase II component utilized fenretinide 900 mg/m 2 twice daily with rituximab. The most common treatment-related adverse events of grade 3 or higher were rash (n = 3) and neutropenia (n = 3). Responses were seen in 6 (24%) patients on the phase II study, with a median duration of response of 47 months (95% confidence interval, 2-56). The combination of fenretinide and rituximab was well tolerated, yielded a modest overall response rate, but with prolonged remission durations. Further study should focus on identifying the responsive subset of B-NHL., Competing Interests: The authors have declared no conflicts of interest., (© 2017 John Wiley & Sons Ltd.)

Background: Cutaneous adverse drug reactions frequently present as a benign maculopapular exanthema (MPE) with a rapid healing. Sometimes systemic signs are present, which could represent a more severe or systemic MPE (sMPE) or even be the initial phase of a drug reaction with eosinophilia and systemic symptoms (DRESS). Histopathology associated with MPE, sMPE and DRESS has not been well characterized., Objectives: To study the cutaneous histopathological changes associated with MPE, sMPE and DRESS., Methods: A retrospective clinicopathological analysis of 13 cases of MPE, 13 of sMPE and 45 of DRESS, collected in one centre from 2005 to 2013., Results: The number of histopathological changes per section increased gradually from MPE to sMPE and DRESS. Prevalence of spongiosis, dermal lymphocytes, eosinophils and neutrophils did not differ between MPE, sMPE and DRESS. Keratinocyte damage, rare in MPE, was regularly found in sMPE and frequent in DRESS. The density of the inflammatory infiltrate increased progressively from MPE to sMPE and DRESS. Atypical lymphocytes were absent in MPE, present in sMPE and more frequent in DRESS. Deep dermal involvement and leukocytoclastic vasculitis were only observed in DRESS., Limitations: This was a retrospective study., Conclusions: Numerous histopathological changes per section in drug-induced exanthema should alert for a more severe form of cutaneous adverse drug reactions, i.e. DRESS., (© 2016 European Academy of Dermatology and Venereology.)

Background/objectives: Maculo-papular drug exanthema (MPE) is the most common type of cutaneous adverse drug reaction (CAR). Exanthematous macules and papules may also be the initial presentation of severe CAR (SCAR). We aimed to identify characteristics associated with the diagnosis of SCAR in CAR-hospitalised patients., Methods: This cross-sectional study was performed in a tertiary hospital in Chile. All CAR patients who were initially evaluated for exanthematous macules and papules were assessed for clinical, laboratory and pathological variables and these were contrasted with MPE or SCAR diagnosis at discharge., Results: We enrolled 86 patients, of whom 25 (29%) had an at-discharge diagnosis of SCAR. SCAR patients were younger and the latency (time from starting drug to development of first skin lesions) was longer than in MPE patients: 43.6 ± 18.7 years versus 54.0 ± 21.8 years (P = 0.039) and 14 days; range 1 to 35, versus 7 days; range 1 to 45 (P = 0.001). The presence of cutaneous pain (OR 7.4 95% CI 1.3-41), mucosal involvement (OR 9.5 CI 95% 2.6- 34.5) and anticonvulsant use (OR 6.11 95% CI 1.91-19.53) were significantly associated with SCAR at discharge. Antibiotics use was significantly associated with MPE diagnosis (OR 2.8 95% CI 1.1-7.6). These six variables together explain 45% of the risk of having SCAR (R2 = 0.449). None of the early laboratory or pathological variables was associated with SCAR., Conclusions: In hospitalised patients assessed for exanthematous macules and papules, the evaluation of these clinical features may aid in the early identification of SCAR cases., (© 2015 The Australasian College of Dermatologists.)