Toxic Epidermal Necrolysis Due to Concomitant Use of Lamotrigine and Valproic Acid

Anti-epileptic drugs can be associated with a wide spectrum of cutaneous adverse reactions ranging from simple maculopapular rashes to more severe and life threatening reactions like Stevens-Johnson syndrome and toxic epidermal necrolysis. These rashes are well documented with older antiepileptic drugs like phenytoin, phenobarbitone and carbamazapine. Lamotrigine is a newer, unrelated antiepileptic drug that causes skin rashes in 3-10% of new users. Higher starting dose or rapid escalation, concurrent treatment with valproic acid, and a previous history of a rash with other antiepileptic drugs are well recognized risk factors for lamotrigine related serious rashes. We report two patients with toxic epidermal necrolysis, resulting from concomitant use of lamotrigine and valproic acid. It is emphasized that clinicians adhere to the recommended dosage guidelines and adopt a slow dose titration when initiating treatment with lamotrigine.     

重型药物不良反应的遗传学研究进展

药物不良反应是指正常剂量的药物用于预防、诊断、治疗疾病或调节生理机能时出现的有害和与用药目的无关的反应。其中药物超敏反应综合征、重症多形红斑、中毒性表皮坏死综合征为常见的重型药物不良反应。本文对目前有关药物不良反应的遗传学研究新进展进行了综述。     

Is drug allergy less prevalent than previously assumed? A 5‐year analysis

Background Rashes are a frequent conundrum in clinical practice as they may be reactive, drug induced or disease specific. Identification of the culprit drug is important as re‐exposure may be harmful or even life‐threatening and unnecessary avoidance of ‘innocent’ drugs leads to limitations of treatment options. Objective To objectify the cause of suspected cutaneous drug reactions in a large patient population. Method Over 5 years (2006–10), 612 patients with suspected cutaneous drug reactions were evaluated. Histology was assessed. About 200 patients were invited for complete work‐up with skin tests (prick/intracutaneous testing and scratch/patch as indicated) and, if necessary, lymphocyte transformation tests (LTT). In special cases, drug provocation tests were conducted. Results A total number of 141 cases with suspected drug reaction underwent full work‐up (age 6–86 years; 75% female, 25% male). In 107 cases (76%) a drug was identified whereas 34 (24%) were reactive rashes or had other causes. Mostly, cutaneous drug reactions were maculopapular rashes, urticaria/angio‐oedema; less frequently, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms, systemic drug‐related intertriginous and flexural exanthema, toxic epidermal necrolysis and fixed drug eruptions were present. Of all the cutaneous drug reactions investigated, 39·8% were caused by antibiotics, 21·2% by anti‐inflammatories, 7·6% by contrast media and 31·4% by others (oral antidiabetics, antimycotics, antipsychotics, antiepileptics and others). Conclusion Clinical assessment overestimates the role of drug allergies in cutaneous reactions. Assessment of suspected drug reactions can be greatly improved by thorough evaluation including dermatological and allergological work‐up with skin testing and assays such as LTT.     

Cutaneous side effects of TNF‐alpha inhibitors

Since the early 1990s, tumor necrosis factor alpha (TNF‐alpha) inhibitors have been successfully used in the treatment of various immune‐mediated inflammatory diseases. By now, comprehensive safety data has been compiled. While adverse reactions do occur, they are – in relation to the frequent use of these agents – rare and usually not serious. Cutaneous side effects include local injection site reactions, infections, immune‐mediated reactions, and neoplasms. The most common serious adverse events are of an infectious nature. Mycobacteria but also non‐mycobacterial pathogens, such as viruses and fungi, may cause serious, even lethal, systemic infections. The present article is meant to review current knowledge with respect to cutaneous side effects of TNF‐alpha inhibitors.     

Fas‐ligand staining in non‐drug‐ and drug‐induced maculopapular rashes

Background: Morphologically and histopathologically, drug‐ and non‐drug‐induced maculopapular rashes can be almost indistinguishable. It has been postulated that Fas‐ligand (Fas‐L) is involved in the pathogenesis of drug rashes but not in the genesis of rashes, such as viral exanthems, that are not induced by medications. Aim: This study sought to determine if epidermal Fas‐L is a distinguishing feature in the pathology of drug and non‐drug maculopapular rashes. Methods: Archived skin biopsies of patients with a confirmed diagnosis of drug or non‐drug maculopapular rashes (n = 10 each) and positive and negative controls were retrieved for immunohistochemical staining for Fas‐L. The proportion of Fas‐L‐positive skin biopsies were compared. The presence of tissue eosinophilia was also evaluated. Results: Ten percent of non‐drug‐induced rashes were Fas‐L positive compared to 50% of drug rashes (p = 0.05). Twenty percent of non‐drug exanthems had moderate tissue eosinophilia, while 60% from drug rashes had moderate to dense tissue eosinophilia (p = 0.17). Conclusion: There is a trend toward Fas‐L being more prevalent in the epidermis of drug maculopapular rashes, although this did not reach statistical significance. This is possibly because of the small sample size. Wang ECE, Lee JSS, Tan AWH, Tang MBY. Fas‐ligand staining in non‐drug‐ and drug‐induced maculopapular rashes.     

The use of skin testing in the investigation of cutaneous adverse drug reactions

Skin testing with the suspected compound has been reported to be helpful in determining the cause of cutaneous adverse drug reactions (ADRs), but the value and specificity of these tests need to be determined. In this study, 72 patients with presumed drug eruptions (27 maculopapular, 18 urticarial, seven erythrodermic, nine eczematous, four photosensitivity, three fixed drug eruptions, three with pruritus and one with acute generalized exanthematous pustulosis) were assessed. All had drug patch tests; 46 also had prick tests and 30 had intradermal tests (performed on hospitalized patients using a sterile solution of the suspected drug, diluted sequentially) with immediate and delayed readings. Among these patients, 52 (72%) had a positive skin test reaction, 43%, 24% and 67% in patch, prick and intradermal skin tests, respectively. The results of skin tests varied with the drug tested and with the clinical type of cutaneous ADR, as a significantly higher number of positive patch tests was observed in maculopapular rashes than in urticarial reactions ( P =  0.001). This study supports the value of careful sequential drug skin testing in establishing the cause of cutaneous ADR. Guidelines are proposed for performing these tests, and these include the use of appropriate negative control patients to avoid false-positive results.     

Health‐related quality of life in children with cutaneous adverse drug reactions

Adverse drug reactions (ADRs) are a common problem in children. Health‐related quality of life in patients with such conditions has not been well studied. In this study we found that health‐related quality of life is adversely affected in children who developed ADRs with cutaneous manifestations.     

Chemotherapeutic agents and the skin: An update

Chemotherapeutic agents give rise to numerous well described adverse effects that may affect the skin, hair, mucous membranes, or nails. The mucocutaneous effects of longstanding agents have been extensively studied and reviewed. Over the last 2 decades, a number of new molecular entities for the treatment of cancer have been approved by the United States Food and Drug Administration (FDA). This article reviews the cutaneous toxicity patterns of these agents. It also reviews one drug that has not received FDA approval but is in use outside the United States and is important dermatologically. Particular emphasis is placed on the novel signal transduction inhibitors as well as on newer literature pertaining to previously described reactions. LEARNING OBJECTIVES: At the completion of this learning activity, participants should able to list the newer chemotherapeutic agents that possess significant mucocutaneous side effects and describe the range of reactions that are seen with each drug. In addition, they should be able to formulate appropriate management strategies for these reactions.     

Comparative analysis of adverse drug reactions to tetracyclines: results of a French national survey and review of the literature

Summary Background The question of quantitative and qualitative differences between adverse drug reactions (ADRs) to tetracyclines was raised many years ago, especially for minocycline and doxycycline. Objectives To assess and compare ADRs related to tetracyclines according to sales figures in France through a national survey. Methods ADR data were collected from the French Pharmacovigilance Database (FPD), marketing authorization holders (MAH) and the literature. Sales analyses were based on MAH data provided annually to the French Drugs Agency. Results Among the tetracyclines available in France, doxycycline and minocycline are the most frequently used. However, their sales decreased between 1995 and 2007, more sharply for minocycline than doxycycline. According to the FPD, based on MAH data and published reports, minocycline‐associated ADRs were more serious and were reported more frequently than for the other tetracyclines. Minocycline and doxycycline ADR patterns differed: gastrointestinal disorders (especially oesophageal lesions) predominated with doxycycline, while intracranial hypertension and hepatic disorders were primarily reported with minocycline. Autoimmune disorders, drug reaction with eosinophilia and systemic symptoms (DRESS) and other hypersensitivity reactions were also more frequent with minocycline. ADRs reported with lymecycline and metacycline were essentially cutaneous and gastrointestinal disorders. Conclusions In the absence of markedly better efficacy against the various indications for tetracyclines, the minocycline benefit/risk ratio was clearly lower than that of doxycycline, and possibly those of lymecycline and metacycline. In light of these findings, minocycline should no longer be considered first‐line therapy for inflammatory skin disorders, especially acne.     

Drug eruptions in the mature patient

The world’s population is now ageing at an unprecedented rate. Declining fertility and improved health and longevity have generated rising numbers and proportions of the older population in most parts of the world. With advancing age, however, comes an increasing incidence of disease (comorbidity or multimorbidity), an increasing use of medications (polypharmacy), and consequently an increase in adverse drug reactions (ADRs). Age-related changes in pharmacodynamics and pharmacokinetics (eg, volumes of drug distribution, metabolism and clearance, altered drug responsiveness and toxicity) and greater vulnerability to ADRs are other reasons for the higher incidence of ADRs in the elderly compared with young adults. Because the clinical patterns of ADRs are very similar for all age groups, including the elderly, the present review will deal mainly with statistics and numbers, rather than the clinical and/or disease patterns.     

How to manage hypersensitivity reactions to biological agents?

Biological agents induce cutaneous adverse drug reactions (CADR) different from those observed with xenobiotics. Type alpha is the cytokine release syndrome, type beta are hypersensitivity reactions and type gamma is a cytokine imbalance syndrome. Infusion-reactions, anaphylactoid reactions occur with various biological agents administered intravenously. In non-severe cases the infusion rate has to be reduced, in severe reactions, the treatment must be stopped and resuscitation carried out with corticosteroids and epinephrine. Reactions may be due to an alpha syndrome but a true allergy could be involved as demonstrated in some patients with IgE antibodies to the galactose-alpha-1,3-galactose portion of the cetuximab or anti infliximab-IgE. Some desensitisation protocols have been published. Non allergic itching and eczema-like lesions are frequent with epidermal growth factor receptor inhibitors. Rash or desquamation was observed in 40% of cases with antiangiogenic agents, 90% of patients treated with imatinib have rashes, oedema or pruritus and a non-allergic periorbital oedema. Severe CADR, such as Stevens-Johnson syndrome, can be provoked. Delayed readings of intradermal tests could be of value in managing patients with a maculopapular rash due to interferon. Anaphylaxis attributed to omalizumab seems to be rare (0.2%) and skin rashes occur in 7% of cases. Anaphylactoid reactions occur in 1% of patients treated with natalizumab. In the case of anti-natalizumab antibody-mediated reactions, treatment should be stopped. These allergic-like side effects of new biological agents must be known and reported to Pharmacovigilance agency networks.     

别嘌醇致药疹36例临床分析

目的探讨别嘌醇致药疹的临床特征。方法回顾性分析36例别嘌醇药疹患者的临床表现、实验室检查、治疗情况、病程、并发症及预后。结果别嘌醇所致药疹潜伏期长、病程长、疹型多样、皮损严重、易反复,糖皮质激素治疗有效。结论别嘌醇所致药疹通常是一种重症药疹,及时停药和早期使用足量糖皮质激素有助于预后的改善。     

Cutaneous adverse drug reactions seen in a tertiary hospital in Johor,Malaysia

Background Adverse drug reactions are most commonly cutaneous in nature. Patterns of cutaneous adverse drug reactions (ADRs) and their causative drugs vary among the different populations previously studied. Objective Our aim is to determine the clinical pattern of drug eruptions and the common drugs implicated, particularly in severe cutaneous ADRs in our population. Materials and Methods This study was done by analyzing the database established for all adverse cutaneous drug reactions seen from January 2001 until December 2008. Results A total of 281 cutaneous ADRs were seen in 280 patients. The most common reaction pattern was maculopapular eruption (111 cases, 39.5%) followed by Stevens‐Johnson Syndrome (SJS: 79 cases, 28.1%), drug reaction with eosinophilia and systemic symptoms (DRESS: 19 cases, 6.8%), toxic epidermal necrolysis (TEN: 16 cases, 5.7 %), urticaria/angioedema (15 cases, 5.3%) and fixed drug eruptions (15 cases, 5.3%). Antibiotics (38.8%) and anticonvulsants (23.8%) accounted for 62.6% of the 281 cutaneous ADRs seen. Allopurinol was implicated in 39 (13.9%), carbamazepine in 29 (10.3%), phenytoin in 27 (9.6%) and cotrimoxazole in 26 (9.3%) cases. Carbamazepine, allopurinol and cotrimoxazole were the three main causative drugs of SJS/TEN accounting for 24.0%, 18.8% and 12.5% respectively of the 96 cases seen whereas DRESS was mainly caused by allopurinol (10 cases, 52.6%) and phenytoin (3 cases, 15.8%). Discussion The reaction patterns and drugs causing cutaneous ADRs in our population are similar to those seen in other countries although we have a much higher proportion of severe cutaneous ADRs probably due to referral bias, different prescribing habit and a higher prevalence of HLA‐B*1502 and HLA‐B*5801 which are genetic markers for carbamazepine‐induced SJS/TEN and allopurinol‐induced SJS/TEN/DRESS respectively. Conclusion The most common reaction pattern seen in our study population was maculopapular eruptions. Antibiotics, anticonvulsants and NSAIDs were the most frequently implicated drug groups. Carbamazepine and allopurinol were the two main causative drugs of severe ADRs in our population.     

Injection site reactions with the use of biological agents

Injection site reactions (ISRs) are a local phenomenon defined as a constellation of symptoms, including swelling, erythema, pruritus, and pain around the site of injection. This article reviews the different aspects of ISRs, including their epidemiology and pathogenesis, and provides practical guidance to diagnose and treat such reactions. More focus is given to food and drug administration (FDA)‐approved biological agents and biosimilars, which are licensed mainly for the treatment of dermatological conditions, including psoriasis, atopic dermatitis, and chronic urticaria. ISRs are major complications of all FDA‐approved self‐injectable biological agents, both in adults and children, with studies showing an incidence rate of 0.5–40%. The article emphasizes that ISRs are not correlated with drug efficacy or development of antidrug antibodies. Therefore, misunderstanding of the pathophysiology of the ISRs, most of them not being allergic or immunogenic reactions, might result in unnecessary discontinuation of the treatment. Almost all local reactions to subcutaneously administered biological agents can be prevented by changing the injection techniques, patient education, and training.     

Adverse cutaneous drug eruptions and HIV: a clinician's global perspective

Adverse drug reactions (ADRs) are common and mostly avoidable. Some ADRs cannot as yet be predicted, but at-risk populations/patients and high-risk drugs are identifiable. HIV-infected patients are at risk of developing cutaneous ADRs, especially Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug hypersensitivity syndrome. Multiple factors of causation variably present in patients with HIV infection best explain the pathogenesis of these cutaneous ADRs. When no effective alternate therapy is available, drug rechallenge in HIV-infected patients can be attempted with little morbidity or mortality if done according to rationalized protocols.     

A review of herbal medicines in wound healing

Herbs have been integral to both traditional and non‐traditional forms of medicine dating back at least 5000 years. The enduring popularity of herbal medicines may be explained by the perception that herbs cause minimal unwanted side effects. More recently, scientists increasingly rely on modern scientific methods and evidence‐based medicine to prove efficacy of herbal medicines and focus on better understanding of mechanisms of their action. However, information concerning quantitative human health benefits of herbal medicines is still rare or dispersed, limiting their proper valuation. Preparations from traditional medicinal plants are often used for wound healing purposes covering a broad area of different skin‐related diseases. Herbal medicines in wound management involve disinfection, debridement, and provision of a suitable environment for aiding the natural course of healing. Here we report on 22 plants used as wound healing agents in traditional medicine around the world. The aim of this review is therefore to review herbal medicines, which pose great potential for effective treatment of minor wounds.     

A systematic review on treatment‐related mucocutaneous reactions in COVID‐19 patients

Most of drugs could have certain mucocutaneous reactions and COVID‐19 drugs are not an exception that we focused. We systematically reviewed databases until August 15, 2020 and among initial 851 articles, 30 articles entered this study (20 case reports, 4 cohorts, and 6 controlled clinical trials). The types of reactions included AGEP, morbiliform drug eruptions, vasculitis, DRESS syndrome, urticarial vasculitis, and so on. The treatments have been used before side effects occur, included: antimalarial, anti‐viral, antibiotics, tocilizumab, enoxaparin and and so on. In pandemic, we found 0.004% to 4.15% of definite drug‐induced mucocutaneous reactions. The interval between drug usage and the eruption varied about few hours to 1 month; tightly dependent to the type of drug and hydroxychloroqine seems to be the drug with highest mean interval. Antivirals, antimalarials, azithromycin, and tocilizumab are most responsive drugs for adverse drug reactions, but antivirals especially in combination with antimalarial drugs are in the first step. Types of skin reactions are usually morbilliform/exanthematous maculopapular rashes or urticarial eruptions, which mostly may manage by steroids during few days. In the setting of HCQ, specific reactions like AGEP should be considered. Lopinavir/ritonavir is the most prevalent used drug among antivirals with the highest skin adverse reaction; ribarivin and remdisivir also could induce cutaneous drug reactions but favipiravir has no or less adverse effects. Logically the rate of dermatologic adverse effects among anivirals may relate to their frequency of usage. Rarely, potentially life‐threatening reactions may occur. Better management strategies could achieve by knowing more about drug‐induced mucocutaneous presentations of COVID‐19.     

Causality Assessment of Cutaneous Adverse Drug Reactions

Background

Cutaneous adverse drug reactions (ADRs) are the most common adverse reactions attributed to drugs. A systematic and effective approach to a patient with suspected drug eruption allows for prompt recognition, classification and treatment of cutaneous ADRs. A standardized and effective approach for objective causality assessment is necessary to make consistent and accurate identification of ADRs.

Objective

Although the Naranjo algorithm is the most widely used assessment tool, it contains many components which are not suitable for clinical assessment of ADRs in Korea. The purpose of this study is to compare correlations of the Naranjo algorithm and the Korean algorithm to evaluate usefulness of both algorithms in order to make a causal link between drugs and cutaneous ADRs. In addition, this study classifies the clinical types and causative agents of cutaneous ADRs.

Methods

The authors retrospectively reviewed the clinical types and laboratory findings of patients who were diagnosed with cutaneous ADRs in the dermatology clinic at Gil hospital. One hundred forty-one patients were enrolled in this evaluation. The causal relationship of ADRs was assessed by using the Naranjo algorithm and Korean algorithm (version 2.0).

Results

A cross-tabulation analysis was applied to the Naranjo algorithm and Korean algorithm (version 2.0). Simple correlation analysis and a Bland-Altman plot were used for statistical analysis. Correlation analysis confirmed that the two assessment algorithms were significantly correlated. Exanthematous eruptions (68.8%), Stevens- Johnson syndrome (10.6%), and urticaria (8.5%) were the most common types of cutaneoues ADRs. The most common causative agents were antibiotics/antimicrobials, antipyretics/non-steroidal anti-inflammatory drugs, and central nervous system depressants.

Conclusion

The Naranjo algorithm and Korean algorithm (version 2.0) were significantly correlated with each other, and thus reliable assessment methods to determine cutaneous ADRs.     

A European multicentre photopatch test study

Background The two most common agent groups currently responsible for photoallergic contact dermatitis (PACD) are organic ultraviolet (UV) absorbers in sunscreens and topical nonsteroidal anti‐inflammatory drugs (NSAIDs). However, availability of information on the photoallergenic potential of these agents is scarce. Objectives To obtain current information on the frequency of PACD to 19 organic UV absorbers and five topical NSAIDs, including newer agents, in common usage in Europe. Methods A prospective, multicentre photopatch test study was conducted with 1031 patients attending for investigation of suspected PACD in 30 centres across 12 European countries. Results A total of 346 PACD reactions in 200 (19·4%) subjects occurred. PACD was most commonly caused by the topical NSAIDs, ketoprofen (128 subjects) and etofenamate (59 subjects). Of the organic UV absorbers, octocrylene, benzophenone‐3 and butyl methoxydibenzoylmethane most frequently elicited PACD. The ‘newer’ organic sunscreen absorbers rarely led to PACD. There appeared to be an association between the agents ketoprofen, octocrylene and benzophenone‐3, with several subjects developing PACD to two or all three agents concomitantly. Allergic contact dermatitis (ACD) was less commonly observed than PACD, comprising 55 reactions in 47 (5%) subjects. Irritant reactions and photoaugmentation and photoinhibition of ACD occurred infrequently. Conclusions The European multicentre photopatch test study has provided current information on the relative frequency of PACD to common photoallergens. Such data will be of value when deciding on which agents to include in a future European ‘baseline’ photopatch test series.