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Acute Generalized Exanthematous Pustulosis Induced by Hydroxychloroquine: First Case Report in Canada and Review of the Literature

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Acute Generalized Exanthematous Pustulosis Induced by Hydroxychloroquine: First Case Report in Canada and Review of the Literature

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Abstract

Background: Acute generalized exanthematous pustulosis (AGEP) is a rare drug eruption presenting with an acute, extensive formation of nonfollicular sterile pustules on an erythematous and edematous base. Typically, the rash is accompanied by fever and leukocytosis, with spontaneous resolution in < 15 days. The incidence of AGEP is estimated at one to five cases per million people per year. Only 18% of these are from nonantibiotics. Hydroxychloroquine (HCQ) is an antimalarial agent that is also used to treat various dermatologic and rheumatologic conditions. Objective: We report the first observation in Canada of a patient with AGEP induced by HCQ. Methods and results: AGEP was diagnosed in a 48-year-old female who had been taking HCQ for 2 weeks and then developed a diffuse erythematous and edematous pustular eruption. Clinical and pathologic findings were consistent with a diagnosis of AGEP. The patient was treated with steroids and supportive measures. The rash resolved after 18 days and a complicated course in hospital. Conclusion: AGEP is a rare drug eruption, usually to antibiotics. We report the first case in Canada of AGEP as an adverse reaction to HCQ. Clinicians should keep in mind the possibility of this severe skin eruption.

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... A total of 41 cases of mild to severe dermatological adverse effects, including 2 cases of fatal toxic epidermal necrolysis, were described in patients treated with HCQ for autoimmune diseases [31,[34][35][36]38,[40][41][42][43][44][45][46][47][48][50][51][52][53][54][55][56][57]59,60,[62][63][64][65]. A smaller number of cases were reported in patients treated with CQ for autoimmune conditions or malaria although one fatal case was reported [27][28][29][30]32,33,37,39,49,54,58,61]. ...
... Assier-Bonnet et al., 1996, Evans CC et al., 2004, Atzori L et al., 2007, Bailey K et al., 2013, Soria A et al., 2015, Pearson KC et al., 2016, Mercogliano C et al., 2018, Matsuda-Hirose H et al., 2020)[38,43,47,51,54,55,59,65] Table 1. Cont. ...
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Chloroquine (CQ) and hydroxychloroquine (HCQ) have recently become the focus of global attention as possible treatments for Coronavirus Disease 2019 (COVID-19). The current systematic review aims to assess their safety in short treatments (≤14 days), whether used alone or in combination with other drugs. Following the PRISMA and SWiM recommendations, a search was conducted using four health databases for all relevant English-, Chinese-, and Spanish-language studies from inception through 30 July 2021. Patients treated for any condition and with any comparator were included. The outcomes of interest were early drug adverse effects and their frequency. A total of 254 articles met the inclusion criteria, including case and case-control reports as well as cross-sectional, cohort, and randomised studies. The results were summarised either qualitatively in table or narrative form or, when possible (99 studies), quantitatively in terms of adverse event frequencies. Quality evaluation was conducted using the CARE, STROBE, and JADAD tools. This systematic review showed that safety depended on drug indication. In COVID-19 patients, cardiac adverse effects, such as corrected QT interval prolongation, were relatively frequent (0–27.3% and up to 33% if combined with azithromycin), though the risk of torsade de pointes was low. Compared to non-COVID-19 patients, COVID-19 patients experienced a higher frequency of cardiac adverse effects regardless of the regimen used. Dermatological adverse effects affected 0–10% of patients with autoimmune diseases and COVID-19. A broad spectrum of neuropsychiatric adverse effects affected patients treated with CQ for malaria with variable frequencies and some cases were reported in COVID-19 patients. Gastrointestinal adverse effects occurred regardless of drug indication affecting 0–50% of patients. In conclusion, CQ and HCQ are two safe drugs widely used in the treatment of malaria and autoimmune diseases. However, recent findings on their cardiac and neuropsychiatric adverse effects should be considered if these drugs were to be proposed as antivirals again.
... 11 These actions have led to the use of HCQ in the treatment of a wide range of skin and rheumatic diseases. 12 In this article, we describe a case of AGEP induced by HCQ in a 49 year old, known case of Rheumatoid arthritis. ...
... Being a self-limiting disease with good prognosis, the condition usually resolves 15 days after exposure to causative agent . 12,17 There is no known treatment that can stop the lesions from spreading or prevent further aggravation of the patient's condition. 2,21 Cessation of the causative drug accompanied by the administration of topical corticosteroids and antipyretics is the principal treatment for AGEP. ...
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Abstract Background: Acute Generalized Exanthematous Pustulosis (AGEP)is a rare, severe skin reactionmainly caused by medications such as antibiotics, anti fungals, Calcium channel blockers and Anti malarias. Although it resolves spontaneously in most patients, systemic corticosteroids are neededin severe cases. Aims: In order to determine the drug that is causing this condition, patch testing must be performed. Hydroxychloroquine is a medication that is used for the treatment of rheumatic and dermatologic conditions. And although it has been rarely seen to cause this reaction, we report a case of Hydroxychloroquine-induced (HCQ) AGEP which was confirmed by Patch testing. Patients: A woman 49 years of age with an18 month history of mild, untreated Rheumatoid Arthritis experienced an acute episode of arthritis in her right elbow. Upon going to a rheumatologist, Prednisolone 5 mg BID and HCQ 200 mg daily were administered for a 30-day period. But after only 17 days of this treatment, the patient developed generalized erythema and painful pustular eruptions. Prednisolone dosage was changedto 7.5 mg per day andHCQ was discontinued one day afterthe appearance of eruptions. The diffuse erythema started improving a week after the patient’s hospitalization.Considering the factthat our patient was receiving multiple potentially causative medications, patch testing was necessary to distinguish the drug responsible for this reaction. Results: After the patch testing was done, HCQ-induced AGEP was confirmed. Conclusions: Patch testing is the gold standard of determining the responsible drug for an AGEP reaction. It should also be kept in mind that HCQ, although rarely, can cause this condition.
... 11 These actions have led to the use of HCQ in the treatment of a wide range of skin and rheumatic diseases. 12 In this article, we describe a case of AGEP induced by HCQ in a 49 year old, known case of Rheumatoid arthritis. ...
... Being a self-limiting disease with good prognosis, the condition usually resolves 15 days after exposure to causative agent . 12,17 There is no known treatment that can stop the lesions from spreading or prevent further aggravation of the patient's condition. 2,21 Cessation of the causative drug accompanied by the administration of topical corticosteroids and antipyretics is the principal treatment for AGEP. ...
Article
Abstract Background: Acute Generalized Exanthematous Pustulosis (AGEP)is a rare, severe skin reactionmainly caused by medications such as antibiotics, anti fungals, Calcium channel blockers and Anti malarias. Although it resolves spontaneously in most patients, systemic corticosteroids are neededin severe cases. Aims: In order to determine the drug that is causing this condition, patch testing must be performed. Hydroxychloroquine is a medication that is used for the treatment of rheumatic and dermatologic conditions. And although it has been rarely seen to cause this reaction, we report a case of Hydroxychloroquine-induced (HCQ) AGEP which was confirmed by Patch testing. Patients: A woman 49 years of age with an18 month history of mild, untreated Rheumatoid Arthritis experienced an acute episode of arthritis in her right elbow. Upon going to a rheumatologist, Prednisolone 5 mg BID and HCQ 200 mg daily were administered for a 30-day period. But after only 17 days of this treatment, the patient developed generalized erythema and painful pustular eruptions. Prednisolone dosage was changedto 7.5 mg per day andHCQ was discontinued one day afterthe appearance of eruptions. The diffuse erythema started improving a week after the patient’s hospitalization.Considering the factthat our patient was receiving multiple potentially causative medications, patch testing was necessary to distinguish the drug responsible for this reaction. Results: After the patch testing was done, HCQ-induced AGEP was confirmed. Conclusions: Patch testing is the gold standard of determining the responsible drug for an AGEP reaction. It should also be kept in mind that HCQ, although rarely, can cause this condition
... There are many reports of unusual AGEPs after usage of HCQ, mainly in the setting of rheumatologic problems, which are somehow similar to PP clinical course and characteristics [16][17][18][19]. These types of HCQ-induced AGEPs usually have longer intervals from drug initiation, as well as a more severe, prolonged, and recalcitrant course [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]. Also, there are many reports of Stevens-Johnson/toxic epidermal necrolysis or drug reaction with eosinophilia and systemic symptoms-like AGEPs, especially as HCQ-induced AGEP [36][37][38][39][40]. ...
... The genetic and immunologic susceptibility to HCQinduced pustular cutaneous reaction may play an important role in this process or HCQ may induce a unique type of cutaneous reaction presented as AGEP-PP overlap. So regarding drug-induced nature, it is really in favor of AGEP, and regarding interval, it is really in favor of PP and about its course and management, it may be consistent with AGEP or PP (45% and 55%, respectively) [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]. ...
... Among the common therapeutics used during a SARS-CoV-2 infection with the probability of inducing AGEP, we can name hydroxychloroquine, which is the most notorious medication for inducing AGEP, favipiravir, azithromycin, NSAIDs, protease inhibitors such as lopinavir-ritonavir, anticoagulants, and glucocorticoids [11][12][13][14][15][16][17][18][19]. Our patient had received azithromycin, dexamethasone, naproxen, and remdesivir for SARS-CoV-2 infection. ...
Article
Full-text available
Acute generalized exanthematous pustulosis (AGEP) is an exanthematous condition, predominantly occurring as a result of drug reactions. We, hereby, present the first case of AGEP following treatment with remdesivir in a patient with COVID-19, without hydroxychloroquine use, which serves as a reminder to consider remdesivir as a possible causative agent when dealing with AGEP presentation in COVID patients.
... Only 18% of AGEP are not due to antibiotics. 5 Schmid et al 6 reported that drugspecific T-cells played an important role in the pathogenesis of AGEP, showing that secretion of interleukin-8 by T-cells and keratinocytes attracted neutrophils that filled the vesicles and transformed them into pustules. Whether the mechanism of this PNS-induced skin reaction is related to drug-specific T-cells and interleukin-8 needs further investigation. ...
Article
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Panax notoginseng saponins (PNS) are a patented product in the People's Republic of China, and have extensive effects on the cardiovascular system. Here we report on four elderly patients (one male and three female) with drug eruption induced by PNS injection. All developed a sudden skin rash with pruritus from head to foot, and subsequently accepted hospitalization. In each case, PNS had been used for less than 1 week before appearance of the rash. No specific short-term medications or changes in diet or exposure to environmental factors immediately prior to appearance of the rash were identified. These four patients had some interesting features in common, ie, pustules, fever, and elevated circulating neutrophil counts, which required high-dose, long-term glucocorticoid therapy. To our knowledge, this is the first report of pustular drug eruption induced by PNS and provides a useful reference and warning for clinicians.
... The absence of personal and family history of psoriasis as well as the presence of targetoid lesions together with pustular eruptions, accentuation of pustules in the intertriginous areas, and the histopathologic presence of eosinophils and necrotic keratinocytes but absence of tortuous or dilated vessels helped us exclude pustular psoriasis in the present case. In the English-language literature, we found 10 cases of rheumatology patients who developed AGEP due to HCQ (Table 1) [3][4][5][6][7][8][9][10] . Nine patients were women; concordantly, AGEP is known to be more common in women 1 . ...
Article
Full-text available
Acute generalized exanthematous pustulosis (AGEP) is a cutaneous reaction principally induced by drugs. Spontaneous resolution is observed in most patients. However, severe cases required systemic corticosteroid administration. Hydroxychloroquine, which is used to treat some dermatologic and rheumatologic diseases because of its anti-inflammatory and immunosuppressive effects, is an uncommon cause of AGEP. A 67-year-old female patient presented with severe AGEP due to hydroxychloroquine treatment. She was recalcitrant to supportive care and systemic corticosteroid treatment butwas successfully treated with cyclosporine. Hydroxychloroquine-induced AGEP occurs in women with underlying rheumatologic diseases, has a longer latent period, and has a severe course usually requiring systemic treatment.
... A retrospective literature review revealed that AGEP is a rare drug reaction, with 1 to 5 cases per million population. 9 There were 8 cases of hypotension referenced, 10-17 of which 7 were reported with sepsis-like presentation. [10][11][12][13][14][15][16] Acute renal failure has been reported in one-third of AGEP cases. ...
Article
This case report demonstrates the challenges of diagnosing and managing acute generalized exanthematous pustulosis (AGEP) presenting as septic shock. The disseminated, erythematous, pustular rash is a common feature. However, extensive organ involvement and life-threatening hypotension are unusual. The constellation of signs has not previously been documented following amoxicillin therapy. Toxic epidermal necrolysis (TEN) and toxic shock syndrome (TSS) were considered in addition to AGEP because of the systemic presentation. AGEP was diagnosed following histopathology (TEN was ruled out based on limited necrotic keratinocytes and lack of epidermal necrosis) and a negative antistreptolysin O titer (eliminated TSS). Antibiotic therapy for septic shock was provided before the diagnosis was confirmed as AGEP. Upon confirmation of the AGEP diagnosis, antibiotics were discontinued and a 5-day course of oral prednisone (40 mg/d) was initiated in addition to topical half-strength (0.05%) betamethasone valerate. The patient rapidly improved and was discharged. Outpatient patch testing confirmed amoxicillin as the culprit drug. In conclusion, it is critical to realize that AGEP cannot be ruled out with a septic shock presentation. Recent drug history is critical in recognizing an adverse drug reaction, and patch testing is useful for determining the culpable drug when the diagnosis is AGEP.
... 1 Hydroxychloroquine (HCQ) has been widely used in the treatment of dermatologic and rheumatologic diseases due to its immunosuppressive and anti-inflammatory properties, and has been reported as a rare cause of AGEP. 2, 3 We report herein a case of HCQ-induced AGEP with atypical clinical presentation. ...
Article
Full-text available
Acute generalized exanthematous pustulosis is a rare drug-induced eruption that is characterized by acute, nonfollicular sterile pustules on an erythematous and edematous base. The most frequently implicated drugs are beta-lactam antibiotics. Hydroxychloroquine has been widely used to treat dermatologic and rheumatologic diseases and has been reported as a rare cause of acute generalized exanthematous pustulosis. A 42-year-old female presented with pustular lesions on the skin surface with erythema, facial edema, and occasional atypical target-like lesions after 21 days of treatment with 200mg/day hydroxychloroquine for rheumatoid arthritis, diagnosed one month previously. We report a case with acute generalized exanthematous pustulosis induced by hydroxychloroquine and treated with dapsone and systemic corticosteroid.
... These drugs had been identified in the (European Study of Scar) EuroScar Study which was an international multicenter case-control study which was conducted in the Europe between 1997 and 2001 to find the drugs inducing the SCAR. In almost 90 percent of cases, drugs ingestion is the underlying cause and resoluteness occurs within one or two weeks after abating the drug administration 6 . Although in most of the cases, the drug is the cause but there are some other causes that provoke this reaction like bacterial infections, viral infections, and parasitic infections. ...
Article
Full-text available
Acute Generalised exanthematous pustulosis (AGEP) is a drug-induced severe cutaneous adverse reaction. This is one of a kind of severe cutaneous adverse reactions that is rare and has the incidence of 1 to 5 cases per million per year. The major characteristic clinical feature of AGEP is the presence of many small, pin-head sized, nonfollicular, sterile pustules on an erythematous oedematous base, and accompanied by fever and leukocytosis. The exact pathophysiology behind is not known but the role of T Cell, IL (Interleukin)-8, the mutation in the IL-36 receptor antagonist has been proposed. The differential diagnosis is required in this case of skin lesions because the clinical features are similar to other SCAR (Severe Cutaneous Adverse Reaction) like generalized pustular psoriasis, TEN (Toxic Epidermal Necrolysis) and SJS (Steven Johnson Syndrome). Pustules resolve if the causative drug is abated and this is a very important feature to distinguish it from GPP (Generalised Pustular Psoriasis). Treatment options are only steroids, supportive care, infection treatment and antipyretics to stabilize the condition of the people with this skin reaction. All the current aspects of Acute Generalized Exanthematous Pustulosis are encompassed that is the sole intention of this review.
... 7 We also reviewed the literature in English since 2008 to 2018 and found nine other cases. [7][8][9][10][11][12][13] The details of the cases are summarized in Table 1. The cases have been cleared within 8-91 days. ...
Article
Full-text available
Key Clinical Message Acute generalized exanthematous pustulosis (AGEP) is a self‐limited drug reaction. Hydroxychloroquine (HCQ) is an uncommon cause of AGEP with a prolonged recovery course; Thus, the physicians should take the possibility of this rare but severe event in their minds and try to diagnose correctly and better management.
... AGEP in association with administration of Hydroxychloroquine has been infrequently reported in the literature, with a total of twenty-one cases following a PubMed search using the terms 'Hydroxychloroquine' and 'Pustolosis.' Typically, this disease process is self-limited and requires basic supportive measures [7][8][9]. Rarely, AGEP can present in an atypical fashion with the development of blisters and vesicles that can coalesce, desquamate and form superficial erosions in an AGEP/SJS Overlap Syndrome [3,10,11]. This overlap syndrome can follow a course similar to that seen with SJS/TEN, which includes severe fluid loss, thermal dysregulation and secondary skin infections [12]. ...
Article
Full-text available
Acute Generalized Exanthematous Pustulosis (AGEP) is a rare drug reaction manifesting as pustular lesions with surrounding erythema following exposure. The disease is often self-limited and treatment is supportive. It may present in an atypical variant with vesicles that desquamate into erosions, which classifies the disease as an AGEP/SJS Overlap. This overlap syndrome can carry a substantial mortality rate and necessitate elevation in the level of care. Hydroxychloroquine has been implicated in cases of AGEP, and we present a case of AGEP/SJS overlap attributed to this common medication. Given the prevalence of drug eruptions, it is critical for the physicians to recognize and not overlook this rare and potentially fatal dermatological emergency.
... Ani başlayan eritemli ve ödemli zeminde non-foliküler püstüllerin eşlik ettiği, ateş (38<) ve lökositoz ile karakterize olup, genelde 15 gün içerisinde gerileyen bir deri reaksiyonudur (8). AGEP görülme sıklığı her yıl milyonda 1-5 olgudur (1,8,9). 2001'de Sidoroff ve ark. ...
... 8 To the best of our knowledge, the present study is the largest series reporting HCQ-induced AGEP cases. 20 and cyclosporine. 13 Our patients have been cleared within 15-91 days ( Table 1). ...
Article
Background: Hydroxychloroquine (HCQ)-induced acute generalized exanthematous pustulosis (AGEP) is poorly described in the literature. The aim of our study was to characterize the clinical, laboratory, allergological, and genetic features of HCQ-induced AGEP. Methods: We conducted a retrospective study of patients with HCQ-induced AGEP diagnosed between 2011 and 2019. We performed molecular analysis to identify variations in the IL36RN gene. We also reviewed similar cases reported between 1991 and March 2020. Results: Seven female patients were included. The mean age was 47 years old, and the average time from HCQ start to onset of symptoms was 40 days. All patients received topical steroids with a full resolution of the rash within an average of 39 days after HCQ withdrawal. Patch tests were performed for three patients with positive results in one case. Genetic analyses were performed for three patients, and no mutation in the IL36RN gene was identified. Conclusion: The latent period and the duration for resolution of HCQ-induced AGEP may be longer than with other drugs due to the metabolic characteristics of HCQ. Mutations in the IL36RN gene were not identified in our patients.
... For other drugs, the duration ranged from 4 to 30 days, with a mean latent period of 11 days. 4,5 In this case, lesions emerged after 10 days of oral HCQ, which is consistent with previous report. ...
Article
Background Hydroxychloroquine is associated with myriad adverse dermatologic effects, most of which are poorly characterized by the literature, with unknown frequencies and risk factors. Objective To conduct a systematic review on the adverse dermatologic effects and predisposing factors of hydroxychloroquine toxicity. Results Ninety-four articles were included for review comprising a total of 689 adverse dermatologic side effects. A total of 21 unique dermatologic reactions were reported, most commonly: drug eruption or rash (358 cases), cutaneous hyperpigmentation (116), pruritis (62), acute generalized exanthematous pustulosis (27), Stevens-Johnson syndrome or toxic epidermal necrolysis (26), hair loss (12), and stomatitis (11). Almost all underlying conditions were rheumatologic or autoimmune in nature, composed primarily of lupus erythematous (72% of all cases) and rheumatoid arthritis (14%). The range of reported mean cumulative dosages was wide, with some adverse reactions found after as little as 3 g or as much as 2500 g. Conclusion Though hydroxychloroquine is generally well-tolerated, dermatologic side effects involving the skin, hair, or nails are a frequent and significant complication. The majority of these reactions occurred after treating autoimmune conditions, often manifesting on the skin after a wide range of cumulative dosages.
Article
Résumé La pustulose exanthématique aiguë généralisée (PEAG) est une toxidermie rare et grave. L’hydroxychloroquine (HC) est rarement incriminé. Nous rapportons un cas de PEAG de survenue tardive induite par l’hydroxychloroquine. L’évolution après l’arrêt du médicament était favorable. La PEAG à l’HC est rare. Elle est caractérisée par un délai d’apparition prolongé et une guérison lente.
Article
The term “drug reactions” is relevant to dermatology in three categories of reactions: cutaneous drug reactions without systemic features, cutaneous drug reactions with systemic features, and systemic drugs prescribed by the dermatologist with systematic adverse effects. This article uses examples from each of these categories to illustrate several important principles central to drug reaction diagnosis and management. The information presented will help clinicians attain the highest possible level of certainty before making clinical decisions.
Article
Acute generalized exanthematous pustulosis (AGEP) is a severe cutaneous adverse reaction, mostly induced by drugs. Hydroxychloroquine have been rarely reported in literature as a causative drug of this reaction. We report a case of AGEP induced by hydroxychloroquine with systemic involvement and confirmed by positive patch testing.
Article
Background: Currently used antimalarial drugs (AM) are hydroxychloroquine and chloroquine, which are prescribed for many autoimmune disorders. The value of skin tests on cutaneous adverse drug reactions (CADR) with AM remains unknown. Objective: The main objective of this retrospective study is to know whether skin tests for AM are useful and how to manage the recovery of AM therapy in these patients. Methods: All patients referred for suspected CADR secondary to AM between 2001 and 2014 in eight French dermatology centers were retrospectively reviewed. Results: We report herein a retrospective series of 20 patients with CADR and AM involvement. Skin tests, performed in 14/20 patients, were negative in all cases. Six patients had an oral provocation test with recurrence of CADR in 1 case. Conclusion: We encourage dermatologists to perform oral provocation tests in nonsevere CADR in order to allow AM rechallenge at progressive doses.
Article
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Acute generalized exanthematous pustulosis (AGEP) is a rare skin reaction, commonly caused by drugs. Available evidence mostly relies on small studies or case reports. We collected published AGEP case reports and, subsequently, described the patient characteristics, suspect and concomitant drugs, time to onset, disease management, and clinical prognosis. This study included 297 AGEP patients (64.3% women) obtained from 250 published case reports or case series with individual patient data. AGEP affected patients of all ages, but the majority of patients (88.2%) were ≥25 years old. The most frequently reported suspect drugs were anti-infectives for systemic use (36.5%), particularly antibacterials for systemic use (31.0%), and especially beta-lactam antibacterials (18.3%) and macrolides (4.3%). Other frequent suspect drugs were antineoplastics (12.2%), and anti-inflammatory/anti-rheumatic products (5.2%) plus hydroxychloroquine (12.8%). Mean time to onset was 9.1 days (standard deviation SD 13.94). Some patients developed fever (64.3%) and systemic involvement (18.9%), and most patients (76.4%) received pharmacological treatment for AGEP. Seven patients died, although five of them were already critically ill prior to AGEP. In conclusion, antibiotics remain the most common suspected cause of AGEP. While case mortality rate may be up to 2.5%, disentangling the role of AGEP on the fatal outcome from the role of the preexisting health conditions remains challenging.
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Antimalarial drugs (e.g. chloroquine and its close structural analogues) were developed primarily to treat malaria; however, they are beneficial for many dermatological, immunological, rheumatological and severe infectious diseases, for which they are used mostly today. Chloroquine and hydroxychloroquine, two of the most fascinating drugs developed in the last 50 years, are increasingly recognized for their effectiveness in myriad non-malarial diseases. In advanced research, chloroquine and hydroxychloroquine have been shown to have various immunomodulatory and immunosuppressive effects, and currently have established roles in the management of rheumatic diseases, lupus erythematosus (different forms) and skin diseases, and in the treatment of different forms of cancer. Recently, chloroquine analogues have also been found to have metabolic, cardiovascular, antithrombotic and antineoplastic effects. This review is concerned with the lysosomotropic, anti-inflammatory and immunomodulatory mechanisms of chloroquine, hydroxychloroquine, quinacrine and related analogues, and the current evidence for both their beneficial effects and potential adverse manifestations in various diseases. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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Invasive fungal infections are a major cause of morbidity and mortality among organ transplant recipients, despite many progresses concerning diagnosis, preventions and treatment. Risk factors for invasive fungal infections in transplanted recipients include type and severity of immunosuppression, especially in life--saving organs as lung or liver, older age at transplantation, and technical complexity of surgery, living in endemic areas or exposure to a contaminated environment. Superficial fungal infections are caused by Candida, Dermatophytes, and Malassezia. In invasive mycoses, skin lesions may occur as a consequence of the systemic dissemination of invasive mycoses, or after direct inoculation in the skin. Aspergillosis, cryptococcosis, Zygomycoses, dark mould infections, fusariosis and infections attributable to Scedosporium and Pseudallescheria species are the most common etiological agents. Cutaneous manifestations of fungal infection are not specific, and a high degree of suspicion is required and, prompt biopsy for histology and culture is needed. Therapy with lyposomal amphotericin B and new triazoles are effective.
Article
Acute generalized exanthematous pustulosis (AGEP) is a rare, drug-related pustular eruption usually starting from folds with edema and erythema and with subsequent spreading. Clinically AGEP is characterized by the sudden appearance of dozen of sterile, non follicular, small pustules on erythematous and edematous skin. Mild non erosive mucosal involvement, mostly oral, may sometimes occur. Fever, neutrophilia and peripheral blood eosinophilia (in a third of patients) are present. Other skin signs such as facial edema, purpura, target-like lesions and blisters have been described but are not typical for AGEP. Diagnostic criteria for AGEP were established by an international committee of experts, the European Study of Severe Cutaneous Adverse Reactions (EuroSCAR). The most relevant histopathological feature is represented by the detection of non-follicular subcorneal and/or intracorneal spongiform pustules that are usually large, contiguous and tend to coalesce. After elimination of the causative drug, pustules usually spontaneously disappear in a few days with desquamation and the reaction fully resolves within 15 days. Internal organs are not usually involved and no systemic treatment is required. Withdrawal of the culprit drug is mandatory. Although AGEP is a self-limiting disease with a favourable prognosis, secondary infections are a not infrequent complication in patients in poor general medical conditions. The reported mortality is about 5%. The most severe cases are associated with drug rechallenge.
Article
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Acute generalized exanthematous pustulosis (AGEP) is a clinical reaction pattern that is principally drug induced and this is characterized by acute, nonfollicular sterile pustules on a background of edematous erythema. Hydroxychloroquine (HCQ) has been widely used to treat rheumatic and dermatologic diseases and HCQ has been reported to be an uncommon cause of AGEP. A 38-year-old woman with a 1-year history of dermatomyositis and polyarthralgia was treated with HCQ due to a lack of response to a previous medication. Three weeks after starting HCQ therapy, the pustular skin lesion developed and then this resolved after the HCQ was withdrawn and steroid treatment was started. A similar pustular eruption developed after HCQ was accidentally readministered.
Article
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Acute generalised exanthematous pustulosis and Stevens-Johnson syndrome (toxic epidermal necrolysis spectrum of severe cutaneous drug reactions) are believed to have distinct underlying pathophysiologies. Our patient, a 28-year-old Chinese woman, represents the first known reported case of clinically-consistent and histologically-proven acute generalised exanthematous pustulosis and toxic epidermal necrolysis overlap induced by carbamazepine in the English literature.
Article
• We retrospectively analyzed 63 observations collected in nine French departments of dermatology of an acute pustular dermatosis, recently named in the French literature acute generalized exanthematous pustulosis (AGEP). Even though 11 of these cases occurred in patients with a history of psoriasis, AGEP appeared distinct from pustular psoriasis based on several slight pathologic differences, drug induction in most cases, and a more acute course of fever and pustulosis, with rapid spontaneous healing. We, therefore, suggest that AGEP is a reaction pattern, perhaps favored by a "psoriatic background." The most frequent causes of AGEP seem to be drug reactions, acute infections with enteroviruses, and hypersensitivity to mercury. With 55 (87%) of 63 cases attributed to drugs in this series, AGEP should be added to the list of cutaneous adverse drug reactions. Among druginduced skin eruptions, AGEP is remarkable by its short time to onset after the administration of the suspected drug (<24 hours in half of our cases) and the great predominance (80%) of antibiotics as causative agents. It is suggested that some cases previously reported as "drug-induced pustular psoriasis" were in fact AGEP. (Arch Dermatol. 1991;127:1333-1338)
Article
Background Drug patch tests (PTs) can reproduce delayed hypersensitivity to drugs and entail a moderate re-exposure of patients to offending drugs. Objectives To determine the value of PTs for identifying the responsible drug in severe cutaneous adverse drug reactions (SCARs) such as acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Methods In a multicentre study, PTs were conducted on patients referred for DRESS, AGEP or SJS/TEN within 1 year of their SCAR. All drugs administered in the 2 months prior to and the week following the onset of the SCAR were tested. Results Among the 134 patients included (48 male, 86 female; mean age 51·7 years), positive drug PTs were obtained for 24 different drugs. These included positive tests for 64% (46/72) of patients with DRESS, 58% (26/45) of those with AGEP and 24% (4/17) of those with SJS/TEN, with only one relapse of AGEP. The value of PTs depended on the type of drug and the type of SCAR (e.g. carbamazepine was positive in 11/13 DRESS cases but none of the five SJS/TEN cases). PTs were frequently positive for beta lactams (22 cases), pristinamycin (11 cases) and in DRESS with pump proton inhibitors (five cases), but were usually negative for allopurinol and salazopyrin. Of 18 patients with DRESS, eight had virus reactivation and positive PTs. In DRESS, multiple drug reactivity was frequent (18% of cases), with patients remaining sensitized many years later. Conclusions PTs are useful and safe for identifying agents inducing SCAR.
Article
Whereas antimalarials have been in use to treat rheumatic disease for over 50 years, their exact mechanism of action remains unclear. Over the past decade, new theories have been proposed in this regard both for rheumatic disease, as well as related conditions. Whereas the classical explanation was an impairment of phago/lysosomal function, antimalarials also appear to have an impact through inhibition of intracellular toll-like receptors (TLRs), particularly TLR9. This may mediate its effect on lupus, rheumatoid arthritis, as well as ancillary conditions including diabetes and hyperlipidemia. The potential role for antimalarials in antiphospholipid syndrome also appears clearer, with an effect proposed through Annexin5 binding. Despite their established clinical utility, the mode of action for antimalarials remains uncertain despite recent advances and still requires further investigation. By better understanding how antimalarials function, their optimal use in the clinical setting can be ensured.
Article
We report a 45-year-old woman who presented an acute generalized exanthematic pustulosis induced by hydroxychloroquine. Acute generalized exanthematic pustulosis is a severe eruption that is usually drug related. This side effect should be known as new therapeutic challenge would induce more severe clinical features. 2009 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.
Article
Acute generalized exanthematous pustulosis (AGEP) and toxic epidermal necrolysis (TEN) are both severe cutaneous adverse reactions, mostly to drugs. Although predominantly involving skin, they differ significantly in presentations, prognosis, pathology, immunogenesis, and treatment. They have very rarely been described to occur simultaneously in a patient, manifesting as AGEP-TEN overlap. We describe a 67-year-old Chinese lady with systemic lupus erythematosus who presented with features of AGEP but evolved to AGEP-TEN overlap as an adverse reaction to hydroxychloroquine (HCQ) treatment. This case is the first reported case of AGEP-TEN overlap secondary to HCQ and highlights the need for constant surveillance for rare adverse events that may manifest even after decades of use of the drug worldwide.
Article
A quantitative method is described for the measurement of intralysosomal pH in living cells. Fluorescein isothiocyanate-labeled dextran (FD) is endocytized and accumulates in lysosomes where it remains without apparent degradation. The fluorescence spectrum of this compound changes with pH in the range 4-7 and is not seriously affected by FD concentration, ionic strength, or protein concentration. Living cells on coverslips are mounted in a spectrofluorometer cell and can be perfused with various media. The normal pH inside macrophage lysosomes seems to be 4.7-4.8, although it can drop transiently as low as 4.5. Exposure of the cells to various weak bases and to acidic potassium ionophores causes the pH to increase. The changes in pH are much more rapid than is the intralysosomal accumulation of the weak bases. Inhibitors of glycolysis (2-deoxyglucose) and of oxidative phosphorylation (cyanide or azide) added together, but not separately, cause the intralysosomal pH to increase. These results provide evidence for the existence of an active proton accumulation mechanism in the lysosomal membrane and support the theory of lysosomal accumulation of weak bases by proton trapping.
Article
A 69-year-old man developed a generalized pustular drug rash 2 weeks after starting on hydroxychloroquine sulfate (HCQ) medication. This form of drug eruption had not previously been attributed to HCQ, although a diagnosis of pustular psoriasis cannot be ruled out.
Article
The effect of chloroquine and hydroxychloroquine on human neutrophil polymorph superoxide (O2-) production stimulated either by opsonized zymosan, phorbol myristate acetate or fluoride was examined in vitro. Both drugs inhibited the response to all 3 stimuli in a dose and time dependent fashion. Inhibition of zymosan stimulated O2- release was only attributable in a minor degree to inhibition of expression of surface receptors (MO-1), and appeared to be mainly due to inhibitory effects on more distal components of the activation pathway. Possible mechanisms for the inhibition of fluoride and phorbol ester stimulated O2- release are discussed in the light of current understanding of metabolic pathways of neutrophil polymorph activation.
Article
We have reviewed the histopathological features of 11 patients with pustular drug eruptions. Two main histological patterns were seen. Eight cases revealed features of toxic pustuloderma with the presence of spongiform intraepidermal pustules in association with papillary oedema and a mixed inflammatory cell infiltrate around upper dermal blood vessels. Pustules were present at different levels within the epidermis. The other three cases exhibited leucocytoclastic vasculitis with neutrophil collections both below and within the epidermis. One case showed continuity between the subepidermal and intra-epidermal pustules. These findings suggest a dynamic process in which neutrophils collect around upper dermal blood vessels and are then eliminated via the overyling epidermis. The presence of extravasated red blood cells within the intra-epidermal pustules indicates that this process is passive rather than the result of specific chemotaxis or cell migration.
Article
Acute generalized exanthematous pustulosis usually occurs as a typical skin reaction to drugs. We observed a case with a photodistribution induced by hydroxychloroquine and/or PUVA. A male subject had been treated for actinic pseudolymphoma since 1988. General corticosteroids had been given initially and were followed by PUVA and azathioprine. A new episode with erythema involving the trunk and the proximal portion of the limbs was treated with corticosteroids and hydroxychloroquine. The symptomatology regressed but pustular erythema developed in exposed areas two days after a PUVA session on the upper part of the body. The eruption did not involve the zones of the phototests one month earlier. The lesions resolved rapidly after withdrawal of hydroxychloroquine and PUVA. Photo-induced acute generalized exanthematous pustulosis with a photodistribution has not been reported previously. The imputability of hydroxychloroquine and PUVA, and their association is suggested. The appearance of pustular lesion on exposed areas and the protection resulting from the phototests would lead to several hypotheses. General corticosteroids were ineffective in preventing and in treating acute generalized exanthematous pustulosis.
Article
In the city of Lima, capital of Peru, the wife of the Viceroy, at that time the Count of Cinchon fell sick... Her illness was tertian fever... The rumour of her illness... became known by the people in the city, spread to neighboring places and reached Loxa. I believe since then thirty or forty years have passed. A Spaniard, the prefect in that place was told of the illness of the Countess, and thought to inform by letter her husband the Viceroy... that he had a secret remedy he could recommend without hesitation ... she accepted at once ... and once taken, like something miraculous, she was cured to the amazement of all.
Article
A wide range of diseases or reactions can cause pustular eruptions of the skin. In this spectrum there seems to be a subgroup with characteristic clinical features and a typical course which is mostly caused by drugs for which the term acute generalized exanthematous pustulosis (AGEP) has been established. To describe the clinical features of AGEP. The authors' experience from a multinational epidemiological study on severe cutaneous adverse reactions and a comprehensive review of the literature were used to provide an overview of the disease and it's possible causes. An algorithm for validating cases which was established for this study is also presented. AGEP typically presents with at least dozens of non follicular sterile pustules occurring on a diffuse, edematous erythema predominantly in the folds and/or on the face. Fever and elevated blood neutrophils are common. Histopathology typically shows spongiform subcorneal and/or intraepidermal pustules, a marked edema of the papillary dermis, and eventually vasculitis, eosinophils and/or focal necrosis of keratinocytes. Onset is acute, most often following drug intake, but viral infections can also trigger the disease. Pustules resolve spontaneously in less than 15 days. The diagnosis AGEP should be considered in cases of acute pustular rashes and detection of the causative drug should be strived for. Knowledge of the clinical features and usual course of this disease can often prevent unnecessary therapeutical measures.
Article
Objective: A dose-response relationship for hydroxychloroquine (HCQ), in terms of the proportion of patients achieving the Paulus 20% criteria for improvement, had previously been observed in patients with rheumatoid arthritis (RA) receiving a 6-week loading regimen of 400, 800, or 1,200 mg HCQ daily. This present retrospective analysis was performed to investigate possible relationships between the blood HCQ and HCQ-metabolite concentrations and measures of efficacy and toxicity. In addition, we sought to ascertain whether further investigation of HCQ/HCQ-metabolite levels might lead to testing of one of these substances as a new antirheumatic drug. Methods: Patients with active RA (n = 212) began a 6-week, double-blind trial comparing 3 different doses of HCQ at 400, 800, or 1,200 mg/day, followed by 18 weeks of open-label HCQ treatment at 400 mg/day. Patients were repeatedly evaluated for treatment efficacy and toxicity. Blood samples were available from 123 patients for analysis of HCQ, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bisdesethylchloroquine (BDCQ) levels using high-performance liquid chromatography. Achievement of the modified Paulus 20% improvement criteria for response in RA was used as the primary efficacy parameter. Spontaneously reported adverse events were categorized and analyzed as toxicity outcome variables. The relationship between response (efficacy and toxicity) and drug levels was evaluated using logistic regression analysis. Results: The subset of patients with blood concentration data was equivalent to the larger study population in all demographic and outcome characteristics. The mean HCQ, DHCQ, and DCQ elimination half-lives were 123, 161, and 180 hours, respectively. There was a positive correlation between the Paulus 20% improvement criteria response and blood DHCQ concentrations during weeks 1-6 (P < 0.001). A potential relationship between ocular adverse events and BDCQ levels was found (P = 0.036). Logistic regression analysis of adverse events data showed that adverse gastrointestinal events were associated with higher HCQ levels (P = 0.001-0.021) during weeks 1, 2, and 3. Conclusion: There is a weak, but predictable, relationship between blood DHCQ concentrations and efficacy of treatment with HCQ. In addition, there is an association between gastrointestinal adverse events and elevated blood HCQ concentrations. Further investigation of these relationships is warranted to see if DHCQ may be introduced as a new antirheumatic drug.
Article
Acute generalized exanthematous pustulosis is a severe eruption which is usually drug related. If the causative drug is discontinued, acute generalized exanthematous pustulosis resolves spontaneously in ten days. The aim of this study was to compare drugs suspected of causing acute generalized exanthematous pustulosis reported to French Pharmacovigilance centres and those reported in the literature. All cases of "pustular eruption" qualified as "serious" reported to the French Pharmacovigilance Centers between January 1985 and December 2001 were analyzed. Cases for which the diagnosis of acute generalized exanthematous pustulosis was not clearly identified were reviewed by a dermatologist. The relationship between acute generalized exanthematous pustulosis and drug exposure was re-examined by one of us. An exhaustive review of the literature was also performed. Review of the data base revealed 207 cases of serious acute generalized exanthematous pustulosis leading to death in 4 cases (2%). Of these cases of acute generalized exanthematous pustulosis, only one drug was suspected in 107 cases (51.6%). The main drugs involved were: pristinamycin (18 cases), amoxicillin (+/- clavulanic acid) (16 cases), hydroxychloroquine (8 cases) and a combination of spiramycin + metronidazole (5 cases). The most frequent causal drugs in our study and in the literature are: amoxicillin +/- clavulanic acid, pristinamycin, hydroxychloroquine, ampicillin, diltiazem, co-trimoxazole, terbinafine, carbamazepine and spiramycin +/- metronidazole. Only pristinamycin and diltiazem have information in their summary of product characteristics regarding the risk of acute generalized exanthematous pustulosis. Because it is essential to discontinue the causative drug as soon as possible if a pustular eruption occurs, physicians must be informed of the risk, which should be added to the "adverse events", and "warnings" sections of the summary of product characteristics of the drugs concerned. Our results show the relevance of notification of side effects by physicians to pharmacovigilance centres, leading to the identification of a signal and public health dissemination of warnings.
Article
Acute generalized exanthematous pustulosis (AGEP) is a disease characterized by the rapid occurrence of many sterile, nonfollicular pustules usually arising on an oedematous erythema often accompanied by leucocytosis and fever. It is usually attributed to drugs. To evaluate the risk for different drugs of causing AGEP. A multinational case-control study (EuroSCAR) conducted to evaluate the risk for different drugs of causing severe cutaneous adverse reactions; the study included 97 validated community cases of AGEP and 1009 controls. Results Strongly associated drugs, i.e. drugs with a lower bound of the 95% confidence interval (CI) of the odds ratio (OR) > 5 were pristinamycin (CI 26-infinity), ampicillin/amoxicillin (CI 10-infinity), quinolones (CI 8.5-infinity), (hydroxy)chloroquine (CI 8-infinity), anti-infective sulphonamides (CI 7.1-infinity), terbinafine (CI 7.1-infinity) and diltiazem (CI 5.0-infinity). No significant risk was found for infections and a personal or family history of psoriasis (CI 0.7-2.2). Medications associated with AGEP differ from those associated with Stevens-Johnson syndrome or toxic epidermal necrolysis. Different timing patterns from drug intake to reaction onset were observed for different drugs. Infections, although possible triggers, played no prominent role in causing AGEP and there was no evidence that AGEP is a variant of pustular psoriasis.
Article
A patient developed toxic epidermal necrolysis (TEN), which was triggered by sun exposure while the patient was on long-term hydroxychloroquine. Phototoxic and photoallergic reactions are known to occur with hydroxychloroquine, but, to our knowledge, this is the first reported case of photo-induced TEN associated with the drug.
Article
Acute generalized exanthematous pustulosis (AGEP) is a clinical reaction pattern that is principally drug induced and is characterized by acute, extensive formation of nonfollicular sterile pustules on an erythematous and edematous substrate. Hydroxychloroquine (HHCQ), an antimalarial drug widely used to treat rheumatic and dermatologic diseases, has been described as an uncommon cause of AGEP. This article reports 3 cases of HCQ-induced AGEP and reviews similar cases in the published literature. The first case involved a 36-year-old woman with a 10-year history of rheumatoid arthritis and Sjögren's syndrome who had begun a 25-day course of HCQ 100 mg BID due to lack of response to a corticosteroid, with a skin reaction developing 21 days into the new treatment. In the second case, a 70-year-old man with poorly controlled rheumatoid arthritis had begun a course of oral HCQ 100 mg BID 20 days before development of AGEP. The final case involved a 79-year-old woman with polymyalgia rheumatica who had been receiving HCQ 100 mg BID as a steroid-sparing agent for 22 days, with rash developing 20 days after the initiation of HCQ. Sixteen cases of HCQ-induced AGEP were identified in the literature, including some that may have been reported under a different name but were consistent with a clinical diagnosis of AGEP. The US Food and Drug Administration has mandated a change to the labeling for HCQ to include AGEP among potential adverse dermatologic reactions to the drug. This article reports 3 cases of AGEP related to administration of HCQ. HCQ-induced AGEP is a rare but severe, extensive, and acute reaction. No specific therapy is available, and correct diagnosis generally leads to spontaneous resolution once the causative drug has been withdrawn.