Acute hepatitis after cutaneous application of an artisanal topical ointment with mercury

There is a risk of severe neurological disease, nephropathy and cutaneous complications during mercury poisoning. We report a case of acute generalized exanthematous pustulosis, associated with histologically confirmed acute cytolytic hepatitis without liver failure, after application of a topical home-made ointment containing mercury. The patient was previously sensitized with mercurothiolate. A high level of mercury was found in the blood (68 microg/L, normal < 5 microg/L). Clinical and biological features disappeared after the ointment was discontinued. Biological acute hepatitis was probably from type IV sensitization, like that seen in acute generalized exanthematous pustulosis, with no evidence of direct mercury poisoning and after lithiasis, viral, immune and drug side effects were excluded. Liver injury during acute generalized exanthematous pustulosis is uncommon and usually mild, but should be searched for.     

Primary biliary cirrhosis associated pustular vasculitis

The association between primary biliary cirrhosis (PBC) and cutaneous vasculitides is well recognized. Pustular skin lesions though, have been described in association with hepatobiliary diseases other than PBC. Once the more common infective pustular rashes have been excluded, the differential diagnoses for a pustular skin rash are acute generalized exanthematous pustulosis (AGEP), Sweet's Syndrome (SS), pyoderma gangrenosum (PG) and pustular vasculitis(PV). We present a case of pustular vasculitis associated with PBC.     

Acute generalized exanthematous pustulosis due to tetrazepam.

Tetrazepam is a benzodiazepine that is widely used in Spain as a muscle relaxant, with occasional cutaneous side effects. We report a patient who developed a generalized pruriginous cutaneous reaction compatible with acute generalized exanthematous pustulosis (AGEP) due to tetrazepam. Patch tests with bromazepam, diazepam, and tetrazepam were negative at 48 and 72 hours; however, the tetrazepam patch showed a positive reaction at 10 days. Immunohistochemical studies revealed a mononuclear infiltrate composed of CD4+ and CD8+ T lymphocytes. Analysis of interleukin (IL) 8 expression by quantitative polymerase chain reaction revealed increased IL-8 mRNA levels in patch test-positive skin. Lymphoblast transformation test (LTT) was positive with tetrazepam but not with diazepam. Positive patch test and LTT suggested that tetrazepam-specific lymphocytes might be responsible for a T cell-mediated reaction.These results support previous data suggesting an important role for IL-8 and drug-specific T cells in the pathogenesis ofAGEP and imply that the reaction was specific to tetrazepam with no cross-reactivity to other benzodiazepines.     

Pustulose exanthématique aiguë généralisée liée à l’hydroxychloroquine : à propos d’une observation

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.     

Acute generalized exanthematous pustulosis due to sulfamethoxazol with positive lymphocyte transformation test (LTT).

We studied an acute generalized exanthematous pustulosis (AGEP) due to sulfamethoxazol in a 48-year-old woman with unusual findings in allergy testing. The histological picture provided evidence for a pustular drug eruption and leukocytoclastic vasculitis. Skin testing with sulfamethoxazol was negative for immediate-type reaction (scratch test) and delayed-type reaction (epicutaneous testing). A lymphocyte transformation test (LTT) showed a significant lymphocyte stimulation (stimulation index 5.04/2.61) toward sulfamethoxazol (200/100 mg/ml) by measuring the rate of built-in tritium-thymidine in the DNS of the patients lymphocytes, implicating a drug-specific hypersensibility of lymphocytes; we could be dealing with a combined type III and IV reaction by Coombs and Gell in this case. LTT may play a possible role in the determination of drug allergy in AGEP despite negative skin testing.     

Acute generalized exanthematous pustulosis induced by omeprazole

Acute generalized exanthematous pustulosis (AGEP) comprises a group of eruptions characterized by several small sterile pustules over an erythematous-edematous skin. These eruptions are usually drug induced and show some characteristics that suggest an immunologic background. Treatment is based on withdrawal of the drug causing the eruption. Prognosis is generally good and the skin lesions usually resolve in a few days with characteristic postpustular pin-point desquamation. We report three cases of AGEP induced by omeprazole, a drug with a good safety profile. Some adverse cutaneous reactions have been described as secondary effects. However, to our knowledge, no cases of omeprazole-induced AGEP have previously been reported. AGEP related to other proton pump inhibitors is exceptional.     

Recent progress of elucidating the mechanisms of drug hypersensitivity

Recent technical approaches to investigating drug hypersensitivity have provided a great deal of information to solve the mechanisms that remain poorly understood. First, immunological investigations and in silico analysis have revealed that a novel interaction between T cells and antigen-presenting cells, namely the pharmacological interaction concept, is involved in drug recognition and the hapten theory. Second, progress in immunology has provided a new concept of CD4+ T cell subsets. Th17 cells have proven to be a critical player in acute generalized exanthematous pustulosis. Our recent findings suggest that this subset might contribute to the pathogenesis of Stevens-Johnson syndrome/toxic epidermal necrolysis. Third, alarmins, molecules associated with innate immunity, are also associated with exaggeration and the persistence of severe drug hypersensitivity. The latest innovative techniques are providing a new landscape to examine drug hypersensitivity.     

Acute generalized exanthematous pustulosis and toxic epidermal necrolysis induced by hydroxychloroquine

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.     

Hépatotoxicité tardive à l’imatinib chez une patiente de 44 ans

Imatinib mesylate is currently used in the treatment of chronic myeloid leukemia (CML), advanced gastrointestinal stromal tumors, and Philadelphia chromosome-positive acute leukemia. Hepatotoxicity is a rare but potentially serious complication of treatment with imatinib.We report the case of a 44-year-old woman treated by imatinib mesylate (Gleevec®) for CML who was admitted to our institution with severe acute hepatitis two years and nine months after the initiation of treatment. The outcome was favorable after stopping the drug, with normalization of serum aminotransferase activity after 6 months. It is recommended that liver function is regularly monitored during treatment with imatinib. With the ascencion of liver function tests, treatment should be discontinued.     

T cells in drug allergy

In recent years, increasing evidence has indicated an important role for T cells in various drug-induced diseases. A detailed analysis of patients with various drug allergies revealed the existence of drug-specific T cells in the circulation or in eluate from skin infiltration in bullous, pustular, and maculopapular drug eruptions. The drug-specific T cells use the aa-T cell receptor CD4+ or CD8+ and react with drugs acting as haptens (covalently bound to larger molecules, such as penicillins), but also recognize drugs if they are bound only in a labile way to major histocompatibility complex molecules (noncovalent drug presentation). Functional analysis revealed a predominant IL-5 production by drug-specific CD4+ T cells in maculopapular exanthema (MPE) and bullous skin diseases, while patients with acute generalized exanthematous pustulosis have a peculiar T cell subset secreting high amounts of IL-8. Moreover, in MPE CD4+, perforin+ T cells were found in vitro and in immunohistology that had cytotoxic potential and killed keratinocytes in vitro and in vivo.     

Acute Generalized Exanthematous Pustulosis (AGEP) Triggered by a Spider Bite

BackgroundAcute generalized exanthematous pustulosis (AGEP) is a rare and severe cutaneous reaction usually triggered by drugs. Other causative factors such as viral infections are rarely involved. In this study, we report a case of AGEP caused by a spider bite.Case SummaryA 56-year-old woman was referred to the allergy unit after a spider bite at the left popliteal fossa, while gardening, 5 days earlier. The offending spider was captured and identified by an entomologist as belonging to the Loxosceles rufescens species. No acute reaction was observed; however, after 24 hours, due to the occurrence of typical dermonecrotic skin lesions associated with erythema and edema, Cefuroxime and Clindamycin were administered intramuscularly after medical advice was given. Almost 72 hours after the spider bite, an erythematous and partly edematous eruption appeared locally in the gluteus area bilaterally, which progressively expanded to the trunk, arms and femors. Within 24 hours dozens of small, pinhead sized, non- follicular pustules were present, mainly in the folds. The patient complained of a burning sensation of the skin in addition to pruritus; and simultaneously had a fever of 38-39 °C as the eruption expanded.DiscussionA spider bite may represent a possible causative factor of AGEP. A spider's venom contains sphingomyelinase that stimulates the release of IL8 and GM-CSF, which are involved in AGEP pathogenesis. Whether or not the con-current use of antibiotics has an effect in AGEP appearance when combined with a spider's venom, cannot be excluded.     

Skin Testing and Patch Testing in Non-IgE-Mediated Drug Allergy

Drug skin tests can reproduce delayed hypersensitivity to drugs and entail a moderate reexposure of patients to offending drugs. Drug patch tests (DPTs) and prick tests can be done with any commercialized form of a drug. In non-severe delayed non-IgE-mediated reactions to drugs, intradermal tests (IDT) with delayed readings have a greater value, but their techniques lack standardization. A negative drug skin test does not exclude the responsibility of a drug, and the drug must be rechallenged in non-severe cases. DPTs are useful in maculopapular rashes, flexural exanthemas, and if done in situ, also in fixed drug eruption. Their best indication is in acute generalized exanthematous pustulosis or drug reaction with eosinophilia and systemic symptoms (DRESS). They should be carried out cautiously, following strict guidelines. Prick tests have a low value but they can sometimes be positive on delayed readings. In non-severe delayed reactions to drugs, intradermal tests with delayed readings are the most sensitive skin tests especially for beta-lactam antibiotics, radiocontrast media, heparins but also some biological agents. The value of patch testing varies according to the implicated drug and the non-immediate adverse drug reaction. In DRESS, DPTs have a good value in testing carbamazepine or proton pump inhibitors but remain negative in testing with allopurinol or salazopyrin. In toxic epidermal necrolysis, DPTs are safe but positive in only 9 to 23 % of the reported cases.     

Acute generalized exanthematous pustulosis (AGEP). Case report

Acute Generalized Exanthematous Pustulosis (AGEP) is a drug-induced dermatosis characterized by an acute episode of sterile pustules over erythematous-edematous skin. It is accompanied by an episode of fever, which regresses a few days after discontinuation of the drug that caused the condition or as a result of corticosteroid treatment. The main triggering drugs are antibiotics, mainly beta-lactam ones. Other medications, such as antifungal agents, non steroid anti-inflammatory drugs, analgesics, antiarrhythmic, anticonvulsant and antidepressant drugs, may also be responsible. Histologically, it is characterized by the existence of vasculitis, associated with non-follicular subcorneal pustules. A case of a Caucasian female outpatient unit of Dermatology with AGEP, who presented with generalized pustulosis lesions after the use of cephalosporin for urinary infection is related. The diagnosis was confirmed by the clinical and pathological correlations, the resolution of the dermatosis after discontinuation of the drug and use of systemic corticosteroid treatment, and the recurrence of the disorder after the introduction of a similar drug. The importance of the recognition of this drug-induced dermatosis is given by its main differential clinical and histological diagnoses: generalized pustular psoriasis and subcorneal pustulosis.     

Preexistence and evolution of imatinib mesylate-resistant clones in chronic myelogenous leukemia detected by a PNA-based PCR clamping technique

Recently, various mutations within the Abl sequence have been described that negatively affect imatinib binding to Bcr/Abl resulting in cellular resistance of chronic myeloid leukemia (CML) cells. So far, little is known as to whether these mutations are preexisting or develop under imatinib therapy as current mutation analyses are limited by a low sensitivity of approximately 1:2 (50%) to 1:5 (20%). By combining peptide nucleic acid (PNA)-based DNA clamping with a fluorescence hybridization probe assay, we developed a new and highly sensitive technique for the detection of known mutations within the Bcr/Abl kinase domain. With this approach we investigated 19 cases of CML refractory to imatinib treatment before and during therapy. By clamping of wild-type Abl through PNA we could effectively enhance the detection sensitivity for the Bcr/Abl mutations Thr315Ile, Glu255Lys, and Tyr253His such that 1 mutant cDNA molecule could be detected in 500 negatives (0.2%). We observed in one case that a Gly255Lys mutation was detectable before treatment. By DNA analysis of buccal swaps, a genetic polymorphism could be excluded. In two cases clonal evolution of known mutations developed gradually under treatment. In another case an initially detectable Tyr253His mutation disappeared after therapy onset but was again observed after 6 weeks of imatinib treatment. Preexisting and evolving Bcr/Abl mutations associated with an unfavorable prognosis could be safely detected by the presented technique. This may facilitate risk stratification in CML and may serve as a model for individualized molecular monitoring and therapeutic strategies in other malignant diseases.     

The kinase inhibitor imatinib mesylate inhibits TNF-{alpha} production in vitro and prevents TNF-dependent acute hepatic inflammation

Imatinib exerts potent antileukemic effects in vitro and in vivo. Despite its well known antitumor activity, the potential of imatinib for the treatment of inflammatory diseases remains elusive so far. Our current report provides strong evidence that imatinib has potent antiinflammatory effects. It potently inhibits LPS- and Con A-induced TNF-alpha production by human myeloid cells in vitro (peripheral blood mononuclear cells, CD14-selected monocytes, and monocyte-derived macrophages). Of note, the production of the antiinflammatory cytokine IL-10 was not significantly regulated by imatinib. In line with this observation, phosphorylation of IkappaB and subsequent DNA binding of NF-kappaB, which is critically involved in TNF-alpha, but not IL-10 expression, was reduced by imatinib. Using several murine models of acute hepatitis, we could corroborate our in vitro findings, as imatinib prevented macrophage- and TNF-alpha-dependent inflammatory damage of the liver induced by injection of either Con A or d-galactosamine/LPS by inhibition of hepatic TNF-alpha production. Of note, d-galactosamine/TNF-induced hepatitis was not affected, showing that imatinib does not directly inhibit TNF-alpha-induced hepatocellular cell death. These findings suggest a potent antiinflammatory role of imatinib by modulation of TNF-alpha production in monocytes/macrophages. This observation might be of therapeutic value for the treatment of TNF-mediated diseases.     

DILI Associated with Skin Reactions

Purpose of Review

Adverse drug reactions (ADR) frequently involve the liver and skin in the form of drug-induced liver injury or cutaneous drug eruption.

Recent Findings

Skin ADR can range from harmless rash to severe skin manifestations such as drug rash with eosinophilia and systemic symptom syndrome (DRESS syndrome), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP), all of which can be associated with severe outcome, including a 30% mortality rate in case of TEN. The association with co-occurring liver injury varies and in DRESS and SJS/TEN can contribute to substantial morbidity and mortality.

Summary

Liver and skin ADR are frequent but rarely severe; however, if severe, they are not uncommonly fatal.

     

Promyelocytic crisis of chronic myelogenous leukaemia during imatinib mesylate treatment

An untreated 66-year-old woman with chronic myelogenous leukaemia (CML) in the chronic phase was initially given imatinib mesylate, rapidly achieving a good cytogenetic response with treatment. However, acute promyelocytic leukaemia complicated by a disseminated intravascular coagulation occurred 9 months after beginning imatinib treatment. Promyelocytic crisis of CML was diagnosed by demonstration of both BCR/ABL and PML/RAR alpha chimeric genes in leukaemic cells by karyotypic and fluorescence in situ hybridization analysis. Clonal evolution with addition of the PML/RAR alpha translocation may have arisen in the early chronic phase of CML, with expansion of this clone during imatinib treatment. Promyelocytic crisis of CML is rare; furthermore, we know of no previous report of promyelocytic crisis occurring during treatment with imatinib.     

Imatinib mesylate-sensitive blast crisis immediately after discontinuation of imatinib mesylate therapy in chronic myelogenous leukemia: report of two cases

Although imatinib mesylate has shown encouraging activity in chronic myelogenous leukemia (CML), disease progression during therapy has been observed, manifested by clonal expansion of imatinib mesylate-resistant leukemia cells. On the other hand, myelosuppression related to treatment of imatinib mesylate is often managed with temporary interruption of treatment or dose reduction. We here report two CML patients who had imatinib mesylate-sensitive blast crisis (BC) immediately after discontinuation of imatinib mesylate therapy. The patients discontinued therapy because of neutropenia. Although there was no evidence of blastic phase during therapy, BC occurred 2 weeks after the withdrawal of treatment in both cases. Interestingly, additional chromosomal abnormalities were detected following the withdrawal of imatinib mesylate and disappeared by re-introduction of this agent. The same doses of imatinib mesylate was still effective and remission was sustained with imatinib mesylate alone again. Our report suggests the possibility that withdrawal of imatinib mesylate may lead to proliferation of blast clones even in patients showing good responses to imatinib mesylate without signs of disease progression.     

Acute generalized exanthematic pustulosis (AGEP) in a patient treated with furosemide

BACKGROUND: Although they appear more rarely than electrolyte disturbances, cutaneous reactions are important adverse effects of furosemide. This is particularly true for bullous skin eruptions, because they may be life-threatening. CASE REPORT: We describe a patient who developed acute generalized exanthematic pustulosis (AGEP) during treatment with furosemide. Because the patient had developed similar skin eruptions during treatment with furosemide years before, furosemide was considered the most likely cause of this reaction. The short period of time between exposure to furosemide and the appearance of the skin reaction, as well as a positive lymphocyte transformation test, suggest an immunological mechanism of the skin disease. CONCLUSION: AGEP is a possible cutaneous side effect of furosemide.     

Severe Cutaneous Adverse Drug Reactions: Presentation,Risk Factors,and Management

Purpose of Study

Immune-mediated adverse drug reactions occur commonly in clinical practice and include mild, self-limited cutaneous eruptions, IgE-mediated hypersensitivity, and severe cutaneous adverse drug reactions (SCAR). SCARs represent an uncommon but potentially life-threatening form of delayed T cell-mediated reaction. The spectrum of illness ranges from acute generalized exanthematous pustulosis (AGEP) to drug reaction with eosinophilia with systemic symptoms (DRESS), to the most severe form of illness, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

Recent Findings

There is emerging literature on the efficacy of cyclosporine in decreasing mortality in SJS/TEN.

Summary

The purpose of our review is to discuss the typical presentations of these conditions, with a special focus on identifying the culprit medication. We review risk factors for developing SCAR, including HLA alleles strongly associated with drug hypersensitivity. We conclude by discussing current strategies for the management of these conditions.