scholarly journals Steatosis, Steatohepatitis and Cancer Immunotherapy: An Intricate Story

2021 ◽  
Vol 22 (23) ◽  
pp. 12947
Author(s):  
Mauro Cataldi ◽  
Federica Manco ◽  
Giovanni Tarantino
Keyword(s):  
Cancer Immunotherapy ◽  
Liver Toxicity ◽  
Checkpoint Inhibitors ◽  
Stevens Johnson Syndrome ◽  
Drug Induced ◽  
Alcoholic Fatty Liver ◽  
Immune Mediated ◽  
Johnson Syndrome ◽  
Lymphocytic Infiltrates ◽  
Alcoholic Fatty Liver Disease

Immune checkpoint inhibitors represent one of the most significant recent advances in clinical oncology, since they dramatically improved the prognosis of deadly cancers such as melanomas and lung cancer. Treatment with these drugs may be complicated by the occurrence of clinically-relevant adverse drug reactions, most of which are immune-mediated, such as pneumonitis, colitis, endocrinopathies, nephritis, Stevens Johnson syndrome and toxic epidermal necrolysis. Drug-induced steatosis and steatohepatitis are not included among the typical forms of cancer immunotherapy-induced liver toxicity, which, instead, usually occurs as a panlobular hepatitis with prominent lymphocytic infiltrates. Nonetheless, non-alcoholic fatty liver disease is a risk factor for immunotherapy-induced hepatitis, and steatosis and steatohepatitis are frequently observed in this condition. In the present review we discuss how these pathology findings could be explained in the context of current models suggesting immune-mediated pathogenesis for steatohepatitis. We also review evidence suggesting that in patients with hepatocellular carcinoma, the presence of steatosis or steatohepatitis could predict a poor therapeutic response to these agents. How these findings could fit with immune-mediated mechanisms of these liver diseases will also be discussed.

scholarly journals The Roles of Immunoregulatory Networks in Severe Drug Hypersensitivity

2021 ◽  
Vol 12 ◽  
Author(s):  
Yun-Shiuan Olivia Hsu ◽  
Kun-Lin Lu ◽  
Yun Fu ◽  
Chuang-Wei Wang ◽  
Chun-Wei Lu ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Drug Hypersensitivity ◽  
Human Leukocyte ◽  
Hypersensitivity Syndrome ◽  
Stevens Johnson Syndrome ◽  
Hypersensitivity Reactions ◽  
Drug Induced ◽  
Johnson Syndrome ◽  
Signaling Receptors ◽  
Systemic Symptoms

The immunomodulatory effects of regulatory T cells (Tregs) and co-signaling receptors have gained much attention, as they help balance immunogenic and immunotolerant responses that may be disrupted in autoimmune and infectious diseases. Drug hypersensitivity has a myriad of manifestations, which ranges from the mild maculopapular exanthema to the severe Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DIHS). While studies have identified high-risk human leukocyte antigen (HLA) allotypes, the presence of the HLA allotype at risk is not sufficient to elicit drug hypersensitivity. Recent studies have suggested that insufficient regulation by Tregs may play a role in severe hypersensitivity reactions. Furthermore, immune checkpoint inhibitors, such as anti-CTLA-4 or anti-PD-1, in cancer treatment also induce hypersensitivity reactions including SJS/TEN and DRESS/DIHS. Taken together, mechanisms involving both Tregs as well as coinhibitory and costimulatory receptors may be crucial in the pathogenesis of drug hypersensitivity. In this review, we summarize the currently implicated roles of co-signaling receptors and Tregs in delayed-type drug hypersensitivity in the hope of identifying potential pharmacologic targets.

scholarly journals Amoxicillin induced erythematous maculopapular rashes: a case report

2020 ◽  
Vol 9 (5) ◽  
pp. 806
Author(s):  
Dhakchinamoorthi Krishna Kumar ◽  
Ravichandran Rajganesh ◽  
Dilli Batcha Jaya Shree ◽  
Sam Nikhil Cherian ◽  
Thayub Mohamed
Keyword(s):  
Adverse Drug Reaction Reporting ◽  
Stevens Johnson Syndrome ◽  
Beta Lactam ◽  
Drug Induced ◽  
Drug Eruptions ◽  
Immune Mediated ◽  
Johnson Syndrome ◽  
Lactam Antibiotic ◽  
Cutaneous Reactions ◽  
Maculopapular Rashes

Cutaneous adverse reactions (CAR) can occur with any class of drugs, however more widely caused by various antibiotics. Amoxicillin is a broad-spectrum, bactericidal, beta-lactam antibiotic, widely used for combating various infections. Cutaneous drug eruptions are known to be reported common while using penicillin class of drugs, specifically among children. These immune-mediated bizarre drug eruptions were range from mild to severe drug-induced cutaneous reactions, such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The present case reported with maculopapular, erythematous rashes induced by amoxicillin in a nine-year-old male patient. Amoxicillin was prescribed for his hyperactive respiratory disease and subsequently after three days developed generalized maculopapular erythematous rashes as a result of an antibiotic-induced skin rash. The present case is being reported to add more data, also to emphasize and gather the information for evidence-based practice and to promote efficient pharmacovigilance adverse drug reaction reporting.

An update on HLA alleles as pharmacogenetic markers for antiepileptic drug-induced cutaneous adverse reaction

2019 ◽  
Vol 2 (2) ◽  
pp. 1-17
Author(s):  
Sue-Mian Then ◽  
Azman Ali Raymond
Keyword(s):  
Single Gene ◽  
Hypersensitivity Syndrome ◽  
Allelic Frequency ◽  
Stevens Johnson Syndrome ◽  
Case Control Studies ◽  
Drug Induced ◽  
Hla Alleles ◽  
Exfoliative Dermatitis ◽  
Johnson Syndrome ◽  
Systemic Symptoms

Epilepsy is a common neurological disorder affecting approximately 50 million people worldwide. Antiepileptic drugs (AEDs) are commonly used to treat the disease depending, mainly on the type of seizure. However, the use of AEDs may also lead to cutaneous adverse drug reactions (cADR) such as toxic epidermal necrolysis (TEN), Stevens–Johnson syndrome (SJS), exfoliative dermatitis (ED) and drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS), which are unwanted comorbidities in epilepsy. It was first discovered that the HLA-B*15:02 allele was strongly associated with carbamazepine (CBZ)-induced SJS/TEN among Han Chinese and this led to the discovery of other HLA alleles and cytochrome P450 (CYP) genes that were significantly associated with various AED-induced cADRs across various populations.  This mini review is an update on the latest findings of the involvement of various HLA alleles and CYP alleles in cADRs caused by CBZ, phenytoin (PHT), oxcarbazepine (OXC) and lamitrogine (LTG) in different case-control studies around the world. From our review, we found that CBZ- and PHT-induced cADRs were more commonly reported than the other AEDs. Therefore, there were more robust pharmacogenetics studies related to these AEDs. OXC- and LTG-induced cADRs were less commonly reported, and so more studies are needed to validate the reported association of the newer reported HLA alleles with these AEDs. It is also important to take into account the allelic frequency within a given population before drawing conclusions about the use of these alleles as genetic markers to prevent AED-induced cADR. Overall, the current body of research point to a combination of alleles as a better pharmacogenetic marker compared to the use of a single gene as a genetic marker for AED-induced cADR.

Genetic susceptibilities and prediction modeling of carbamazepine and allopurinol-induced severe cutaneous adverse reactions in Vietnamese

2020 ◽  
Author(s):  
Dinh van Nguyen ◽  
Hieu Chi Chu ◽  
Christopher Vidal ◽  
Richard B Fulton ◽  
Nguyet Nhu Nguyen ◽  
...  
Keyword(s):  
Adverse Reactions ◽  
Surrogate Marker ◽  
Hypersensitivity Syndrome ◽  
Stevens Johnson Syndrome ◽  
Strongly Correlated ◽  
Drug Induced ◽  
Johnson Syndrome ◽  
Severe Cutaneous Adverse Reactions ◽  
Systemic Symptoms ◽  
Cutaneous Adverse Reactions

Aims: To determine genetic susceptibility markers for carbamazepine (CBZ) and allopurinol-induced severe cutaneous adverse reactions (SCARs) in Vietnamese. Methods: A case control study was performed involving 122 patients with CBZ or allopurinol induced SCARs and 120 drug tolerant controls. Results: HLA-B*58:01 was strongly associated with allopurinol-induced SCARs and strongly correlated with SNP rs9263726. HLA-B*15:02 was associated with CBZ-induced Stevens–Johnson syndrome/toxic epidermal necrolysis but not with drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms. No association was found between HLA-A*31:01 and CBZ-induced SCARs. HLA-B*58:01 and rs3909184 allele A with renal insufficiency were shown to increase the risk of allopurinol-induced SCARs. Conclusion: HLA-B*58:01 and HLA-B*15:02 confer susceptibility to allopurinol-induced SCARs and CBZ-induced SJS/TEN in Vietnamese. Single nucleotide polymorphism rs9263726 can be used as a surrogate marker in identifying HLA-B*58:01.

scholarly journals T cell mediated hypersensitivity to previously tolerated iodinated contrast media precipitated by introduction of atezolizumab

2021 ◽  
Vol 9 (5) ◽  
pp. e002521
Author(s):  
Sean Hammond ◽  
Anna Olsson-Brown ◽  
Joshua Gardner ◽  
Paul Thomson ◽  
Serat-E Ali ◽  
...  
Keyword(s):  
Contrast Media ◽  
Adverse Reactions ◽  
Stevens Johnson Syndrome ◽  
Iodinated Contrast ◽  
Immune Mediated ◽  
Johnson Syndrome ◽  
Healthy Donors ◽  
Concomitant Medications

Many adverse reactions associated with immune checkpoint inhibitor (ICI) treatments are immunologically driven and may necessitate discontinuation of the ICI. Herein, we present a patient who had been administered the radio contrast media amidotrizoate multiple times without issue but who then developed a Stevens-Johnson syndrome reaction after coadministration of atezolizumab. Causality was confirmed by a positive re-challenge with amidotrizoate and laboratory investigations that implicated T cells. Importantly, the introduction of atezolizumab appears to have altered the immunologic response to amidotrizoate in terms of the tolerance–elicitation continuum. Proof of concept studies demonstrated enhancement of recall responses to a surrogate antigen panel following in-vitro (healthy donors) and in-vivo (ICI patients) administrations of ICIs. Our findings highlight the importance of considering all concomitant medications in patients on ICIs who develop immune-mediated adverse reactions. In the event of some immune-related adverse reactions, it may be critical to identify the culprit antigen-forming entity that the ICIs have altered the perception of rather than simply attribute causality to the ICI itself in order to optimize both patient safety and treatment of malignancies.

scholarly journals Stevens - Johnson Syndrome and Toxic Epidermal Necrolysis; Extensive Review of Reports of Drug-Induced Etiologies, and Possible Therapeutic Modalities

2018 ◽  
Vol 6 (4) ◽  
pp. 730-738 ◽  
Author(s):  
Adegbenro Omotuyi John Fakoya ◽  
Princess Omenyi ◽  
Precious Anthony ◽  
Favour Anthony ◽  
Precious Etti ◽  
...  
Keyword(s):  
Adverse Drug Reaction ◽  
Toxic Epidermal Necrolysis ◽  
Stevens Johnson Syndrome ◽  
Hypersensitivity Reactions ◽  
Extensive Review ◽  
Drug Induced ◽  
Therapeutic Modalities ◽  
Johnson Syndrome ◽  
Mucous Membranes ◽  
Degrees Of Severity

Stevens - Johnson Syndrome and Toxic Epidermal Necrolysis are adverse hypersensitivity reactions that affect the skin and mucous membranes. They are characterised by erythematous macules and hemorrhagic erosions of the mucous membranes. Epidermal detachments of varying degrees of severity also occur in these conditions. Various aetiologies are associated with these conditions, with adverse drug reaction being the most common. Though the worldwide incidence of these conditions is recorded as low, diverse types of medication are being observed to lead to these conditions. This review compiles information on the details of Stevens-Johnson syndrome and Toxic Epidermal Necrolysis, the pathophysiology, therapeutic management, and largely considers the drug-induced etiologies associated with these conditions.

scholarly journals When steroids are not enough in immune-related hepatitis: current clinical challenges discussed on the basis of a case report

2020 ◽  
Vol 8 (2) ◽  
pp. e001322 ◽  
Author(s):  
Dimitrios C Ziogas ◽  
Aikaterini Gkoufa ◽  
Evangelos Cholongitas ◽  
Panagiotis Diamantopoulos ◽  
Amalia Anastasopoulou ◽  
...  
Keyword(s):  
Immune Checkpoint Inhibitors ◽  
Liver Toxicity ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Phase Iii ◽  
Steroid Resistant ◽  
Immune Mediated ◽  
Cancer Types ◽  
Clinical Considerations ◽  
Steroid Refractory

Unleashing adaptive immunity via immune checkpoint inhibitors (ICPIs) in many cancer types led to durable antitumor responses and prolonged survivals and also added some new immune-related adverse events (irAEs) to the ‘old-fashioned’ safety profile of chemotherapy. Among bowel and endocrine irAEs, immune-mediated hepatotoxicity/hepatitis is a less common and far less well-studied toxicity, which, however, could develop into a serious complication, especially when it becomes persistent or refractory to steroids. Its incidence, onset and severity vary widely, depending on the type of underlying treated cancer, the class, the dosage and the duration of immunotherapy as well as the way of its administration (as a single agent or in combination with other ICPI or chemotherapy). In this study, we present a patient with metastatic melanoma who developed severe steroid-resistant ir-hepatitis after treatment with ipilimumab and required triple concurrent immunosuppression with prednisolone, mycofenolate mofetil and tacrolimus in order for his liver toxicity to be resolved. Intrigued by this case, we focused further on melanoma, as the disease-paradigm of immunotherapy in cancer, reviewed the reported incidence of hepatotoxicity among phase III ICPIs-containing trials on melanoma and discussed the main clinical considerations regarding the diagnosis and the management of persistent/steroid-refractory ir-hepatitis. As more clinical experience is gradually gained on this challenging topic, better answers are provided to questions about the appropriate diagnostic workup, the necessity of liver biopsy, the available immunosuppressive options beyond corticosteroids (their combinations and/or their sequence) as well as the correct decision on withdrawing or resuming immunotherapy. Nonetheless, a thorough multidisciplinary discussion is still required to individualize the overall approach in each case after failure of steroids.

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