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Frontiers in Toxicology 2023Cutaneous hypersensitivity reactions represent the most common manifestation of drug allergy seen in the clinic, with 25% of all adverse drug reactions appearing in the... (Review)
Review
Cutaneous hypersensitivity reactions represent the most common manifestation of drug allergy seen in the clinic, with 25% of all adverse drug reactions appearing in the skin. The severity of cutaneous eruptions can vastly differ depending on the cellular mechanisms involved from a minor, self-resolving maculopapular rash to major, life-threatening pathologies such as the T-cell mediated bullous eruptions, i.e., Stevens Johnson syndrome/toxic epidermal necrolysis. It remains a significant question as to why these reactions are so frequently associated with the skin and what factors polarise these reactions towards more serious disease states. The barrier function which the skin performs means it is constantly subject to a barrage of danger signals, creating an environment that favors elicitation. Therefore, a critical question is what drives the expansion of cutaneous lymphocyte antigen positive, skin homing, T-cell sub-populations in draining lymph nodes. One answer could be the heterologous immunity hypothesis whereby tissue resident memory T-cells that express T-cell receptors (TCRs) for pathogen derived antigens cross-react with drug antigen. A significant amount of research has been conducted on skin immunity in the context of contact allergy and the role of tissue specific antigen presenting cells in presenting drug antigen to T-cells, but it is unclear how this relates to epitopes derived from circulation. Studies have shown that the skin is a metabolically active organ, capable of generating reactive drug metabolites. However, we know that drug antigens are displayed systemically so what factors permit tolerance in one part of the body, but reactivity in the skin. Most adverse drug reactions are mild, and skin eruptions tend to be visible to the patient, whereas minor organ injury such as transient transaminase elevation is often not apparent. Systemic hypersensitivity reactions tend to have early cutaneous manifestations, the progression of which is halted by early diagnosis and treatment. It is apparent that the preference for cutaneous involvement of drug hypersensitivity reactions is multi-faceted, therefore this review aims to abridge the findings from literature on the current state of the field and provide insight into the cellular and metabolic mechanisms which may contribute to severe cutaneous adverse reactions.
PubMed: 37795379
DOI: 10.3389/ftox.2023.1268107 -
The American Journal of Case Reports Oct 2023BACKGROUND Different medication classes have been implicated in cutaneous eruptions that may lead to significant morbidity and mortality. In drug reaction with...
BACKGROUND Different medication classes have been implicated in cutaneous eruptions that may lead to significant morbidity and mortality. In drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, the patient may initially present with a cutaneous eruption and hematologic abnormalities which can lead to acute visceral organ involvement if the offending drug is not discontinued. There is also a potential for long-term sequelae such as autoimmune disorders. CASE REPORT A 47-year-old woman with an unknown past medical history and no known drug allergies was admitted to the Behavioral Health Unit, where she was diagnosed with disorganized schizophrenia and started on olanzapine. On day 17 of admission, she developed a diffuse, macular, and erythematous rash on her abdomen, which spread to involve over 50% of her total body surface area. Occipital and posterior auricular lymphadenopathy was present. The patient was treated with prednisone and diphenhydramine. Olanzapine was subsequently discontinued and the patient's rash cleared up. CONCLUSIONS This case report highlights the challenges in diagnosing DRESS syndrome and the potential for antipsychotics to cause DRESS syndrome. DRESS syndrome is a clinical diagnosis augmented by laboratory tests with a wide range of patient presentations. Although there are probability criteria to assist with diagnosis, not all patients will fall exactly into these criteria, which can lead to missed diagnoses and poor patient outcomes. A challenge with DRESS syndrome diagnosis is the latency period between drug initiation and cutaneous eruption. Thus, in differential diagnoses for skin eruptions, temporal associations (minutes, days, weeks) with medications are crucial.
Topics: Female; Humans; Middle Aged; Drug Hypersensitivity Syndrome; Olanzapine; Exanthema; Eosinophilia; Disease Progression
PubMed: 37777823
DOI: 10.12659/AJCR.941379 -
Bone May 2024Osteogenesis imperfecta (OI) is a congenital disease comprising a heterogeneous group of inherited connective tissue disorders. The main treatment in children is...
INTRODUCTION
Osteogenesis imperfecta (OI) is a congenital disease comprising a heterogeneous group of inherited connective tissue disorders. The main treatment in children is bisphosphonate therapy. Previous animal studies have shown that bisphosphonates delay tooth eruption. The aim of this study is to determine whether patients with OI treated with pamidronate and/or zoledronic acid have a delayed eruption age compared to a control group of healthy children.
METHODS
An ambispective longitudinal cohort study evaluating the age of eruption of the first stage mixed dentition in a group of children with OI (n = 37) all treated with intravenous bisphosphonates compared with a group of healthy children (n = 89). Within the study group, the correlation (Pearson correlation test) between the type of medication administered (pamidronate and/or zoledronic acid) and the chronology of tooth eruption is established, as well as the relationship between the amount of cumulative dose received and tooth eruption.
RESULTS
The age of eruption of the study group was significantly delayed compared to the age of eruption of the control group for molars and lateral incisors (p < 0.05). Patients who received higher cumulative doses had a delayed eruption age compared to those with lower cumulative doses (p < 0.05). There is a high positive correlation between age of delayed tooth eruption and Zoledronic acid administration.
CONCLUSION
Patients with OI have a delayed eruption of the 1st stage mixed dentition compared to a control group of healthy children. This delayed eruption is directly related to the cumulative dose of bisphosphonates and the administration of zoledronic ac.
Topics: Child; Animals; Humans; Pamidronate; Zoledronic Acid; Osteogenesis Imperfecta; Tooth Eruption; Bone Density Conservation Agents; Longitudinal Studies; Diphosphonates; Bone Density
PubMed: 38458305
DOI: 10.1016/j.bone.2024.117069 -
Frontiers in Immunology 2023Inflammatory bowel disease (IBD) is a chronic inflammatory disease typically involving the gastrointestinal tract but not limited to it. IBD can be subdivided into... (Review)
Review
Inflammatory bowel disease (IBD) is a chronic inflammatory disease typically involving the gastrointestinal tract but not limited to it. IBD can be subdivided into Crohn's disease (CD) and ulcerative colitis (UC). Extraintestinal manifestations (EIMs) are observed in up to 47% of patients with IBD, with the most frequent reports of cutaneous manifestations. Among these, pyoderma gangrenosum (PG) and erythema nodosum (EN) are the two most common skin manifestations in IBD, and both are immune-related inflammatory skin diseases. The presence of cutaneous EIMs may either be concordant with intestinal disease activity or have an independent course. Despite some progress in research on EIMs, for instance, ectopic expression of gut-specific mucosal address cell adhesion molecule-1 (MAdCAM-1) and chemokine CCL25 on the vascular endothelium of the portal tract have been demonstrated in IBD-related primary sclerosing cholangitis (PSC), little is understood about the potential pathophysiological associations between IBD and cutaneous EIMs. Whether cutaneous EIMs are inflammatory events with a commonly shared genetic background or environmental risk factors with IBD but independent of IBD or are the result of an extraintestinal extension of intestinal inflammation, remains unclear. The review aims to provide an overview of the two most representative cutaneous manifestations of IBD, describe IBD's epidemiology, clinical characteristics, and histology, and discuss the immunopathophysiology and existing treatment strategies with biologic agents, with a focus on the potential pathophysiological associations between IBD and cutaneous EIMs.
Topics: Humans; Inflammatory Bowel Diseases; Crohn Disease; Colitis, Ulcerative; Pyoderma Gangrenosum; Erythema Nodosum
PubMed: 37954590
DOI: 10.3389/fimmu.2023.1234535 -
Allergy Nov 2023Allopurinol (ALP) is a successful drug used in the treatment of gout. However, this drug has been implicated in hypersensitivity reactions that can cause severe to...
Allopurinol (ALP) is a successful drug used in the treatment of gout. However, this drug has been implicated in hypersensitivity reactions that can cause severe to life-threatening reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Individuals who carry the human leukocyte antigen (HLA)-B*58:01 allotype are at higher risk of experiencing a hypersensitivity reaction (odds ratios ranging from 5.62 to 580.3 for mild to severe reactions, respectively). In addition to the parent drug, the metabolite oxypurinol (OXP) is implicated in triggering T cell-mediated immunopathology via a labile interaction with HLA-B*58:01. To date, there has been limited information regarding the T-cell receptor (TCR) repertoire usage of reactive T cells in patients with ALP-induced SJS or TEN and, in particular, there are no reports examining paired αβTCRs. Here, using in vitro drug-treated PBMCs isolated from both resolved ALP-induced SJS/TEN cases and drug-naïve healthy donors, we show that OXP is the driver of CD8 T cell-mediated responses and that drug-exposed memory T cells can exhibit a proinflammatory immunophenotype similar to T cells described during active disease. Furthermore, this response supported the pharmacological interaction with immune receptors (p-i) concept by showcasing (i) the labile metabolite interaction with peptide/HLA complexes, (ii) immunogenic complex formation at the cell surface, and (iii) lack of requirement for antigen processing to elicit drug-induced T cell responsiveness. Examination of paired OXP-induced αβTCR repertoires highlighted an oligoclonal and private clonotypic profile in both resolved ALP-induced SJS/TEN cases and drug-naïve healthy donors.
Topics: Humans; Allopurinol; Oxypurinol; Stevens-Johnson Syndrome; CD8-Positive T-Lymphocytes; HLA-B Antigens
PubMed: 37452515
DOI: 10.1111/all.15814 -
Frontiers in Immunology 2024Idiopathic granulomatous mastitis (IGM) is a noncancerous, chronic inflammatory disorder of breast with unknown causes, posing significant challenges to the quality of... (Review)
Review
Idiopathic granulomatous mastitis (IGM) is a noncancerous, chronic inflammatory disorder of breast with unknown causes, posing significant challenges to the quality of life due to its high refractoriness and local aggressiveness. The typical symptoms of this disease involve skin redness, a firm and tender breast mass and mastalgia; others may include swelling, fistula, abscess (often without fever), nipple retraction, and peau d'orange appearance. IGM often mimics breast abscesses or malignancies, particularly inflammatory breast cancer, and is characterized by absent standardized treatment options, inconsistent patient response and unknown mechanism. Definite diagnosis of this disease relies on core needle biopsy and histopathological examination. The prevailing etiological theory suggests that IGM is an autoimmune disease, as some patients respond well to steroid treatment. Additionally, the presence of concurrent erythema nodosum or other autoimmune conditions supports the autoimmune nature of the disease. Based on current knowledge, this review aims to elucidate the autoimmune-favored features of IGM and explore its potential etiologies. Furthermore, we discuss the immune-mediated pathogenesis of IGM using existing research and propose immunotherapeutic strategies for managing this condition.
Topics: Female; Humans; Granulomatous Mastitis; Quality of Life; Fever; Erythema Nodosum; Immunoglobulin M
PubMed: 38529282
DOI: 10.3389/fimmu.2024.1295759 -
Discoveries (Craiova, Romania) 2023Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug induced hypersensitivity (DiHS) is a rare, however a severe hypersensitivity reaction...
Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug induced hypersensitivity (DiHS) is a rare, however a severe hypersensitivity reaction with a mortality rate of up to 10%, accounting for 10 to 20% of all cutaneous drug reactions in hospitalized patients. The clinical features of DRESS/DiHS may be challenging to recognize and diagnose, since they are delayed, stepwise, and heterogeneous. The classic presentation of DRRSS/DiHS involves a combination of cutaneous, hematologic, and internal organ involvement with a 2 to 8 weeks latency between drug exposure and the onset of symptoms. Finding the culprit drug in our case was difficult as the patient was taking multiple antibiotics. Drugs such as vancomycin and cefepime used before the rash outbreak for post-reconstructive surgery for left toal knee arthroplasty (TKA) approximately four weeks before the onset of the rash are likely offending agents. This patient also had multi-visceral involvement with eosinophilia and systemic symptoms. The current treatment guidelines for DRESS/DiHS are primarily based on expert opinion, as no randomized control trials exist. After the prompt withdrawal of the offending drug, systemic corticosteroids seem to have shown the best outcome for patients. Delaying discontinuing offending medications and initiating corticosteroid treatment may lead to poor results. The present case emphasizes that the close observation of patients with drug eruption induced by antibiotics is imperative. Primary care team should be able to promptly diagnose patients with DRESS syndrome, detect causative drug, and play a crucial role in the timely evaluation and treatment to reduce mortality rate. The later phase disease relapse or autoimmune complications may occur up to 5 years following the initial presentation. Therefore, we advised the patient to have an outpatient follow up for appropriate testing, including but not limited to genetic susceptibility due to the high risk of relapse and emerging risk of autoimmune diseases.
PubMed: 37680345
DOI: 10.15190/d.2023.9 -
Drugs Jan 2024Generalized pustular psoriasis (GPP) is a rare but severe skin inflammatory disorder characterized by the eruption of widespread sterile neutrophilic pustules, often... (Review)
Review
Generalized pustular psoriasis (GPP) is a rare but severe skin inflammatory disorder characterized by the eruption of widespread sterile neutrophilic pustules, often accompanied by systemic inflammation. Given its life-threatening potential, GPP requires prompt accurate diagnosis and effective treatment, but its rarity and relapsing-remitting nature pose challenges in performing large-scale randomized controlled clinical trials. Established international guidelines are currently lacking and management guidance often follows that for plaque psoriasis. However, while it can co-exist with plaque psoriasis and has traditionally been classified as a most severe form of psoriasis, GPP is now recognized as a distinct entity, with its own clinicopathological, autoinflammatory, immunologic and genetic features. Research conducted over the past decade revealed that an imbalance of interleukin (IL)-36 signaling favoring the proinflammatory activity is the central driver of the pathogenesis of GPP, thereby laying the groundwork for the development of targeted therapies for the disease. This article reviews the evidence thus far on spesolimab, a selective humanized antibody against the IL-36 receptor that was recently licensed in Europe and the United States for the treatment of GPP flares in adults. In phase II, randomized controlled clinical trials, spesolimab led to rapid and effective skin clearance in patients experiencing a GPP flare and demonstrated superiority to placebo in preventing flares for up to 48 weeks with maintenance treatment, with reassuring safety and tolerability profiles. Spesolimab is considered to be a first-in-class medication establishing itself as the standard of care for the treatment of GPP flares, thus changing the paradigm of the management of GPP to a new era of scientifically- and evidence-based targeted therapy for this distinctive disease.
Topics: Adult; Humans; Psoriasis; Skin; Antibodies, Monoclonal, Humanized; Treatment Outcome; Skin Diseases, Vesiculobullous
PubMed: 38114719
DOI: 10.1007/s40265-023-01988-0 -
Acta Dermato-venereologica Dec 2023
Topics: Humans; Everolimus; Drug Eruptions; Exanthema
PubMed: 38112207
DOI: 10.2340/actadv.v103.12197 -
International Journal of Molecular... Jul 2023Psoriasis is a chronic inflammatory skin disease characterized by cutaneous eruptions and pruritus. Because the genetic backgrounds of psoriasis are only partially...
Psoriasis is a chronic inflammatory skin disease characterized by cutaneous eruptions and pruritus. Because the genetic backgrounds of psoriasis are only partially revealed, an integrative and rigorous study is necessary. We conducted a transcriptome-wide association study (TWAS) with the new Genotype-Tissue Expression version 8 reference panels, including some tissue and multi-tissue panels that were not used previously. We performed tissue-specific heritability analyses on genome-wide association study data to prioritize the tissue panels for TWAS analysis. TWAS and colocalization (COLOC) analyses were performed with eight tissues from the single-tissue panels and the multi-tissue panels of context-specific genetics (CONTENT) to increase tissue specificity and statistical power. From TWAS, we identified the significant associations of 101 genes in the single-tissue panels and 64 genes in the multi-tissue panels, of which 26 genes were replicated in the COLOC. Functional annotation and network analyses identified that the genes were associated with psoriasis and/or immune responses. We also suggested drug candidates that interact with jointly significant genes through a conditional and joint analysis. Together, our findings may contribute to revealing the underlying genetic mechanisms and provide new insights into treatments for psoriasis.
Topics: Humans; Transcriptome; Genome-Wide Association Study; Gene Expression Profiling; Organ Specificity; Psoriasis; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide
PubMed: 37511476
DOI: 10.3390/ijms241411717