Materiały źródłowe

• #1 Erythema Multiforme – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK470259/

  Erythema multiforme is an immune-mediated hypersensitivity reaction affecting both the skin and mucous membranes, characterized by the appearance of macular, papular, or bullous lesions that often form distinct „target lesions,” primarily found on the extremities. […] The exact pathophysiology behind erythema multiforme is unknown. Most data has been collected to study the underlying pathogenesis behind HSV-associated erythema multiforme. The mechanism by which HSV causes erythema multiforme is thought to involve a cell-mediated immune response against viral antigens in skin lesions. […] In the development of mucocutaneous lesions of HSV-associated erythema multiforme, an interplay between cluster of differentiation (CD)34+ Langerhans cell precursors, viral DNA fragments, epidermal keratinocytes, HSV-specific CD4 TH1 cells, interferon (IFN)-, and autoreactive T cells is observed. These interactions lead to epidermal damage and the characteristic inflammatory infiltration of cutaneous lesions of erythema multiforme.

• #2 Erythema Multiforme: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1122915-questions-and-answers

  The pathophysiology of EM has not been fully elucidated, but it is probably immunologically mediated and appears to involve a hypersensitivity reaction that can be triggered by a variety of stimuli (particularly bacterial, viral, or chemical). […] Cell-mediated immunity appears to be responsible for the destruction of epithelial cells. Early in the disease process, the epidermis becomes infiltrated with CD8 T lymphocytes and macrophages, whereas the dermis displays a slight influx of CD4 lymphocytes. These immunologically active cells are not present in sufficient numbers to be directly responsible for epithelial cell death. Instead, they release diffusable cytokines, which mediate the inflammatory reaction and resultant apoptosis of epithelial cells. […] In some patients, circulating T cells transiently (for 30 d) demonstrate a T-helper cell type 1 (Th1) cytokine response (interferon [IFN] gamma, tumor necrosis factor [TNF]-, interleukin [IL]-2). Results of immunohistochemical analysis have also shown lesion blister fluid to contain TNF, an important proinflammatory cytokine.

• #3 Erythema multiforme: Pathogenesis, clinical features, and diagnosis – UpToDate

  http://www.uptodate.com/contents/pathogenesis-clinical-features-and-diagnosis-of-erythema-multiforme

  Erythema multiforme (EM) is an acute, immune-mediated condition characterized by the appearance of distinctive target-like lesions on the skin. A variety of factors have been implicated in the pathogenesis of EM. The disorder is most commonly induced by infection, with herpes simplex virus being the most frequent precipitator. […] However, in a minority of cases, the disease recurs frequently over the course of years. […] There is suggestive evidence that EM with mucous membrane involvement and SJS are different diseases with distinct causes.

• #4 Understanding the pathogenesis of HSV-associated erythema multiforme – PubMed

  https://pubmed.ncbi.nlm.nih.gov/9812024/

  Erythema multiforme (EM) is a polymorphic, often recurring eruption caused by exposure to medication or various infections, notably herpes simplex virus (HSV). […] Understanding the pathogenesis of HSV-associated EM (HAEM) is essential for patient management. We suggest that HAEM results from the combination of viropathic effects mediated by HSV proteins, notably DNA polymerase (Pol), and an immunological reaction to viral antigens. Presumably, viral DNA and proteins ingested by macrophages at HSV lesion sites undergo fragmentation and processing for presentation to T cells with HSV memory. HSV DNA is deposited on the skin, where it is expressed. Activated T cells are recruited to the skin site of Pol expression, directly or indirectly resulting in the generation of an inflammatory cascade. Factors potentially involved in the incidence of recurrences, lesion severity and anatomical localization include the identity of the deposited HSV genes, cutaneous capillary size, degree of vasoconstriction and ambient temperature. Evidence in support of this interpretation is reviewed.

• #5 Erythema multiforme – DermNet

  https://dermnetnz.org/topics/erythema-multiforme

  Erythema multiforme is an immune-mediated, typically self-limiting, mucocutaneous condition characterised by target lesions. […] In most cases, erythema multiforme is precipitated by herpes simplex virus (HSV) infection; alternative triggers include other infections, medications, and vaccinations. […] Most research on the mechanism of disease has focused on the herpes-associated presentation. The herpes virus is phagocytosed by mononuclear cells which express cutaneous lymphocyte antigen (a skin-homing receptor). Engulfed viral DNA is then transferred to the epidermis and into keratinocytes. Within the keratinocyte layer, expression of viral DNA fragments induces a cell-mediated immune response, including the production of interferon- which upregulates the inflammatory process.

• #6 Erythema Multiforme | AAFP

  https://www.aafp.org/pubs/afp/issues/2006/1201/p1883.html

  Erythema multiforme is a skin condition considered to be a hypersensitivity reaction to infections or drugs. […] The pathogenesis of herpes-associated erythema multiforme has been well studied and is consistent with a delayed-type hypersensitivity reaction. […] The disease begins with the transport of viral DNA fragments to distant skin sites by peripheral blood mononuclear cells. HSV genes within DNA fragments are expressed on keratinocytes, leading to the recruitment of HSV-specific CD4+ TH1 cells (helper T cells involved in cell-mediated immunity). The CD4+ cells respond to viral antigens with production of interferon-, initiating an inflammatory cascade. […] Drug-associated erythema multiforme lesions test positive for tumor necrosis factor and not interferon- as in herpes-associated erythema multiforme lesions, suggesting a varying mechanism.

• #7 Erythema Multiforme: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1122915-questions-and-answers

  Other evidence supports the hypothesis that the disease is the result of cell-mediated immune reactions. Individuals possessing human leukocyte antigen (HLA)-B12 are three times more likely to develop this disorder. The classic timing for a primary cell-mediated immune reaction is 9-14 days after the initiation of the offending drug. In recurrent exposure, the reaction occurs within several hours to 1-2 days, which is consistent with the timing of a secondary cell-mediated immune response. […] HSV is a major cause of EM; in fact, recent or recurrent herpes has been reported as the principal risk factor for EM. Herpes-associated EM (HAEM) appears to represent the result of a cell-mediated immune reaction associated with HSV antigen. The immunologic reaction affects HSV-expressing keratinocytes. Cytotoxic effector cells, CD8+ T lymphocytes in the epidermis, induce apoptosis of scattered keratinocytes and lead to satellite cell necrosis. Neighboring epidermal cells are HLA-DR positive.

• #8 Erythema multiforme – Dermatology Advisor

  https://www.dermatologyadvisor.com/home/decision-support-in-medicine/dermatology/erythema-multiforme-3/

  Erythema multiforme (EM) is an acute, immune-mediated, self-limited mucocutaneous condition characterized by distinctive target lesions with concentric color variations. […] Much of the data exploring the pathogenesis of EM has been derived from studies investigating HSV-associated EM. The presence of HSV DNA has been demonstrated in skin biopsy specimens from patients with EM using polymerase chain reaction (PCR) testing. The development of EM secondary to HSV infection is postulated to involve a cell-mediated immune process directed against viral antigens deposited in lesional skin. A proposed mechanism for the development of EM lesions in the setting of HSV infection is as follows: […] Virus released into the blood during reactivation of HSV infection is phagocytosed by circulating peripheral blood mononuclear cells, particularly CD34+ Langerhans cell precursors.

• #9

  https://journals.lww.com/cocd/fulltext/2011/02040/herpes_associated_erythema_multiforme.23.aspx

  Erythema multiforme is an acute and a self-limiting mucocutaneous hypersensitivity reaction triggered by certain infections and medications. […] One of the most common predisposing factors for erythema multiforme is infection with herpes simplex virus. […] Herpes associated erythema multiforme (HAEM) is an acute exudative dermatic and mucosal disease caused by the infecting herpes simplex virus. […] Several studies have demonstrated that the pathogenesis of HAEM is consistent with a delayed hypersensitivity reaction. […] The disease begins with the transport of HSV DNA fragments by circulating peripheral blood mononuclear CD34+ cells (Langerhans cell precursors) to keratinocytes, which leads to the recruitment of HSV-specific CD4+ TH1 cells. […] The inflammatory cascade is initiated by interferon- (IFN-), which is released from the CD4+ cells in response to viral antigens, and immunomediated epidermal damage subsequently begins.

• #10 Erythema multiforme – Dermatology Advisor

  https://www.dermatologyadvisor.com/home/decision-support-in-medicine/dermatology/erythema-multiforme-3/

  Langerhans cells containing HSV travel to the epidermis, where they transfer viral DNA fragments (including those that encode viral DNA polymerase) to epidermal keratinocytes. The migration of Langerhans cells to the epidermis is facilitated by virus-induced upregulation of E-cadherin expression on Langerhans cells and the presence of adhesion molecules (ICAM-1) on microvascular endothelial cells. […] Expression of HSV genes encoded within DNA fragments deposited on the skin leads to recruitment of HSV-specific CD4+ Th1 cells that produce interferon (IFN) gamma in response to viral antigens. […] The release of IFN-gamma initiates an inflammatory cascade that promotes the lysis of HSV-infected keratinocytes and the recruitment of autoreactive T-cells, leading to the epidermal damage and the inflammatory infiltrate that characterize cutaneous lesions of EM.

• #11

  https://austinpublishinggroup.com/dental-disorders/fulltext/jdod-v2-id1027.php

  Erythema multiforme is an acute vesiculobullous, mucocutaneous disease that most often occurs concomitantly with exposure to infections or medications most often. […] EM has often been linked to a subsequent exposure to the Herpes Simplex Virus (HSV-1) and is thought to be an immune mediated complication of the viral infection. […] One proposed pathogenesis involves Langerhans cells infected with HSV traveling to the epidermis and transferring viral DNA fragments to epidermal Keratinocytes. […] HSV genes expressed in the skin leads to recruitment of HSV specific CD4+ T helper 1 cell that produce IFN (interferon) gamma in response to viral antigens. […] Release of IFN gamma initiates an inflammatory cascade that leads to epidermal damage and the inflammatory infiltrate that characterize cutaneous lesions, i.e.; macular, papular, urticarial, bullous, or purpuric symmetric lesions of EM on extensor surfaces as well as oral mucous membrane involvement. […] Target lesions with clear centers and concentric erythematous rings may also be observed presenting within a wide spectrum of severity.

• #12 Treatment of Drug-Induced Erythema Multiforme: Case Report

  https://www.journalomp.org/journal/view.html?doi=10.14476/jomp.2019.44.4.183

  Erythema multiforme (EM) is an inflammatory immune-mediated mucosal disease. EM is classified as EM minor or EM major, depending on the severity of symptoms. […] EM is a mucocutaneous condition characterized by blistering, ulcerative, and symmetrically distributed targets or iris lesions at the extremities and trunk. […] The pathogenesis pathway of EM is based on the research studies of HSV associated EM (HAEM). Autoreactive T-cell triggers by viral antigen-positive cells containing the HSV-DNA polymerase gene have been suggested to play an important role. EM is initiated by the expression of HSV-DNA fragments, probably transported and produced by peripheral blood mononuclear cell, mainly macrophages and CD34+ Langerhans cell precursors, possibly by the vascular pathway. The inflammatory responses are initiated by viral gene expression in the skin and recruitment of HSV-specific CD4+ Th1 cells. Interferon- (IFN-) generated by this reaction upregulates cytokines and chemokines to amplify skin inflammatory events through increased sequestration of circulating leukocytes, monocytes and NK cells and recruitment of autoreactive T-cells to the epidermis.

• #13 Erythema multiforme – Wikipedia

  https://en.wikipedia.org/wiki/Erythema_multiforme

  Erythema multiforme (EM) is an immune-mediated inflammatory skin condition associated with several viral infections, that appears with red patches evolving into target lesions, typically on both hands. […] It is a type IV hypersensitivity reaction in which T-lymphocytes target skin keratinocytes due to the presence of specific proteins that resemble antigens of HSV, Mycoplasma, or other pathogens and foreign substances. […] The pathogenic immune response in EM involves both CD4+ helper T cells and CD8+ cytotoxic T cells, which orchestrate a type IV hypersensitivity reaction. Upon activation, these T cells release proinflammatory cytokines such as IFN- and TNF-. Despite the known association with IFN-, erythema multiforme is not considered a humorally-mediated autoimmune reaction. […] 100% of HSV-associated EM cases are found to have DNA for viral-type DNA polymerase (Pol) gene within keratinocytes. Despite this association, an active and infectious form of HSV has never been found in a patient suffering from EM, indicating that it is exclusively a post-viral hypersensitivity syndrome in these patients, rather than a symptom of the virus itself. The viral DNA polymerase protein is synthesized by basal keratinocytes, which then present the protein or fragments of its DNA to immune cells via MHC I. The resulting immune reaction results in the creation of CD8+ T-cells specific to HSV, which then induce a strong inflammatory response, recruiting other immune cells to places where infected keratinocytes are identified.

• #14 Erythema Multiforme – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK470259/

  A slight difference in drug-induced erythema multiforme is the presence of tumor necrosis factor (TNF)-alpha instead of IFN-gamma, making the earliest pathological feature the necrosis of keratinocytes. […] Genetic susceptibility also plays a role in the development of erythema multiforme. Recurrent erythema multiforme has been found to have an association with human leukocyte antigen (HLA) types A33, B35, DR4, DQB1*03:01, DQ3, and DR53. […] Study results have demonstrated the presence of HSV DNA by a polymerase chain reaction in acute or sequellae erythema multiforme lesions. The predisposing factors are unknown. HLA-DQ3 is reported to be associated with postherpetic erythema multiforme and has been suggested as an additional diagnostic marker. Other human leukocyte antigen groups have also been reported as markers of recurrent erythema multiforme.

• #15 Treatment of Drug-Induced Erythema Multiforme: Case Report

  https://www.journalomp.org/journal/view.html?doi=10.14476/jomp.2019.44.4.183

  In drug-induced EM (DIEM), the reactive metabolites of the initiating drug are thought to induce disease, but the mechanism of injury is variable and unlike HAEM, does not appear to be the result of the delayed-type hypersensitivity reaction. […] In contrast, TNF- was not detected in HAEM and it was suggested that it can be used as a laboratory test to distinguish drug-induced lesions from HAEM. […] The mechanism may play an important role in mild forms of DIEM.

• #16 Erythema multiforme: histological features and mechanisms

  https://dermnetnz.org/topics/erythema-multiforme-histological-features-and-mechanisms

  Herpes simplex (HSV)-associated EM is a delayed type hypersensitivity (DTH) reaction that develops in response to infection in predisposed individuals. The process has been well studied and involves several steps. […] Drug-induced EM involves a different mechanism with elevated tumour necrosis factor alpha rather than gamma-interferon and CD8+ cells and not CD4+ T helper cells. […] Mechanisms EM involves CD4+ T cells and gamma-interferon whereas SJS/TEN involves Fas ligand, tumour necrosis factor alpha and CD8+ cells.

• #17 Erythema multiforme, Steven-Johnson syndrome and Toxic Epidermal Necrolysis | PPT

  https://www.slideshare.net/slideshow/erythema-multiforme-stevenjohnson-syndrome-and-toxic-epidermal-necrolysis/116506244

  Pathogenesis of Drug induced Erythema Multiforme Involves expression of tumor necrosis factor alpha (TNF- ) and not interferon- suggesting a varying mechanism. The disease process also often involves an abnormal metabolism of a responsible drugs. Drug metabolism is directed toward the alternative pathway of oxidation by the cytochrome P-450 enzymes, resulting in increased production of reactive and potentially toxic metabolites. Affected individuals have a defect in the ability to detoxify these reactive metabolites, which may bind covalently to proteins on the surface of epithelial cells. This may then induce the immune response, leading to the severe skin reaction Much of the tissue damage in drug-induced lesions appears to be due to apoptosis by to activation of cytotoxic T cells and NK cells.

• #18 Erythema Multiforme: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1122915-questions-and-answers

  A relationship exists between HLA types A33, B35, B62 (B15), DR4, DQB1*0301, DQ3, and DR53 and recurrent EM. In particular, HLA-DQ3 is specifically related to recurrent EM and may be a helpful marker for distinguishing HAEM from other cutaneous diseases. […] The disease process also often involves an abnormal metabolism of a responsible drug. As noted above, the keratinocyte is the ultimate target of this disease process, with keratinocyte necrosis being the earliest pathologic finding. […] Patients frequently display an altered metabolism of the responsible drug and are considered to be slow acetylators, both genotypically and phenotypically. This means that an increased proportion of drug metabolism is directed toward the alternative pathway of oxidation by the cytochrome P-450 system, resulting in increased production of reactive and potentially toxic metabolites. Affected individuals have a defect in the ability to detoxify these reactive metabolites, which may then behave as haptens by binding covalently to proteins on the surface of epithelial cells. This may then induce the immune response, leading to the severe skin reaction.

• #19 Pulsenotes | Erythema multiforme

  https://app.pulsenotes.com/medicine/dermatology/notes/erythema-multiforme

  Erythema multiforme is considered a cell-mediated (type IV) hypersensitivity reaction. […] EM is considered a type IV hypersensitivity reaction, which is an abnormal cell-mediated reaction initiated by T cells. […] The exact mechanism leading to EM is incompletely understood, but it appears to be an abnormal immune reaction to a drug metabolite or viral antigen that becomes expressed by keratinocytes within the skin. This leads to a localised immune reaction within the epidermis that occurs days to weeks after the initial infection. There is evidence for genetic susceptibility with some human leucocyte antigens (HLA) shown to increase the risk of developing EM. HLA genes encode proteins that are involved in antigen processing by the immune system to help immune recognition between self and foreign substances. There are many different forms (known as alleles) of these genes with some increasing the risk of autoimmune reactions.

• #20 Erythema multiforme: a case series and review of literature – MedCrave online

  https://medcraveonline.com/OAJTMR/erythema-multiforme-a-case-series-and-review-of-literature.html

  In HSV associated EM, HSVDNA fragments in the skin or mucosa trigger the disease. […] CD4+ T helper 1 (Th1) lymphocytes, produce IFN-, characteristic of a delayed type hypersensitivity reaction. […] Unlike virus-induced EM, mechanism of damage in drug-induced EM does not appear to be a result of the delayed type of hypersensitivity. […] In drug-induced EM, reactive metabolites of the particular drug induce the disease and keratinocyte apoptosis is induced by tumor necrosis factor alpha (TNF-) released from keratinocytes, macrophages, and monocytes leading to tissue damage. […] In TEN and SJS, the Fas/FasL apoptotic pathway is thought to be implicated in tissue damage. […] However, there is also some evidence that shows the direct activation of cytotoxic T cells, leading to keratinocyte cell death in TEN, in the presence of the precipitating drug.

• #21 Erythema multiforme: a case series and review of literature – MedCrave online

  https://medcraveonline.com/OAJTMR/erythema-multiforme-a-case-series-and-review-of-literature.html

  Auto antibodies against desmoplakins I II and anti-epidermal auto antibodies have been reported in a subset of EM patients. […] Currently, EM, SJS, and TEN are not considered to be variants of the same immune disorder, but SJS and TEN are probably the variants, of a single disease spectrum differing only in the area of involvement and the severity of systemic findings.

• #22 Erythema multiforme, Steven-Johnson syndrome and Toxic Epidermal Necrolysis | PPT

  https://www.slideshare.net/slideshow/erythema-multiforme-stevenjohnson-syndrome-and-toxic-epidermal-necrolysis/116506244

  Erythema Multiforme is an acute self limiting dermatitis characterized by distinctive clinical eruption manifested as the iris or target lesion. […] It exhibits the spectrum of severity ranging from Erthema Multiforme Minor Erythema Multiforme Major Steven-Johnson Syndrome (Traditionally considered to be synonymous with EM major) Toxic Epidermal Necrolysis (TEN) Currently, EM major and minor are considered distinctly different process form the latter two conditions. […] Not fully understood but is probably an immunologically mediated process. May be precipitated by some bacterial, fungal and viral infections: Herpes Simplex Virus infections (HSV-1 HSV-2) trigger EM- minor in almost 100% of cases Besides herpetic infection (55%), Mycoplasma Pneumoniae appears to be common cause in EM Major and in Children. Some other viruses like CMV, VZV and HIV have been frequently associated with EM.

• #23 Erythema Multiforme (Clinical) | Concise Medical Knowledge

  https://www.lecturio.com/concepts/erythema-multiforme-clinical/

  Erythema multiforme (EM) is a cell-mediated immune reaction (type IV reaction) directed against the antigens of the offending agent, which deposit in the skin. […] A significant number of cases are idiopathic; however, there are many etiologies that may be identified. […] Erythema multiforme is classified based on the presence of mucosal lesions and systemic symptoms into EM minor and major. […] Erythema multiforme is often self-limiting and does not require treatment. […] The majority of cases will require only supportive therapy.

• #24 EBV-induced erythema multiforme: a case report | Allergologia et Immunopathologia

  https://www.elsevier.es/es-revista-allergologia-et-immunopathologia-105-articulo-ebv-induced-erythema-multiforme-case-report-S0301054610002818

  Erythema multiforme (EM) is a type of dermatosis that occurs as a hypersensitivity reaction in response to medications or infections. […] Erythema multiforme is acute, usually self-limited and at times life threatening dermatosis which may present with multiforme lesions. They include multiple, symmetric, persistent macules, papules, vesicles, and bullae. What has become pathognomonic for erythema multiforme is the so-called iris or targetoid lesions, representing plaques of central duskiness in expanding erythematous macules and papules. […] In EM, aetiology mostly consists of herpes simplex and mycoplasma. Medications and some vaccines also participate in the aetiology, but in half of the cases an underlying cause cannot be found. […] Although it is not certain, the pathophysiological mechanism for the EBV-related EM is thought to be immunocomplex mediated.

• #25 Erythema multiforme: distinguishing hypersensitivity reactions, drug allergy, or herpes simplex infection

  https://www.explorationpub.com/Journals/ei/Article/1003188

  Consequently, clinical presentations vary between herpes virus-induced and drug-induced reactions, with distinct lesion distribution and mucosal involvement patterns. […] In HSV-triggered EM, typically target lesions predilection sites are in the acral extremities, while mucosal lesions are absent or minimal, with no or mild prodromal signs/symptoms. […] In contrast, drug-triggered EM is typically presented first with the prodromal flu-like syndrome and followed by blistering lesions on acral extremities, with mucosal involvement (predominantly orally).

• #26 Paediatric Erythema Multiforme: Epidemiological, Clinical and Laboratory Characteristics | HTML | Acta Dermato-Venereologica

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-2569

  Erythema multiforme (EM) is an immune-mediated reaction presenting as acrofacial target lesions. […] EM has several different aetiologies; the most common cause is infectious, encompassing approximately 90% of cases. […] Herpes simplex virus (HSV) is estimated to be the cause of EM in approximately 70% of patients and preceding herpes labialis is noted in 50% of subjects with EM. […] Mycoplasma pneumoniae is also a prominent pathogen, which may also be associated with SJS. […] In our study, medications were associated with EM in only 16% of cases. […] Four of our patients were shown to have an infection with M. pneumoniae. Recently, a new entity was suggested for patients with EM or SJS associated with M. pneumoniae infection: Mycoplasma-induced rash and mucositis (MIRM). […] It should be noted that we observed a high rate of C-reactive protein (CRP) and/or erythrocyte sedimentation rate in our study.

• #27 Erythema multiforme, Steven-Johnson syndrome and Toxic Epidermal Necrolysis | PPT

  https://www.slideshare.net/slideshow/erythema-multiforme-stevenjohnson-syndrome-and-toxic-epidermal-necrolysis/116506244

  Pathogenesis of SJS and TEN Involves expression of tumor necrosis factor alpha (TNF- ) and not interferon- suggesting a varying mechanism. The disease process also often involves an abnormal metabolism of a responsible drugs. Drug metabolism is directed toward the alternative pathway of oxidation by the cytochrome P-450 enzymes, resulting in increased production of reactive and potentially toxic metabolites. Affected individuals have a defect in the ability to detoxify these reactive metabolites, which may bind covalently to proteins on the surface of epithelial cells. This may then induce the immune response, leading to the severe skin reaction Much of the tissue damage in drug-induced lesions appears to be due to apoptosis by to activation of cytotoxic T cells and NK cells.

• #28 Recent Updates in the Treatment of Erythema Multiforme

  https://www.mdpi.com/1648-9144/57/9/921

  Erythema multiforme (EM) is an immune-mediated condition that classically presents with discrete targetoid lesions and can involve both mucosal and cutaneous sites. […] While acute disease is usually self-limiting, some patients experience recurrent disease. Identifying the etiology of EM is crucial in developing a successful treatment modality. […] A Mayo Clinic series of 48 patients diagnosed with recurrent EM suggested that HSV infection was the most common cause; however, over 60% of patients were determined to have idiopathic recurrent EM. […] A rarer type of EM is known as persistent EM, which is defined by the continuous appearance of EM lesions with marked resistance to therapy. […] In recurrent EM, treatment focuses on addressing the etiology through systemic antiviral prophylactic therapy.

• #29 Erythema multiforme – Dermatology Advisor

  https://www.dermatologyadvisor.com/home/decision-support-in-medicine/hospital-medicine/erythema-multiforme-2/

  Erythema Multiforme (EM) is an acute usually self-limiting but occasionally recurrent dermatologic condition that is considered to be the result of a hypersensitivity reaction. […] The majority of causes of EM are induced by acute or chronic infections (viral, bacterial, fungal) with acute herpes simplex virus (HSV) infections being the most common. Additionally, underlying malignancy, autoimmune disorders (Systemic Lupus Erythematosus, Behcets etc.), sarcoidosis, radiation treatment, menstrual abnormalities and importantly a large number of drugs and vaccines have all been linked to cases of EM. […] Common drugs implicated in causing EM include the following classes of drugs: antibiotics, antiepileptics, sulfonamides and nonsteroidal anti-inflammatory drugs. Recurrent EM is most commonly associated with the presence of recurrent outbreaks of oral/genital HSV, however, it has been reported in association with other recurrent infection with Mycoplasma pneumoniae, vulvovaginal candidiasis, chronic hepatitis C and even autoimmune disorders like Systemic Lupus Erythematosus, Behcets.

• #30 Pathology Outlines – Erythema multiforme

  https://www.pathologyoutlines.com/topic/skinnontumorerythemamultiforme.html

  Acute, self limited, hypersensitivity reaction to infections (coccidioidomycosis, herpes simplex, histoplasmosis, leprosy, mycoplasma, typhoid), drugs (penicillin, phenylbutazone, phenytoin, salicylates, sulfa), carcinoma / lymphoma, or collagen vascular disorders […] Severe dermal inflammatory infiltrate (includes lymphocytes, histiocytes) […] Erythema multiforme may have variable histologic changes from toxic epidermal necrolysis to dermal disturbances.

• #31 Management of Erythema Multiforme in the Urgent Care Setting – Journal of Urgent Care Medicine

  https://www.jucm.com/management-of-erythema-multiforme-in-the-urgent-care-setting/

  Satellite cell necrosis (i.e., lymphocytes surrounding necrotic keratinocytes) is another characteristic histological feature. […] Studies have shown that individuals with HLA-DQB1 are especially susceptible to the disease; HLA-B62, HLA-B35, and HLA-DQ3 are commonly seen in patients with recurrent EM. […] Many different etiologies have been proposed in the pathogenesis of EM. […] Currently, herpes simplex virus (HSV) is thought to be the trigger in nearly 100% of cases of EM minor and nearly 50% of cases of EM major. […] Other viral causes include adenovirus, hepatitis, coxsackievirus, and echoviruses. […] Mycoplasma pneumoniae infection is the most common bacterial trigger. […] Other bacterial causes include pneumococcus, Proteus, Neisseria, and Salmonella. […] Drugs, especially sulfonamides, have been implicated in EM major. […] Some of the other drugs commonly implicated include NSAIDs, aspirin, barbiturates, phenytoin, and penicillin.

• #32 Erythema Multiforme: Treatment, Symptoms, and Causes

  https://www.webmd.com/skin-problems-and-treatments/erythema-multiforme

  Erythema multiforme is a skin disorder that results from an allergic reaction to either a medication or an infection. Its hallmark sign is red, patchy, raised areas that are shaped like targets (a center sore surrounded by pale red rings). […] Erythema multiforme is a skin reaction to a stressor such as an illness, infection, or medication. […] There is no clear cause of erythema multiforme. Its thought that about 90% of the time, its caused by a viral infection such as the herpes simplex virus. […] About 90% of the time, its caused by a viral, fungal, or bacterial infection, with the herpes simplex virus being the most common infection (in 70%-80% of cases).

• #33 Erythema multiforme, minus-type – Altmeyers Encyclopedia – Department Dermatology

  https://www.altmeyers.org/en/dermatology/erythema-multiforme-minus-type-119267

  Associations with other infectious diseases such as HSV type II (HSV-2), varicella, parapoxviruses(Orf virus), parvovirus B19, hepatitis C, SARS-CoV-2 (Thielmann CM et al. 2022), Histoplasma capsulatum, EBV infections, streptococci or mycoplasma (mycoplasma infections occur more frequently in children – see below). Mycoplasma pneumoniae – see also RIME) have been reported. […] More rarely, EM has been associated with severe mycotic or Gardnerella vaginalis infections. […] EEM and SARS-CoV-2: In a cross-sectional analysis (n= 43,547 patients with a history of SARS-CoV-2 infection), the risk of EM was 6.68 times higher than in patients without COVID-19 (Saleh W et al. 2024). […] Vaccinations: Vaccinations (mumps-rubella vaccinations, hepatitis B vaccinations, vaccinations with the polyvalent HPV vaccine) often precede erythema multiforme. At 2.7, the risk of developing EM after a SARS-CoV-2 vaccination is significantly higher than in the general population. The prevalence of EM after SARS-CoV-2 infection or vaccination differs significantly from that of the general population (Saleh W et al. 2024).

• #34 Increased prevalence of erythema multiforme in patients with COVID-19 infection or vaccination | Scientific Reports

  https://www.nature.com/articles/s41598-024-52099-z

  Several reports stated that erythema multiforme (EM) was associated with COVID-19 with detrimental outcomes in patients. […] The pathophysiological mechanism of EM after COVID-19 infection may be due to targeting the SARS-CoV-2 antigens in the skin by the lymphocytes inducing a hypersensitivity reaction with apoptosis of the epithelial cells similar to what was reported for EM associated with other infections. […] Besides the viral cytopathic effect, it was reported that SARS-CoV-2 can induce Type II and Type IV hypersensitivity reactions. […] The cytokine storm which refers to the release of cytokines from host cells was linked to COVID-19 infection. […] All these factors may explain the possible relationship between EM and COVID-19. […] The occurrence of EM following COVID-19 vaccination may indicate an adverse drug reaction.

• #35 Erythema Multiforme: Symptoms, Causes & Treatment

  https://my.clevelandclinic.org/health/diseases/24475-erythema-multiforme

  Erythema multiforme is a skin reaction usually due to an infection or a medication. […] The exact cause of erythema multiforme is unknown, but studies show that erythema multiforme can be triggered by: […] An infection (mycoplasma pneumoniae or herpes simplex virus). […] A medication. […] A reaction to medication is a less common cause of erythema multiforme. Medications that trigger the condition vary for each person, but include: […] Antiseizure medications […] Antibiotics. […] Nonsteroidal anti-inflammatory drugs (NSAIDs).

• #36 Erythema Multiforme Major Due to Fluconazole: A Case Report

  https://practicaldermatology.com/youngmd-connect/resident-resource-center/erythema-multiforme-major-due-to-fluconazole-a-case-report/23887/

  Erythema multiforme (EM) is an immune-mediated hypersensitivity reaction that presents with painful cutaneous and mucosal targetoid lesions. An estimated 90% of cases are the result of infection, with herpes simplex virus (HSV) and Mycoplasma pneumoniae the most common inciting agents. […] Erythema multiforme has also been reported to occur in response to drugs such as NSAIDS, sulfonamides, and other antibiotics. An estimated 10% of cases are thought to be drug induced. […] Erythema multiforme in response to infectious agents commonly manifests as diffuse targetoid lesions on the trunk and extremities, whereas drug-induced EM manifests with oral mucosal lesions. […] The patients clinical presentation and punch biopsy results raised suspicion for Stevens-Johnsons syndrome versus EM. Given the acrofacial distribution of targetoid lesions, as well as lack of bullae, ocular involvement, and constitutional symptoms such as fever, myalgias, and other flu-like symptoms, a diagnosis of EMM was favored.

• #37 Erythema Multiforme Major Due to Fluconazole: A Case Report

  https://practicaldermatology.com/youngmd-connect/resident-resource-center/erythema-multiforme-major-due-to-fluconazole-a-case-report/23887/

  EMM has been described as an immune-mediated reaction to infectious agents, such as HSV, and numerous medications including NSAIDS and sulfonamide drugs, but very few case reports have detailed encounters of EMM induced by antifungals such as fluconazole. […] Careful consideration as to the presenting features, disease course, and medication exposures is required for an accurate diagnosis of EM or EMM. Although EMM is commonly associated with HSV infection, negative HSV PCR, IgG, or IgM should not deter clinicians from considering EMM in a patient with an otherwise supportive clinical presentation. […] A careful review of new medications or exposures should be started in patients presenting with suspected EM. Patients with repeated exposure to previously benign medications should not preclude physicians from considering medication-associated EMM as a differential diagnosis.

• #38 Photodistributed Erythema Multiforme | Actas Dermo-Sifiliográficas

  https://www.actasdermo.org/en-photodistributed-erythema-multiforme-articulo-S1578219013001728

  Erythema multiforme (EM) is an acute mucocutaneous syndrome that runs a self-limiting, usually mild, course. It is considered a hypersensitivity reaction to different antigenic stimuli, the most common of which is herpes simplex virus (HSV). EM is classified among the photoaggravated or photoaccentuated dermatoses. In PEM, UV radiation might contribute to the development of lesions by inducing the release of inflammatory mediators, such as quinines, prostaglandins, and histamine, which would increase vascular permeability, thereby facilitating the passage of skin antigens into the bloodstream and favoring the formation of circulating antibodies in sun-exposed areas. The source of the antigenic stimulus is not always known. […] Short sequences of viral DNA have been detected in keratinocytes in patients with HSV-associated EM, leading to the hypothesis that these sequences might act as antigens and induce the release of interferon.

• #39 Increased prevalence of erythema multiforme in patients with COVID-19 infection or vaccination | Scientific Reports

  https://www.nature.com/articles/s41598-024-52099-z

  However, the causal relationship between the vaccine and EM has not yet been established. […] The exact mechanism by which the COVID-19 vaccine triggers EM is not yet fully understood. […] However, it is believed to be related to the immune response generated by the vaccine, which can result in the development of an immune-mediated skin reaction.

• #40 Erythema Multiforme Following Allergic Contact Dermatitis: Case Report and Literature Review | HTML | Acta Dermato-Venereologica

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-0316

  Erythema multiforme (EM) is characterized by symmetrically distributed target or iris lesions with specific histopathological features that may be accompanied by mucous membrane involvement. The most common and best-described cause of EM is a recent herpes simplex virus (HSV) type 1 or type 2 infection. Other common factors comprise mycoplasma infection, drug hypersensitivity, particularly to anticonvulsives and antibiotics, vaccination and drug-virus interaction. EM arises during acute contact dermatitis or after the primary site of inflammation has nearly resolved. EM due to contact dermatitis shows the same features as common EM caused by infection. The underlying pathogenetic mechanism has not yet been clarified. A possible explanation is acute type IV hypersensitivity characterized by cytotoxic T cells. Another hypothesis discusses the allergen absorption through the skin and a subsequent type III allergic reaction involving circulating immune complexes that deposit in the cutaneous microvasculature. In fact, IgM, IgA, C3 and fibrin deposition can be detected in the superficial blood vessels of some iris lesions in EM.

• #41 Erythema Multiforme Minor Secondary to Pesticide Exposure: A Case Series | Consultant360

  https://www.consultant360.com/article/consultant360/erythema-multiforme-minor-secondary-pesticide-exposure-case-series

  EM is a hypersensitivity reaction to infections or drugs. Infectious etiologies account for 90% of cases, with the other 10% caused by drugs. The most common trigger is herpes simplex virus. Other commonly reported triggers include Mycoplasma pneumoniae, sulfonamides, barbiturates, penicillin, and nonsteroidal anti-inflammatory drugs. EM can be subclassified as minor or major depending on whether mucous membranes are involved. The diagnosis is clinical; skin biopsy usually shows nonspecific changes. We suspect that a pesticide was the culprit in these EM eruptions. The EM rash presented in an almost identical fashion among all 3 patients […] Therefore, we suspect that the pesticide was the precipitator of the cases of EM minor. In conclusion, pesticides may be a trigger of EM minor. The condition self-limited, without significant involvement of mucosal surfaces.

• #42 Management of Erythema Multiforme in the Urgent Care Setting – Journal of Urgent Care Medicine

  https://www.jucm.com/management-of-erythema-multiforme-in-the-urgent-care-setting/

  Even though the exact pathogenesis of EM is not completely understood, it is thought to be caused by viral, bacterial, or chemical triggers that initiate a hypersensitivity reaction. […] It may represent a type III immune complex-mediated hypersensitivity reaction, with a portion of the pathology arising from a type IV delayed hypersensitivity reaction. […] A majority of the patients with EM have deposits of complement 3, immunoglobulin M, and fibrin around the dermal blood vessels. […] In early stages, a lymphocytic infiltrate is characteristically seen at the dermo-epidermal junction. […] The pathognomic finding in later stages is dermal edema along with lymphocytic infiltration (predominantly CD-4 cells) accompanied by epidermal necrosis (which may involve the entire epidermal thickness but is usually predominant in the stratum basale).

• #43 Erythema Multiforme Versus Herpes Simplex Virus, What is the Diagnosis? A Review and a Case Report. – Biomedical and Pharmacology Journal

  https://biomedpharmajournal.org/vol12no4/erythema-multiforme-versus-herpes-simplex-virus-what-is-the-diagnosis-a-review-and-a-case-report/

  Erythema multiforme (EM) is thought to be a type IV hypersensitivity reaction. A variety of factors have been implicated in the etio-pathogenesis of EM. It may be triggered by viral (herpes simplex virus in particular), fungal and bacterial infections. More than 50% of all cases are attributed to medications, and is thought to be an immune mediated complication of the infection. […] The histo-pathological profile of EM lesion is not pathognomonic but predicted for EM diagnosis, (H E section) revealed focal ulcers on the surface, keratinocytes necrosis, intraepithelial vesicle in the upper spinous layer, liquefactive degeneration in the basal epidermal cells, an enormous infiltrate of chronic inflammatory cells in the lamina propria, in addition to sub-mucosa, a perivascular inflammatory cells infiltration. Other feasible findings is the granular deposition of complement (C3) and immunoglobulin M (IgM) at the dermoepidermal junction in the superficial blood vessels.

• #44 Erythema Multiforme Following Allergic Contact Dermatitis: Case Report and Literature Review | HTML | Acta Dermato-Venereologica

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-0316

  The epidermal expression of adhesion molecule intercellular adhesion molecule-1 (ICAM-1) is increased in targetoid lesions, as is the number of CD4+ T cells. ICAM-1 may facilitate the epidermal invasion of lymphocytes in targetoid lesions where the expression of retained allergen particles takes place. […] The exact pathogenetic mechanism of EM remains unclear. It is not known what initiates the inflammatory process in the skin that causes the morphology of an iris lesion and what the details of this immune reaction are. Histopathologically, increased expression of intercellular ICAM-1 and HLA-DR molecules by keratinocytes is found in the epidermis. The inflammatory infiltrate is composed of lymphocytes, mainly T-helper cells and cytotoxic T cells as well as histiocytes. There is also an increase in the number of Langerhans cells. Further research is necessary to fully understand the underlying immune phenomenon of EM.

• #45 Erythema multiforme – Dermatology Advisor

  https://www.dermatologyadvisor.com/home/decision-support-in-medicine/dermatology/erythema-multiforme-3/

  It is unclear whether EM related to other inciting agents follows a similar pathway. In drug-induced EM, the presence of tumor necrosis factor (TNF) alpha in lesional skin rather than IFN-gamma correlates with the development of skin lesions. […] It is unknown why EM does not occur in most people infected with HSV, and why it does not appear with every recurrence of HSV infection among those with a history of HSV-associated EM. Factors that may determine whether a particular patient develops EM after HSV infection include: […] Presence of the specific peripheral blood mononuclear cell subset involved in DNA transport […] Differences in the processing of viral DNA by phagocytic cells […] Variation in the specific viral proteins expressed in the skin […] Presence of epitopes shared with cellular proteins that affect the development of an autoreactive immune response.

• #46 Erythema Multiforme and COVID-19: What Do We Know?

  https://www.mdpi.com/1648-9144/57/8/828

  Erythema multiforme (EM) is an acute cutaneous eruption often associated with infections and more rarely with drugs. […] EM is mainly associated with infectious diseases and rarely with drug exposure. […] Recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coronavirus disease 2019; COVID-19) has been linked to EM or EM-like eruptions. […] The skin disease was strongly associated with a viral infection. […] In most cases, EM and EM-like eruptions were not related to a severe evolution of COVID-19. […] The pathophysiological mechanism could be a hypersensitivity reaction mediated by lymphocytes targeting SARS-CoV-2 antigens in the skin, similar to what was reported for EM associated with other infections. […] CD8+ T lymphocytes induce the apoptosis of scattered keratinocytes and lead to satellite cell necrosis.

• #47 Photodistributed Erythema Multiforme | Actas Dermo-Sifiliográficas

  https://www.actasdermo.org/en-photodistributed-erythema-multiforme-articulo-S1578219013001728

  In drug-induced PEM, either a photoproduct or the actual drug activated by UV radiation might act as an antigen, triggering the immune response, or as a phototoxic agent, favoring the rupture of cells and the release of nuclear antigens, which would then pass into the bloodstream, facilitated by the increased vascular permeability induced by sun radiation. It has also been speculated that alterations of porphyrin metabolism induced by several drugs might be involved in the development of lesions. […] It has been postulated that following the initial episodes of PEM, the skin might retain traces of photoactive substances, but not in sufficient quantities to cause the development of lesions. The presence of additional, nonspecific, antigenic stimuli, such as HSV reactivation or contact dermatitis due to R verniciflua might then have an add-on effect and trigger the development of skin photosensitivity.

• #48 Recent Updates in the Treatment of Erythema Multiforme

  https://www.mdpi.com/1648-9144/57/9/921

  The greatest efficacy of antiviral therapy is observed in patients whose disease has a clear association with HSV infection. […] Patients with recurrent EM that are unresponsive to antiviral therapy can try other antiviral drugs or double the dosage of the current drug. […] Adalimumab is a human recombinant immunoglobin G1 monoclonal antibody that binds Tumor Necrosis Factor alpha (TNF-alpha) and neutralizes this membrane soluble receptor so that it can no longer interact with p55 and p57, leading to the induction of apoptosis of TNF-expressing cells. […] It is speculated that TNF-alpha plays a role in drug-induced EM lesions, whereas the lesions from herpes-associated EM is driven predominantly by a delayed hypersensitivity reaction through T-helper 1 cells and interferon-gamma. […] Rituximab has also shown to be beneficial in a case series from 2016 with 5 patients with recurrent severe EM major.

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