Erythema Multiforme (Clinical)

Overview

Epidemiology^[1,2,7]

• Estimated annual incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency far less than < 1%
• More common in young adults (20‒40 years of age)
• Men > women

Etiology^[1–3,7]

Erythema multiforme Erythema multiforme Erythema multiforme (EM) is an acute hypersensitivity reaction characterized by targetoid skin lesions with multiple rings and dusky centers. Lesions may be accompanied by systemic symptoms (e.g., fever) and mucosal lesions (e.g., bullae). 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 Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions.

A significant number of cases are idiopathic Idiopathic Dermatomyositis; however, there are many etiologies that may be identified:

Classification^[3,5]

Erythema multiforme Erythema multiforme Erythema multiforme (EM) is an acute hypersensitivity reaction characterized by targetoid skin lesions with multiple rings and dusky centers. Lesions may be accompanied by systemic symptoms (e.g., fever) and mucosal lesions (e.g., bullae). Erythema Multiforme is classified based on the presence of mucosal lesions and systemic symptoms into EM minor and major.

Clinical Presentation

Erythema multiforme Erythema multiforme Erythema multiforme (EM) is an acute hypersensitivity reaction characterized by targetoid skin lesions with multiple rings and dusky centers. Lesions may be accompanied by systemic symptoms (e.g., fever) and mucosal lesions (e.g., bullae). Erythema Multiforme usually resolves spontaneously within 1 month, with no long-term sequelae. Rarely, EM may recur around 6 times/year for up to 10 years, on average (usually associated with HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 and 2 infection).^[1,2,5,7]

Cutaneous lesions^[1,2,5]

• Begin as erythematous macules that develop over 3–5 days into papules → target lesions with 3 different zones
  • Central zone: dark and erythematous 
  • Middle zone: pale surrounding ring
  • Peripheral zone: erythematous outer ring with well-defined margins 
• Location of lesions:
  • Symmetrical Symmetrical Dermatologic Examination, acral distribution Acral Distribution Erythema Multiforme (i.e., hands, feet, and face)
  • Extensor surfaces of the extremities
  • Trunk may also be involved, though is typically less affected
• Centripetal spread (distal to proximal)
• Rounded, < 3 cm in diameter
• Pruritus Pruritus An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. Atopic Dermatitis (Eczema) or burning sensation can be present.
• Atypical lesions:
  • Only 2 distinct zones
  • Raised edematous lesions
  • Poorly defined borders

Mucosal lesions^[1,2,5]

• Present in 25‒60% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
• Bullous → painful erosions Erosions Corneal Abrasions, Erosion, and Ulcers/ulcers
• Diffuse areas of mucosal erythema Erythema Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of disease processes. Chalazion
• 3 locations:
  • Oral mucosa Oral mucosa Lining of the oral cavity, including mucosa on the gums; the palate; the lip; the cheek; floor of the mouth; and other structures. The mucosa is generally a nonkeratinized stratified squamous epithelium covering muscle, bone, or glands but can show varying degree of keratinization at specific locations. Stomatitis (most common)
  • Ocular mucosa
  • Genital mucosa

Systemic symptoms^[1,2]

Systemic symptoms are common with mucosal involvement (EM major):

• Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever 
• Malaise Malaise Tick-borne Encephalitis Virus 
• Myalgia Myalgia Painful sensation in the muscles. Ion Channel Myopathy 
• Arthralgia Arthralgia Pain in the joint. Rheumatic Fever/ arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis

Diagnosis

Clinical diagnosis^[1–3]

EM is usually diagnosed clinically based on: 

• Acute appearance of classic target lesions, typically persisting for 7‒14 days
• +/– Mucosal involvement
• +/– Systemic symptoms
• Signs/symptoms associated with recent infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease (especially HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 and 2 or M. pneumoniae)
• History of new, potentially causative medications

Laboratory and imaging^[1,2,5]

• Often not needed to make the diagnosis
• Nonspecific findings may include elevations in:
  • WBC count
  • Erythrocyte sedimentation rate Erythrocyte Sedimentation Rate Soft Tissue Abscess ( ESR ESR Soft Tissue Abscess)
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
• May be indicated to look for potential causes:
  • M. pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia: serologic testing, chest X-ray Chest X-ray X-ray visualization of the chest and organs of the thoracic cavity. It is not restricted to visualization of the lungs. Pulmonary Function Tests, throat Throat The pharynx is a component of the digestive system that lies posterior to the nasal cavity, oral cavity, and larynx. The pharynx can be divided into the oropharynx, nasopharynx, and laryngopharynx. Pharyngeal muscles play an integral role in vital processes such as breathing, swallowing, and speaking. Pharynx: Anatomy swab
  • HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 and 2 (especially in recurrent EM): serologic testing, swab of suspicious lesions for PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR)/culture
  • Selected tests to rule out other inflammatory, autoimmune, or malignant disorders

Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma^[1,2,5] 

Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma is usually reserved for cases of diagnostic uncertainty.

• Microscopy may show:
  • Vacuolated degeneration of basal cells
  • Scattered keratinocyte Keratinocyte Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. Erythema Multiforme necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage
  • Inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
• Direct immunofluorescence:
  • Findings in EM are nonspecific.
  • Can help differentiate EM from autoimmune blistering diseases (e.g., bullous pemphigoid Bullous pemphigoid Bullous pemphigoid and pemphigus vulgaris are two different blistering autoimmune diseases. In bullous pemphigoid, autoantibodies attack the hemidesmosomes, which connect epidermal keratinocytes to the basement membrane. This attack results in large, tense subepidermal blisters. Bullous Pemphigoid and Pemphigus Vulgaris), which have more specific findings

Differential Diagnosis

• Urticaria Urticaria Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives): a self-limiting Self-Limiting Meningitis in Children disease consisting of superficial, erythematous, pruritic lesions resulting from mast cell Mast cell Granulated cells that are found in almost all tissues, most abundantly in the skin and the gastrointestinal tract. Like the basophils, mast cells contain large amounts of histamine and heparin. Unlike basophils, mast cells normally remain in the tissues and do not circulate in the blood. Mast cells, derived from the bone marrow stem cells, are regulated by the stem cell factor. Angioedema activation and histamine release in the dermis Dermis A layer of vascularized connective tissue underneath the epidermis. The surface of the dermis contains innervated papillae. Embedded in or beneath the dermis are sweat glands; hair follicles; and sebaceous glands. Skin: Structure and Functions. Lesions may last < 24 hours up to > 6 weeks. Commonly caused by viral infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease or by allergic reactions Allergic Reactions Type I hypersensitivity reaction against plasma proteins in donor blood Transfusion Reactions to drugs or food, other infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease, stress, cold/ heat Heat Inflammation, and autoimmune disorders. Treatment, besides addressing the underlying condition, includes antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines and steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors.
• Bullous pemphigoid Bullous pemphigoid Bullous pemphigoid and pemphigus vulgaris are two different blistering autoimmune diseases. In bullous pemphigoid, autoantibodies attack the hemidesmosomes, which connect epidermal keratinocytes to the basement membrane. This attack results in large, tense subepidermal blisters. Bullous Pemphigoid and Pemphigus Vulgaris: an immune-mediated condition characterized by the destruction of extracellular adhesive proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis (e.g., hemidesmosomes) by immunoglobulin G autoantibodies Autoantibodies Antibodies that react with self-antigens (autoantigens) of the organism that produced them. Blotting Techniques. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship present with urticaria Urticaria Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives) and eczematous papules during the prodromal stage. After that, cutaneous, tense bullae Bullae Erythema Multiforme develop. This may last months to years, and treatment is focused on supportive, symptomatic care with steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors and antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines. 
• Stevens-Johnson syndrome Stevens-Johnson syndrome Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome ( SJS SJS Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome): a life-threatening immune-mediated hypersensitivity reaction that involves the mucous membranes and skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions (< 10% of body surface area). Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship generally have a history of taking certain medications (e.g., sulfa drugs) or recent infection. Clinical presentation involves macular skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions lesions with 2 zones of color change, vesicles Vesicles Female Genitourinary Examination, bullae Bullae Erythema Multiforme, and systemic symptoms (e.g., fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever). Treatment comprises supportive skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions and eye care and symptom control. 
• Toxic epidermal necrolysis Toxic Epidermal Necrolysis Stevens-Johnson Syndrome (TEN): a life-threatening immune-mediated hypersensitivity disease process that is an extension Extension Examination of the Upper Limbs of SJS SJS Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome. Toxic epidermal necrolysis Toxic Epidermal Necrolysis Stevens-Johnson Syndrome is an immune-mediated hypersensitivity reaction with mucocutaneous involvement (> 30% of body surface area). Mortality rate Mortality rate Calculated as the ratio of the total number of people who die due to all causes over a specific time period to the total number of people in the selected population. Measures of Health Status depends on severity in both SJS SJS Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome and TEN, at approximately 10% for SJS SJS Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome and up to 50% for TEN. Both conditions require admission to a burn unit Burn unit Specialized hospital facilities which provide intensive care for burn patients. Staphylococcal Scalded Skin Syndrome (SSSS) for skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions care.