Immunobullous Diseases Lecture Notes PDF

Immunobullous Diseases By: Salsabiela Bani Hamad Revision: A blister is a circumscribed collection of clear fluid in the skin. Vesicle 0.5 cm. vesicle Bulla Introduction: The integrity of normal skin depends on intricate connecting structures between cells. Loss of adhesion between the cells may occ...

Immunobullous Diseases By: Salsabiela Bani Hamad Revision: A blister is a circumscribed collection of clear fluid in the skin. Vesicle 0.5 cm. vesicle Bulla Introduction: The integrity of normal skin depends on intricate connecting structures between cells. Loss of adhesion between the cells may occur within the epidermis or at the basement membrane leading my to blister formation. an Level of blister and its characteristics depend on the area targeted by the disease. alien pismo Bein aim subapiderm Bullas Blistering Causes: 1. The destruction of epidermal cells e.g. burn or a herpes virus infection. 2. Autoantibodies attacking the adhesion structures between keratinocytes e.g. In autoimmune blistering conditions. Loss of adhesion between the cells may occur I - Within the epidermis (pemphigus) - At the basement membrane (pemphigoid). 3. Edema between the epidermal cells, resulting in spongiosis and then vesicle formation e.g. Eczema. i me Sometimes, there are associated inflammatory changes in the dermis (erythema multiforme/vasculitis) or a noninflammatory metabolic defect (as in porphyria). Level of blister: The level of the separation of epidermal cells within the epidermis is determined by the specific structure that is the target antigen. 1. Intraepidermal split: - Superficial blisters: Fragile and flaccid - More erosions, less intact blisters mm - E.g. PemphiguS 2. Subepidermal split: - Deep blisters; Tense, Intact - More intact blisters, less erosions - E.g. Pemphigoid Mmmmm More erosion stable Less more stable Less erosion intraapidermal sa dermigggermis epidermal sup normal acantholysis 7259181593 pm uscon - In skin Desmoglein 1 > Desmoglein 3 - In Mucous Membranes Desmoglein 3 > Desmoglein 1 - In skin Desmoglein 1 is more at the upper epidermis and decreases in concentration as we go deeper - In mucous Membranes Desmoglein 3 is more in the Lower epidermis and decreases in concentration as we go superficially. Levels of Blisters: Sub-corneal blisters have a very thin roof with little structural integrity and hence easily collapse. E.g. pemphigus foliaceus. immune Intra-epidermal blisters have a thicker roof and are more substantial e.g. Pemphigus. Sub-epidermal blisters have great structural integrity and can remain intact even when firmly compressed e.g. Pemphigoid mi imum Pathophysiology: Susceptibility to develop autoimmune disorders may be inherited, but the triggers for the production of these skin-damaging autoantibodies remain unknown. In some patients possible triggers have been identified including:  Drugs (rifampicin, captopril and D-penicillamine).  Certain foods (garlic, onions, and leeks)  Viral infection  Hormones.  UV radiation  X-rays Autoimmune Blistering diseases Impaired adhesion of epidermal cells to each other or impaired adhesion of the epidermis to the epidermal basement membrane mediated by our own immune system; auto-immune. Pathophysiology: Bullous pemphigoid Pemphigus vulgaris Pemphigus foliaceus Results from autoantibodies that target the basement membrane cells (hemidesmosome proteins BP180 and BP230). Results from autoantibodies directed against desmosomal cadherin desmoglein 3 (Dsg3) found between epidermal cells in mucous membranes and skin Results from autoantibodies directed against desmoglein 1 t (Dsg1) Subepidermal split leads to tense bullae formation. Intraepidermal split leads to flaccid bullae formation. Subcorneal split leads to rapidly easily rapturing bullae. Tense bullae, less erosions Flaccid bullae, more erosions More erosions, rare bullae. Usually at upper body me mine mummi s Bullous diseases: Pemphigus:  Pemphigus Vulgaris  Pemphigus foliaceus  Pemphigus erythematosus  Drug-induced Pemphigus  Para-neoplastic pemphigus Pemphigoid:  Bullous pemphigoid  Localized/Cicatricial/Mucous membrane pemphigoid  Pemphigoid Gestationis (Herpes gerstationis)  IgA Mediated Bullous Dermatoses  Dermatitis Herpetiformis  Linear IgA Pemphigoid-like disease: Epidermolysis bullosa acquisita Differential diagnosis: The history of the blister formation can give important clues to the diagnosis, in particular, the development, duration, durability, and distribution of the lesions – the ‘four Ds’. 1. Development: fanatic - If erosions or blisters are present at birth >> Genodermatoses, OR Cutaneous infections. ever - Preceding systemic symptoms may >> infectious causes such as chicken pox OR hand, foot, and mouth disease. - A tingling sensation may herald >> herpes simplex OR herpes zoster. - If the lesions are pruritic >> DH OR pompholyx eczema. - Eczema may precede bullous pemphigoid. Dermatitis herpitophormis 2. Duration: Rapid Acute Eruption: Allergic reactions Impetigo Erythema multiforme Pemphigus Gradual onset and chronic course eruption: DH Pityriasis lichenoides Porphyria cutanea tarda Bullous pemphigoid. Appear at birth with a chronic course: Epidermolysis bullosa 3. Durability: The blisters themselves may remain intact or rupture easily and this sign can help elude the underlying diagnosis. Superficial blisters in the epidermis have a fragile roof that sloughs off easily leaving eroded areas typically seen in pemphigus vulgaris, Stevens–Johnson syndrome, toxic epidermal necrolysis, staphylococcal scalded skin and herpes viruses. Subepidermal blisters have a stronger roof and usually remain intact and are classically seen in bullous pemphigoid, linear IgA, and erythema multiforme. Scratching can result in the traumatic removal of blister roofs, which may confuse the clinical picture. 4. Distribution: In general, immunobullous diseases present with widespread eruptions with frequent mucous membrane involvement. Herpes infections usually remain localized to lips, genitals, or dermatomes. Photosensitive blistering disorders involve sun-exposed skin. Investigation of immunobullous disease: Direct immunofluorescent: From perilesional skin. (The gold standard ) The level and pattern of immunoglobulin staining on direct immunofluorescence is diagnostic. Skin biopsies: Are taken across a blister/erosion (the lesional part) Indirect immunofluorescent: Involves taking the patient’s serum and applying this to a substrate such as a monkey esophagus or salt-split human skin substrate. Circulating intercellular antibodies may be detected in patients with pemphigus, leading to titer measurement which may help guide management. Direct vs. Indirect Immunofluorescence General management of immunobullous disease: Tense intact blisters can be deflated using a sterile needle (the roof of the blister should be preserved as this provides a ‘natural wound covering’). Use of non-adherent dressings or can be used to cover painful cutaneous erosions. Liquid paraffin should be applied regularly to eroded areas to help retain fluid and prevent secondary infection. In most cases of immunobullous disease immunosuppressive treatments are required. Pemphigus A rare group of autoimmune, intra-epidermal blistering diseases involving the skin and mucous membranes. Main variants: 1. Pemphigus Vulgaris meAaDs 2. Pemphigus Foliaceus 3. Pemphigus Erythematosus 4. Drug-Induced Pemphigus 5. Para-neoplastic pemphigus Pathophysiology: Circulating IgG autoantibodies are directed against the normal proteins within the desmosomal structure on the cell surface of keratinocytes. The autoantibodies destroy the adhesion between epidermal cells, allowing fluid to accumulate in the gaps in the epidermis to form blisters. PlaitAcummiation oBallas Acantholysis Pemphigus Vulgaris(PV) toBP Most common form of pemphigus. 60 opposite Affects middle-aged people (40-60). more in mucosmammbranz Desmosomal protein desmoglein 3 is the autoantigen of pemphigus vulgaris. Seventy percent of patients develop painful oral erosions which usually precede the onset of 781 skin blisters by weeks or months. epidermal Characterized by painful flaccid blisters and erosions arising on normal skin. Intra The bullae are easily broken and even rubbing normal skin causes the superficial epidermis to slough off (Positive Nikolsky’s sign). Drug triggers include rifampicin, ACE-I, and penicillamine. Few flaccid bullae and multiple erosions. - Multiple erosions and bullae at oral mucosa - Ocular pemphigus urethral Vaginal Esophageal Pemphigus vulgaris: Slow-healing painful erosions occur in the mouth, particularly on the soft/hard palate and buccal mucosae, but the larynx may also be affected. The oral cavity lesions may be so severe that patients have difficulty eating, drinking, and brushing their teeth. Patient is ill Diagnosis of PV: 1. Histopathology from the new blister edge: Intraepidermal cleft Supra-basal epidermal cells separate from the basal cells to form clefts and blisters. Basal cells are separated from one another and stand like a row of tombstones on the floor of the blister, Blister cells contain some acantholytic cells. D Basal call IT take Diagnosis of PV: 2. Direct immunofluorescence (DIF): From normal-appearing perilesional skin shows immunoglobulin G (IgG) deposited on the surface of the keratinocytes in and around lesions (chicken wire pattern). 3. Indirect immunofluorescence (IDIF): Using the patient's serum (if DIF results are positive) In the patient's serum, IDIF demonstrates the presence of circulating IgG autoantibodies that bind to the epidermis. The titer of circulating antibodies correlates with the disease course. PV treatment: 1. Systemic steroids 2. Rituximab: - A biological agent with an anti-CD20 activity that depletes antibody-producing B-cells. Pemphigus foliaceus (PF): Tends to affect patients in middle age Characterized by flaccid small bullae on the trunk, face, and scalp that rapidly erode and crust. Antibodies against desmoglein 1. Dugs may induce PF; the most commonly reported are penicillamine, nifedipine, captopril, and NSAIDs. saver more BEmacos Affetmmbram sik I Para-neoplastic pemphigus: Clinically similar to pemphigus vulgaris. Associated with an underlying malignancy such as non-Hodgkin’s lymphoma or chronic lymphocytic leukemia. There are severe painful mucosal ulcerations. Pemphigoid: Autoimmune sub-epidermal blistering diseases with circulating IgG and basement membrane zone–bound IgG antibodies and C3. The hemidesmosome is a membrane-associated protein complex that links the cytoskeleton of the basal keratinocyte to the dermis. Diseases of hemidesmosomes show sub-epidermal blisters. By DIF, linear deposits of IgG, C3, or IgA at the dermo-epidermal junction. La cicatricial Includes: 1. Bullous pemphigoid 2. Cicatricial/Mucous membrane pemphigoid 3. Pemphigoid Gestationis (Herpes gestationis) Bullous Pemphigoid: Bullous pemphigoid (BP) is a disease of hemidesmosomes. It is the most common autoimmune blistering skin disease. It is associated with neurologic diseases such as cerebrovascular disease, and Multiple Sclerosis. Potential triggers include vaccinations, drugs (NSAIDs, furosemide, ACE-I, and antibiotics), UV radiation, and X-rays. It usually presents over the age of 65 years(vs. pemphigus) Lo Cao 60 Bullous Pemphigoid: Tense blisters and erosions on a background of dermatitis or normal skin. The condition may present acutely or be insidious in onset but usually enters a chronic intermittent phase. Some patients have a prolonged pre-bullous period in which persistent pruritic urticated plaques or eczema, precedes the blisters. The amount of itching varies but is usually moderate to severe(vs. pemphigus). It is sometimes the ONLY presenting symptom. to painful Tense erosion Bullous Pemphigoid: Characteristically, blisters have a predilection for flexural sites on the limbs and trunk. Mucous membrane involvement occurs in about 20% of cases. (vs. pemphigus). 701 The bullae are tense with good structural integrity (vs. pemphigus). Flaccid Healing occurs without scarring. Nikolsky’s sign is negative. (vs. pemphigus) erythema Bullous Pemphigoid: In children bullous pemphigoid usually follows vaccination, where the condition characteristically affects the face, palms, and soles. Algiers Diagnosis: 1. Histopathology: - From the edge of a blister demonstrates a sub-epidermal blister with eosinophil predominate infiltrate. 2. Direct immunofluorescence: - On normal-appearing, perilesional skin AM - Usually demonstrates IgG and C3 deposition in a linear band at the dermalepidermal junction 3. Indirect immunofluorescence: - Studies performed on the patient’s serum (if DIF is positive) detect immunoglobulin G class circulating autoantibodies in the patient’s serum that bind to the skin basement membrane. t linear Band Esinophils o o 0 Treatment: Localized: Intensive potent topical steroids to affected skin. Extensive: - Systemic corticosteroids (short-term) - Azathioprine or minocycline (for maintenance). - Other treatments used include methotrexate, cyclophosphamide, mycophenolate mofetil, and the anti-CD-20 biological agent rituximab. BE Asossiated Pemphigoid Gestationis: with pregnancy Rare autoimmune disorder. Usually occurs in the second/third trimester of pregnancy. Mothers may have other associated autoimmune conditions. Acute-onset intensely pruritic papules, plaques, and blisters spread from the periumbilical area outwards.(umbilical involvement) aims Ya Mucous membrane involvement can occur. Babies may be born prematurely or small for dates and can have a transient blistering eruption that rapidly resolves. The maternal cutaneous eruption usually resolves within weeks after birth but may flare immediately postpartum. Pemphigoid Gestationis: Treatment: Systemic corticosteroids High doses Can be rapidly reduced during the postpartum period. Care should be taken if mothers are breastfeeding as most drugs pass into breast milk. Mucous membrane pemphigoid (cicatricial pemphigoid) BP skin macos 30 70 Cicatricial 701 sot staring Patients usually present with painful sores in their mouth, nasal and genital mucosae, and may complain of a gritty feeling in their eyes. Cutaneous lesions occur in around 30% of patients; tense blisters may be hemorrhagic and heal with scarring. (opposite to BP, more mucosa, less skin involvement). Scalp involvement can lead to scarring alopecia. Ocular damage can include symblepharon (tethering of conjunctival epithelium), synechiae (adhesion of the iris to the cornea), and fibrosis of the lacrimal duct (dry eyes) resulting in opacification, fixed globe, and eventually blindness. gyrenia Mucous membrane pemphigoid (cicatricial pemphigoid) Chronic and resistant to many treatments, making management difficult. Oral disease: May respond to topical steroids and tetracycline mouthwashes. Ophthalmic disease: Should be managed carefully as scarring can result in blindness. Topical steroid drops and mitomycin may be useful, but usually, systemic immunosuppression such as mycophenolate mofetil is required itchy Groupof Papalovesiculareruption Dermatitis Herpetiformis Intensely pruritic autoimmune blistering disorder Affects young/middle ages adults Associated with an underlying gluten-sensitive enteropathy i.e. celiac disease (might be asymptomatic, i.e no GI sx) IgA antibodies develop against tissue transglutaminase (found in the gut) and these cross-react with epidermal transglutaminase leading to cutaneous blistering. Intermittent cutaneous lesions affecting mainly the Extensors (buttocks, knees, and elbows). The intense pruritus leads to excoriation of the small vesicle, which as a consequence, is rarely seen intact by clinicians. Increased frequency of small bowel lymphoma in patients with enteropathy. Dermatitis Herpetiformis Histological finding: small vesicles containing neutrophils(micro-abscesses) in the upper dermis. DIF: granular deposition of IgA in the upper dermis. Management: 1. Strict gluten-free diet: - Controls the cutaneous and GI symptoms. - Reduce the risk of small bowel lymphoma. - Patients should avoid wheat, rye, and barley. Pt 8 can Get EIN 2. Dapsone or sulphapyridine 3. DH is a chronic condition and therefore lifelong management is needed. Linear IgA: Autoimmune subepidermal blistering disorder. Children and adults can be affected. The clinical picture ranges from acute onset of blistering to insidious pruritus before chronic tense bullae. Blisters location: In children >> lower abdomen and perineum In adults >> limbs and trunk Blisters are usually intact and are classically seen around the periphery of annular lesions (‘string of beads sign’) or in clusters (‘jewel sign’). Mucous membrane involvement is common. Management: dapsone or sulphapyridine. Thank you