DERMATITIS HERPETIFORMISLINEAR IgA DISEASE

PEMPHIGOID GESTATIONIS

ESTHER NIMISHA

DEFINITION

• Dermatitis herpetiformis is a rare, chronic blistering skin disease characterised by intensely pruritic grouped vesicles arising on an erythematous base, by granular IgA deposit in the dermal papillae on direct immunoflorescence ,associated with gluten sensitivity and a mostly asymptomatic enteropathy.

EPIDEMIOLOGY1) AGENT:- exact etiology unknown- Epidermal transglutaminase predominant autoantigen- strong association with HLA-DR3,DQ2, DQ8

2) HOST FACTOR: age -present most often in second or third decade sex -male predominanceRace- less often in blacks and in Asians than in whites-first degree relatives of pts -family h/o DH & Coelic ds in 10% of pts-both concordant and discordant in monozygotic twins

3) ENVIRONMENTAL FACTORS:- although there is a gluten sensitive enteropathy,

antibodies to gliadin, the antigenic component of gluten are not present in all patients. Gluten is a protein present in grasses of the species Triticeae, which include wheat, rye and barley.

- Trigger factors: dermal pressure or trauma, sunexposure & topical or oral iodine administration .

ETIOPATHOGENESIS

• Not well understood• Archetypal features are neutrophilic

infiltration in the dermal papillae, granular IgA deposition in the papillary dermis and gluten sensitive enteropathy

•Marked similarities are noted between DH and celiac disease(CD)

• Enzyme tissue transglutaminase(tTG) autoantigen in celiac ds & epidermal transglutaminase (TGe ) DH

• DH Th 2 mediated Celiac disease Th 1 mediated

• Process of blistering in DH is also not clear

• Neutrophils may bind to the deposited IgA and release proinflammatory cytokines and elastase that damage DEJ resulting in blister.

CLINICAL FEATURES

• Onset may be acute or gradual• Eruption is characteristically polymorphous,

although at a given time any one type of lesion (papular, uticarial,vesicular or bullous) may predominate

• Primary lesion is a small vesicle on an erythematous edematous base

• Symmetrical distributed over the extensors• Vesicle grouped in a herpetiform manner on an

erythematous plaque

• Intense itching , burning or stinging sensation , preceded by new lesion by 8- 12 hrs.

• If the rash is chronic, there are often lichenified plaque at the site of involvement.

• Scarring is rare• Areas of predilection- elbow, knees, buttock,

sacrum , shoulder, posterior hairline and scalp• Face occassionally affected • Mucous membrane only rarely.

INTACT TENSE BULLAE ON THE ELBOW

EXTENSIVE ERUPTION WITH GROUPED PAPULES, VESICLES AND CRUST ON BACK

VESICLES ARRANGED IN AN ANNULAR PATTERN

ASSOCIATIONS

1) GLUTEN SENSITIVE ENTEROPATHY GLUTEN SENSITIVE ENTEROPATHY

• Less than 10% have gastrointestinal symptoms suggestive of celiac ds

• Enteropathy is usually asymptomatic but some pts exhibit consequences of malabsorption such as diarrhoea, steatorrhea, abdominal distension & weight loss.

• Abnormal absorption of D- xylose, iron, folate, glucose, water , bicarbonate and low serum level of iron and folate have been documented

• Patchy involvement of jejunum, biopsies from which shows flattening of surface of epithelial cells, blunting of villi, elongation of intestinal crypts and an inflammatory infitrate primarily lymphocyte and plasma cells in the lamina propria.

2) AUTOIMMUNE DISORDERS - Insulin dependent diabetes, connective

tissue disorder, gastric hypochlorhydria and atrophy & thyroid ds.

3) LYMPHOMAIncreased risk for developing lymphoma especially of gastrointestinal tract b/c of long standing T cell proliferation in the intestine.

HISTOPATHOLOGY

• Neutrophilic microabscesses seen within an adjoining dermal papillae intermingled with few eosinophils Multilocular appearance

• However, within a few days, the tips of the dermal papillae separate from the overlying epidermis and the blister become unilocular. These may coalesce to form a subepidermal blister.

• Moderately severe inflammatory infiltrate of neutrophils and eosinophils in subpapillary dermis.

Dermal papillary collection of neutrophils & eosinophils

IMMUNOPATHOLOGY

• DIRECT IMMUNOFLORESCENCE- Granular deposit of IgA in the dermal papillae,

vertically elongated giving ‘ PICKET FENCE’ appearance.

• INDIRECT IMMUNOFLORESCENCE-No circulating anti-BMZ ab are found.

GRANULAR Ig A IN THE DERMAL PAPILLAEON DIF

IMMUNOELECTRON MICROSCOPY

• IgA deposit in the form of amorphous grain ( DH bodies) mostly in the subbasal memb region and upper papillary dermis. Probably represent immune complex aggregates.

• IMMUNOMAPPING STUDIES reveals that ultrastructural site of blister formation is the LAMINA LUCIDA.

SEROLOGICAL TEST

• Anti endomysial ab• Anti reticulin ab• Anti tissue transglutaminase ab

IgA

These three autoantibodies are highly pathognomic for untreated celiac ds.

DIFFERENTIAL DIAGNOSIS

• Bullous erythema multiforme

• Transient acantholytic disorder

• Papular urticaria• Scabies• Neurotic excoriation• Atopic dermatitis• Bullous pemphigoid• Pemphigoid gestationis• Linear IgA disease

MANAGEMENT

CURATIVE:-• DAPSONE- Dose :100 -200 mg /day • Maintanence dose : 50 mg/day to 50 mg/wk• S/e – hemolysis & methemoglobinemia Hence CBC and LFT should be done at baseline CBC – repeated fortnightly during the first 3 months of

therapy and every 3 months thereafter LFT – at 6 months and annually thereafter• Oral vitamin E ( 800 u/d) protect against dapsone induced

hemolysis

• Sulfasalazine ( 0.5 g three times a day increased to 2 g/d ) when sensitivity to dapsone

• Colchicine ( 0.6 mg tid ) - when dapsone or sulfasalazine are C/I or when a gluten free diet cannot be instituted.

• Heparin with/ out tetracycline plus nicotinamide can be used who cannot tolerate dapsone or sulfonamides.

• Other – cyclosporine, azathioprine , prednisolone

PREVENTIVE MEASURES :

• GLUTEN FREE DIET- mandates strict avoidance of wheat, rye , barley- reduce the dose of dapsone in 70-100% of pts

following a strict dietary regimen, after 8 months & even stop it, in 40-70% after about 2-5 yrs.

- If dietary restriction are discontinued, the rash returns after an average of 3 months , suggesting that the restriction should be continued life long.

LINEAR IgA DISEASE

• Is defined as chronic autoimmune subepidermal blistering disease characterised by linear deposition of IgA along the dermoepidermal junction on direct immunoflorescence.

• CHRONIC BULLOUS DS OF CHILDHOOD – subepidermal vesiculobullous disease characterised by tense blister , often in an annular arrangement predominantly in flexural especially the lower trunk, thigh & groin.

EPIDEMIOLOGY

• ADULT- mean age of onset 5th decade

• CHILDREN – below the age of 5 yrs

• FEMALE preponderance in adult.

ETIOPATHOGENESIS

• Unknown• HLA haplotype HLA B8,DR3 (Autoimmune

extended haplotype) • Linkage disequilibrium b/w this haplotype and

tumor necrosis factor polymorphism• heterogenous disease with regard to its

antigen , with many different target protein within the epithelial adhesion complex.

• Major antigens: - BP 180 ( BPAg 2) - 285 kDa antigen( LAD 285)

• Other antigen: - BP 230 ( BPAg 1) - collagen VII - protein under 100 kDa - 200 & 280 kDa hemidesmosomal- protein - beta 4 integrin

• IgA is the immunodominant ab , some pts also have IgG ab directed at BP 180.

• Triggers such as drugs, infection and autoimmune conditions have been implicated.

• Sensitised against external antigen (virus antigen)

CLINICAL FEATURES

• Can be categorised into CBDC ADULT LAD • CHILDREN : - usually starts below 5 yrs - onset is abrupt with large tense

bulla filled with hemorrhagic or clear fluid .• Sites – genitilia, buttocks, scalp and face• Blisters may also appear in a generalised but

asymmetric distribution.

• Typical features are:

- Herpetiform clustering of blister- Bizzare, irregular shaped bullae as they enlarge &

coalesce- Rosette or cluster of jewels which represent the

annular arrangement of new, small , tense blister around a crusted healing erythematous plaque (STRING OF PEARL SIGN)

• Pruritus is variable in intensity.

CLUSTERING OF BULLAE IN PERINEAL REGION

EXTENSIVE CBDC

• ADULT: - onset may be insidious or abrupt- Symptoms vary from mild to severe pruritus and

burning- Sites: flexure and trunk with scattered vesicles

and tense blister similar to BP.- Bullae may be linear, sausage shaped &

hemorrhagic.- Some may have DH like itchy eruption.- Perineal & perioral involvement is less common

TYPICAL ARRANGEMENT OF TENSE BLISTER AROUND A HEALING ERYTHEMATOUS PLAQUE

CRUSTED EROSIONS, PAPULES AND VESICLES ON THE BACK AND NECK

SCATTERED TENSE BULLAE

• mucosal lesions - painful erosions or ulcers following rupture of

bullae. Occasionally , manifest as chronic desquammative gingivitis.

• eye involvement- irritation, redness, dryness, light sensitivity, blurred

vision, conjuntival scarring & blindness.

• Nasal involvement – crusting, stuffiness & bleeding

• Laryngeal involvement- hoarseness

• Occasional association with infection, pre-existing inflammatory

bowel ds , autoimmune ds( SLE, dermatomyositis) and malignancy.

DRUG INDUCED LAD• Vancomycin• Penicillin• Cephalosporin• Diclofenac and other

NSAIDs• Captopril• Lithium• Amiodarone• carbamazepine

• Amoxicillin• Moxifloxacin• PUVA• Furosemide• Interferon alpha• Phenytoin• Statins• Angiotensin receptor

antagonist• Self limited eruption, generally resolving within 2-6 wks of stopping the drug.

• These drugs stimulate the immune system to produce an IgA class ab in a predisposed individual

HISTOPATHOLOGY

• Subepidermal split with a sparse superficial dermal infiltrate composed of neutrophils and few eosinophils.

• In early urticarial papules and plaques, neutrophils may percolate all along the dermoepidermal junction with basal vacuolization.

• Neutrophilic microabscesses at the tip of dermal papillae are occassionly seen resembling DH.

SUBEPIDERMAL BLISTER FILLED WITH NEUTROPHILS

IMMUNOPATHOLOGY

• DIRECT IMMUNOFLUORESCENCE - Homogeneous linear ( toothpaste or tubular) pattern

of IgA deposit at basement membrane zone• INDIRECT IMMUNOFLUORECENCE- Circulating IgA anti BMZ ab are detectable in approx

30% of adult and 80% of children during the active phase

• IMMUNOGOLD IMMUNOELECTRON MICROSCOPY- target antigens localised to either the hemidesomes,

lamina lucida, lamina densa or the anchoring fibrils

DIF OF LAD

DIFFERENTIAL DIAGNOSIS

• Dermatitis herpetiformis• Bullous pemphigoid• Epidermolysis bullous acquista• Cicatricial pemphigoid• Lichen planus• Toxic epidermal necrolysis

MANAGEMENT

• Topical steroid used for mild cases and for oral lesions.

• Dapsone ( 50- 200 mg/day;1-2 mg/kg/day in children ) is m/c used, either alone or in combination with prednisolone.

• Sulfamethoxypyridazine ( 0.5 -1.5 g/day) - used as first line t/t in children b/c it less commonly causes hemolysis.

• Sulfapyridine ( 1-2 g/day)

• Most pts respond to dapsone or sulfonamide within 48- 72 hrs.

• Prednisolone ( 60 mg/day in adult and 30 mg/day in children ) which can be used in combination with dapsone or azathioprine.

• Others- flucloxacillin, colchicine(0.5-2mg/day) Cyclosporine, tetracycline, nicotinamide,

mycophenolate mofetil & erythromycin.

PEMPHIGOID GESTATIONIS

• DEFINITION: Rare autoimmune pruritic, polymorphic

dermatosis of pregnancy and puerperium

• INCIDENCE:Estimated to be 1 in 10,000 to 1 in 50,000

deliveries in white North American women

ETIOPATHOGENESIS

• Increased frequency of HLA antigen B8, DR3 and DR4 • PG antigen is 180 kDa BP antigen (BPAg2) present in

the hemidesmosome of the basement membrane.• Anti BMZ ab, mainly IgG 1 are pathogenic.• Complement activation by ab deposited at BMZ and

subsequent inflammation result in basal cell degeneration and DE separation.

• Inflammatory infiltrate including Th2 probably involved in production of bullous lesion.

CLINICAL FEATURES

• occur in the 1st or any subsequent pregnancy. • Usually begins in the 2nd or 3rd trimester.

• Polymorphic eruption of erythematous urticarial papules & plaques, vesicles or bullae arising on inflamed or normal skin.

• Sites: abdomen, especially around the umbilicus or on the extremities and then spread to the rest of trunk, palms & soles.

• Facial & mucosal lesions are rare.

• In the a/b of excoriation or secondary infection, healing occurs without scarring.

ERYTHEMATOUS URTICARIAL AND BULLOUS LESION ON THE CHEST AND SHOULDERS

URTICARIAL PAPULES AND PLAQUE ON THE TRUNK

HISTOPATHOLOGY

• Perivascular , eosinophil rich leukocytic infiltrate , papillary dermal edema, focal areas of necrotic basal cells and spongiosis.

• Presence of inverted teardrop shaped edematous dermal papillae is characteristic of urticarial stage.

• Electron microscopy reveals a level of cleavage in the lamina lucida .

INVERTED TEAR DROP LIKE VESICLES

IMMUNOPATHOLOGY• DIRECT IMMUNOFLUORESCENCE- linear deposition of C3 along the BMZ and IgG in 40-50% of pts.- On salt split skin, the immunoreactant are on the epidermal side.

• INDIRECT IMMUNOFLUORESCENCE- circulating IgG anti -BMZ ab in 20-60% of pts, but complement

fixing ab are found in almost all cases.

- IMMUNOELECTRON MICROSCOPY deposit are found in the upper portion of lamina lucida, just beneath the plasma membrane of basal keratinocyte.

DIFFERENTIAL DIAGNOSIS

• Papular dermatitis of pregnancy• PUPPP • Erythema multiforme

PROGNOSIS

• Self limited ds• Maternal prognosis is good • However, PG is associated with perinatal

complication like prematurity, still birth , low birth weight and small for date infants.

MANAGEMENT

• Prednisolone - 40 mg/day.• Post partum exacerbation may require an

increased dose of steroid.• Oral antihistamines and topical steroid are

sometime useful.• Cyclosporine, IVIG and post partum use of

tetracycline can be helpful.