1. Autoimmune blistering diseases
Autoimmune blistering diseases
Pemphigus
Pemphigoid
Dermatitis herpetiformis (Duhring)
Dr. Kejian Zhu
Sir Run Run Shaw Hospital

2. Blister---classification
Intraepithelial vesicles:
Acantholytic vesicles:
the break down of specialized
attachments (desmosomes)
Nonacantholytic vesicles:
the death or the rupture of
the group of cells, usually seen in viral infections
Subepithelial vesicles:

3. Autoimmune blistering diseases
Diseases with intraepidermal blistering (pemphigus-group)
Pemphigus vulgaris
Pemphigus vegetans
Pemphigus foliaceus
Pemphigus erythematosus
Paraneoplastic pemphigus
Drug-induced pemphigus
Neonatal pemphigus
Intercellular IgA dermatosis
Brazilian pemphigus

4. Autoimmune blistering diseases
Diseases with subepidermal blistering (pemphigoid group)
Bullous pemphigoid (BP)
Herpes gestationis
Cicatricial pemphigoid
Epidermolysis bullosa acquisita
Dermatitis herpetiformis (Duhring)
Linear IgA bullous dermatosis (LAD)
Bullous SLE

5. Diseases with intraepidermal blistering (pemphigus-group)
Pemphigus vulgaris
Pemphigus vegetans
Pemphigus foliaceus
Pemphigus erythematosus

6. Outline Middle-aged and elderly people are most commonly affected
Flaccid blisters
Two main groups: vulgaris & foliaceus
Nikolsky’s sign and Tzanck test are positive
Autoimmune diseases
Acantholytic intraepidermal blistering is produced by autoantibodies against desmoglein
Anti-desmoglein antibodies are detected by ELISA
In vivo IgG deposition and IgG antibodies are observed by immunofluorescence
Oral steroids & immunosuppressants are mainly administered.

7. Adhesion of keratinocytes
Keratinocytes are firmly adhered by desmosomes.
Transmembrane adhesion molecules in the cadherin superfamily, such as desmoglein 1 (Dsg 1), Dsg3, and desmocolin cadherin (DC), are important to intercellular adhesion.
In pemphigus, autoantibodies are produced against Dsg1 and Dsg3, some of whose molecular functions are disturbed. This causes acantholysis.

8. Acantholysis
Acantholysis: dissociation of intercellular connections in the epidermis.
As dissociation progresses, epidermal cleavage and blistering occurs.
Acantholytic cells: deformed keratinocytes become spherical from loss of intercellular connection within the blisters.

9. Tzanck test Tzanck test is a kind of cytological diagnosis method.
It is induced by applying a slide glass to the bottom of a broken blister and staining the adhered cellular components in Giemsa for observation under a light microscope.
Tzanck cells are acantholytic cells observed in pemphigus.
Tzanck cells can also be
observed in blisters of
herpes simplex and herpes
zoster, ballooning cells
produced by viral infection.

10. Nikolsky’s sign
Nikolsky's sign: blistering or exfoliation of the skin’s outmost layer produced by slight rubbing of the normal-looking skin
It is positive in pemphigus, epidermolysis bullosa, staphylococcal scalded-skin syndrome (SSSS), and toxic epidermal necrolysis (TEN).
Nikolsky's sign is useful in differentiating between pemphigus vulgaris (where it is present or positive) and bullous pemphigoid (where it is absent)
When the blisters are pressed without breaking, the fluid contents extend to the peripheral normal skin around the blisters (blister diffusion phenomena, or false Nikolsky’s sign)

11. Pemphigus vulgaris Pemphigus vegetans Pemphigus foliaceus Pemphigus erythematosus

12. Outline The most common variety of pemphigus
The disease most frequently occurs in the middle-aged and elderly.
The disease is caused by autoantibodies against desmoglein 3, which is a desmosomal adhesion factor in keratinocytes.
Acantholytic blisters form immediately above epidermal basal cells。
It tends to manifest as oral enanthema.
Nikolsky’s sign is positive.
Oral steroids and immunosuppressants are the first-line treatment.

13. Clinical features Most frequently affects the middle-aged and elderly
Erosions and ulcers develop acutely in the oral mucosa in 70-80% of cases
Blisters of various sizes occur on normal skin, easily rupture to form erosions and crusts
Painful, esp. when touched
Anywhere on the body, esp. at sites of pressure and friction (back, buttocks and feet)
Nikolsky’s sign
When widespread, electrolyte abnormalities due to loss of body fluid or hypoprotein
Be fatal when there is secondary infection

14. Workup
Pathology: acantholysis, intraepidermal blistering, leaving one basal layer at the bottom
Immunofluorescence: intercellular in vivo IgG deposition
ELISA: anti-Dsg3 IgG Ab, sometimes also anti-Dsg1 IgG Ab

15. Diagnosis Clinical features Pathology Immunofluorescence ELISA
DDx: bullous pemphigoid, impetigo, bullous
drug eruption, dermatitis herpetiformis,
erythema multiforme,
Stevens-Johnson syndrome, etc.

16. Treatment
Systemic application of steroids is the first-line treatment ( mg/kg/d).
Taper off to a maintenance dose or until it can be discontinued.
Immunosuppressants (mycophenolate mofetil, CTX, AZT, MTX, cyclosporine) may be used.
In intractable cases, plasma exchange therapy and IVIG can be performed.
Antibiotics, fluid transfusion, nutrition management are conducted supplementarily.

17. Pemphigus vulgaris Pemphigus vegetans Pemphigus foliaceus Pemphigus erythematosus

18. Clinical features
A subtype of pemphigus vulgaris, the most uncommon variety of pemphigus
Characterized by the formation of vesicles and erosions that do not re-epithelialize but gradually proliferate and elevate
Frequently occurs on areas of friction (axillary fossa, umbilical fossa, periphery of the oculonasal and perioral regions) and exposure (face, neck, scalp)
Oral mucosa is often involved
Strong odor

19. Workup
Pathology: suprabasal cell acantholysis, downward proliferation of rete ridges
Immunofluoscence: intercellular deposition of IgG and C3
Culture: bacteria and/or candida

20. Diagnosis Vesicles and erosions Areas of friction, exposure
Proliferate and elevate
Suprabasal cell acantholysis
DDx: chronic pyoderma and fungal granuloma,
Hailey-Hailey disease, condyloma
acuminatum, etc.

21. Treatment The same as for pemphigus vulgaris Treat local infections
Consider topical and systemic antibiotics
Consider antifungal agents for candida
Surgical excision of large vegetative growths
Better prognosis than pemphigus vulgaris

22. Pemphigus vulgaris Pemphigus vegetans Pemphigus foliaceus Pemphigus erythematosus

23. Outline Autoantibodies are produced exclusively against Dsg 1
Acantholysis and blistering are seen in the superficial epidermis (in the granular cell layer)
Fragile blisters, scaling and erosion, accompanied by crusts
Lesions are not/occasionally produced in the mucosa
Examinations and treatments are the same as for pemphigus vulgaris. The steroid dosage is usually less than for pemphigus vulgaris

24. Clinical features Most commonly affects the middle-aged and elderly
Extremely fragile flaccid vesicles
Some of the blisters dry to become leafy and to exfoliate successively
The face, head, back and chest are most commonly affected
When spreads over the whole body, it resembles exfoliative erythroderma
Mucosa is not or occasionally involved
Nikolsky’s sign is positive

25. Workup
Pathology: acantholytic blistering is found in the epidermal upper layer.
Immunofluorescence: intercellular in vivo IgG deposition is observed
ELISA: anti-desmoglein 1 antibodies

26. Diagnosis Clinical features Pathology Immunofluorescence ELISA
DDx: pemphigus vulgaris, pemphigus
erythematosus, drug-induced
bullous disease, paraneoplastic
pemphigus, etc.

27. Treatment The same as for pemphigus vulgaris
Oral steroid dosage may be less than that for pemphigus vulgaris
In limited involvement cases, topical steroid are sufficient

28. Pemphigus vulgaris Pemphigus vegetans Pemphigus foliaceus Pemphigus erythematosus

29. Clinical features A subtype of pemphigus foliaceus
Occurs most commonly in the middle-aged and elderly
Frequently affects the seborrheic zones (head, face, chest and back)
The mucosa is not involved
Involvement of SLE is seen in some cases

30. Workup
Pathology: intraepidermal superficial bullae within the granular layer or just below it. Acantholysis may occur in the blister floor or roof.
Immunofluorescence: linear deposits of IgG and C3 in the intercellular space of the epidermis
May have lab abnormalities of SLE

31. Diagnosis Clinical features Pathology Immunofluorescence
DDx: paraneoplastic pemphigus,
seborrheic dermatitis, lupus
erythematosus, pemphigus
foliaceus, etc.

32. Treatment
The same as for pemphigus foliaceus

33. Diseases with subepidermal blstering (pemphigoid group)
Bullous pemphigoid (BP)
Dermatitis herpetiformis (Duhring)

34. Outline
Subepidermal blistering occurs as a result of autoantibody action against epidermal basement membrane structural proteins
Blisters are tense and do not rupture easily
Divided into pemphigoid, linear IgA bullous dermatosis, epidermolysis bullosa acquisita, dermatitis herpetiformis, herpes gestations, etc.
Immunofluorescence is useful for diagnosis
Steroids and dapsone are applied

35. Basement membrane zone
the area corresponding to the dermo-epidermal junction
stains with periodic acid-Schiff
consists of
the basal cell plasma membrane
the lamina lucida
the basal lamina
the sub-basal lamina
fibrous components
acts as a mechanical barrier
and penetration of substance
between dermis and epidermis

36. Bullous pemphigoid (BP) Dermatitis herpetiformis

37. pathogenesis
Autoantibodies are produced against hemidesmosome, type XVII collagen (BP180) and BP230 in the epidermal basement membranes, which leads to blistering.
Autoantibodies against BP180 play a major role.

38. Outline Autoantibodies against hemidesmosomes
The major pathogenic antigen is type XVII collagen (BP180).
The roof of the blister has the full thickness of the epidermis
Elderly people account for the majority of cases
Characterized by subepidermal blisters
Blisters do not rupture easily
Oral steroids are effective

39. Clinical features The elderly are more commonly affected
Multiple relatively large and severe tense blisters form immediately
Often accompanied by edematous erythema
Much less invasively to the mucous membranes (20% involved)
The general condition is favourable
May be complicated by malignant tumors

40. Workup
Pathology: subepidermal blistering, accompanied by eosinophilic infiltration
Immunofluorescence: linear IgG and C3 deposition in the basement membranes
ELISA: autoantibodies against type XVII collagen (BP180) proteins
High IgE values and elevated levels of eosinophils in peripheral blood

41. Diagnosis Clinical features Pathology Immunofluorescence ELISA
DDx: drug-induced bullous disorders,
epidermolysis bullosa,
epidermolysis bullosa acquisita,
erythema multiforme,
dermatitis herpetifomis,
linear IgA dermatosis, etc.

42. Treatment Oral steroids (0.5mg/kg/d) Gradually reduced
Combination therapy of Immunosuppressants (CTX), DDS, tetracyclines and nicotinic-acid amide are also useful
Avoid secondary infections
Nutrition management is important for elderly
Topical steroid application may be sufficient in mild cases
Plasma exchange therapy and IVIG may also be used in severe cases

43. Bullous pemphigoid (BP) Dermatitis herpetiformis

44. Outline
Characterized by extremely intense itching and irritation, chronically recurrent erythema and vesicles
Vesicles tend to form circular patterns
Common in Caucasians, rare in Asians
Granular IgA deposition in the dermal papillary
Gluten-induced enteropathy develops as a complication
Oral dapsone is effective

45. Gluten composed of the sticky, storage proteins found in wheat
exist conjoined with starch in the same grass-related grains, notably wheat, rye and barley

46. Pathogenesis IgA antibodies against tissue transglutaminase
The granular IgA deposition in the skin is an immuno-complex

47. Clinical features Extremely intense itching
Erythema and urticarial lesions
Vesicles in a ring-shaped pattern
Scratch and resulted crusts
Heal with abnormal pigmentation or depigmentation
Appear symmetrically on the entire body, esp. on the elbows, knees and buttocks
Gluten-induce enteropathy is found in more than 90% of cases

48. Workup
Pathology: subepidermal blistering, micro-abscesses of neutrophils in dermal papillary
Immunofluorescence: granular IgA deposition in the dermal papillary

49. Diagnosis Clinical features Pathology Immunofluorescence
DDx: linear IgA bullous dermatosis,
bullous pemphigoid,
herpes gestationis,
erythema multiforme, ect.

50. Treatment
Dapsone is effective
Gluten-free diet
antihistamines