Pemphigus group of disorders

immunobullous intraepidermal disorders

1. Pemphigus Group of Disorders Dr . Kriti Maheshwari 1 st year Resident M.D. Skin & V.D.

2. Term ‘ pemphigus ’ refers to a group of autoimmune blistering disorders of skin and mucous membrane that are characterised histologically by intraepidermal blisters due to acantholysis and immunopathologically by in vivo bound and circulating immunoglobulins directed against the cells. It can broadly be categorize into 5 types : Pemphigus vulgaris (PV), Pemphigus foliaceus (PF), Pemphigus vegetans , Paraneoplastic pemphigus(PNP) and drug induced pemphigus.

3. The incidence of pemphigus worldwide varied widely 0.09% to 2%. Pemphigus is more common in Jews and in people of Mediterranean descent and from Middle East. In India Pemphigus occurs in younger age group (<45 years) as compared to western country. Male to female ratio is almost equal with few studies showing female predominance. Epidemiology

4. Genetic Determinants Susceptibility to pemphigus has been linked to HLA-DRB1 and HLA-DQB1. Jews are affected > non-Jews. Circulating PV- IgG antibodies have been detected in 40%–70% of sera of first-degree relatives of PV. Etiology and Pathogenesis

5. Environmetal factors: Thiols are present in garlic and onion. Phenols and tannins are present in high concentration in foods like nuts, mangoes, bananas and tomatoes. The earlier age of onset in Indians may be related to greater consumption of such foods. Sunlight exposure can worsen PV and Endemic PF.

6. Immunological factors: - Pemphigus antigens are desmogleins , transmembrane glycoproteins of desmosomes - Desmogleins are part of the cadherin superfamily of calcium- dependent cell adhesion molecules. - The PF antigen (as well as the fogo selvagem antigen) is desmoglein 1, a 160-kDa protein. The PV antigen is desmoglein 3, a 130-kDa protein - All patients with PV have antidesmoglein 3 antibodies, and some of these patients also have antidesmoglein 1 antibodies - PF patients typically have antibodies against only desmoglein 1

7. 1. Steric hindrance: Binding of auto-antibodies to their specific antigens can disrupt adhesion of the bound antigens by causing steric hindrance. Pathophysiology of Acantholysis

8. 2. Basal Cell Shrinkage Theory : - PV IgG -induced phosphorylation of adhesion molecules and structural proteins leads to weakening of intercellular junction and collapse of cytoskeleton respectively. - This leads to reorganization of the Keratinocyte cytoskeleton leading to cellular shrinkage and separation of keratinocytes. - Desmosomes do not split and disappear until late in acantholysis.

9. 3. Apoptolysis Hypothesis: The apoptolysis hypothesis links the basal cell shrinkage to suprabasal acantholysis and cell death and emphasizes that apoptotic enzymes contribute to acantholysis in terms of both molecular events and chronologic sequence. Pathogenic auto antibodies bind to keratinocytes and leads to elevation of intracellular Calcium which initiates cell death enzymatic caspases .

10. 4. Multiple Hit hypothesis: Involvement of multiple autoantibody specificities in pemphigus pathogenesis is explained through the “multiple hit hypothesis”. Anti- AChR antibodies trigger acantholysis by weakening cohesion between keratinocytes causing them to shrink and desmosomes to slough into intercellular spaces. The sloughed desmosomes stimulate production of antibodies that saturate epidermis and prevent desmosome formation by steric hindrance.

11. 5. Role of T cells: The role of T lymphocytes in the pathogenesis of pemphigus vulgaris is not clear, but auto reactive T cell responses to Dsg3 may be critical in its pathogenesis. These auto reactive CD4+ T cells preferentially produce Th2 cytokines such as IL-4 and IL-10. A disturbance in the regulatory mechanisms of Dsg3-specific T cells that leads to loss of tolerance at the B cell level leading to the production of a uto antibodies.

12. The most common subtype, pemphigus vulgaris (PV) presents with oral blisters and erosions in 50%–70% of patients. Skin lesions may appear after a period of several weeks to a year or more. The cutaneous lesions are vesicles and bullae on apparently normal or erythematous skin. Clinical Features – P. Vulgaris

13. They may be localized or generalized. The sites most commonly involved are the scalp, face, axillae and the oral cavity. The bullae are initially tense and clear, but become flaccid and turbid in two to three days. Blisters rupture easily to leave behind painful areas of oozing and denuded skin that continue to extend showing little tendency to heal. Erosions are a/w pain and lesions often become crusted.

14. It is a rare and more benign variant of PV. Two forms of Pemphigus vegetans Neumann (an early type with vesiculopustules ) Hallopeau types (later vegetating type) Pemphigus vegetations may resolve as such or may turn into classical PV lesions prior to resolution. Pemphigus Vegetans

15. Tumid, vegetating, papillomatous and hypertrophic plaques are formed in the intertriginous area and the flexural surfaces. Local moisture, heat and friction are important factors in their development. Characteristic glossal changes termed “ cerebriform Tongue” may be seen. Exuberant vegetating granules occur in the oral cavity as well.

16. Pemphigus foliaceus (PF) is characterized by small flaccid bullae with crusting and scaling. The initial lesions are scaly papules or superficial flaccid bullae on normal or erythematous skin. The bullae readily rupture, resulting in moist erosions and corn flake-like crusts . Lesions are usually sharply demarcated, as opposed to the extending erosions of pemphigus vulgaris. The seborrheic areas (i.e. face, scalp and upper trunk) are initially involved, but later the disease may become generalized and can present as erythroderma . Pemphigus Foliaceus

17. There is a characteristic musty odor. Small vesicles may be present along the borders of the lesions. Nikolsky’s sign is positive

18. It is a localized variant of PF characterized by erythematous scaly plaques, thin walled bulla and denuded areas, mostly on the butterfly area of the face, upper part of back, chest and intertriginous areas. Exacerbation of lesions on exposure to sunlight. The disease resembles pemphigus foliaceus in its lack of oral involvement. Patients have immuno -pathologic features of both pemphigus and lupus erythematosus (LE). PE is a distinct disorder that represents the concomitant presence of immunological abnormalities resembling those of LE. Pemphigus Erythematosus

19. Endemic pemphigus foliaceus (EPF) is a distinctive form of pemphigus that is clinically, histologically and immuno -pathologically identical to PF. A striking distribution of lesions on skin that is exposed to the sun. It occurs endemically in densely forested areas of South America, most commonly in Brazil, but disappears when the jungle is cleared. It is called name ‘ fogo selvagem ’ (Portuguese for ‘wild fire’). it is believed that endemic pemphigus foliaceus may be an infectious disease caused by a virus transmitted by a black fly. Endemic Pemphigus Foliaceus

20. The target antigen is Dsg1 in most cases, followed by Dsg3 in the remainder cases. It is characterized by herpetiform arrangement of tense vesicles and occurrence of pruritus (resembling DH). There may be erythematous or urticarial plaques with central healing and peripheral papulovesicles . Not severe as Pemphigus vulgaris but follows a chronic course. Treated with dapsone and low dose of prednisolone. Pemphigus Herpetiformis

21. Rare disease with neutrophilic infiltration and occasional acantholysis. k/a Intraepidermal neutrophilic (IEN) IgA dermatosis , Sub-corneal pustular dermatosis type, IgA PF, IgA Herpetiform pemphigus. Flaccid bullae or pustules are seen on normal or erythemtous skin. IgA Pemphigus

22. The pustules tend to coalesce in an annular or circinate pattern with central crusting, though a “sun-flower” configuration is more characteristic for IEN type. Dapsone is the drug of choice. Acitretin, topical steroid, PUVA therapy and colchicine have been used.

23. PNP is a rare autoimmune mucocutaneous blistering disorder characterized by an associated neoplasm and the presence of unique antibodies directed at desmosomal plakins . HLA-DRB1 allele was found in 61.5% of patients. Both humoral and cellular autoimmunity responses are involved in the pathogenesis. The antibodies are predominantly of the IgG1 subclass and directed at multiple auto antigens including members of the plakin family of cytoplasmic proteins as well as desmoglein 1 and desmoglein 3. Paraneoplastic pemphigus (PNP)

24. The majority of patients are between the ages of 45 and 70 years. The commonest clinical feature, which is also usually the earliest presenting sign, is recalcitrant stomatitis, seen as painful erosions and ulcerations of the oropharynx and vermilion border of the lips .

25. The different disorders associated with PNP include lymphoproliferative neoplasms like Non-Hodgkin’s lymphoma Chronic lymphocytic leukemia Castleman tumor ( growth of lymphoid tissue, usually in the mediastinum or retroperitoneum ) Waldenström’s macroglobulinemia , Thymoma (malignant and benign) Retroperitoneal sarcomas.

26. The causes of drug-induced pemphigus can be divided into two groups: Thiol drugs (SH)drugs, whose molecules contain a sulfhydryl or thiol group in their chemical structure (e.g. penicllamine , captopril , pyritinol , piroxicam and thiopronine ). Non- thiol drugs (e.g. penicillin, ampicillin , amoxicillin, cefadroxil , rifampicin , propranolol , phenytoin and phenobarbitone ). Drug Induced Pemphigus

27. Pemphigus vulgaris is the commonest form induced and PF seen in only 15%. The drugs appear to have stimulated the disease in those with a predisposition to develop pemphigus (“triggered pemphigus”) Possible mechanism could be a direct toxic effect of the drug or an allergic mechanism where pemphigus is induced by contact with plants containing polyphenolic compounds. Contact causes alteration in skin structure that leads o formation of neoantigens , which then provoke pemphigus auto antibodies. (thus called contact pemphigus)

28. Pregnancy may aggravate pemphigus. Adverse events such as preterm births or IUD can occur. A mother with pemphigus may passively transfer the antibodies to the fetus, leading to pemphigus in the newborn. The physiological variation in Dsg distribution in neonatal skin (both Dsg1 and Dsg3 are present in the upper layers, while Dsg3 is predominant in the suprabasal layer) as compared to adult skin accounts for a greater chance of a pregnant woman with PV (anti-Dsg3) antibodies delivering an affected child than a pregnant woman with PF (anti-Dsg1 antibodies). Neonatal Pemphigus

29. Myasthenia gravis Thymoma Polymyositis Sjögren’s syndrome Rheumatoid arthritis Lupus erythematosus Pernicious anemia Clinical Associations

30. Nikolsky’s Sign: The sign is elicited by applying tangential pressure with a finger or thumb to the affected skin, peri- lesional skin, or normal skin in patients with suspected pemphigus. It is termed positive if there is extension of the blister and/or removal of epidermis in the rubbed area. “Marginal Nikolsky's sign” describes the extension of the erosion on the surrounding normal-appearing skin by rubbing the skin surrounding existing lesions. “Direct Nikolsky's sign” is the induction of an erosion on normal-appearing skin, distant from the lesions. Bedside Tests

31. Nikolsky’s Sign

32. A positive direct Nikolsky’s sign indicates disease severity. Pseudo-Nikolsky’s sign is positive in Stevens-Johnson syndrome, toxic epidermal necrolysis and in some cases of burns and bullous ichthyosiform erythroderma . (the sign is positive due to necrolyis of cells and NOT acantholysis) False Nikolsky’s sign or Sheklakov’s sign is positive in sub-epidermal blistering disorders. It involves pulling the peripheral remnant roof of a ruptured blister, thereby extending the erosion on the surrounding normal skin.

33. It is considered positive when unidirectional pressure applied by a finger causes peripheral extension of the bulla beyond marked margin. Asboe -Hansen sign is a variation of bulla spread sign where the pressure is applied to the centre of the lesion (when the bulla is small) Bulla spread sign is positive in all varieties of pemphigus. In PV, the blister extension has a sharp angle, whereas in BP, the advanced border is rounded. Bulla Spread Sign/Lutz Sign

34. The base of an unroofed blister is gently scraped; the material obtained is gently smeared onto a clean glass slide, allowed to air dry and stained with Giemsa . Tzanck cell is a rounded keratinocyte with a hypertrophic or dysmorphic nucleus, hazy or absent nucleoli, with increased N:C ratio and a rim of eosinophilic cytoplasm. The staining is more intensely basophilic near the cell membrane (‘mourning edge’) because of cytoplasmic condensation at the periphery, resulting in a perinuclear halo. Tzank Smear

35. Pemphigus Vulgaris: T he earliest change seen is eosinophilic spongiosis . Loss of coherence between epidermal cells (acantholysis) leads to the formation of clefts and then of bullae in the suprabasal zone. The basal cells remain attached to the dermis, producing a ‘tombstone’ appearance Superficial dermis shows scant perivascular lymphocytic infiltrate. Investigations – Histopathological Examination.

36. shows a suprabasal cleft similar to that in PV. but it is dominated by papillomatosis and acanthosis with occasional formation of intraepidermal eosinophilic abscesses. Villi formation and downward proliferation of epithelial strands are more marked. The papillary and reticular dermal infiltrate is mainly of eosinophils . Pemphigus Vegetans - HPE

37. The cleft in pemphigus foliaceus is superficial, usually in the granular layer or right beneath it. It may develop into a bulla with acantholysis. Old lesion shows acanthosis and a mild degree of hyperkeratosis and papillomatosis . Dyskeratotic changes in the cells of the granular layer are diagnostic and is a frequently observed feature in old lesions. Pemphigus Foliaceus - HPE

38. The biopsy specimen is treated with fluorescein - labeled antibodies to human immunoglobulin. When the section is viewed under a fluorescence microscope, Fluorescence is seen at sites where the antibodies are bound Intercellular fluorescence is observed. DIF testing is best performed on biopsy specimens of apparently normal peri-lesional skin. Direct Immunofluorescence (DIF)

39. When seen under fluorescein microscope, antibodies are bound at the intercellular area which is similar in both PV and PF

40. In PV, IgG antibodies are predominantly seen in the intercellular space giving a green coloured FISH-NET appearance. In PF, fluorescence predominantly present in the superficial layers of epidermis

41. Indirect immunofluorescence (IIF) is a two-stage procedure for in vitro demonstration of circulating antibodies in the patient’s serum. The serum is added to a substrate, resulting in fixation of circulating antibodies to the antigen in the substrate. IIF testing of serum demonstrates circulating IgG antibodies directed against cell surface of keratinocytes in 90% of patients. Indirect Immunofluorescence

42. Enzyme-linked immunosorbent assays (ELISA) that detect IgG autoantibodies to Dsg1 and Dsg3 have also been developed. These assays are highly sensitive and specific for the diagnosis of both PF and PV, and simpler and more quantifiable than immunofluorescence . They are useful for distinguishing subtypes of PV and PF and for monitoring disease activity as well. ELISA

43. It helps to detect the location of antibody and complement deposits in the epidermis Immunoelectron microscopy

44. Early PV lesions may resemble: 1. Aphthous ulcers 2. Erythema multiforme 3. primary herpetic gingivostomatitis 4. Oral Candidiasis 5. Erosive LP PF may resemble : 1. Seborrheic dermatitis 2. Pustular psoriasis PE has to be differentiated from SD or LE. Differential Diagnosis

45. The most common causes of death are septicemia(d/t S. aureus ) and pulmonary embolism. Various prognostic factors I course of pemphigus are : 1. Type of pemphigus - PV & PNP have worst prognosis. 2. Age – elder patients have poorer prognosis than younger ones. 3. Disease progression before starting therapy – patients with minimal disease activity for longer periods have better prognosis. 4. Involvement of mucosa or skin – patients with only cutaneous lesions have better prognosis than those with mucosal involvement Course and prognosis

46. Treatment

47. Mild cases of pemphigus can sometimes be treated by topical therapy alone. Topical clobetasol proprionate can be used. It is particularly useful in treating localize relapses after controlling the disease. Topical tacrolimus has also been found to be effective in such localized and refractory lesions. Topical EGF significantly reduces the healing time of skin lesions in patients with PV Intralesional triamcinolone acetonide (5-10 mg/ml) is helpful for intractable oral ulcers and cutaneous lesions respectively. Topical therapy

48. Systemic Corticosteroids It is mainstay of treatment of pemphigus and prednisolone is the preferred drug. For mild to moderate disease, the starting dose of prednisolone is 60–80 mg/day, for severe disease treatment is started with 80–120 mg/day and can be up to 180-240mg/day. The dose can be stepped up in increments of 50% every 4–7 days until the disease activity is controlled (i.e. no new lesions) Tapering off by 50% every 2 weeks is started only after 80%–90% of the lesions have healed. Concomitant immunosuppressive or other adjuvants are advocated if there are relative contraindications to the use of corticosteroids

49. Day 1 - IV administration of 100 mg of dexamethasone (equivalent to 667 mg of prednisolone) in 500 ml of 5% dextrose over 3 hours. Day 2 - 500 mg of cyclophosphamide is dissolved in the same infusion on the second day. Day 3 - 100 mg of dexamethasone in 500 ml of 5% dextrose. These pulses are repeated every 28 days. Also patient recieves 50 mg of cyclophosphamide orally every day. Dexamethesone Cyclophosphamide Pulse (DCP)

50. Azathioprine : most commonly used adjuvants for Pemphigus. Less effective than Cyclophosphamide . It is less toxic, lower risk of infertility and lower lifetime risk of malignancy, making it suitable for the younger populations. The usual dose is 2-4mg/kg/day. Cyclophosphamide : Apart from DCP regime, Cyclophosphamide pulse can be given at the interval of 28 days. Cyclophosphamide 15mg/kg is dissolved in 200ml of 5% Dextrose and infused over one hour. It is followed by hydration with 500ml of 5% dextrose given intravenously over 4 to 5 hours. Immunosuppresive Agents

51. Mycophenolate Mofetil : (MMF) MMF is an antimetabolite that inhibits the de novo pathway of purine synthesis in T and B cells by selectively inhibiting inosine monophosphate dehydrogenase enzyme. It is usually given along with corticosteroid. P atients shows faster response. Dose - 1gm BD, taken orally. Cyclosporine: Cyclosporine (3–6 mg/kg body weight per day) has been used in combination with steroids in patients otherwise unresponsive to moderate doses (1 mg/kg per day) of prednisolone. Cyclosporine suppresses cellular immunity resulting in reduced expression of several lymphokines .

52. Methotrexate MTX can be used as a adjuvant drug along with corticosteroid. Unresponsive to DCP showed good response when patients were treated with DMP pulse. (C is susbstituted with weekly dose of MTX) Dapsone Although dapsone alone in the dose of 100–300 mg per day has been tried, there are no studies to support the claim that it is truly effective when administered alone. However, it has been found very useful as a steroid- sparing agent. The maintenance dose of corticosteroids could be reduced by 50%.

53. Rituximab IV Ig Plasmapheresis Pulsed IV high dose Glucocorticoids Immunoadsorption Extracorporeal photochemotherapy TNF α antagonists Cholinergic agents Additional therapies

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