Auto immune disorders of the oral cavity

ppt

1. Auto-immune disorders of the oral cavity By Dr.Prashanth

2. Introduction Auto immunity – production of auto antibodies against one’s own body constituents and the disease is the manifestation of such aberrations In oral cavity auto antibodies are directed against the components of the epithelium, either against the cell attachments like desmosomes or cell to basement membrane attachment like hemi- desmosomes or against the basement membrane itself.

3. Epithelial attachment apparatus

4. Related terminologies Vesicle – superficial blister, 5mm or less in diameter, usually filled with clear fluid Bulla – large blister greater than 5mm in diameter Pustule – blister with pus Ulcer – loss of surface epithelium, often appears depressed Erosion – which arise secondary to rupture of a vesicle or bulla

5. Lab tests Direct immunofluorescence In-direct immunofluorescence

6. Pemphigus Pemphigus   is a rare group of blistering autoimmune diseases that affect the skin and mucous membranes.  The name is derived from the Greek word " pemphix ," meaning "pustule.“ Four types of pemphigus exist among which pemphigus vulgaris is most common : Pemiphigus vulgaris Pemphigus vegetans Pemphigus erythematosus Pemphigus foliaceus Only vulgaris and vegetans affect the oral cavity.

7. Pemphigus vulgaris Latin ‘ vulgaris ’ means ‘common’ Oral lesions are called as ‘ first to show and last to go’ If untreated may result in death Shows intra- epithelial blister formation Auto antibodies are produced against desmoglein-3 and 1 The desmogleins are the components of the desmosomes , which are targeted in this disease

8. Pathogenesis

9. Eitiology –triggering factors Genetic predisposition to class II HLA antigen Drugs – captopril , penicillin, rifampicin Radiation Surgery Diet – garlic Stress Virus –HHV8 Pesticide exposure Pregnant females

10. Clinical features Typically an adult disease, rare cases may be seen in children Average age is around 50 years Oral examination shows , superficial, ragged erosions and ulcerations distributed haphazardly on the oral mucosa Palate, labial mucosa, buccal mucosa,ventral tongue and gingiva are common sites Vesicles and bulla are rarely seen because of easy and early rupture Over 50% of people show oral lesions before skin lesions , sometimes a year before

11. Signs in pemphigus vulgaris Nikolsky sign - in patients with active blistering, firm sliding pressure with a finger separates normal-appearing epidermis, producing an erosion. This sign is not specific for pemphigus vulgaris and is found in other active blistering diseases. Asboe -Hansen sign - lateral pressure on the edge of a blister may spread the blister into clinically unaffected skin.

12. Histopathology Show intra epithelial separation just above the basal cell layer Spinous cell layer shows – acantholysis Loose cells of spinous layer show round shape – tzanck cells

13. Direct immunofluorescence Confirmatory procedure Antibodies can be demonstrated in the intercellular spaces - fishnet/scale or chicken mesh wire pattern

14. Treatment Systemic corticosteroids Immunosuppressive drugs ( steroid –sparing) – azathioprine Topical corticosteriods in oral lesions

15. Paraneoplastic pemphigus Rare disorder that affects patients with a neoplasm usually lymphoma or chronic lymphocytic leukemia Occurs due to cross reactivity between the antibodies produced against tumor antigens Sometimes this lesion develops before the commencement of the lymphoreticular neoplasm Multiple vesiculobullous lesions develop both on the skin and oral mucous membrane Lips show hemorrhagic crusting and conjunctiva shows cicatrizing Histopathology shows both intra-epithelial and sub-epithelial clefting Treating the underlying tumor reduces the symptoms

16. Cicatricial pemphigoid (benign mucous membrane pemphigoid ) Chronic vesiculobullous autoimmune disease in which auto-antibodies are produced against one or more components of the basement membrane Cicatrix – means scar, pemphigoid – appears similar to pemphigus Risk factor lies in cicatricial conjuctivitis resulting in blindness Oral lesions rarely exhibit scarring

17. Clinical features Affects older individuals with an average age of 50 -60 years Females commonly affected Oral mucosa, conjunctiva, genital mucosa, nasla mucosa and skin are affected Begins as a large bulla that eventually ruptures to form an ulcer The ulcers are very painful and persists for weeks together if left untreated Complication is cicatricial conjunctivitis and loss of vision

18. Histopathology Split between surface epithelium and underlying connective tissue Direct immunofluorescence shows a continuos linear band of fluorescence at the basement membrane zone Indirect immunofluorescence is positive only in 5% of cases For accurate diagnosis perilesional tissue should be obtained during biopsy

19. Treatment Ophthalmic complications will be best addressed by an ophthalmologist Oral lesions are treated by proper oral hygiene maintenance and topical corticosteroids Systemic corticosteriods in case if the disease is severe

20. Bullous pemphigoid Most common autoimmune blistering disease Auto-antibodies are directed against the components of basement membrane Resembles cicatricial pemphigoid , but with certain differences One such difference is clinical course in bullous pemphigoid is limited, whereas in cicatricial it is severe

21. Clinical features Develops in older age people who are between 60 to 80 years of age No age or gender predilection seen Pruritus is the earliest sign, followed by multiple tense bullae on normal or erythematous skin These lesions rupture and form a superficial crust and eventually heal without scarring Oral mucosa shows rare involvement, bullae form and tend to rupture early to form ulcers

22. Histopathology Split at basement membrane from the connective tissue Presence of eosinophils within bulla is characteristic Direct immunofluorescence shows linear band of immunofluorescence at basement membrane zone 60% of people show similar pattren in indirect immunofluorescence

23. Treatment Systemic immunosuppresive therapy Oral lesions are treated with topical corticosteroid therapy

24. Erythema multiforme Erythema multiforme – erythematous skin lesions; in a variety of appearances It is a blistering ulcerative mucocutaneous condition of uncertain etiopathogenesis Associated with herpes simplex infection- hypersensitivity reaction Drugs – antibiotics and analgesics Sophisticated techniques of molecular biology have demonstrated herpes DNA in patients with recurrent erythema multiforme

25. Clinical features Acute onset Prodromal symptoms are seen one week before the commencement of the disease Early skin lesions are flat, round, dusky red colored Later stages they become slightly elevated to become a bulla with necrotic centers The characteristic skin lesions appear as concentric circular erythematous rings resembling a ‘TARGET’ or ‘BULL’S EYE’ –seen in more than 50% of people.

26. Clinical features Types - Erythema multiforme minor - Erythema multiforme major also called as Stevens- Johnson syndrome -Toxic epidermal necrolysis or Lyell’s disease Oral lesions begin as erythematous patches and evolve into large, shallow erosions with irregular borders Hemorrhagic crusting of lips is commonly seen These oral ulcerations are painful and patient avoids drinking fluids and easily becomes dehydrated

27. Stevens – Johnson syndrome ( erythema multiforme major) Triggered by drugs For the diagnosis of Stevens-Johnson syndrome either ocular or genital mucosa should be affected in conjugation with oral and skin lesions. Ocular involvement sometimes may result in loss of vision

28. Toxic epidermal necrolysis Most severe form of erythema multiforme Almost always triggered by drug exposure Diffuse sloughing of epidermis occurs resulting in badly scalded appearance of patient Female predilection If patient survives , resolves in 3-4 weeks

29. Histopathology Characteristic but not pathognomonic Sub-epithelial or intra epithelial bulla formation Necrotic basal cells Mixed inflammatory infiltrate , which are sometimes arranged peri-vascularly .

30. Treatment Systemic corticosteriods If causative drug is identified should be stopped Patient should be rehydrated Herpes simplex infection should be treated Intravenous administration of pooled human immunoglobulins is used in Stevens – Johnson syndrome and toxic epidermal necrolysis

31. LICHEN PLANUS Chronic auto-immune dermatological disease that often affects oral mucosa Erasmus Wilson described the condition first time in 1869 Planus – flat ; lichen – algae like growth on rocks and trees A similar condition is called lichenoid reaction that develops due to drugs or foreign body reaction A relationship exists between mental stress and disease expression

32. Clinical features Middle aged adults are more affected than children Women more affected than men Prevalence of oral lichen planus is more than skin lichen planus Skin lesion exhibit 3p’s – purple, pruritic and polygonal papules Exhibit Kobner’s phenomenon and surface of papule show thin lace like network of white lines called Wickham’s striae Occurs on the flexor surface of the extremities

33. Types Clinically Six types Reticular (fine white striae cross each other in the lesion) Atrophic (areas of erythematous lesion surrounded by reticular components) Papular type Bullous type Plaque type Erosive or ulcerative type

34. Reticular type Reticular and erosive are common types and reticular type is more common than erosive type Reticular type occurs in the buccal mucosa bilaterally and asymptomatic Named as reticular type because of its characteristic pattern of interlacing white lines – here also called as Wickham’s striae Lesions are not constant, they wax and wane over months Can also involve other areas of mouth specially tongue

35. Erosive type Lesions are symptomatic unlike reticular type which is asymptomatic Ulcerations are seen along with peripheral radiating white striae On gingiva causes desquamative gingivitis On tongue shows varying degrees of depapillation and ulceration , which resolves to normal after therapy

36. Papular type Plaque type Atrophic type Bullous type

37. Histopathology Hyperkeratosis Acanthosis – increased thickness of spinous layer Saw- tooth shaped rete ridges Destruction of basal cell layer – hydropic degeneration Sub epithelial band of lymphocytic infiltration Civatte bodies – also called as colloid bodies, cytoid bodies or hyaline bodies – degenerating keratinocytes at the epithelium and connective tissue interface DIF - Deposition of fibrinogen in a shaggy pattern along the basement membrane zone (BMZ)

38. Civatte bodies

39. Pathogenesis ( i ) Why and how do T-cells accumulate in the superficial lamina propria in OLP? (ii) Why and how do T-cells enter the oral epithelium in OLP? and (iii) What triggers basal keratinocyte apoptosis in OLP? Both antigen-specific and non-specific mechanisms might be involved

40. i ) Why and how do T-cells accumulate in the superficial lamina propria in OLP? Two types of lymphocytes – cytotoxic CD8+ cells and non cytotoxic CD4+ cells Antigens – drugs, allergens or virus ( i ) on routine surveillance in the epithelium and encounter the keratinocyte antigen by chance (“chance encounter” hypothesis) or (ii) attracted to the epithelium, along with T-cells of irrelevant specificity, by keratinocyte -derived chemokines (“directed migration” hypothesis).

41. Why and how do T-cells enter the oral epithelium in OLP? Inability of basal keratinocytes to repair routine damage to Basement membrane Keratinocytes release chemokines that attract CD8+ cells

42. What triggers basal keratinocyte apoptosis in OLP? ( i ) T-cell-secreted TNF-a binding TNF-a receptor 1 (TNF R1) on the keratinocyte surface, (ii) T-cell surface CD95L ( Fas ligand ) binding CD95 ( Fas ) on the keratinocyte surface, or (iii) T-cell-secreted granzyme B entering the keratinocyte via perforin -induced membrane pores.

43. Non-specific mechanisms Inability to repair BMZ damage by basal keratinocytes , the damaged basement membrane triggers the apoptosis Up regulation of MMPs Mast cell recruitment and degranulation and release of pro-inflammatory mediators Up regulation of TNF-a – adhesion increased –hyperkeratosis Epithelial cells release RANTES, a chronic inflammatory cell mediator – up regulated in OLP

44. Triggering factors Genetic background Dental materials Drugs Infectious agents Allergens Stress Trauma Malignancies Diabetes

45. Malignant potential Controversial A small percentage develops into oral squamous cell carcinoma

46. Treatment Topical corticosteroids Intralesional injections Treatment of superimposed candidiasis if exists

47. Psoriasis Chronic skin disorder Characterized by increased proliferative activity of keratinocytes , turn over rate is reduced to 3 -4 days in affected areas from normal 23days. Triggering factors are yet to be identified Activated T-lymphocytes lead to secretion of cytokines and adhesion molecules Genetic factors also play a role Autoimmune etiology may also be involved

48. Clinical features Onset during second or third decade of life and persists for years Periods of exacerbation and quiescence are seen Lesions improve during summer and worsen during winter : exposure to UV light reduces the lesions Lesions are small, sharply delineated dry papules covered by thin silver scales, and when these scales are removed one or more tiny bleeding points are seen , a characteristic feature known as AUSPITZ’S SIGN

49. Lesions are often symmetrically distributed in certain favored locations such as scalp, elbows and knees Oral lesions are very rare , some investigators prefer to call Erythema migrans /benign migratory glossitis as oral form of Psoriasis

50. Histopathology Increased parakeratosis Thin elongated rete ridges – test tube shaped rete ridges Connective tissue papillae contain dilated capillaries approach close to the epithelial surface - responsible for bleeding points Collections of neutrophils are seen in the parakeratin layer – Munro’s abscess

51. Treatment UV light therapy Topical corticosteriods Keratolytic agents Vitamin D Methotrexate Cyclosporin

52. Classification of vesiculo – bullous lesions Fitzpatrick classification According to separation at intraepithelial level

53. According to separation at dermoepidermal junction

54. Diagrammatic representation of vesiculobullous disorders

55. Lupus erythematosus Auto immune condition , common collagen vascular disorder 3 types – a. systemic lupus erythematosus b. chronic cutaneous lupus erythematosus (skin lesions are called Discoid lupus erythematosus ) c. subacute cutaneous lupus erythematosus Systemic LE – multisystem disease where increase in the activity of B-lymphocytes occur in conjugation with abnormal functioning of T-lymphocytes CCLE( discoidLP ) – primarily affects skin and oral mucosa and prognosis is good SCLE has clinical features in between SLE and CCLE

56. Systemic lupus erythematosus Auto immune disorder , immune complex formation occurs and cause damage to kidneys, skin , blood cells and CNS Genetics , hormonal imbalance, environmental factors like sunlight, drugs etc trigger the disease May be symptomless for years or may be acute with life threatening consequences Early diagnosis and treatment will improve the prognosis

57. Clinical features It is a cutaneous - systemic disorder Third or fourth decade onset Female predilection is more The skin lesions usually occur on face and are called butterfly type of distribution - erythematous patches coalesce to form a roughly symmetrical pattren over the cheeks and across the bridge of the nose Lesions can also be seen on neck, upper arm, shoulders and fingers Lesions show itching or burning sensation

58. General or systemic manifestations show involvement of kidney, heart and other vital organs Kidneys show fibrinoid thickening of glomerular capillaries - renal insufficiency Heart shows endocarditis , which inculde valves ( Libman -Sacks endocarditis ), epicardium and myocardium Blood disorders include anemia, thrombocytopenia etc Oral mucosa shows ulcers surrounded by a red halo Sometimes oral mucosa show ulcerations of lower lip and called as lupus cheilitis Oral lesions occur only in 25% of people

59. Chronic cutaneous lupus erythematosus (Discoid LE) Few or no systemic signs Skin lesions are called as discoid lupus erythematosus Lesions appear as scaly, erythematous patches that are distributed on sun exposed areas, especially in head and neck Lesions heal in one area and appear in another area Healing results in scarring Oral manifestations are similar to erosive lichen planus , but here the lesions are always associated with skin lesions Oral lesions are painful , particularly when exposed to acidic or salty foods

60. Subacute cutaneous LE Clinical manifestations are intermediate between other two types Skin lesions are prominent features of this type No scarring upon healing No renal or cardiac abnormalities Only arthritis or musculoskeletal pain

61. Histopathology Show some features in common but with certain distinguishing features Skin lesions of CCLE – hyperkeratosis with keratin packed into openings of hair follicles ( follicular plugging) Degeneration of basal cells is seen in all forms Dense aggregates of lymphocytes are seen in connective tissue In deeper connective tissue , the inflammatory infiltrate surrounds the small blood vessels

62. Oral lesions show hyperkeratosis, alternating atrophy and thickening of spinous layer , degeneration of basal cell layer and sub-epithelial lymphocytic infiltrate Distinguishing factors from lichen planus are patchy deposits of PAS positive material in BMZ , subepithelial edema and perivascularly oriented deep inflammatory infiltrate DIF easily distinguishes LE from lichen planus

63. Lupus band test DIF testing of lesional tissue shows deposition of one or more immune reactants (usually IgM , IgG or C3 ) in a shaggy or granular band at the BMZ In adition , DIF testing of normal skin also shows a similar deposition - this finding is known as positive lupus band test

64. Treatment Avoiding exposure to sunlight Anti inflammatory agents Anti malarial drugs Immunosuppressive drugs Low dose thalidomide Topical corticosteriods in case of oral lesions