MetLife designates this activity for 1.0 continuing education credit for the review of this Quality Resource Guide and successful completion of the post test. Quality Resource Guide FOURTH EDITION Oral Ulcerative and Vesiculobullous Diseases – Part 2

Pemphigus Vulgaris Educational Objectives Author Acknowledgements emphigus vulgaris is a life-threatening, James J. Sciubba, DMD PhD Following this unit of instruction, the autoimmune, mucocutaneous disease Professor, The Johns Hopkins School practitioner should be able to: characterized by intraepithelial blister formation. of Medicine P The Milton J. Dance Head and Neck Center The characteristic blisters develop from a breakdown or 1. Recognize the clinical presentation of The Greater Baltimore Medical Center loss of keratinocyte to keratinocyte adhesion, producing Baltimore, Maryland vulgaris, mucous membrane epithelial cell separation known as . Dr. Sciubba has no relevant and oral lichen planus. Widespread mucocutaneous ulceration following rupture financial relationships to disclose. of the blisters leads to painful debilitation, fluid loss, and 2. Gain an appreciation of oral mucosal The following commentary highlights fundamental and commonly accepted autoimmune disease presentation. Figures 1 and 2 practices on the subject matter. The information is intended as a general 3. Recognize the antigenic specificity in overview and is for educational purposes and mucous membrane only. This information does not constitute legal advice, which can only be provided by pemphigoid and their anatomic location. an attorney. © Metropolitan Life Insurance Company, 4. Appreciate the varied presentations of oral New York, NY. All materials subject to this copyright may be photocopied for the lichen planus. noncommercial purpose of scientific or educational advancement. 5. Understand the treatment options for lichen Originally published June 2006. Updated planus, pemphigus vulgaris and mucous and revised September 2009, April 2012 and November 2015. Expiration date: membrane pemphigoid and potential December 2018. The content of this Guide morbidities, with the need to manage these is subject to change as new scientific information becomes available. in conjunction with the patient’s physicians if systemic agents are to be employed. MetLife is an ADA CERP Recognized Provider. Introduction ADA CERP is a service of the American Pemphigus Vulgaris Dental Association to assist dental professionals in identifying quality iseases of the oral mucosa are common, affecting providers of continuing dental education. essentially all individuals at some point in their electrolyte imbalance. Before the use of corticosteroids, ADA CERP does not approve or endorse individual courses or instructors, nor does it lives. While most conditions are self-limiting, death was not an uncommon outcome for patients D imply acceptance of credit hours by boards short-lived and minimally bothersome, others may be with pemphigus vulgaris. Only pemphigus vulgaris and of dentistry. chronic, disabling and, though uncommon, life-altering or involve the oral mucosa. Pemphigus Concerns or complaints about a CE provider life-threatening, either as a direct effect of the disease or vegetans is very rare and is generally considered a may be directed to the provider or to ADA CERP at www.ada.org/goto/cerp. variant of pemphigus vulgaris. The overall incidence is up the medications necessary to control the condition. Accepted Program Provider FAGD/MAGD to 0.7 per 100,000 person years, with greater risks noted Credit 11/01/12 - 12/31/16. While not complete, this two part series will describe in certain subpopulations, particularly Ashkenazi Jews, Address comments to: five conditions in a comprehensive but brief manner. A and inhabitants if India, the Middle East and southeast [email protected] greater depth of understanding in terms of mechanisms, Europe. A higher incidence is associated with increasing MetLife Dental treatment and current directions of research in each age. Women are affected in approximately two-thirds of Quality Initiatives Program 501 US Highway 22 area are noted within the Further Reading section. cases. Bridgewater, NJ 08807 www.metdental.com Quality Resource Guide – Oral Ulcerative and Vesiculobullous Diseases Part 2 - 4th Edition

Etiology and Pathogenesis A drug-induced form of pemphigus also may be in Ashkenazic Jews and in individuals with certain All forms of the disease retain distinctive seen in which lesions arise in response to use of histocompatibility antigen phenotypes (HLA-DR, presentations both clinically and microscopically but thiol group drugs, most commonly penicillamine HLA-A10, HLA-B, HLA-DQB, HLA-DRB1). and captopril, in addition to cephalosporins, share a common autoimmune etiology. Evident are Other autoimmune diseases may occur in penicillins, enalapril, rifampin and nonsteroidal circulating autoantibodies of the immunoglobulin association with pemphigus vulgaris, such anti-inflammatory agents. G type (IgG4) that are reactive against and bind to as myasthenia gravis, erythematosus, components of epithelial desmosome-tonofilament Clinical Features rheumatoid arthritis, Hashimoto’s thyroiditis, complexes, more specifically, the epithelial Lesions of pemphigus present as painful superficial thymoma, and Sjogren’s syndrome. A wide age adhesion molecules (cadherin family) within these ulcers that are preceded by flaccid vesicles or bullae range has been noted from childhood to the elderly submicroscopic structures. In pemphigus vulgaris, (Table 1). The first signs of the disease appear in age-groups, although most cases are noted within the specific protein target within the oral mucosal the oral mucosa and oropharynx in approximately the fourth and fifth decades of life. epithelium has been identified as desmoglein 3, 80% of cases, with all untreated cases ultimately Histopathology and one of several proteins in the desmosomal complex. developing oral lesions. Oral mucosal lesions may Immunopathology The circulating autoantibodies are responsible for precede the onset of cutaneous lesions by periods of Pemphigus vulgaris demonstrates intraepithelial the earliest morphologic event: the dissolution or up to one year. Bullae rapidly rupture, leaving a red, clefting with keratinocyte acantholysis. Loss disruption of intercellular junctions and loss of cell- painful, ulcerated base. Ulcers range in appearance of desmosomal attachments and retraction of to-cell adhesion. The ease and extent of epithelial from small aphthous-like lesions (Figure 1) to large tonofilaments result in free- floating, or acantholytic, cell separation are generally directly proportional to irregularly-shaped lesions (Figure 2). Gentle traction Tzanck cells. Bullae and epithelial separation are the titer or concentration of circulating desmoglein on clinically unaffected mucosa at the edge of an suprabasal in location. The basal layer remains antibody. While still debated, it was formerly believed existing ulcer may produce stripping of epithelium, attached to the basement membrane, producing a a positive Nikolsky sign. A great deal of discomfort that the pemphigus antibody, once bound to the so-called “row of tombstones” configuration. target antigen, activates an epithelial intracellular often occurs with confluence and ulceration of proteolytic enzyme or group of enzymes that act smaller vesicles of the soft palate, buccal mucosa, In addition to a standard biopsy, confirmation of at the desmosome-tonofilament complex. More and the floor of the mouth. pemphigus vulgaris can routinely be made with the use of direct immunofluorescence (DIF) testing. DIF recent evidence, however, favors a direct effect of The incidence of pemphigus vulgaris is equal testing uses a biopsy specimen in an attempt to the antibody on desmoglein structure and integrity in both genders. Genetic and ethnic factors demonstrate autoantibody already attached to the by way of altered signal transduction, triggering appear to predispose to the development of the tissue. This is preferable to less sensitive indirect cell separation. disease. An increased incidence has been noted immunofluorescence, which uses patient serum to identify circulating antibody. In pemphigus vulgaris, Table 1 - Pemphigus Vulgaris DIF testing of perilesional tissue almost always demonstrates intercellular autoantibodies of the Etiology IgG subtype within the suprabasal region of the epithelium, and less commonly IgA within the • Autoimmune reaction to intercellular keratinocyte protein (desmoglein 3) same region and with the same pattern. Activated • Autoantibodies cause intraepithelial blisters complement (C3) is also noted to co-localize with IgG in almost all instances where IgG staining Clinical Features is positive. An additional serum-based study • Affects skin and/or mucosa that is very sensitive (>90%) for identification of pathogenic antibodies is the enzyme-linked • 80% or more of cases begin in the mouth (“first to show, last to go”) immunosorbent assay (ELISA). • Presents as ulcers preceded by vesicles or bullae Differential Diagnosis • Persistent and progressive Clinically, the oral lesions of pemphigus vulgaris must be distinguished from other vesiculobullous Treatment and ulcerative diseases, especially mucous • Controlled with immunosuppressive agents (corticosteroids, mycophenolate and membrane pemphigoid, erythema multiforme, and azathioprine/cyclophosphamide) and monoclonal antibody infusion aphthous ulcers. Also, a rare syndrome known • High mortality when untreated (dehydration, electrolyte imbalance, malnutrition, as may simulate ) pemphigus vulgaris. Patients with this syndrome will have a lymphoma or other malignancy and a www.metdental.com Page 2 Quality Resource Guide – Oral Ulcerative and Vesiculobullous Diseases Part 2 - 4th Edition mucocutaneous pemphigus-like blistering disorder Mucous Membrane Pemphigoid Clinical Features in which intraepithelial separation (acantholysis) (Cicatricial Pemphigoid) MMP is typically relapsing and remitting, a chronic is seen, as can subepithelial separation. Unlike ucous membrane pemphigoid (MMP) disease of adults and the elderly that tends to pemphigus, the autoantibodies are directed at several is a group of chronic blistering or affect women more than men. MMP has rarely antigenic targets, in both epithelium and basement been reported in children. Oral mucosal lesions membrane zones. The underlying malignancy is M vesiculobullous diseases predominantly typically present as inflamed, eroded and painful believed to be responsible for the induction of the affecting oral and ocular mucous membranes, but superficial ulcers (Figure 2), often limited to attached broadly directed autoimmune response. rarely involving the skin. MMP diseases are also known as cicatricial pemphigoid, benign mucous gingiva, and less commonly, the buccal mucosa, with accompanying intense erythema and tenderness Treatment and Prognosis membrane pemphigoid, ocular pemphigus, with ease of desquamation and mucosal friability The high morbidity and mortality rates previously childhood pemphigoid and mucosal pemphigoid. associated with pemphigus vulgaris have been (Table 2). Bullae are uncommonly seen as the reduced since the introduction of systemic Etiology and Pathogenesis blisters are short-lived. Lesions are chronic and corticosteroids and later, steroid-sparing agents. MMP is an autoimmune process with an persistent, and may heal with a scar (cicatrix) – The reduction in mortality, however, does carry unknown stimulus. Deposits of immunoglobulin particularly with lesions involving the conjunctival a degree of iatrogenic morbidity associated with and complement components along the basement mucosa, but lesser so in the oral cavity. Here there is chronic corticosteroid and immunosuppressive drug zone (on DIF testing) are characteristic. The the risk of lid adhesion to the globe (symblepharon), use. Disease control can usually be achieved with antigenic targets are many and include laminin inversion of the eyelashes (entropion), and resultant an intermediate dose of steroid (prednisone), along 332 (epiligrin), other laminin subunits, alpha 6 trauma to the cornea (trichiasis). To prevent corneal with nonsteroidal forms of immunosuppression beta-4 integrin, and a 180-kd protein that is damage, many patients with ocular pemphigoid including but not restricted to mycophenolate also known as antigen 180 will have their eyelashes permanently removed by mofeteil (Cellcept®). For more severely affected (BP180). Circulating autoantibodies against the electrolysis. Extraoral sites in the order of frequency patients, a high- dose corticosteroid regimen plus following oral mucosa are the conjunctiva, skin, other immunosuppressive drugs with or without basement membrane zone (BMZ) antigens in larynx, genitalia, nasal cavity, larynx, and esophagus. plasmapheresis (plasma exchange) may be MMP are usually difficult to detect by routine Cutaneous lesions are uncommon and usually necessary. The use of the anti CD 20 monoclonal methods, presumably because of relatively low appear in the head and neck and extremities. antibody, rituximab (Rituxan®) may be used in serum levels. Other antigenic subsets or targets refractory cases with or without intravenous IgG. within the basement membrane region have Topical corticosteroid applications may be used been described, however, these are relatively Figure 2 intraorally as an adjunct to systemic therapy. uncommon.

Table 2 - Mucous Membrane Pemphigoid

Etiology • Autoimmune reaction to basement membrane proteins (including laminin 5 and BP180) • Autoantibodies cause subepithelial blisters Mucous Membrane Pemphigoid Clinical Features • Oral mucosa (gingival often only site) and conjunctiva; skin rarely affected Figure 3 • Present as ulcers/redness in older adults (over 50 years of age) • Persistent, uncomfortable to painful

Treatment • Usually symptomatic and supportive • Controlled with corticosteroids; sometimes resistant to systemic therapy; topical agents useful • Significant morbidity if untreated, including pain and scarring, especially of eye Mucous Membrane Pemphigoid

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Gingival lesions typically present as ulcers Treatment and Prognosis Although oral MMP has a relatively benign clinical extending to unattached gingival mucosa with Corticosteroids are typically used to control MMP. course, significant debilitation and morbidity lasting associated mild-to-moderate discomfort (Figure 3). Topical steroids can be used as monotherapy for years can occur. Natural history is unpredictable; Concomitant ulcers may be seen on marginal for most cases of oral MMP or as an adjunct to in some cases a slow spontaneous improvement and attached gingiva. With chronicity, the pain systemic treatment. Prednisone is used for control may be noted, whereas in other cases the course associated with oral MMP typically diminishes of moderate to severe disease and long term may be especially protracted, with alternating in intensity. Intact epithelium especially adjacent maintenance. High systemic doses are occasionally periods of improvement and exacerbation. to ulcers can often be stripped away with ease, required initially to achieve significant results for Of importance for patients with oral MMP is the leaving denuded submucosa. This is one of some cases of recalcitrant gingival MMP. Because possible appearance of ocular disease. With ocular several mucocutaneous diseases in which side effects of systemic therapy may outweigh benefits, high-potency topical steroids may be involvement, definitive early treatment is critical to a positive Nikolsky sign may be elicited. When used instead (e.g., clobetasol, betamethasone avoid conjunctival ulceration and scarring that can skin involvement is present, it usually involves dipropionate, fluocinonide, desoximetasone). A lead to corneal scarring and blindness. Therefore the face, scalp and upper trunk. Because of custom-made, flexible mouth guard may be used ophthalmologic examination must be an initial part oral mucosal discomfort, routine oral hygiene is to keep the topical medication in place. Scrupulous of the treatment plan for patients diagnosed with often compromised, resulting in dental plaque oral hygiene measures, including incorporation oral MMP. accumulation, which in turn superimposes an of chlorhexidine rinses, further enhances the additional, but nonspecific, inflammatory response effectiveness of topical corticosteroids when Lichen Planus over the attached gingiva. gingival involvement is marked. ichen planus is a chronic mucocutaneous disease of autoimmune origin. It is relatively Histopathology and In cases in which standard therapy has failed, common, affecting between 0.2% and Immunopathology other systemic agents have been used with L varying success rates. These have included the 3% in most parts of the world. Intraorally it MMP is a subepithelial clefting or separation use of tetracycline and niacinamide, sulfapyridine, typically presents as symmetrically disposed disorder, without associated individual epithelial sulfones, antibiotics, gold injections, and bilaterally distributed white lesions, occasionally cell separation, or acantholysis. In early stages nutritional supplementation. In severe cases with associated ulcers, commonly involving few lymphocytes are seen within the lamina immunosuppressive agents (azathioprine, the buccal mucosa, lateral tongue margins and propria, but with time, the infiltrate becomes cyclophosphamide, cyclosporine, mycophenolate attached gingiva, most commonly in middle aged denser and mixed in this region. mofeteil, Dapsone), may occasionally be added to individuals, with women affected more commonly than men. Far less commonly the floor of the Direct immunofluorescence ((DIF) studies of intact or in place of the prednisone regimen and thus help mouth and palatal mucosa may be involved. The oral mucosa adjacent to clinically evident lesions avoid or reduce the risks of developing steroid- importance of this disease relates to its degree of demonstrate a linear pattern of homogenous associated complications. Following achievement of clinical remission, treatment intensity can be frequency of occurrence, its occasional similarity IgG fluorescence along the basement membrane slowly tapered to the lowest topical or systemic to other mucosal diseases, and its occasionally zone. C3 is commonly found in the same agent dosing schedule. More recently, rituximab painful nature. It may occur as oral disease only or distribution. Although the fluorescence pattern is has been used effectively in severe cases. in conjunction with other forms of this condition. not distinguishable from that of cutaneous bullous pemphigoid, the submicroscopic location of the Table 3 - Pemphigus Vulgaris vs. Mucous membrane Pemphigoid antigenic target (lower part of the lamina lucida) Pemphigus Vulgaris Pemphigoid is distinctive. Tissue Antibody IgG, Circulating autoab-IgG IgG, IgA, No circulating autoab-IgG Differential Diagnosis Target Protein(s) Desmoglein3 (desmosomes) Laminin 5, BP 180, others The clinical differential diagnosis for this (basement membrane zone antigens) vesiculobullous disease must include pemphigus Vesicles Intraepithelial Subepithelial vulgaris (Table 3). When the attached gingiva is Sites Oral and skin Oral, oropharyngeal and ocular the exclusive site of involvement, atrophic lichen planus, linear IgA disease (IgA pemphigoid), discoid Corticosteroids; Corticosteroids, cyclophosphamide, Treatment systemic immunosuppression other immunosuppression agents lupus erythematosus, and contact allergy should also be considered. Final diagnosis generally Fair, significant morbidity; Prognosis occasional mortality Good, significant morbidity requires confirmation by way of DIF evaluation.

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Etiology and Pathogenesis Table 4 - Lichen Planus The cause of lichen planus, while not fully understood, is generally considered to represent Etiology an immunologically-mediated process that • Autoimmune; basal keratinocyte destruction by T lymphocytes microscopically resembles a hypersensitivity reaction. It is characterized by an intense T-cell Clinical Features infiltrate (CD-4 and especially CD-8 cells) that • Adults; relatively common (0.2% to 1% of population); persistent is generally localized along the epithelium- connective tissue interface. Other immune • White keratotic striae are characteristic regulating cells (macrophages, factor XIIIa- • Types: reticular, erosive (ulcerative), plaque, popular, erythematous (atrophic) positive dendrocytes, Langerhans cells) are seen • Pain-erosive form (occasionally erythematous form) in increased numbers in lichen planus tissue, as are mast cells. The disease mechanism appears Treatment to involve several steps that could be described • Observation, topical and systemic corticosteroids, or other immunosuppressive agents if as follows: an initiating factor/ event, focal release needed of regulatory cytokines, up-regulation of vascular adhesion molecules, recruitment and retention of T lymphocytes in the region, and cytotoxicity of basal This latter role seems to be enhanced through keratinocytes mediated by the T lymphocytes. keratinocyte expression of the adhesion molecule Figure 5 The factor that initiates lichen planus is ICAM-1, which would be attractive to lymphocytes unknown. It is apparent, however, that recruitment with corresponding receptor molecules and retention of lymphocytes is a requisite (LFA-1). This could set up a favorable relationship process. From what is known of leukocyte between T cells and keratinocytes for cytotoxicity. kinetics in tissue, attraction of lymphocytes to The T cells appear to mediate basal cell death a particular site would require cytokine-mediated (apoptosis) through the triggering of cell death up-regulation of adhesion molecules on endothelial or apoptotic pathways. Non-specific mechanisms cells and concomitant expression of receptor involved in pathogenesis include mast cell Reticular form of Lichen Planus molecules by circulating lymphocytes. In oral degranulation and matrix metalloproteinase lichen planus there is an increased expression activation. of several vascular adhesion molecules (known Figure 6 by acronyms ELAM-1, ICAM-1, VCAM-1) and Clinical Features infiltrating lymphocytes that express reciprocal Lichen planus is a disease of middle age that receptors (known as L-selectin, LFA-1, and VLA4), affects men and women in nearly equal numbers. supporting the hypothesis that there is activation Children and adolescents are rarely affected. The of a lymphocyte homing mechanism in lichen severity of the disease may parallel the patient’s planus. Some of the cytokines that are believed level of stress, with the latter acting as a mediator to be responsible for the up-regulated adhesion rather than a true etiologic factor. An association molecules are tumor necrosis factor (TNF-alpha), between lichen planus and hepatitis C infection interleukin-1, and interferon- gamma. The source has been suggested in a recent meta-analysis, Plaque form of Lichen Planus of these cytokines is thought to be from resident though such a relationship is heavily influenced by macrophages, factor XIIIa-positive dendrocytes, geographic bias where the Mediterranean basin Langerhans cells, and the lymphocytes themselves. region and Japan seem to be the sites of this Several types of lichen planus within the oral The overlying keratinocytes in lichen planus have a particular association. There appears to be no cavity have been described. The most common significant role in disease pathogenesis. including relationship between lichen planus and either type is the reticular form (Figure 5), which antigen presentation by basal keratinocytes. They hypertension or diabetes mellitus, as previously is characterized by minimally asymptomatic may be another source of chemoattractive and proposed. Many of these cases likely represent numerous interlacing white keratotic lines or proinflammatory cytokines mentioned earlier, lichenoid drug reactions to the medications used to striae (so-called Wickham’s striae) that produce and more important, they appear to be the manage these conditions, which may mimic lichen an annular or lacy pattern (Table 4). The buccal immunologic target of the recruited lymphocytes. planus clinically (lichenoid reaction). mucosa is the site most commonly involved.

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The striae, although occurring typically in of the lips. Reticular or striated keratotic areas ridge pattern. Within the epithelium are increased asymmetric pattern on the buccal mucosa should be seen elsewhere in the oral cavity with numbers of Langerhans cells (as demonstrated bilaterally, may also be noted on the tongue and this variant of lichen planus. with immunohistochemistry), presumably as less commonly on the gingival mucosa and the an antigen processor to the subjacent On the skin, lichen planus is characterized by the lips. Almost any mucosal tissue may demonstrate T lymphocytes. Discrete eosinophilic ovoid presence of small, violaceous, polygonal, flat- manifestations of lichen planus. This form (reticular) bodies representing the apoptotic keratinocytes topped, pruritic papules on the flexor surfaces. generally presents with minimal clinical symptoms are noted at the basal zone. These colloid, or Other clinical varieties include hypertrophic, and is often an incidental discovery. Civatte, bodies are seen in other conditions atrophic, bullous, follicular, and linear forms. The plaque form of lichen planus (Figure 6) such as drug reactions, contact hypersensitivity, Cutaneous lesions have been reported in 20% tends to resemble leukoplakia clinically but has lupus erythematosus, and some nonspecific to 60% of patients presenting with oral lichen a multifocal, generally bilateral distribution. Such inflammatory reaction. planus. Although the oral changes are relatively plaques generally range from slightly elevated to persistent over time, corresponding skin lesions Direct immunofluorescence demonstrates smooth and flat. The primary sites for this variant tend to wax and wane and exhibit a relatively the presence of fibrinogen in the basement are the dorsum of the tongue and the buccal short natural history (1 to 2 years). membrane zone in 90% to 100% of cases. mucosa. Although immunoglobulins and complement The erythematous or atrophic form of lichen Figure 7 planus (Figure 7) appears as red patches with factors may be found as well, they are far less very fine white striae at the periphery. It may common than fibrinogen deposits. be seen in conjunction with reticular or erosive Differential Diagnosis variants. The proportion of keratinized areas to Other diseases with a multifocal bilateral atrophic areas varies from one area to another. presentation should be included in a clinical The attached gingiva, commonly involved in differential diagnosis are lichenoid drug reaction, this form of lichen planus, exhibits a patchy distribution, often in four quadrants, with lupus erythematosus, white sponge nevus, hairy labial /buccal sites more commonly affected leukoplakia, cheek chewing, graft-versus-host Erythematous or Atropic form of Lichen Planus versus palatal and lingual areas. Patients may disease, and candidiasis. Idiopathic leukoplakia complain of burning, sensitivity, and generalized and squamous cell carcinoma might be considered when lesions are plaque like. Erosive discomfort. Figure 8 or atrophic lichen planus affecting the attached In the erosive form of lichen planus gingiva must be differentiated from cicatricial (Figure 8) the central area of the lesion is pemphigoid, chronic lupus erythematosus, ulcerated. A well-defined fibrinous plaque or contact hypersensitivity and chronic candidiasis. pseudomembrane covers the ulcer. The process demonstrates changing patterns of involvement Treatment and Prognosis noted from week to week. Although oral lichen planus cannot generally Careful examination usually demonstrates be cured completely after a course of treatment, keratotic striae, peripheral to the site of erosion, Erosive form of Lichen Planus some drugs can provide satisfactory control. and erythema. Topically applied potent corticosteroids are A rarely encountered form of lichen planus is the single most useful group of drugs in the the bullous variant. The bullae range from a Histopathology management of lichen planus. The rationale for few millimeters to centimeters in diameter. The microscopic criteria for lichen planus include their use is their ability to modulate inflammation Such bullae are generally short lived and upon hyperkeratosis, basal layer vacuolization with and the immune response. Topical application and rupturing, leave a painful ulcer. Lesions are apoptotic keratinocytes, and a lymphocytic local injection of steroids have been successfully usually seen on the buccal mucosa, especially in infiltrate at the epithelium-connective tissue used in controlling but not curing this disease. the posterior and inferior regions adjacent to interface. With time, the epithelium undergoes In circumstances in which symptoms are the second and third molars. Lesions are less gradual remodeling, resulting in reduced severe, systemic steroids may be used for initial common on the tongue, gingiva, and inner aspect thickness and occasionally a saw-tooth rete management. The addition of antifungal therapy

www.metdental.com Page 6 Quality Resource Guide – Oral Ulcerative and Vesiculobullous Diseases Part 2 - 4th Edition to a corticosteroid regimen typically enhances therapy must be carefully weighed against the Commentary clinical results. This is likely a result of rather significant side effects including cheilitis, Clinical over-diagnosis of lichen planus, coincidental elimination of secondary C. albicans growth in elevation of serum liver enzyme and triglyceride occurrence of lichen planus and oral cancer, and lichen planus-involved tissue. Antifungals also levels, and teratogenicity. In cases with microscopic confusion with dysplasia demonstrating prevent the overgrowth of C. albicans that may significant tissue involvement, use of more than lichenoid features have contributed to the be associated with topical corticosteroid use. one drug may be indicated. Various combinations controversy of malignant potential of this disease. Applications of topical tacrolimus have shown of systemic steroids, topical steroids, and Nonetheless, it appears that there is a bona fide risk promising results in the treatment of symptomatic retinoids may be used with some success. Some of oral squamous cell carcinoma developing in oral oral lichen planus in recent studies. cases or oral lichen planus may also respond lichen planus, but this risk is low and probably to systemic hydroxychloroquine. More recently, lower overall than in some reported series. If Because of their anti-keratinizing and topically placed calcineurin inhibitors (tacrolimus/ malignant transformation occurs, it is more likely immunomodulating affects, systemic and topical pimecrolimus) have proven to be helpful, with to be associated with the erosive and atrophic vitamin A analogs (retinoids) have been used in some studies showing therapeutic equivalency to forms of the disease. Because lichen planus is a the management of lichen planus. Reversal of potent topical steroids. chronic condition, patients should be observed white striae can be achieved with topical retinoids, periodically and should be offered education about although the effects may be only temporary. As is the case with management of mucous the clinical course, rationale of therapy, and possible Systemic retinoids have been used in cases membrane pemphigoid, gingival erosive lesions risk of malignant transformation. In cases where of severe lichen planus with various degrees of lichen planus must include routine thorough suspicious changes are noted over a follow-up of success. The benefits of systemic retinoid oral hygiene measures. course, a biopsy should be performed.

FURTHER READING 1. Mignogna MD, Russo LL, Fedele S. Gingival involvement of oral lichen planus in a series of 700 patients. J Clin Periodontol. 2005 Oct; 32 (10):1029-33. PMID: 16174264 2. Byrd JA, Davis MD, Bruce AJ, et al. Response of oral lichen planus to topical tacrolimus in 37 patients. Arch Dermatol. 2004 Dec; 140(12):1508-12. Erratum in: Arch Dermatol. 2005 Mar; 141(3):370. PMID: 15611431 3. Bystryn JD, Rudolph JL. Pemphigus. Lancet. 2005 July 2-8;366 (9479):61-73. Review. PMID: 15993235 4. Zagorodniuk I, Weltfriend S, Shtruminger L, et al. A comparison of anti-desmoglein antibodies and indirect immunofluorescence in the serodiagnosis of pemphigus vulgaris. Int J Dermatol. 2005 Jul;44(7):541-4. PMID: 15985020 5. Yancey KB. The pathophysiology of autoimmune blistering diseases. J Clin Invest. 2005 Apr;115(4):825-8 PMID: 15841169 6. Ettlin DA. Pemphigus. Dent Clin North Am. 2005 Jan;49(1):107-25, viii-ix. Review. PMID: 15567364 7. Brenner S, Goldberg I. Drug-induced pemphigus. Clin Dermatol 2011;29:455-77. PMID 21679874 8. Kourosh AS, Yancey KB. Therapeutic approaches to patients with mucous membrane pemphigoid. Dermatol Clin 2011; 29: 637-41. PMID: 21925010 9. Ciarrocca KN, Greenberg MS. A retrospective study of the management of oral mucous membrane pemphigoid with Dapsone. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999 Aug; 88 (2):159-63. PMID: 10468458 10. Scully C, Carrozzo M, Gandolfo S, et al. Update on mucous membrane pemphigoid: a heterogeneous immune-mediated subepithelial blistering entity. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999 Jul; 88(1):56-68. Review. PMID: 10442946 11. Sciubba JJ. Autoimmune oral mucosal diseases: Clinical, etiologic, diagnostic, and treatment considerations. Dent Clin N Am 2011; 55(1):89-103. 12. Lodi G, Pellicano R, Carozzo M. Hepatitis C virus infection and lichen planus: a systematic review with meta-analysis. Oral Dis 2010; 16(7):602-612). PMID: 20112447 13. Sonthalia S, Singal A. Comparative efficacy of tacrolimus 0.1% ointment and clobetasol propionate 0.05% ointment in oral lichen planus: a controlled ran- domized double-blind trial. Int J Dermatol 2012; 51:1371-78. PMID: 23067089 14. Segura S, Rozas-Munoz E, Toll A, et al. Evaluation of MYC status in oral lichen planus in patients with progression to oral squamous cell carcinoma. Br J Dermatoil 2013; 69:106-114. PMID: 23461699

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POST-TEST Internet Users: This page is intended to assist you in fast and accurate testing when completing the “Online Exam.” We suggest reviewing the questions and then circling your answers on this page prior to completing the online exam. (1.0 CE Credit Contact Hour) Please circle the correct answer. 70% equals passing grade.

1. In pemphigus vulgaris, the application of a gentle lateral or 6. Oral pemphigus vulgaris has as its basis the presence and direct shearing force will produce a stripping of the surface epithelium involvement of circulating autoantibodies to which specific which is due to: protein target? a. drug toxicity a. myelin basic protein b. hemidesmosomal dissolution b. cadherins 1 and 3 c. keratin filament depolymerization c. desmoglein 1 d. coagulative necrosis d. desmoglein 3 e. desmosome breakdown e. plasminogen

2. In the management of pemphigus vulgaris, the chief iatrogenic 7. The micro-anatomic separation of the epithelium in pemphigus morbidities are usually related to the use of which group of vulgaris is located at which specific site? systemic agents? a. at the basement membrane site a. CD20 antibodies b. at the sub-basement membrane site b. glucocorticosteroids c. beneath the keratin layer c. calcineurin inhibitors d. at the suprabasal site d. non-steroidal immunosuppressants e. at the level of the stratum granulosum e. monoclonal antibodies 8. The autoantigen most commonly attacked in the basement 3. Cutaneous lichen planus affects which sites preferentially? membrane region in cases of cicatricial pemphigoid is: a. extensor surfaces a. BP 180 b. glabrous skin surfaces b. DSG 3 c. palmar surfaces c. BP 240 d. plantar surfaces d. epiligrin e. flexor surfaces e. laminin 332

4. The process of epithelial cell separation in pemphigus vulgaris is 9. In cases of malignant transformation of oral lichen planus, the known as: most common subtype to be associated with such is most likely a. calciphylaxis to be: b. apoptosis a. hypertrophic c. acantholysis b. bullous d. necrosis c. reticular e. diapedesis d. erosive-ulcerative e. papular 5. Multifocal and bilateral presentation is most common in which of the following? 10. The most common sites for the plaque form of oral lichen planus a. recurrent infection include which pair of the following? b. oral lichen planus a. dorsum of the tongue and floor of the mouth c. pemphigus vulgaris b. buccal mucosa and floor of the mouth d. aphthous stomatitis c. buccal mucosa and lateral tongue margin e. mucous membrane pemphigoid d. buccal mucosa and dorsum of the tongue e. hard palatal mucosa and dorsum of the tongue

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Quality Resource Guide – Oral Ulcerative and Vesiculobullous Diseases Part 2 - 4th Edition

Providing dentists with the opportunity for continuing dental education is an essential part of MetLife’s commitment to helping dentists improve the oral health of their patients through education. You can help in this effort by providing feedback regarding the continuing education offering you have just completed.

Please respond to the statements below by checking the appropriate box, 1 = POOR 5 = Excellent using the scale on the right. 1 2 3 4 5

1. How well did this course meet its stated educational objectives? 2. How would you rate the quality of the content? 3. Please rate the effectiveness of the author. 4. Please rate the written materials and visual aids used. 5. The use of evidence-based dentistry on the topic when applicable. N/A 6. How relevant was the course material to your practice? 7. The extent to which the course enhanced your current knowledge or skill? 8. The level to which your personal objectives were satisfied. 9. Please rate the administrative arrangements for this course. 10. How likely are you to recommend MetLife’s CE program to a friend or colleague? (please circle one number below:)

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11. Please identify future topics that you would like to see:

Thank you for your time and feedback. To Complete Program Traditionally, Please Mail Your Post Test and Evaluation Forms To: MetLife Dental Quality Initiatives Program 501 US Highway 22 Bridgewater, NJ 08807 www.metdental.com