Accepted Manuscript Oral lichen planus pemphigoides: A series of four cases Ahmed Sultan, BDentSc, Ivan James Stojanov, DMD, Mark Adam Lerman, DMD, Sadru Kabani, DMD, MS, Jerome Haber, DDS, DMSc, Jeffrey Freedman, DDS, SookBin Woo, DMD, MMSc, FDSRCS (Edin) PII:

S2212-4403(15)00615-X

DOI:

10.1016/j.oooo.2015.03.012

Reference:

OOOO 1176

To appear in:

Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology

Received Date: 3 December 2014 Revised Date:

23 March 2015

Accepted Date: 26 March 2015

Please cite this article as: Sultan A, Stojanov IJ, Lerman MA, Kabani S, Haber J, Freedman J, Woo SB, Oral lichen planus pemphigoides: A series of four cases, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology (2015), doi: 10.1016/j.oooo.2015.03.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Oral lichen planus pemphigoides: A series of four cases

a

SC

Corresponding Author: Ahmed Sultan BDentSc Email: [email protected] Tel: 617-943-1700 Fax: 617-264-6312

RI PT

Ahmed Sultan BDentSc, a, b Ivan James Stojanov DMD, c Mark Adam Lerman DMD, d, e Sadru Kabani DMD, MS, e Jerome Haber DDS, DMSc, f Jeffrey Freedman DDS, g Sook-Bin Woo DMD, MMSc, FDSRCS (Edin), e, h, i

AC C

EP

TE D

M AN U

Oral Medicine Resident, Division of Oral Medicine and Dentistry, Brigham and Women's Hospital, Boston, MA, USA; b Oral Medicine Resident, Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115 c Oral and Maxillofacial Pathology Resident, Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA d Clinical Associate Professor of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA e Center for Oral Pathology, StrataDx f Periodontist, Private practice, Wellesley, MA g Periodontist, Private practice, Concord, MA h Associate Professor of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA i Chief of Clinical Affairs, Division of Oral Medicine and Dentistry, Brigham and Women's Hospital, Boston, MA, USA

This abstract was presented in poster form at the annual American Academy of Oral and Maxillofacial Pathology meeting in St. Augustine, Florida on 04/29/2014. There are no conflicts of interest or disclosures. Abstract word count =165 words. Manuscript word count = 6676 words. Number of tables = 1. Number of figures = 6.

1

ACCEPTED MANUSCRIPT Abstract

RI PT

Objective. Lichen planus pemphigoides (LPP) is a rare autoimmune blistering muco-cutaneous disease of the pemphigoid family of diseases that is characterized by the development of vesiculobullous lesions on or adjacent to areas of lichen planus (LP). LPP primarily affects the skin and oral involvement alone is rare. The objective of this case series was to report 4 new cases of oral lichen planus pemphigoides. Study Design. We present 4 cases with clinical, histologic and direct immunofluorescence (DIF) features characteristic of LPP, 3 cases with oral involvement only.

M AN U

SC

Results. The patients (2 males) were aged 49, 50, 51, and 61; only one patient had skin lesions. All patients had typical reticular, erythematous or ulcerative oral LP involving the gingiva and buccal mucosa. Mucosal biopsies showed features consistent with LP and/or mucous membrane pemphigoid (MMP) and DIF studies in all 4 cases showed linear deposition of IgG and C3 at the interface. Conclusions. Correlation of clinical findings, routine histopathology and DIF studies is essential for the diagnosis. Clinical Significance

TE D

Oral lichen planus pemphigoides is a rare autoimmune blistering disease that arises from pre-existing lichen planus. Careful clinical evaluation, and histopathologic and direct immunofluorescence studies are required to make the diagnosis. Introduction

AC C

EP

Lichen planus pemphigoides (LPP) is a rare, acquired immunobullous disease of the pemphigoid family that clinically and histopathologically presents with features of lichen planus (LP) and either bullous pemphigoid (BP) or mucous membrane pemphigoid (MMP) when affecting the skin or mucosa, respectively.15 It is a disease, predominantly of adults, in which blistering and erosive lesions arise on or around pre-existing lesions of mucocutaneous LP. Skin lesions take the form of tense bullae, most commonly seen on the upper and lower extremities. They tend to develop within a mean time of 8.3 months after first presentation of cutaneous LP.6 Cutaneous LP presents as pruritic, papular, polygonal plaques often with lacy Wickham striations. LP in the oral cavity usually presents as a reticular white lace-like network that is typically bilateral and symmetrical in nature.7 The histologic criteria of oral LP includes hyperkeratosis, varying thickness of the epithelium, colloid bodies in the epithelium, degeneration of the basal cell layer and a lymphocytic band at the interface; sub-epithelial clefting is often noted.8

2

ACCEPTED MANUSCRIPT Cutaneous BP clinically presents as tense bullae with crusting and pruritic erosions on an erythematous base and involves the oral mucosa in up to 30% of cases.9 MMP is the most common autoimmune vesiculo-bullous disorder in the oral cavity and presents as desquamative gingivitis with erosions and ulcers, often on the gingiva.8 The classic histologic feature of both BP and MMP is a subepithelial bulla or clefting with a variable chronic inflammatory infiltrate that in cases of BP, usually contains many eosinophils.10

RI PT

The histopathology of oral LPP demonstrates features of LP and/or BP/MMP, with direct immunofluorescence (DIF) studies showing linear deposition of IgG, IgA and/or C3 at the basement membrane zone (BMZ).

M AN U

SC

The aim of this paper is to present 4 new cases of LPP, three limited to the oral mucosa, and to provide a comprehensive review of the literature of oral LPP.

Case Reports Cases 1-2 were seen and managed at the Division of Oral Medicine and Dentistry at the Brigham and Women’s Hospital while cases 3 and 4 were seen and managed in private dental offices.

AC C

EP

TE D

Case 1: A 49 year-old Indian male was referred by his dentist for evaluation of a 4month history of “blisters and inflammation of the gums and cheeks.” He had been prescribed dexamethasone rinses and clobetasol gel by his primary care physician (PCP) which he felt had reduced inflammation but caused his blood sugar to rise to 290 mg/dl. His past medical history was significant for type II diabetes mellitus and hypertension and his medications were lisinopril, simvastatin, metformin, glipizide and baby aspirin. In March 2010, a biopsy of his penis showed LP. In April 2012, as his mouth problems were progressing, a biopsy of his buccal gingiva interproximal to teeth #30/31 that was submitted by his dentist for direct immunofluorescence (DIF) studies alone showed faint deposition of C3 along the basement membrane zone and was interpreted as negative. In May 2012 a repeat biopsy from the same location by his dentist was again submitted for DIF studies alone and these were non-specific with weak deposition of fibrinogen (1+) and trace linear deposition of C3 and IgA. Extraoral examination was within normal limits and he reported no skin lesions and genital lesions were quiescent. Intraoral examination showed typical Wickham striae on the lingual and facial mandibular gingiva and subtle reticulations on the buccal mucosa with minimal erythema; ulcers were not noted (Figs. 1a-d). With a working diagnosis of mild reticular and erythematous/erosive LP, possibly medication-induced (lisinopril and metformin were possible agents), the patient was managed with fluocinonide 0.05% gel twice a day.

3

ACCEPTED MANUSCRIPT

RI PT

Over the ensuing 12 months, his mouth gradually worsened in spite of using topical steroids and receiving intralesional steroid injections. He was biopsied at an outside institution again in January 2013 and a biopsy of the gingiva adjacent to tooth #15 showed findings suspicious of bullous pemphigoid. In May 2013, white reticulations were present on the palatal mucosa and he had ulcers and erosions on the buccal and lingual mandibular gingiva (Fig. 2a-d). The patient also reported developing new penile lesions. A biopsy from the buccal gingiva between teeth #5/6 was performed and this showed preservation of the basal cells and subepithelial clefting with a moderate lympho-plasmacytic infiltrate consistent with MMP (Fig. 2d). The DIF studies showed linear deposition of IgG (3+) and C3 (3-4+) at the epithelium-connective tissue interface (Fig. 3).

M AN U

SC

The clinical findings together with the histopathologic and DIF studies were consistent with a diagnosis of LPP. He was prescribed fluocinonide to be used in a custom tray twice a day to control symptoms and asked to keep a log of his glucose levels after treatment with the steroids. His ophthalmology examination was within normal limits and his PCP prescribed sertraline to manage his anxiety over this diagnosis. The dermatology consultation showed a hyperpigmented patch involving the glans penis, approaching the urethral orifice, which appeared to be resolving.

TE D

At the most recent follow up visit, 26 months from the first appointment; he reported that he has only needed to use the fluocinonide gel once a month, as his symptoms were very mild. He reported that his penile lesions waxed and waned over time but he had not needed to use any topical treatments for this. Examination showed mild lacy striations on the mandibular lingual gingiva and palatal gingiva as before, with focal areas of erythema.

AC C

EP

Case 2: A 61 year-old white female was referred by her primary care provider for the evaluation of a 1.5-year history of oral discomfort and “irritation”. She also reported gingival bleeding that occurred spontaneously or when brushing her teeth. Her medical history was significant for type 2 diabetes mellitus, hypertension, hyperlipidemia and allergies to dust, pollen, walnuts and penicillin. Her medications included aspirin, atorvastatin, cetirizine, losartan, metformin and calcitriol. She had two previous biopsies of the facial attached gingiva adjacent to tooth #18, both of which lacked epithelium and had negative DIF findings. She reported no skin or genital lesions. The extraoral examination was within normal limits and she reported no skin lesions. Intra-oral examination revealed white reticulations on the left buccal mucosa and anterior mandibular vestibule. The maxillary and mandibular attached gingivae were bright red and 2-6 mm ulcers were present in the right mandibular vestibule and buccal gingiva (Fig. 4a-b). A biopsy performed from the right mandibular vestibule in the area of the right mandibular canine showed parakeratosis, epithelial atrophy, degeneration of the basal cells and a lymphocytic band consistent with LP (Fig. 4c). DIF studies revealed linear deposition of IgG (4+), IgA (2+) and C3 (1-2+) at the epithelium-

4

ACCEPTED MANUSCRIPT connective tissue interface in a similar pattern to Fig. 3. Her clinical and histopathologic findings were consistent with a diagnosis of LPP. She was prescribed clobetasol 0.05% gel to use in a custom tray. She was also prescribed a nystatin rinse as prophylaxis because her fungal carriage cultures were positive for Candida albicans.

RI PT

Over the ensuing months, she was prescribed clobetasol 0.05% gel and dexamethasone rinses with 60-70% improvement in symptoms, although the erythema persisted. She is currently on dexamethasone oral rinse and tacrolimus 0.1% ointment to be used in a tray. She has developed nasal symptoms and is currently being treated with intranasal topical steroids. She has been seen by a dermatologist and ophthalmologist and continues to have no skin or eye lesions.

M AN U

SC

Case 3 A 50 year-old Caucasian male was seen at a private practice by a periodontist for evaluation of a 2-year history of non-specific burning oral symptoms and 8month history of severe discomfort along the gingiva and buccal mucosa with gingival bleeding; he had difficulty eating. The patient’s medical history was significant for non-Hodgkin lymphoma, hypercholesterolemia and gastroesophageal reflux disease. His medications included omeprazole, atorvastatin and baby aspirin. He reported no skin or genital lesions.

AC C

EP

TE D

The extraoral examination was within normal limits and he reported no skin lesions. Intraoral exam showed Wickham striae present on the buccal mucosa and attached gingiva. In addition, multiple pinpoint ulcerations and flaccid bullae were noted on the attached gingiva (Fig 5a-c). He was treated with clobetasol gel and the following week, a biopsy was obtained from the left mandibular buccal gingiva and this showed both areas of preservation of basal cells with subepithelial clefting (Fig. 5d) and areas of degenerated basal cells with colloid bodies with a mild lymphocytic infiltrate (patient had been treated with clobetasol gel) (Fig. 5e). The biopsy was read as subepithelial separation suggestive of MMP with focal features of LP. The DIF study showed deposition of IgG and variable linear deposition of IgA, C3 and fibrinogen in a pattern similar to Fig. 3. The patient was referred by his periodontist to an immunologist and began treatment with dapsone. At this time he was also seen by an ophthalmologist and an otolaryngologist who ruled out conjunctival and pharyngeal involvement, respectively. Due to fatigue and nausea from dapsone treatment he was recommended treatment with intravenous immunoglobulin (IVIG), at which point the patient decided to get a second opinion on treatment. A repeat biopsy was performed at another institution and was signed out as “suggestive of LPP.” He was treated with mycophenolate mofetil 1000 mg BID and reported complete resolution of symptoms with only occasional flare-ups. The patient reports that the flare-ups are associated with manipulation of the oral mucosa during regular dental visits but are well managed with 5-10 mg of prednisone. Case 4

5

ACCEPTED MANUSCRIPT A 51-year-old Caucasian female was seen at a private practice by a periodontist for evaluation of oral discomfort of unknown duration. She did not report any skin or genital lesions. Her past medical history was non-contributory, she was not on any medications and she had no allergies.

SC

RI PT

Extraoral examination was within normal limits. Intraoral examination was significant for finely reticulated, keratotic striations on the maxillary and mandibular attached gingiva with mild diffuse erythema, more prominent on the maxillary gingiva. (Fig. 6a-b). A biopsy was performed from the maxillary left gingiva and histopathologic examination showed degeneration of the basal cells, saw-tooth rete ridges, colloid bodies and a lymphocytic band consistent with LP (Fig. 6c). The DIF study showed linear deposition of IgG (1-2+) and C3 (3+) at the epithelium-connective tissue interface in a similar to Fig. 3. The patient continues to be followed by her periodontist. Discussion

TE D

M AN U

LPP is a rare autoimmune blistering disease that belongs to the pemphigoid family.11 This family of diseases is characterized by subepithelial blisters secondary to autoantibodies that target structural proteins in the hemidesmosmal plaque or basement membrane zone. The most commonly recognized antigens in pemphigoid are BP180 and BP230 while other antigens include laminin 332, laminin 311, laminin γ (p200 protein), type VII collagen, LAD-1, and α6β4 integrin.11-13 LPP is characterized by autoantibodies primarily against region 4 within the C-terminal of the NC16A domain of the BP180 domain.14

EP

Less than 80 cases of cutaneous LPP have been reported. The typical clinical presentation of LPP consists of tense blisters that occur on or around cutaneous lesions of LP.6 These lesions tend to involve the upper and lower extremities, but also involve - in descending order of frequency - the oral mucosa, trunk, back, nails, and palms/soles.6

AC C

A total of 27 cases of LPP with oral involvement (Table 1) were identified which had confirmatory DIF to support the diagnosis of LPP.1, 3, 4, 6, 15-32 One case was excluded from the review because DIF studies were not performed.33 Six further cases were excluded from the review because the oral features were not welldocumented.34-38 Furthermore, LPP-like eruptions fall within the spectrum of manifestations of paraneoplastic pemphigus and these cases were also excluded.39-41 Of the 27 cases, 8 were males and 19 were females (1:2.4). The mean age was 45 years and the median age was 47 years (median age in the current series was 50.5 years). Only 1 out of the 27 cases had oral involvement without any cutaneous manifestations1 and there were 2 cases of oral and ocular LPP in the absence of cutaneous lesions.28 Three of our four cases did not have cutaneous involvement. The time for the development of vesiculobullous lesions on pre-existing LP was variable, ranging from concomitant to 17 years, with a median time of 10 weeks. In a minority of cases the onset of LPP was associated with the use of pharmacotherapeutic agents such as ACE inhibitors,2, 5, 6, 26, 42

6

ACCEPTED MANUSCRIPT Chinese herbal medications,4 simvastatin,43 psoralen-ultraviolet A therapy26 and varicella zoster infection.30

RI PT

The fact that three of the patients were on statins is of interest because statins (as well as other medications) are associated with the occurrence of both LP44-46 and LPP.43 However, it is difficult to determine causality as opposed to association. One possible scenario is that patients developed LP after being on statins but oral lesions were asymptomatic and as such, went unnoticed. By the time LPP developed and lesions became symptomatic, it is difficult to be certain if the statin caused the LP or the LPP unless all lesions resolved on discontinuation of the statin.

SC

Only one previously reported case31 revealed the presence of linear IgA deposition in the BMZ while we had two cases (Cases 2 and 3) that showed this. Linear IgA deposition in patients with oral mucosal disease may represent a form of MMP that may be more resistant to conventional therapy.12 Linear IgA disease involving the oral cavity alone is not universally accepted.

TE D

M AN U

Clinically, oral LPP most frequently affects the gingiva and buccal mucosa. Affected sites are characterized by white striations (Wickham striae), erosions, desquamative gingivitis, ulcerations and sometimes bullae. Such findings may also be seen in other conditions such as lupus erythematosus and linear IgA disease, and correlation with skin findings and biopsy for DIF are essential for differentiating between them. Our series describes four cases of LPP of the oral cavity: all four patients had gingival involvement ranging from finely reticulated Wickham striae with concomitant ulceration to severe desquamative gingivitis, as well as Wickham striae on other mucosal sites. Of these four patients, only one had cutaneous LP (Case 1 with penile lesion). Therefore we add three new cases of oral LPP in the absence of cutaneous lesions to the literature.

AC C

EP

The histopathology resembled LP with degeneration of basal cells and a lymphocytic band at the interface, or MMP with preservation of basal cells; subepithelial clefting may be present in both. However, DIF studies in our cases and those in the literature show linear deposition of IgG, IgA and C3 along the basement membrane zone.1, 3, 4, 6, 15-30 This is in contrast to LP which may show shaggy fibrinogen deposition as well as a granular C3 deposition along the basement membrane zone.47 It is the clinical evidence of typical LP, histopathology of LP or MMP and the DIF findings consistent with pemphigoid that make the diagnosis of LPP. One explanation for why more cases of LPP with only oral involvement have not been reported may be that oral LPP clinically resembles oral LP with typical reticulations, erythema/erosion and ulcers, and most clinicians would not therefore request DIF studies. If the original histopathologic diagnosis was LP as in Case 4, it is also unlikely that a clinician would pursue DIF studies. The etiology of this condition is not completely understood but three hypotheses have been proposed: (1) LPP is a simple association between LP and BP/MMP; (2) LPP is a variant of BP; (3) LP may lead to exposure of a previously sequestered antigen, against which an autoimmune response is triggered.

7

ACCEPTED MANUSCRIPT

RI PT

One reason why LPP may not be a simple association of LP and BP/MMP is that the median age of LPP patients is in the fourth and fifth decades, whereas in BP and MMP the median age is in the eighth and seventh decades, respectively.27, 42, 48 BP rarely occurs in individuals under 50 years49 but it is not unusual for LPP to be reported in children.21, 24, 30, 32, 33, 42 Another reason against a simple association is that BP manifests as a more severe disease with a poorer treatment response than LPP.27, 42, 50 In addition, LPP has shown antibody reactivity against a novel epitope of region 4 within the C-terminal of the NC16A domain of the BP180 antigen, which has not been seen in the sera of patients with BP.14 This strengthens the hypothesis that LPP has a unique target antigen and is a unique blistering disease, distinct from BP or MMP.

M AN U

SC

The prevailing theory for the pathophysiology of LPP is epitope spreading. Lehmann et al. first described epitope spreading- as they termed it, determinant spreading- when immunizing mice with myelin basic protein (MBP) to induce experimental allergic encephalomyelitis.51 They found that determinants of MBP that were cryptic during primary immunization later behaved as dominant determinants in chronically diseased mice and attributed this change in epitope dominance to the enhanced antigen presentation occurring in T-cell mediated inflammation that led to a broadening of the immune response. Vanderlugt and Miller further defined epitope spreading as a specific autoreactive lymphocytic response to endogenous epitopes that do not cross-react with and are distinct from the disease causing epitopes. 52 These epitopes may or may not be on the same protein of the disease-inducing epitope.

AC C

EP

TE D

The pathogenesis of LP is still incompletely understood, but non-specific mechanisms such as mast cell degranulation and matrix metalloproteinase activation by activated CD8+ T cells are believed to play a role in basement membrane zone damage characteristic of LP.53-55 This damage takes the form of breaks, branches, or patch-like thickenings of the basement membrane. Once this breakage to the basement membrane has occurred, novel and previously sequestered antigens within the hemidesmosomal apparatus that trigger an autoimmune response become exposed. In light of this, the clinical presentation of case 1 is quite interesting. This patient was biopsied twice prior to his initial appointment with us and both times DIF studies were negative; however, a biopsy performed one year later showed strong linear deposition of IgG. It is conceivable that the LP, which was refractory to treatment, resulted in profound levels of inflammation and this inflammation led to unremitting damage to the basement membrane zone and, ultimately, exposure of and antibody affinity to the LPP-inducing antigens. As antibodies acquired specificity against antigens such as the NC16A domain of BP180, it is possible that the condition matured into the clinical presentation that was seen 12 months later, at which point a biopsy was performed. This mechanism may be true for many if not all cases of LPP but it is difficult to substantiate without biopsy proven LP followed up by biopsy proven LPP. Management depends on clinical severity and topical corticosteroids (in a tray for gingival involvement) are the first line of therapy. More severe disease may

8

ACCEPTED MANUSCRIPT be treated with topical and systemic corticosteroid therapy and/or with steroidsparing agents such as dapsone4, 24, 27, 29, 33 or azathioprine.20, 21, 23 Patients who have cutaneous manifestations should be referred to a dermatologist for further management and a baseline ophthalomology consultation is appropriate. LPP is usually a mild bullous dermatosis that resolves following treatment and has few relapses, however the re-appearance of LP lesions has been reported in the literature.2, 4, 24, 33, 37

RI PT

Conclusion

AC C

EP

TE D

M AN U

SC

LPP is a rare, acquired immunobullous disease of the pemphigoid family that clinically and histopathologically presents with features of both LP and BP. Our review of the English- language literature revealed 27 cases of LPP with oral involvement supported by confirmatory histopathology and DIF studies. Oral LPP most frequently affects the gingiva as desquamative gingivitis and the buccal mucosa with typical keratotic striations. The histopathology of oral LPP demonstrates either features of LP and/or MMP. The prevailing theory for the pathophysiology of LPP is epitope spreading where damage to the basement membrane from lichenoid inflammation exposes previously sequestered antigens to which autoreactive lymphocytes may develop an affinity. Management of LPP, as with other mucosal inflammatory conditions is with topical steroids, systemic steroids and steroid-sparing agents.

9

ACCEPTED MANUSCRIPT Table 1: Oral LPP Literature review Age

Description of oral lesions

Histopathology

DIF

56 F

Time from LP to LPP 7 yrs

Sobel et al. 197615

1

Retiform pattern of fine white papules on buccal mucosa

Skin: linear deposits of IgG & C3 along BMZ

59 M

12 wks

Fine pattern of keratotic striae and solitary shallow ulcerations

Skin: hyaline body formation, sawtooth elongation of rete ridges, band-like pattern of lymphocytes Skin: typical features of LP

Allen et al. 198716

1

1

42 M

8 wks

Lips and buccal mucosa with fine white striations

Davis et al. 199118

1

44 M

10 wks

Network of white streaks on the palate

Archer et al. 199220

1

61 M

7 wks

Typical LP on buccal mucosa

Borrego Hernando et al. 199232

1

10 F

8 wks

Retiform pattern of fine white papules with some scattered vesicles on the buccal mucosa

Maceyko et al. 199219

1

65 F

3 yrs

Tense bullae, numerous erosions & pseudomembrane formation of labial, gingival, buccal and palatal mucosa

Paige et al. 199321

1

11 M

5 wks

Wickham’s striae on the oral mucosa

Sapadin et al. 199822

1

44 F

8 wks

Violaceous patches with a lacy pattern on the buccal mucosa

Swale et al. 199823

1

42 F

8 wks

Wickham’s striae in the mouth

Bouloc et al. 199824

3

61 F

8 wks

White reticulated network on the buccal mucosa

AC C

EP

TE D

M AN U

Murphy et al. 198917

Oral: epithelial separation at BMZ with a mild lymphohistiocytic infiltrate Skin: band-like upper dermal infiltrate with liquefaction degeneration of basal cells and colloid bodies typical of LP Skin: subepidermal clefts & typical LP changes

Skin: linear deposits of IgG & C3 along BMZ Oral: linear deposits of IgG & C3 along BMZ Skin: band of IgG & faint C3 along BMZ

RI PT

No.

SC

Study

Skin: lichenoid inflammatory infiltrate & liquefaction degeneration of basal layer typical of LP Skin: subepidermal blister overlying a lichenoid infiltrate of lymphocytes

Skin: dense bandlike lymphohistiocytic inflammatory infiltrate, colloid bodies & subepidermal blister Skin: subepidermal split, lichenoid lymphohistocytic infiltrate Skin: band-like lymphohistiocytic infiltrate, sawtoothed acanthosis consistent with LP Skin: saw-toothing of epidermis, lymphohistocytic upper dermal infiltrate Skin: all 3 cases had typical

Skin: linear binding of IgG & C3 along BMZ Skin: linear C3 & IgG deposition along BMZ

Skin: IgG, C3, fibrinogen deposited linearly along the dermoepidermal junction Skin: linear C3 & IgG deposition along BMZ

Skin: linear deposits of IgG, IgM, C3 & fibrin along BMZ Skin: linear deposits of IgG, C3 & fibrinogen along BMZ Skin: linear deposits of IgG, IgM & C3 along BMZ Skin: linear C3 & IgG

10

ACCEPTED MANUSCRIPT 26 F

20 wks

White reticulated network on the buccal mucosa Buccal mucosa with typical LP lesions Typical LP lesions of the oral mucosa

1

47 F

12 wks

Zhu et al. 200626

1

69 F

3 wks

Superficial ulcerations present on the oral mucosa

Solomon et al. 20071

1

*63 F

3 yrs

Xu et al. 20094

1

62 F

2 yrs

Scalloping white striae encircling erythematous patches of mandibular vestibule and multifocal areas of linear white patches and erythema on the attached gingiva. A flaccid circular bulla was present on the buccal mucosa White dots and streaks were found on the buccal mucosa. Shallow 10 mm ulcer with a hemorrhagic crust found on the lower lip

Skvara et al. 200927

1

30 M

2 wks

Reticulated white asymptomatic plaques in the oral cavity

Mignogna et al. 201028

2

72 F

1 yr

Keratotic and bullous/erosive lesions of the hard palate and right mandibular attached gingiva

64 F

2 yrs

Keratotic and erosive lesions of the hard palate and left mandibular vestibule

16 wks

TE D

EP

1

58 F

Ilknur et al. 201130

1

10 F

8 wks

White reticulated network on the buccal mucosa

Washio et al. 20133

1

35 F

8 wks

Lace-like reticulated whitish lesions on the buccal mucosa

Zaraa et al. 20136

3

53 F

Concomitant 12 wks 17 yrs

Erosions, white dots and streaks in the oral cavity White dots in the oral cavity White reticulated network with erosions in the oral cavity Reticular white lines on the buccal mucosa bilaterally

Hacklander et al. 201431

1

Vesicles and ulcers on the oral mucosa

AC C

Barnadas et al. 201029

47 F 51 F 21 M

Not reported

deposition along BMZ in all 3 cases

Skin: subepidermal blister with some lichenoid changes of basal cell layer & sparse inflammatory infiltrate in the upper dermis Skin: lichenoid dermatitis, bandlike infiltrate of lymphocytes, vacuolar alterations & colloid bodies Oral: colloid bodies, saw-tooth rete ridges, moderately dense lymphohistiocytic infiltrate in superficial lamnia propria Skin: basal cell liquefaction with a bandlike like lymphocytic infiltrate in the upper dermis Skin: typical features of LP

Skin: linear deposits of C3 along BMZ

M AN U

Skaria et al. 199925

features of LP

RI PT

8 wks

Skin: linear C3 & IgG deposition along BMZ

Oral: linear C3 & IgG deposition along BMZ

SC

14 M

Oral: dense bandlike monomorphous lymphocytic infiltrate Oral: lymphocytic exocytosis, aggressive monomorphous lymphocytic infiltrate Skin: lichenoid dermatitis consistent with LP Skin: acanthosis, saw-tooth elongation of rete ridges, colloid body formation Skin: acanthosis, liquefaction degeneration, band-like lymphocytic infiltrate Skin: all 3 cases had typical features of LP

Skin: hyperkeratosis, subepidermal blister formation,

Skin: linear C3 & IgG deposition along BMZ

Skin: linear deposits of IgG, C3 & fibrin along BMZ Oral: linear deposits of IgG along BMZ

Oral: linear deposits of IgG along BMZ

Skin: linear C3 & IgG deposition along BMZ Skin: linear deposits of IgG, IgM & C3 along BMZ Skin: linear C3 & IgG deposition along BMZ

Skin: linear C3 & IgG deposition along BMZ in all 3 cases Skin: Linear C3 & fibrinogen deposits along the BMZ as

11

ACCEPTED MANUSCRIPT

*61 F

1.5 yr

*50 M

32 wks

*51 F

Unknown duration

Wickham striate on the left buccal mucosa and anterior mandibular vestibule. Maxillary and mandibular attached gingivae were bright red and ulcers were present in the right mandibular vestibule and buccal gingiva Wickham striae present on the buccal mucosa and attached gingiva. Multiple pinpoint ulcerations and flaccid bullae were noted on the attached gingiva Finely Wickham striae on the maxillary and mandibular attached gingiva with mild diffuse erythema, more prominent on the maxillary gingiva

Oral: linear C3 & IgG deposition along BMZ in all 4 cases. Case 2 exhibited linear deposition of IgA along BMZ and Case 3 exhibited variable linear deposition of IgA.

RI PT

Typical Wickham striae on the lingual and facial mandibular gingiva, and palatal gingiva and subtle reticulations on the buccal mucosa with minimal erythema

SC

1 yr

Oral: degeneration of basal cells, sawtooth rete ridges, colloid bodies, lymphocytic band consistent with LP

M AN U

49 M

TE D

LP, lichen planus; LPP, lichen planus pemphigoides; F, female; M, male; DIF, direct immunofluorescence; BMZ, basement membrane zone; wks, weeks; yrs, years. *Oral involvement without skin or ocular involvement.

EP

4

well as IgM & IgA reactive cytoid bodies

AC C

Current case series

band-like lymphohistiocytic infiltrate in the adjacent dermis Oral: preservation of basal cells, subepithelial clefting with a moderate lymphoplasmacytic infiltrate consistent with MMP Oral: parakeratosis, epithelial atrophy, degeneration of basal cells, lymphocytic band consistent with LP Oral: subepithelial separation suggestive of MMP with focal features of LP

12

ACCEPTED MANUSCRIPT Figure Legend Figure 1. Case 1 at initial presentation Wickham striae with post-inflammatory hypermelanosis of the right (A) and left (B) palatal gingiva Wickham striae and mild, patchy erythema of the right (C) and left (D) lingual mandibular gingiva

SC

RI PT

Figure 2. Case 1, 12 months after initial presentation Ulcerations and erythema of the right mandibular buccal gingiva (A) and left maxillary buccal gingiva (B), and ulcer of the right mandibular lingual gingiva (C) D: Hyperkeratosis, acanthosis, subepithelial cleft with preservation of the basal layer and a patchy lymphocytic band at the interface (Hematoxylin and eosin, original magnification x100). A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM00556.

M AN U

Figure 3. Direct immunofluorescence study showed linear deposition of IgG along the basement membrane zone (Hematoxylin and eosin, original magnification x100)

TE D

Figure 4. Case 2 A,B: Severe, diffuse erythema of the maxillary and mandibular facial attached gingiva with Wickham striae in the mandibular vestibule (arrows) C: Parakeratosis, degeneration of the basal cells and a moderate lymphocytic band at the interface (Hematoxylin and eosin, original magnification x200). A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM00557.

AC C

EP

Figure 5. Case 3 A: Keratosis and diffuse erythema of posterior maxillary and mandibular attached gingiva B: Flaccid bulla on the attached gingiva C: Wickham striae on the left buccal mucosa D: Subepithelial cleft with preservation of the basal layer and scant lymphocytic infiltrate (Hematoxylin and eosin, original magnification x100) E: Basal cell degeneration, colloid body formation and mild lymphocytic band at interface (consistent with topical steroid treatment effect) (Hematoxylin and eosin, original magnification x400). A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM00558. Figure 6: Case 4 Wickham striae with erythema on the right (A) and left (B) maxillary facial gingiva C: Hyperkeratosis, degeneration of basal cells, colloid body formation, and a moderate lymphocytic band at the interface (Hematoxylin and eosin, original magnification x100) D: Hyperkeratosis, degeneration of basal cells, colloid body formation, and a moderate lymphocytic band at the interface (Hematoxylin and eosin, original

13

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

magnification x 200). A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM00559.

14

ACCEPTED MANUSCRIPT References:

AC C

EP

TE D

M AN U

SC

RI PT

1. Solomon LW, Helm TN, Stevens C, Neiders ME, Kumar V. Clinical and immunopathologic findings in oral lichen planus pemphigoides. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;103:808-13. 2. Anand D, Bernardin R, Rubin AI. Blisters and plaques on the extremities. What is your diagnosis? Lichen planus pemphigoides. Int J Dermatol. 2011;50:147-9. 3. Washio K, Nakamura A, Fukuda S, Hashimoto T, Horikawa T. A case of lichen planus pemphigoides successfully treated with a combination of cyclosporine a and prednisolone. Case Rep Dermatol. 2013;5:84-7. 4. Xu HH, Xiao T, He CD, Jin GY, Wang YK, Gao XH, et al. Lichen planus pemphigoides associated with Chinese herbs. Clin Exp Dermatol. 2009;34:329-32. 5. Ben Salem C, Chenguel L, Ghariani N, Denguezli M, Hmouda H, Bouraoui K. Captopril-induced lichen planus pemphigoides. Pharmacoepidemiol Drug Saf. 2008;17:722-4. 6. Zaraa I, Mahfoudh A, Sellami MK, Chelly I, El Euch D, Zitouna M, et al. Lichen planus pemphigoides: four new cases and a review of the literature. Int J Dermatol. 2013;52:406-12. 7. van der Meij EH, van der Waal I. Lack of clinicopathologic correlation in the diagnosis of oral lichen planus based on the presently available diagnostic criteria and suggestions for modifications. J Oral Pathol Med. 2003;32:507-12. 8. Woo S-b. Oral pathology : a comprehensive atlas and text. 1st ed. Philadelphia, PA: Elsevier/Saunders: 2012. 9. Kneisel A, Hertl M. Autoimmune bullous skin diseases. Part 1: Clinical manifestations. J Dtsch Dermatol Ges. 2011;9:844-56; quiz 57. 10. Said S, Golitz L. Vesiculobullous eruptions of the oral cavity. Otolaryngol Clin North Am. 2011;44:133-60, vi. 11. Schmidt E, Zillikens D. Pemphigoid diseases. Lancet. 2013;381:320-32. 12. Chan LS, Ahmed AR, Anhalt GJ, Bernauer W, Cooper KD, Elder MJ, et al. The first international consensus on mucous membrane pemphigoid: definition, diagnostic criteria, pathogenic factors, medical treatment, and prognostic indicators. Arch Dermatol. 2002;138:370-9. 13. Woo SB, Stone JH, Kraft S. Case Records of the Massachusetts General Hospital: Case 22-2013: A 51-year-old woman with epistaxis and oral mucosal ulcers. The New England journal of medicine. 2013;369:265-74. 14. Zillikens D, Caux F, Mascaro JM, Wesselmann U, Schmidt E, Prost C, et al. Autoantibodies in lichen planus pemphigoides react with a novel epitope within the C-terminal NC16A domain of BP180. J Invest Dermatol. 1999;113:117-21. 15. Sobel S, Miller R, Shatin H. Lichen planus pemphigoides. Immunofluorescence findings. Arch Dermatol. 1976;112:1280-3. 16. Allen CM, Camisa C, Grimwood R. Lichen planus pemphigoides: report of a case with oral lesions. Oral Surg Oral Med Oral Pathol. 1987;63:184-8. 17. Murphy GM, Cronin E. Lichen planus pemphigoides. Clin Exp Dermatol. 1989;14:322-4.

15

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

18. Davis AL, Bhogal BS, Whitehead P, Frith P, Murdoch ME, Leigh IM, et al. Lichen planus pemphigoides: its relationship to bullous pemphigoid. Br J Dermatol. 1991;125:263-71. 19. Maceyko RF, Camisa C, Bergfeld WF, Valenzuela R. Oral and cutaneous lichen planus pemphigoides. J Am Acad Dermatol. 1992;27:889-92. 20. Archer CB, Cronin E, Smith NP. Diagnosis of lichen planus pemphigoides in the absence of bullae on normal-appearing skin. Clin Exp Dermatol. 1992;17:433-6. 21. Paige DG, Bhogal BS, Black MM, Harper JI. Lichen planus pemphigoides in a child--immunopathological findings. Clin Exp Dermatol. 1993;18:552-4. 22. Sapadin AN, Phelps RG, Fellner MJ, Kantor I. Lichen planus pemphigoides presenting with a strikingly unilateral distribution. Int J Dermatol. 1998;37:9426. 23. Swale VJ, Black MM, Bhogal BS. Lichen planus pemphigoides: two case reports. Clin Exp Dermatol. 1998;23:132-5. 24. Bouloc A, Vignon-Pennamen MD, Caux F, Teillac D, Wechsler J, Heller M, et al. Lichen planus pemphigoides is a heterogeneous disease: a report of five cases studied by immunoelectron microscopy. Br J Dermatol. 1998;138:972-80. 25. Skaria M, Salomon D, Jaunin F, Friedli A, Saurat JH, Borradori L. IgG autoantibodies from a lichen planus pemphigoides patient recognize the NC16A domain of the bullous pemphigoid antigen 180. Dermatology. 1999;199:253-5. 26. Zhu YI, Fitzpatrick JE, Kornfeld BW. Lichen planus pemphigoides associated with ramipril. Int J Dermatol. 2006;45:1453-5. 27. Skvara H, Stingl G. Lichenoid eruption with single plantar blisters: a very rare case of lichen planus pemphigoides. J Eur Acad Dermatol Venereol. 2009;23:596-7. 28. Mignogna MD, Fortuna G, Leuci S, Stasio L, Mezza E, Ruoppo E. Lichen planus pemphigoides, a possible example of epitope spreading. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010;109:837-43. 29. Barnadas MA, Roé E, Dalmau J, Alomar A, Martínez L, Gelpí C. Lichen planus pemphigoides: detection of anti-BP 180 antibodies by ELISA and immunoblotting tests. J Eur Acad Dermatol Venereol. 2010;24:1360-1. 30. İlknur T, Akarsu S, Uzun S, Özer E, Fetil E. Heterogeneous disease: a child case of lichen planus pemphigoides triggered by varicella. J Dermatol. 2011;38:707-10. 31. Hackländer K, Lehmann P, Hofmann SC. Successful treatment of lichen planus pemphigoides using acitretin as monotherapy. J Dtsch Dermatol Ges. 2014;12:818-9. 32. Borrego Hernando L, Vanaclocha Sebastián F, Hergueta Sánchez J, Ortiz Romero P, Iglesias Diez L. Lichen planus pemphigoides in a 10-year-old girl. J Am Acad Dermatol. 1992;26:124-5. 33. Harjai B, Mendiratta V, Kakkar S, Koranne RV. Childhood lichen planus pemphigoides - a rare entity. Journal of the European Academy of Dermatology and Venereology : JEADV. 2006;20:117-8. 34. Mora RG, Nesbitt LT, Brantley JB. Lichen planus pemphigoides: clinical and immunofluorescent findings in four cases. J Am Acad Dermatol. 1983;8:331-6. 35. Gawkrodger DJ, Stavropoulos PG, McLaren KM, Buxton PK. Bullous lichen planus and lichen planus pemphigoides--clinico-pathological comparisons. Clin Exp Dermatol. 1989;14:150-3.

16

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

36. Lotem M, Ingber A, Sandbank M, Hazaz B. Lichen planus pemphigoides with features of lichen planus and pemphigus vulgaris. Arch Dermatol. 1989;125:707-8. 37. Sakuma-Oyama Y, Powell AM, Albert S, Oyama N, Bhogal BS, Black MM. Lichen planus pemphigoides evolving into pemphigoid nodularis. Clin Exp Dermatol. 2003;28:613-6. 38. Sekiya A, Kodera M, Yamaoka T, Iwata Y, Usuda T, Ohzono A, et al. A case of lichen planus pemphigoides with autoantibodies to the NC16a and C-terminal domains of BP180 and to desmoglein-1. Br J Dermatol. 2014 39. Stevens SR, Griffiths CE, Anhalt GJ, Cooper KD. Paraneoplastic pemphigus presenting as a lichen planus pemphigoides-like eruption. Arch Dermatol. 1993;129:866-9. 40. Krunic AL, Kokai D, Bacetic B, Kesic V, Nikolic MM, Petkovic S, et al. Retroperitoneal round-cell liposarcoma associated with paraneoplastic pemphigus presenting as lichen planus pemphigoides-like eruption. Int J Dermatol. 1997;36:526-9. 41. Hamada T, Fujimoto W, Okazaki F, Asagoe K, Arata J, Iwatsuki K. Lichen planus pemphigoides and multiple keratoacanthomas associated with colon adenocarcinoma. Br J Dermatol. 2004;151:252-4. 42. Cohen DM, Ben-Amitai D, Feinmesser M, Zvulunov A. Childhood lichen planus pemphigoides: a case report and review of the literature. Pediatr Dermatol. 2009;26:569-74. 43. Stoebner PE, Michot C, Ligeron C, Durand L, Meynadier J, Meunier L. [Simvastatin-induced lichen planus pemphigoides]. Ann Dermatol Venereol. 2003;130:187-90. 44. Sebök B, Tóth M, Anga B, Harangi F, Schneider I. Lichenoid drug eruption with HMG-CoA reductase inhibitors (fluvastatin and lovastatin). Acta Derm Venereol. 2004;84:229-30. 45. Habbab KM, Moles DR, Porter SR. Potential oral manifestations of cardiovascular drugs. Oral Dis. 2010;16:769-73. 46. Pua VS, Scolyer RA, Barnetson RS. Pravastatin-induced lichenoid drug eruption. Australas J Dermatol. 2006;47:57-9. 47. Kulthanan K, Jiamton S, Varothai S, Pinkaew S, Sutthipinittharm P. Direct immunofluorescence study in patients with lichen planus. Int J Dermatol. 2007;46:1237-41. 48. Thorne JE, Anhalt GJ, Jabs DA. Mucous membrane pemphigoid and pseudopemphigoid. Ophthalmology. 2004;111:45-52. 49. Jung M, Kippes W, Messer G, Zillikens D, Rzany B. Increased risk of bullous pemphigoid in male and very old patients: A population-based study on incidence. J Am Acad Dermatol. 1999;41:266-8. 50. Kasperkiewicz M, Zillikens D, Schmidt E. Pemphigoid diseases: pathogenesis, diagnosis, and treatment. Autoimmunity. 2012;45:55-70. 51. Lehmann PV, Forsthuber T, Miller A, Sercarz EE. Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature. 1992;358:1557. 52. Vanderlugt CJ, Miller SD. Epitope spreading. Current opinion in immunology. 1996;8:831-6. 53. Zhao ZZ, Savage NW, Sugerman PB, Walsh LJ. Mast cell/T cell interactions in oral lichen planus. Journal of oral pathology & medicine : official publication of

17

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

the International Association of Oral Pathologists and the American Academy of Oral Pathology. 2002;31:189-95. 54. Roopashree MR, Gondhalekar RV, Shashikanth MC, George J, Thippeswamy SH, Shukla A. Pathogenesis of oral lichen planus--a review. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 2010;39:72934. 55. Payeras MR, Cherubini K, Figueiredo MA, Salum FG. Oral lichen planus: focus on etiopathogenesis. Archives of oral biology. 2013;58:1057-69.

18

ACCEPTED MANUSCRIPT Table 1: Oral LPP Literature review Age

Description of oral lesions

Histopathology

DIF

56 F

Time from LP to LPP 7 yrs

Sobel et al. 197615

1

Retiform pattern of fine white papules on buccal mucosa

Skin: linear deposits of IgG & C3 along BMZ

59 M

12 wks

Fine pattern of keratotic striae and solitary shallow ulcerations

Skin: hyaline body formation, sawtooth elongation of rete ridges, band-like pattern of lymphocytes Skin: typical features of LP

Allen et al. 198716

1

1

42 M

8 wks

Lips and buccal mucosa with fine white striations

Davis et al. 199118

1

44 M

10 wks

Network of white streaks on the palate

Archer et al. 199220

1

61 M

7 wks

Typical LP on buccal mucosa

Borrego Hernando et al. 199232

1

10 F

8 wks

Retiform pattern of fine white papules with some scattered vesicles on the buccal mucosa

Maceyko et al. 199219

1

65 F

3 yrs

Tense bullae, numerous erosions & pseudomembrane formation of labial, gingival, buccal and palatal mucosa

Paige et al. 199321

1

11 M

5 wks

Wickham’s striae on the oral mucosa

Sapadin et al. 199822

1

44 F

8 wks

Violaceous patches with a lacy pattern on the buccal mucosa

Swale et al. 199823

1

42 F

8 wks

Wickham’s striae in the mouth

Bouloc et al. 199824

3

61 F

8 wks

White reticulated network on the buccal mucosa

AC C

EP

TE D

M AN U

Murphy et al. 198917

Oral: epithelial separation at BMZ with a mild lymphohistiocytic infiltrate Skin: band-like upper dermal infiltrate with liquefaction degeneration of basal cells and colloid bodies typical of LP Skin: subepidermal clefts & typical LP changes

Skin: linear deposits of IgG & C3 along BMZ Oral: linear deposits of IgG & C3 along BMZ Skin: band of IgG & faint C3 along BMZ

RI PT

No.

SC

Study

Skin: lichenoid inflammatory infiltrate & liquefaction degeneration of basal layer typical of LP Skin: subepidermal blister overlying a lichenoid infiltrate of lymphocytes

Skin: dense bandlike lymphohistiocytic inflammatory infiltrate, colloid bodies & subepidermal blister Skin: subepidermal split, lichenoid lymphohistocytic infiltrate Skin: band-like lymphohistiocytic infiltrate, sawtoothed acanthosis consistent with LP Skin: saw-toothing of epidermis, lymphohistocytic upper dermal infiltrate Skin: all 3 cases had typical

Skin: linear binding of IgG & C3 along BMZ Skin: linear C3 & IgG deposition along BMZ

Skin: IgG, C3, fibrinogen deposited linearly along the dermoepidermal junction Skin: linear C3 & IgG deposition along BMZ

Skin: linear deposits of IgG, IgM, C3 & fibrin along BMZ Skin: linear deposits of IgG, C3 & fibrinogen along BMZ Skin: linear deposits of IgG, IgM & C3 along BMZ Skin: linear C3 & IgG

ACCEPTED MANUSCRIPT 26 F

20 wks

White reticulated network on the buccal mucosa Buccal mucosa with typical LP lesions Typical LP lesions of the oral mucosa

1

47 F

12 wks

Zhu et al. 200626

1

69 F

3 wks

Superficial ulcerations present on the oral mucosa

Solomon et al. 20071

1

*63 F

3 yrs

Xu et al. 20094

1

62 F

2 yrs

Scalloping white striae encircling erythematous patches of mandibular vestibule and multifocal areas of linear white patches and erythema on the attached gingiva. A flaccid circular bulla was present on the buccal mucosa White dots and streaks were found on the buccal mucosa. Shallow 10 mm ulcer with a hemorrhagic crust found on the lower lip

Skvara et al. 200927

1

30 M

2 wks

Reticulated white asymptomatic plaques in the oral cavity

Mignogna et al. 201028

2

72 F

1 yr

Keratotic and bullous/erosive lesions of the hard palate and right mandibular attached gingiva

64 F

2 yrs

Keratotic and erosive lesions of the hard palate and left mandibular vestibule

16 wks

TE D

EP

1

58 F

Ilknur et al. 201130

1

10 F

8 wks

White reticulated network on the buccal mucosa

Washio et al. 20133

1

35 F

8 wks

Lace-like reticulated whitish lesions on the buccal mucosa

Zaraa et al. 20136

3

53 F

Concomitant 12 wks 17 yrs

Erosions, white dots and streaks in the oral cavity White dots in the oral cavity White reticulated network with erosions in the oral cavity Reticular white lines on the buccal mucosa bilaterally

Hacklander et al. 201431

1

Vesicles and ulcers on the oral mucosa

AC C

Barnadas et al. 201029

47 F 51 F 21 M

Not reported

deposition along BMZ in all 3 cases

Skin: subepidermal blister with some lichenoid changes of basal cell layer & sparse inflammatory infiltrate in the upper dermis Skin: lichenoid dermatitis, bandlike infiltrate of lymphocytes, vacuolar alterations & colloid bodies Oral: colloid bodies, saw-tooth rete ridges, moderately dense lymphohistiocytic infiltrate in superficial lamnia propria Skin: basal cell liquefaction with a bandlike like lymphocytic infiltrate in the upper dermis Skin: typical features of LP

Skin: linear deposits of C3 along BMZ

M AN U

Skaria et al. 199925

features of LP

RI PT

8 wks

Skin: linear C3 & IgG deposition along BMZ

Oral: linear C3 & IgG deposition along BMZ

SC

14 M

Oral: dense bandlike monomorphous lymphocytic infiltrate Oral: lymphocytic exocytosis, aggressive monomorphous lymphocytic infiltrate Skin: lichenoid dermatitis consistent with LP Skin: acanthosis, saw-tooth elongation of rete ridges, colloid body formation Skin: acanthosis, liquefaction degeneration, band-like lymphocytic infiltrate Skin: all 3 cases had typical features of LP

Skin: hyperkeratosis, subepidermal blister formation,

Skin: linear C3 & IgG deposition along BMZ

Skin: linear deposits of IgG, C3 & fibrin along BMZ Oral: linear deposits of IgG along BMZ

Oral: linear deposits of IgG along BMZ

Skin: linear C3 & IgG deposition along BMZ Skin: linear deposits of IgG, IgM & C3 along BMZ Skin: linear C3 & IgG deposition along BMZ

Skin: linear C3 & IgG deposition along BMZ in all 3 cases Skin: Linear C3 & fibrinogen deposits along the BMZ as

ACCEPTED MANUSCRIPT

*61 F

1.5 yr

*50 M

32 wks

*51 F

Unknown duration

Wickham striate on the left buccal mucosa and anterior mandibular vestibule. Maxillary and mandibular attached gingivae were bright red and ulcers were present in the right mandibular vestibule and buccal gingiva Wickham striae present on the buccal mucosa and attached gingiva. Multiple pinpoint ulcerations and flaccid bullae were noted on the attached gingiva Finely Wickham striae on the maxillary and mandibular attached gingiva with mild diffuse erythema, more prominent on the maxillary gingiva

Oral: linear C3 & IgG deposition along BMZ in all 4 cases. Case 2 exhibited linear deposition of IgA along BMZ and Case 3 exhibited variable linear deposition of IgA.

RI PT

Typical Wickham striae on the lingual and facial mandibular gingiva, and palatal gingiva and subtle reticulations on the buccal mucosa with minimal erythema

well as IgM & IgA reactive cytoid bodies

SC

1 yr

Oral: degeneration of basal cells, sawtooth rete ridges, colloid bodies, lymphocytic band consistent with LP

M AN U

49 M

TE D

LP, lichen planus; LPP, lichen planus pemphigoides; F, female; M, male; DIF, direct immunofluorescence; BMZ, basement membrane zone; wks, weeks; yrs, years. *Oral involvement without skin or ocular involvement.

EP

4

AC C

Current case series

band-like lymphohistiocytic infiltrate in the adjacent dermis Oral: preservation of basal cells, subepithelial clefting with a moderate lymphoplasmacytic infiltrate consistent with MMP Oral: parakeratosis, epithelial atrophy, degeneration of basal cells, lymphocytic band consistent with LP Oral: subepithelial separation suggestive of MMP with focal features of LP

ACCEPTED MANUSCRIPT Figure Legend Figure 1. Case 1 at initial presentation Wickham striae with post-inflammatory hypermelanosis of the right (A) and left (B) palatal gingiva Wickham striae and mild, patchy erythema of the right (C) and left (D) lingual mandibular gingiva

SC

RI PT

Figure 2. Case 1, 12 months after initial presentation Ulcerations and erythema of the right mandibular buccal gingiva (A) and left maxillary buccal gingiva (B), and ulcer of the right mandibular lingual gingiva (C) D: Hyperkeratosis, acanthosis, subepithelial cleft with preservation of the basal layer and a patchy lymphocytic band at the interface (Hematoxylin and eosin, original magnification x100). A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM00556.

M AN U

Figure 3. Direct immunofluorescence study showed linear deposition of IgG along the basement membrane zone (Hematoxylin and eosin, original magnification x100)

TE D

Figure 4. Case 2 A,B: Severe, diffuse erythema of the maxillary and mandibular facial attached gingiva with Wickham striae in the mandibular vestibule (arrows) C: Parakeratosis, degeneration of the basal cells and a moderate lymphocytic band at the interface (Hematoxylin and eosin, original magnification x200). A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM00557.

AC C

EP

Figure 5. Case 3 A: Keratosis and diffuse erythema of posterior maxillary and mandibular attached gingiva B: Flaccid bulla on the attached gingiva C: Wickham striae on the left buccal mucosa D: Subepithelial cleft with preservation of the basal layer and scant lymphocytic infiltrate (Hematoxylin and eosin, original magnification x100) E: Basal cell degeneration, colloid body formation and mild lymphocytic band at interface (consistent with topical steroid treatment effect) (Hematoxylin and eosin, original magnification x400). A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM00558. Figure 6: Case 4 Wickham striae with erythema on the right (A) and left (B) maxillary facial gingiva C: Hyperkeratosis, degeneration of basal cells, colloid body formation, and a moderate lymphocytic band at the interface (Hematoxylin and eosin, original magnification x100) D: Hyperkeratosis, degeneration of basal cells, colloid body formation, and a moderate lymphocytic band at the interface (Hematoxylin and eosin, original

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

magnification x 200). A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM00559.

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

TRIPLEO-D-14-01405R3

Clinical Significance

AC C

EP

TE D

M AN U

SC

RI PT

Oral lichen planus pemphigoides is a rare autoimmune blistering disease that arises from preexisting lichen planus. Careful clinical evaluation, and histopathologic and direct immunofluorescence studies are required to make the diagnosis.