Assessment of the Prevalence of Mucosal Involvement in Bullous Pemphigoid | Dermatology | JAMA Dermatology | JAMA Network
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Table.  Demographics, Clinical Characteristics, and Treatment of Patients With BP With Mucosal Involvement vs Other Patients With BP
Demographics, Clinical Characteristics, and Treatment of Patients With BP With Mucosal Involvement vs Other Patients With BP
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Vaillant  L, Bernard  P, Joly  P,  et al; French Bullous Study Group.  Evaluation of clinical criteria for diagnosis of bullous pemphigoid.  Arch Dermatol. 1998;134(9):1075-1080. doi:10.1001/archderm.134.9.1075PubMedGoogle ScholarCrossref
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Schmidt  E, della Torre  R, Borradori  L.  Clinical features and practical diagnosis of bullous pemphigoid.  Immunol Allergy Clin North Am. 2012;32(2):217-232, v. doi:10.1016/j.iac.2012.04.002PubMedGoogle ScholarCrossref
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Clapé  A, Muller  C, Gatouillat  G,  et al.  Mucosal involvement in bullous pemphigoid is mostly associated with disease severity and to absence of anti-BP230 autoantibody.  Front Immunol. 2018;9:479. doi:10.3389/fimmu.2018.00479PubMedGoogle ScholarCrossref
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Vivek Abraham  FB, Rashid Al Abri  C, Al Abri  R.  Bullous lesion of larynx? an airway emergency.  Otolaryngology. 2015;5(5). doi:10.4172/2161-119X.1000206Google Scholar
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Konstadt  JW, Remlinger  K, Schild  J, Aronson  I, Bennin  B, Solomon  L.  Refractory bullous pemphigoid leading to respiratory arrest and successfully treated with plasmapheresis.  Arch Dermatol. 1990;126(9):1241-1242. doi:10.1001/archderm.1990.01670330121028PubMedGoogle ScholarCrossref
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Ohki  M, Kikuchi  S, Ohata  A, Baba  Y, Ishikawa  J, Sugimoto  H.  Features of oral, pharyngeal, and laryngeal lesions in bullous pemphigoid.  Ear Nose Throat J. 2016;95(10-11):E1-E5.PubMedGoogle Scholar
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Iqbal  M, Ahmed  R, Kashef  SH, Bahame  PS.  Laryngeal involvement in a patient with bullous pemphigoid.  Ann Saudi Med. 2006;26(2):152-154. doi:10.5144/0256-4947.2006.152PubMedGoogle ScholarCrossref
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Yasir  M, Khan  FA.  Airway management in a patient with bullous pemphigoid.  J Coll Physicians Surg Pak. 2013;23(8):583-585.PubMedGoogle Scholar
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Thoma-Uszynski  S, Uter  W, Schwietzke  S,  et al.  BP230- and BP180-specific auto-antibodies in bullous pemphigoid.  J Invest Dermatol. 2004;122(6):1413-1422. doi:10.1111/j.0022-202X.2004.22603.xPubMedGoogle ScholarCrossref
15.
Chan  LS, Ahmed  AR, Anhalt  GJ,  et al.  The first international consensus on mucous membrane pemphigoid: definition, diagnostic criteria, pathogenic factors, medical treatment, and prognostic indicators.  Arch Dermatol. 2002;138(3):370-379. doi:10.1001/archderm.138.3.370PubMedGoogle ScholarCrossref
16.
Meijer  JM, Diercks  GFH, Schmidt  E, Pas  HH, Jonkman  MF.  Laboratory diagnosis and clinical profile of Anti-p200 pemphigoid.  JAMA Dermatol. 2016;152(8):897-904. doi:10.1001/jamadermatol.2016.1099PubMedGoogle ScholarCrossref
17.
García-Díez  I, Martínez-Escala  ME, Ishii  N,  et al.  Usefulness of a simple immunohistochemical staining technique to differentiate anti-p200 pemphigoid from other autoimmune blistering diseases: a report of 2 cases.  Actas Dermosifiliogr. 2017;108(1):e1-e5. doi:10.1016/j.ad.2015.10.019PubMedGoogle ScholarCrossref
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Olivry  T, Dunston  SM.  Usefulness of collagen IV immunostaining for diagnosis of canine epidermolysis bullosa acquisita.  Vet Pathol. 2010;47(3):565-568. doi:10.1177/0300985809359609PubMedGoogle ScholarCrossref
19.
Kridin  K.  Accessible diagnostic methods to differentiate between epidermolysis bullosa acquisita and other subepidermal autoimmune bullous diseases.  Indian J Dermatol. 2018;63(5):445-448. doi:10.4103/ijd.IJD_75_18PubMedGoogle ScholarCrossref
20.
Parker  SRS, Dyson  S, Brisman  S,  et al.  Mortality of bullous pemphigoid: an evaluation of 223 patients and comparison with the mortality in the general population in the United States.  J Am Acad Dermatol. 2008;59(4):582-588. doi:10.1016/j.jaad.2008.07.022PubMedGoogle ScholarCrossref
21.
Lee  JH, Kim  S-C.  Mortality of patients with bullous pemphigoid in Korea.  J Am Acad Dermatol. 2014;71(4):676-683. doi:10.1016/j.jaad.2014.05.006PubMedGoogle ScholarCrossref
22.
Cai  SCS, Allen  JC, Lim  YL, Chua  SH, Tan  SH, Tang  MBY.  Mortality of bullous pemphigoid in Singapore: risk factors and causes of death in 359 patients seen at the National Skin Centre.  Br J Dermatol. 2014;170(6):1319-1326. doi:10.1111/bjd.12806PubMedGoogle ScholarCrossref
23.
Joly  P, Baricault  S, Sparsa  A,  et al.  Incidence and mortality of bullous pemphigoid in France.  J Invest Dermatol. 2012;132(8):1998-2004. doi:10.1038/jid.2012.35PubMedGoogle ScholarCrossref
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Di Zenzo  G, Thoma-Uszynski  S, Fontao  L,  et al.  Multicenter prospective study of the humoral autoimmune response in bullous pemphigoid.  Clin Immunol. 2008;128(3):415-426. doi:10.1016/j.clim.2008.04.012PubMedGoogle ScholarCrossref
25.
Chorzelski  TP, Jablońska  S.  Clinical variants of pemphigoid.  Int J Dermatol. 1986;25(10):669-670. doi:10.1111/j.1365-4362.1986.tb04538.xPubMedGoogle ScholarCrossref
26.
Lee  CM, Leadbetter  HK, Fishman  JM.  Case report a case of oropharyngeal bullous pemphigoid presenting with haemoptysis.  Case Rep Otolaryngol. 2015;2015. doi:10.1155/2015/631098Google Scholar
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Kirtschig  G, Wojnarowska  F, Marsden  RA, Edwards  S, Bhogal  B, Black  MM.  Acquired bullous diseases of childhood: re-evaluation of diagnosis by indirect immunofluorescence examination on 1 M NaCl split skin and immunoblotting.  Br J Dermatol. 1994;130(5):610-616. doi:10.1111/j.1365-2133.1994.tb13108.xPubMedGoogle ScholarCrossref
28.
Farrell  AM, Kirtschig  G, Dalziel  KL,  et al.  Childhood vulval pemphigoid: a clinical and immunopathological study of five patients.  Br J Dermatol. 1999;140(2):308-312. doi:10.1046/j.1365-2133.1999.02668.xPubMedGoogle ScholarCrossref
29.
Yancey  KB, Egan  CA.  Pemphigoid: clinical, histologic, immunopathologic, and therapeutic considerations.  JAMA. 2000;284(3):350-356. doi:10.1001/jama.284.3.350PubMedGoogle ScholarCrossref
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Yancey  KB, Lawley  TJ. Immunologically Mediated Skin Diseases. In: Kasper DL, Fauci AS, Hauser SL,  et al Eds;  Harrison’s Principles of Internal Medicine, 19e. McGraw-Hill Education; New York, New York. 2015.
31.
Kridin  K.  Peripheral eosinophilia in bullous pemphigoid: prevalence and influence on the clinical manifestation.  Br J Dermatol. 2018;179(5):1141-1147. doi:10.1111/bjd.16679PubMedGoogle ScholarCrossref
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Kridin  K, Bergman  R.  Ethnic variations in the epidemiology of bullous pemphigoid in Israel.  Int J Dermatol. 2018;57(1):34-39. doi:10.1111/ijd.13813PubMedGoogle ScholarCrossref
33.
Chijiwa  C, Takeoka  S, Kamata  M,  et al.  Decrease in eosinophils infiltrating into the skin of patients with dipeptidyl peptidase-4 inhibitor-related bullous pemphigoid.  J Dermatol. 2018;45(5):596-599. doi:10.1111/1346-8138.14245PubMedGoogle ScholarCrossref
34.
Kridin  K, Bergman  R.  Association of bullous pemphigoid with dipeptidyl-peptidase 4 inhibitors in patients with diabetes: estimating the risk of the new agents and characterizing the patients.  JAMA Dermatol. 2018;154(10):1152-1158. doi:10.1001/jamadermatol.2018.2352PubMedGoogle ScholarCrossref
Original Investigation
January 9, 2019

Assessment of the Prevalence of Mucosal Involvement in Bullous Pemphigoid

Author Affiliations
  • 1Department of Dermatology, Rambam Health Care Campus, Haifa, Israel
  • 2School of Public Health, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel
  • 3Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
JAMA Dermatol. 2019;155(2):166-171. doi:10.1001/jamadermatol.2018.5049
Key Points

Question  What is the precise prevalence and distribution of mucosal involvement in patients with bullous pemphigoid (BP), and what are the clinical characteristics of patients with mucosal affection?

Findings  In this cohort study of 328 patients, mucosal involvement was present in 17.1% of patients with BP and was associated with disease severity. The prevalence of laryngeal involvement was higher than previously reported (4.9%).

Meaning  Clinicians should be aware of the notable prevalence of mucosal involvement in BP, particularly of the previously underestimated laryngeal involvement.

Abstract

Importance  The prevalence of mucosal involvement in bullous pemphigoid (BP) is inconsistent. Nonoral mucosal involvement was reported anecdotally in few patients with BP.

Objective  To evaluate the prevalence of mucosal involvement in patients with BP, and to characterize the subgroup of patients with mucosal lesions.

Design, Setting, and Participants  A retrospective cohort study was performed including 328 consecutive patients diagnosed with immunopathologically validated BP at a tertiary care referral center for autoimmune bullous diseases in northern Israel between January 1, 2000, and December 31, 2017.

Main Outcome and Measures  The study was conducted to estimate the prevalence and distribution of mucosal involvement among patients with BP. Patients with mucosal involvement were compared with the remaining BP patients regarding clinical and immunological features, laboratory analyses, and treatments.

Results  The study cohort included 139 (42.4%) male and 189 (57.6%) female patients, with a mean (SD) age of 78.0 (11.8) years at presentation. Fifty-six patients (17.1%) presented with mucosal lesions. The oral mucosa was the most frequently affected mucosal surface (n = 44; 13.7%), followed by the laryngeal (n = 16; 4.9%) and the genital (n = 10; 3.0%) mucosae. Among patients with oral lesions, the most involved oral structures were the buccal mucosa (n = 25; 55.6%) and the soft palate (n = 24; 53.3%). Compared with other patients with BP, patients with mucosal involvement were younger (71.8 [14.4] years vs 79.3 [10.8] years; P < .001), presented more frequently with extensive disease (55.4% vs 39.7%; P = .002), had less peripheral eosinophilia (17.8% vs 41.9%; P < .001), and were treated with higher doses of corticosteroids (prednisone >1 mg/kg: 67.9% vs 51.8%; P = .03).

Conclusions and Relevance  Mucosal lesions are present in a notable subgroup of patients with BP and are associated with disease severity. Laryngeal involvement is more common than previously appreciated.

Introduction

Most patients with bullous pemphigoid (BP) classically present with tense blisters and erythema, seen predominantly in the limb flexures and the abdomen, and often in conjunction with urticarial plaques. Meanwhile, 20% present with atypical manifestations, including prurigo-like type,1 urticaria-like type,2 eczema-like type,3 and dyshidrosiform type.4 Involvement of the mucous membranes was considered an atypical physical feature by the clinical criteria of Vaillant et al,5 which yields a positive predictive value of 95% for a clinical diagnosis of BP. Mucosal lesions in BP are typically restricted to the oral mucosa and may be observed in up to 20% of patients.6-8 The involvement of other mucosal surfaces is less established and based on anecdotal case reports.9-13

To our knowledge, the frequency of nonoral mucosal involvement among patients with BP was not evaluated previously in the setting of cohort or large case series studies. The knowledge about the precise mucosal structures that may be affected in BP and of the distinct features of patients with BP who have mucosal involvement is very limited.

The objectives of the current study were to evaluate the prevalence of general mucosal involvement in patients with BP and to characterize the subgroup of patients with mucosal lesions, using a large cohort of patients with well-defined and immunopathologically validated BP.

Methods
Design and Study Population

This was a retrospective prevalence study comprising all patients who received a new diagnosis of BP between January 1, 2000, and July 31, 2017, at Rambam Health Care Campus, Haifa, Israel.

Bullous pemphigoid was diagnosed as a blistering disease appearing predominantly in the skin with suggestive clinical features5,6 and typical histopathology of BP, including a subepidermal blister with inflammatory-cell infiltrate in the superficial dermis, often containing eosinophils, alongside at least 1 of the following immunopathological features: (1) linear deposits of IgG and/or C3 along the basement membrane zone by direct immunofluorescence (IF); (2) circulating IgG autoantibodies binding to the basement membrane as demonstrated by the use of monkey esophagus and a standard indirect IF technique; (3) the presence of circulating IgG antibodies against the immunodominant domain of BP180 (NC-16A) using enzyme-linked immunosorbent assay (ELISA).14

Cases with predominant mucosal involvement were defined as mucous membrane pemphigoid (MMP) and excluded from the current study according to the international consensus on MMP.15 This consensus statement concludes that the main clinical feature of MMP is being a mucous membrane–dominant disease, thus distinguishing it from all other immune-mediated blistering skin diseases that may have mucous membrane involvement.15 In cases where inflammatory epidermolysis bullosa acquisita (EBA) or anti–laminin γ1 pemphigoid were clinically suspected, direct IF microscopy was conducted after the perilesional biopsy was incubated with 1 M NaCl solution (in BP, in contrast to the 2 aforementioned conditions, immunoreactant depositions are detected along the roof of the artificial split).16 In addition, type IV collagen immunostaining on paraffin sections was performed in several cases to differentiate BP from EBA (in the latter, type IV collagen is expected to be demonstrated in the epidermal roof of the blister).17-19

Every new-onset BP patient underwent a thorough physical examination by a trained dermatologist, and standardized medical charts were filled. Physical examination was systematically oriented to inspect for mucosal lesions on the oral, genital, and nasal mucosae. An indirect laryngoscopy was performed by a trained otorhinolaryngologist to evaluate the involvement of the larynx whenever other mucosal surfaces were involved, or when patients complained about laryngeal symptoms like sore throat, dysphagia, or hoarseness. All patients underwent a systematic eye examination by a trained ophthalmologist before the initiation of treatment.

This retrospective, noninterventional study was approved by the institutional ethical board of Rambam Health Care Campus, waiving patient written informed consent because data were collected as part of standard care.

Definition of Covariates

Disease severity was divided, based on the clinical description, into “mild or moderate” and “extensive.”20,21 Eosinophil count and other hematological parameters of the cases were recorded on the admission of patients with new-onset BP (before the initiation of any systemic therapy).

Statistical Analysis

All continuous parameters were expressed as means with standard deviation (SD). Comparisons of percentages between different patient groups were carried out using the χ2 test. All normally distributed data were analyzed using unpaired or paired student t-test. Data found to be non-normally distributed were analyzed using the Mann-Whitney U test for independent subgroups and the Wilcoxon test for dependent subgroups. All statistical analyses were performed using SPSS statistical software (version 22, IBM).

Results
Characteristics of the Study Population

The study cohort comprised 328 patients with BP, of whom 139 (42.4%) were men, and 189 (57.6%) were women. The mean (SD) age at diagnosis was 78.0 (11.8) years, and the median age was 80.0 (range, 22.0-99.0) years. Most of the patients were of Ashkenazi Jewish origin (n = 196; 59.7%), followed by Sephardic Jews (n = 95; 29.0%), and Arabs (n = 37; 11.3%). Patients of Arab ancestry were significantly younger than Jews at the onset of the disease (70.7 [14.9] years vs 78.9 [11.0] years, respectively; P < .001).

General Mucosal Involvement

Fifty-six patients (17.1%) presented with mucosal lesions. The oral mucosa was the most frequently involved mucosal surface (n = 45; 13.7%). Mucosal lesions on the larynx had been observed in 16 (4.9%) of the patients, being the second most common involved mucosal surface. Ten patients (3.0%) had genital, 1 (0.3%) had anal, and 1 (0.3%) had ocular involvement. Of patients with mucosal involvement, 39 (69.7%) had isolated involvement of 1 mucosal surface, whereas 17 (30.3%) patients had 2 mucosal surfaces involved concomitantly. None of these patients had a simultaneous involvement of more than 2 mucosal surfaces.

The mucosal manifestation followed the skin lesions in 27 (48.2%) patients with an average latency of 6.5 (14.1) months, and preceded the skin lesions in 5 (8.9%) patients with an average latency of 2.5 (1.7) months. Eight (14.3%) patients presented with concomitant cutaneous and mucosal involvement, whereas the temporal sequence could not be determined in the remaining 16 (28.6%) patients.

In patients presenting with oral involvement, the most frequent mucosal lesions were erosions on the buccal mucosa (n = 25; 55.6%), followed by erosions on the soft palate (n = 24; 53.3%), the gingiva (n = 10; 22.2%), the labial mucosa (n = 8; 17.8%), the dorsum of tongue (n = 5; 11.1%), and the floor of mouth (n = 5; 11.1%). Twenty-three (51.1%) patients had isolated involvement of 1 oral mucosal structure, whereas 13 (28.9%), 8 (17.8%), and 1 (2.2%) patient had lesions on 2, 3, and 4 concomitant oral structures, respectively.

The most frequent laryngeal lesions were erosions on the laryngeal surface of the epiglottis, occurring in all 16 patients. One patient (6.3%) had coexisting erosion on the arytenoids, whereas another 1 (6.3%) had concomitant erosion on the false vocal cords. Fourteen (87.5%) patients had concomitant oral or genital lesions, whereas 2 (12.5%) patients had isolated laryngeal mucosal involvement. The leading laryngeal symptom was dysphagia in 7 patients (43.8%), whereas 3 (18.8%) patients presented with a sore throat, and 1 (6.3%) patient with hoarseness. Importantly, 5 (31.3%) patients did not complain about a laryngeal-specific symptom at presentation; these patients underwent laryngoscopic inspection owing to the involvement of other mucosal surfaces. None of these patients presented with shortness of breath or other respiratory symptoms and no scarring lesions were observed. All patients underwent a follow-up endoscopy to assure the resolution of these lesions before the corticosteroid treatment could be tapered down.

Genital involvement was observed in 10 patients, of whom 6 (60%) were women. All 4 male patients presented with erosions on the glans penis, whereas 5 of 6 female patients had erosions on the labia, and 1 had erosions on the vulval vestibule. In 6 (60%) patients, the genital mucosa was the isolated involved mucosal surface, whereas in the remaining 4 (40%), 1 more mucosal surface was concomitantly involved.

Ocular involvement was detected only in 1 patient presenting with unilateral blepharochalasis and conjunctival swelling with nonspecific hyperemia resolving without ophthalmic sequelae.

Characterizing BP Patients With Mucosal Involvement

We then addressed the clinical differences between BP patients with mucosal involvement (n = 56) in relation to the remaining BP patients (n = 272). Patients with mucosal involvement were significantly younger at presentation (71.8 [14.4] years vs 79.3 [10.8] years, respectively; P < .001), whereas no significant differences were seen between the groups regarding sex and ethnic composition (Table).

No evident differences in the delay from the onset of symptoms until the immunopathologic diagnosis of BP were noted between the 2 groups (P = .15). Regarding the anatomical distribution of bullous lesions, patients with mucosal involvement had an increased cutaneous involvement of the head and neck (51.8% vs 30.1%, respectively; P = .002). Involvement of other body sites and the proportion of atypical clinical variants of BP (including the prurigo-like type,1 urticaria-like type,2 eczema-like type,3 and dyshidrosiform type4) were comparable between the 2 subgroups (Table). Patients with mucosal involvement presented more frequently with extensive cutaneous disease (55.4% vs 39.7%, respectively; P = .03).

Patients with mucosal involvement were treated by higher dosage of systemic corticosteroids; 38 (67.9%) were administered prednisone at an initial dose exceeding 1 mg/kg (compared with 141 [51.8%] in the remaining patients; P = .03) to achieve disease control, and their mean dose of prednisone at discharge was significantly higher (0.88 [0.32] mg/kg vs 0.75 [0.34] mg/kg, respectively; P = .01). The administration of adjuvant immunosuppressants and doxycycline to achieve disease control was higher among patients presenting with mucosal lesions (33.9% vs 20.6%, respectively; P = .03). Overall, methotrexate was the most frequently administered adjuvant agent (n = 56; 17.1%), followed by azathioprine (n = 10; 3.0%), doxycycline (n = 5; 1.5%), dapsone (n = 3; 0.9%), and mycophenolate mofetil (n = 1; 0.3%).

Patients with BP with mucosal involvement had significantly lower circulating eosinophil counts (509.7 [1292.7] vs 836.7 [1023.7]/μL; P = .04) and lower prevalence of peripheral eosinophilia (17.8% vs 41.9%; P < .001). Other biomarkers did not differ substantially between the 2 subgroups, except erythrocyte sedimentation rate (ESR) being higher in patients with mucosal involvement (40.2 [23.9] vs 26.8 [21.4] mm/h, respectively; P < .001).

Of interest, patients with mucosal involvement tended to develop their disease in association with the intake of dipeptidyl peptidase-4 inhibitors (DPP4i), albeit this difference did not reach the level of statistical significance (16.1% vs 9.9%, respectively; P = .18).

In a subgroup analysis, the clinical features of 17 patients with concomitant involvement of 2 mucosal surfaces were compared with patients with only 1 mucosal surface affected (n = 39). The former subgroup had more frequent cutaneous involvement of the head and neck (76.5% vs 41.0%, respectively; P = .02). The following variables were comparable between the 2 subgroups: involvement of other body sites, disease severity, prevalence of exposure to DPP4i, indirect IF positivity, frequency of adjuvant immunosuppressants, and the mean dosage of prednisone required for disease control.

Discussion

This prevalence study reveals that mucosal involvement had been encountered in 56 (17.1%) patients with BP. The oral mucosa was the most frequently involved mucosal surface (n = 45; 13.7%), followed by the laryngeal (n = 16; 4.9%) and the genital (n = 10; 3.0%) mucosae.

Mucosal Involvement in Previous Literature

The frequency of mucosal involvement among patients with BP varied substantially in different study cohorts. A low prevalence of 5.7% was reported in Singapore,22 whereas higher prevalence rates of 14.5% and 18.6% were observed in Switzerland6 and North France,8 respectively. Intermediate figures of 7.7% and 10.2% had been reported in 3 French regions23 and in a multicenter Pan-European study,24 respectively. The general mucosal involvement observed in our cohort is within the range of the higher figures in the literature.

It is well established that mucosal lesions in patients with BP are usually confined to the oral cavity and tend to take a less aggressive course, compared with pemphigus vulgaris and MMP.7,25,26 The oral mucosa was by far the most frequently involved mucosal surface in previous cohorts; although Joly et al23 reported that all of their 42 patients with mucosal involvement had oral lesions, the corresponding figures in other studies were 94.4% (17/18),8 94.1% (16/17),6 and 80% (4/5).24 The relative prevalence of oral involvement in our study (80.4%; 45/56) is lower than most previous reports. Our findings indicate that the oral involvement in BP is mainly confined to the nonkeratinized mucosal surfaces; lesions on the buccal mucosa and soft palate were observed in 25 (55.6%) and 24 (53.3%) patients with oral involvement, respectively, whereas the involvement of keratinized mucosal structures, like the gingiva and the dorsum of tongue, was less frequent. The isolated involvement of 1 oral structure in most of the patients lends weight to the previous reports attributing an indolent course to oral lesions in BP.7,25,26

Laryngeal mucosal involvement among patients with BP was believed to be a very rare and atypical presentation. Anecdotal case reports depicted concomitant laryngeal and cutaneous involvement in several patients with BP,10-12 whereas previous cohort studies did not identify patients with laryngeal lesions. Our relatively large study reveals that laryngeal involvement is more common than previously appreciated, with a prevalence estimated to be of at least 4.9%. The higher detection of laryngeal lesions may be attributable to our policy of performing indirect fiberoptic laryngoscopy whenever other mucosal surfaces were involved, even in the lack of laryngeal symptoms. It should be noted that determination of laryngeal involvement was based on experienced otolaryngologist visual inspection as well as on response to BP treatment in parallel with the cutaneous response, but lacked histopathologic confirmation. Thus, the estimated prevalence may represent an overestimate and should be viewed as an upper bound of laryngeal involvement.

The genital lesions constituted up to 17.9% (10/56) of the general mucosal involvement in this cohort. The corresponding figures in other studies were 0% (0/42),23 5.6% (1/18),8 17.6% (3/17),6 and 20% (1/5).24 Although most reports of genital involvement in patients with BP were restricted to younger women,27,28 genital lesions in our study affected both elderly male and female patients.

Characteristics of Patients With BP With Mucosal Involvement

Our findings indicate that mucosal involvement is associated with the presence of extensive cutaneous disease. This aligns with a recent French study demonstrating that patients with mucosal involvement had both a more active and extensive disease (as assessed by number of daily new blisters and BPDAI scores, respectively).8 It was previously suggested that patients with BP presenting with mucosal lesions require more aggressive therapy to achieve clinical remission.12,29,30 Our experience seems to lend weight to this approach, and patients with mucosal involvement were treated with higher doses of systemic corticosteroids and adjuvant agents compared with other BP patients. Taken together, the more aggressive treatment regimen administered for patients with BP with mucosal involvement may be justified.

Importantly, patients with mucosal involvement presented more frequently with cutaneous lesions on the head and neck area (n = 29; 51.8%). This distribution was considered as an atypical clinical feature, which decreases the likelihood of a clinical diagnosis of BP when approaching patients with subepidermal autoimmune bullous diseases.5 This clinical feature may be another clue to raise suspicion about mucosal involvement in relevant patients. Furthermore, we found less peripheral eosinophilia among patients with mucosal involvement; this accords with the findings of a recent study31 observing a higher prevalence of mucosal lesions among BP patients with normal eosinophil counts relative to those with peripheral eosinophilia. Further research is required to elucidate whether circulating or infiltrating eosinophils exert a protective role against the development of mucocutaneous BP. Patients with mucosal involvement were significantly younger at the onset of their disease. This finding was not reported previously and worth investigating in the future. The younger age of patients of Arab ancestry may be ascribed to the younger age of the Arab population in Israel.32

Our study revealed that patients with mucosal involvement tended to have an increased exposure to DPP4i, though lacking statistical significance. Recently, Chijiwa et al,33 comparing 9 patients with DPP4i-associated BP with 21 patients with non–DPP4i-associated BP, reported that the former had more severe mucosal involvement. Furthermore, 36 patients with DPP4-associated BP had been recently found to present more frequently with mucosal lesions compared with their 46 diabetic non–DPP4i-associated BP counterparts (22.2% vs 6.5%, respectively; P = .04).34 Further studies are warranted to elucidate the pathomechanism underlying this observation.

Strengths and Limitation

The main limitation of the current study originates from the retrospective data collection that interfered with a precise assessment of the acceptable severity index (BPDAI) and autoantibodies titers. Given that the study was performed in a tertiary referral center setting, it is susceptible to the selection of more severe and recalcitrant patients. The lack of consistent longitudinal follow-up interfered with drawing firm conclusions with regard to clinical outcomes of patients as well as to the efficacy of immunosuppressive agents. In addition, thorough immunological profiling of the patients was lacking because ELISA was not performed in all cases. However, our study comprises a relatively large sample of immunopathologically proven cases aged 18 years or older and address questions that were not previously investigated. To our knowledge, this study characterizes the largest subgroup of patients with BP with mucosal involvement and is among the first to shed light on the precise involved mucosal structures.

Conclusions

This study indicates that mucosal involvement in BP may occur in 17.1% of patients. The oral mucosa was the most frequently affected mucosal surface, particularly its nonkeratinized structures, whereas the laryngeal mucosa was more involved than previously reported. Mucosal involvement in BP is associated with extensive cutaneous disease, lower peripheral eosinophilia, and more aggressive treatment. Clinicians should be aware of the notable prevalence of mucosal involvement in BP. Awareness may be specifically raised of the underreported laryngeal involvement.

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Article Information

Corresponding Author: Khalaf Kridin, MD, PhD, Department of Dermatology, Rambam Health Care Campus, PO Box 9602, Haifa 31096, Israel (dr_kridin@hotmail.com).

Accepted for Publication: November 11, 2018.

Published Online: January 9, 2019. doi:10.1001/jamadermatol.2018.5049

Author Contributions: Dr Kridin had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Kridin.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Kridin.

Administrative, technical, or material support: All authors.

Study supervision: All authors.

Conflict of Interest Disclosures: None reported.

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