On the Current Care Situation and Treatment of Ocular Mucous Membrane Pemphigoid in Germany. / Zur Versorgungssituation und konservativen Therapie des okulären vernarbenden Schleimhautpemphigoids in Deutschland.

BACKGROUND: Ocular involvement in mucous membrane pemphigoid (MMP) is relatively rare, with a prevalence of 25 cases per million population, equating to approx. 2,100 patients throughout Germany. Diagnosis can be difficult - especially in cases of isolated ocular involvement - and treatment can be complex and lengthy. Immunosuppressants or immunomodulatory drugs are often used. Due to the complexity of diagnosis and treatment, MMP patients are usually referred to specialized centers. The aim of this project was to evaluate the current care situation of patients with ocular MMP in Germany. METHODS: A paper-based survey was designed and sent to all university eye clinics and other specialized centers in Germany in April 2020. The survey asked about the existence of a specialized outpatient service, the total annual number of patients with MMP, the annual number of newly diagnosed patients, any interdisciplinary collaboration for diagnostic or therapeutic purposes, as well as the local and systemic therapy used. RESULTS: Of a total of 44 clinics, 28 (64%) responded, reporting a total average of 27 ± 42 (0 - 200) patients and 3.6 ± 2.2 (0 - 10) new cases per year. This corresponds to a total of 741 patients. Only nine (32%) of the responding clinics offer specialized MMP clinics. 93% of the centers collaborate with the local dermatology department. 79% perform serological and histological diagnostics in-house. About half of the centers (n = 16) apply a standardized treatment regime. Systemic glucocorticoids (66.7%) are most commonly used, followed by mycophenolate mofetil and dapsone (57.1%), rituximab (33.3%), azathioprine and cyclophosphamide (28.6%), as well as methotrexate (19.0%). The least frequently used treatment is intravenous immunoglobulin (14.3%). CONCLUSION: This survey of German ophthalmology departments obtained data from about one third of the estimated total cohort of all patients with MMP in Germany. These are presumed to be exclusively patients with at least one ocular involvement. The complex care of these patients is usually provided in collaboration with a dermatologist and with the use of systemic anti-inflammatory medication. Currently, an ophthalmological MMP register is being established to better record the epidemiology and care situation of this rare disease in Germany and to improve it in the long term.

Autoimmune mucocutaneous blistering diseases in the south of Italy: a 25-year retrospective study on 169 patients.

BACKGROUND: Autoimmune mucocutaneous blistering diseases (AMBDs) represent a heterogeneous group of organ-specific and potentially life-threatening diseases. We sought to determine the relationship between clinical remission and therapeutic regimens with clinical type and phenotype of AMBDs, as well as clinical outcomes achieved based on different therapeutic regimens. METHODS: A retrospective single-center study on 169 AMBDs patients, including pemphigus vulgaris (PV), mucous membrane pemphigoid (MMP), paraneoplastic autoimmune multiorgan syndrome (PAMS), and lichen planus pemphigoides (LPP), was performed from 1994 to 2019 in an oral medicine tertiary center, where we collected sociodemographic data, clinical type and phenotype, prescribed therapies, and related outcomes. RESULTS: The mean age of AMBDs patients was 55.0 ± 16.4 years. They were followed for a mean of 8.4 ± 5.8 years. The majority of these patients (62.1%) were successfully managed with conventional immunosuppressive therapy (CIST) alone. However, 37.9% of patients required additional biological treatments, either because they were non-responders or developed severe side effects from CIST, or because of the rapid and severe progression of the disease. Overall, complete clinical remission was achieved in 92.3% of patients. A statistically significant difference was noted between the frequency distribution of AMBDs patients among different therapeutic regimens (P = .002), of different clinical phenotype and type of AMBDs patients and clinical remission (P = .012 and P = .005, respectively). No difference was reported regarding clinical outcomes and different therapeutic regimens. CONCLUSIONS: AMBDs' management may be challenging, nonetheless CIST and biologic regimens introduced, when needed as reliable alternatives to CIST, result in a very high percentage of CCR.

Gastrointestinal symptoms, gastrointestinal bleeding and the role of diet in patients with autoimmune blistering disease: a survey of the International Pemphigus and Pemphigoid Foundation.

BACKGROUND: Autoimmune blistering diseases are a group of severe mucocutaneous conditions that typically require the use of prolonged corticosteroids and immunosuppression. Properly managing associated comorbidities is an integral part of these patients' care. The frequency of gastrointestinal symptoms, particularly gastrointestinal bleeding in these patients, is not known. Likewise, the effect of diet on disease is unknown. OBJECTIVE: To determine the incidence of gastrointestinal comorbidities and the role of diet in patients with autoimmune blistering disease. METHODS: We distributed an e-survey to patients with autoimmune blistering disease utilizing the International Pemphigus and Pemphigoid Foundation's listserv. The incidence of gastrointestinal symptoms and gastrointestinal bleeding were recorded, as were foods avoided and those noted to be beneficial in patients' disease. Historical incidences in the general population were used as controls. RESULTS: A total of 200 responses were collected. 30.3% of patients experienced gastroesophageal reflux following treatment of their autoimmune blistering disease, with 51.7% utilizing some form of gastrointestinal symptomatic treatment. The incidence of gastrointestinal bleeding following an autoimmune blistering diagnosis was 2.1%, which remained significant despite correction for non-steroidal anti-inflammatory use (NSAID), but not corticosteroid use. 65.2% of patients reported dietary limitations because of their autoimmune blistering disease. Significant intolerances after correction for multiple comparisons included alcohol, citrus and spicy foods. Greater than 10% of patients reported improvements in their disease with vegetables and dairy. CONCLUSIONS: Gastrointestinal comorbidities are common in patients with autoimmune blistering diseases, with gastrointestinal bleeding occurring in 2.1% of patients following a diagnosis of autoimmune blistering disease. While further work is needed to determine the relative risk of routine gastrointestinal prophylaxis in this population, gastrointestinal bleeding prophylaxis should be considered in patients receiving corticosteroids, particularly those taking NSAIDs. Dietary limitations are additionally frequent in this population. Patients should be cautious of alcohol, citrus and spicy foods.

Structured Diagnostic Approach and Risk Assessment in Mucous Membrane Pemphigoid with Oesophageal Involvement.

Oesophageal involvement in mucous membrane pemphigoid is considered rare, but it may be underdiagnosed. To assess the incidence of oesophageal involvement in a group of patients with newly diagnosed mucous membrane pemphigoid we retrospectively analysed the medical records of 30 consecutive patients with mucous membrane pemphigoid diagnosed between 2006 and 2016 at the Department of Dermatology, University Hospital Würzburg. Twenty-one patients (70%) reported symptoms indicative of oesophageal mucous membrane pemphigoid. Twelve patients (40%) underwent oesophagogastroduodenoscopy, and oesophageal pathology compatible with mucous membrane pemphigoid was endoscopically found in 9 cases (30%). In all patients indirect and direct immunofluorescence were performed. Patients with and without oesophageal involvement did not differ with regard to the results of indirect immunofluorescence on salt-split human skin and monkey oesophagus. Study results demonstrate the necessity of a standardized diagnostic work-up, including adequate tissue samples for direct immunofluorescence, to prevent underdiagnosis of oesophageal mucous membrane pemphigoid.

Spectrum of orocutaneous disease associations: Immune-mediated conditions.

There are a number of diseases that manifest both on the skin and the oral mucosa, and therefore the importance for dermatologists in clinical practice to be aware of these associations is paramount. In the following continuing medical education series, we outline orocutaneous disease associations with both immunologic and inflammatory etiologies.

Evaluation of Autoimmune Bullous Diseases in Elderly Patients in Iran: A 10-Year Retrospective Study.

Autoimmune bullous diseases (ABDs) are uncommon but significant skin disorders with relatively high morbidity and mortality. Some surveys have been carried out to describe the spectrum of ABDs in a region, but this is the first that has focused on ABDs in elderly patients. This study was conducted to determine the clinicoepidemiologic features of ABDs in elderly patients. Medical records of all ABD patients with disease onset after the age of 60 years who presented to the Autoimmune Bullous Diseases Research Center, Tehran, Iran between April 2003 and March 2013 were reviewed. Patients with dermatitis herpetiformis were not included. During the 10-year period studied, 296 patients with ABD and disease onset after 60 years of age were diagnosed. Bullous pemphigoid (BP) was observed to be the most common ABD (48.3%), followed by pemphigus vulgaris (45.3%), pemphigus foliaceus (3.7%), mucous membrane pemphigoid (1.4%), paraneoplastic pemphigus (0.7%), epidermolysis bullosa acquisita (0.3%), and linear IgA bullous disease (0.3%). A predominance in women was observed for total ABDs, BP, and pemphigus vulgaris. Although Iran is known to have a high prevalence of pemphigus, BP is the most frequent ABD among elderly patients in Iran, highlighting the importance of the clinical diagnosis of BP in elderly patients.

Spectrum of Autoimmune Bullous Diseases in the Middle East: A 15-Year Review.

Characteristics of autoimmune bullous diseases (AIBDs) show wide geographic variation. The aim of this study was to determine retrospectively the characteristics of patients with AIBD admitted to Hôtel-Dieu de France Hospital in Beirut, Lebanon, between 1999 and 2014 and to compare them with those from other areas in the Middle East, the Far East, Asia, North Africa, Europe, and North America. For the patients with AIBDs and who were hospitalized at a major tertiary referral center between 1999 and 2004, we studied demographics, diagnosis, length of stay, department/floor, comorbidities, clinical features, in-hospital evolution, diagnostic tests, and treatment. Bullous pemphigoides was the most frequent bullous disease in Lebanon. This and other findings contrast with those of studies conducted in regional countries. This is the first report of AIBD from the Middle Eastern region.

Clinical and demographic overlaps among immunologically mediated oral diseases: a challenge for clinicians.

This study sought to assess and compare retrospective demographic and clinical data of oral lesions of lichen planus, pemphigus vulgaris, and mucous membrane pemphigoid from the records of the Department of Oral Pathology and Surgery, School of Dentistry, Universidade Federal de Minas Gerais, Brazil, covering a period of 55 years. Out of 25,435 specimens, these immunologically-mediated diseases accounted for 301 (1.18%) cases, of which 250 (0.98%) were lichen planus, 27 (0.11%) were pemphigus vulgaris, and 24 (0.09%) were mucous membrane pemphigoid. Lichen planus presented mainly as white asymptomatic plaques on buccal mucosa. Pemphigus vulgaris was usually characterized by multiple symptomatic erithematous ulcers on the buccal mucosa. Painful ulcers and/or blisters on the gingiva were the most common presentation for mucous membrane pemphigoid. Desquamative gingivitis was noted for all 3 diseases, but mainly for mucous membrane pemphigoid. Overall, lesions were more frequent in white women >50 years. Oral manifestations of immunologically-mediated diseases are relatively rare, and the correct diagnosis can be a challenge for dentists as the lesions often share similar clinical and demographic features.

[Mucous membrane pemphigoid: a review]. / Pemphigoïde cicatricielle: revue de la littérature.

BACKGROUND: Mucous membrane pemphigoid is a rare autoimmune bullous disorder. Numerous treatment regimens have been proposed in the literature. OBJECTIVE: To assess the efficacy and tolerance of treatment regimens proposed in mucous membrane pemphigoid (MMP), from a systematic review of the literature. METHODS: Randomized control trials have been identified using the PubMed and Embase databases up to April 2009. Uncontrolled prospective and retrospective studies have also been analyzed. RESULTS: Literature analysis confirms that clinical and therapeutic trials are very uncommon in MMP; only retrospective series or case reports are available and have been analyzed. Therefore, the level of evidence is usually weak. Twenty-four series have been analyzed in this review. Dapsone remains the first line treatment in non-ocular forms of MMP. Sulfasalazine or cyclins can be used when dapsone is not tolerated or effective. Corticosteroids can be used to control inflammatory flares of the disease. Immunosuppressants are not used as the first line of treatment and can be added to anti-inflammatory drugs for a better control of MMP. Cyclophophamide or mycophenolate mofetil can be used, especially in the elderly. In ocular forms of the disease, the severity and chronicity of ocular involvement is the main therapeutical target. Non-scarring conjunctivitis can be treated by dapsone monotherapy. Ocular flares of the disease can be treated with systemic corticosteroids or cyclophosphamide. Many immunomodulating drugs are under evaluation. Intravenous immunoglobulins, etanercept or rituximab can be proposed when cyclophosphamide is not able to control the disease. CONCLUSION: Data from the literature did not allow identifying the best therapeutic regimen, mainly because of the lack of prospective comparative studies. Dapsone remains the first line treatment in MMP. Immunosuppressive or immunomodulating drugs should be discussed patient by patient.

The epidemiology of autoimmune bullous diseases in Sudan between 2000 and 2016.

OBJECTIVES: Autoimmune bullous diseases vary in their clinico-epidemiological features and burden across populations. Data about these diseases was lacking in Sudan. We aimed to describe the epidemiological profile and to estimate the burden of autoimmune bullous diseases in Sudan. METHODS: This was a retrospective cross-sectional study conducted at Khartoum Dermatological and Venereal Diseases Teaching Hospital. We used routinely collected health care data, and included all patients with an autoimmune bullous disease who presented to the hospital between 2001 and 2016. RESULTS: Out of the 4736 patients who were admitted to the hospital during the study period, 923 (19.5%) had an autoimmune bullous disease. The average rate of patients at the hospital was 57.7 per year representing 1.3 per 100,000 population per year. After exclusion of patients where the final diagnosis was missing, 585 were included in the further analysis. Pemphigus vulgaris was the most common disease (50.9%), followed by bullous pemphigoid (28.2%), linear IgA disease/chronic bullous disease of childhood (8.4%), and pemphigus foliaceous (8.2%). Pemphigoid gestationis and IgA pemphigus constituted 1.4% and 1.2% of the cohort, respectively. Paraneoplastic pemphigus, mucous membrane pemphigoid, lichen planus pemphigoidis, bullous systemic lupus erythematosus, and dermatitis herpetiformis were rare. None of the patients had epidermolysis bullosa acquisita. CONCLUSIONS: The clinico-epidemiological characteristics vary among the types of autoimmune bullous diseases. Females were more predominant in most of them. Sudanese patients tended in general to present at a younger age than other populations. The pool of Sudanese patients with autoimmune bullous diseases is large which requires investigation for the local risk factors and presents a field for future trials.

Disease Relapse After Drug-Free Remission in Ocular Mucous Membrane Pemphigoid.

PURPOSE: To quantitate the risk of relapse of ocular and extraocular disease among patients with mucous membrane pemphigoid (MMP) who had undergone drug-free remission. DESIGN: Retrospective, comparative, interventional case series. METHODS: There were 167 patients with biopsy-proven MMP who were seen at the Wilmer Eye Institute between November 1984 and December 2019. Among the 167 patients, 119 patients had ocular involvement and 103 of those patients received systemic treatment for MMP. The main outcome measures were the incidence of ocular remission, incidence rate of disease relapse after remission, and risk factors for disease relapse. RESULTS: Over a median follow-up time of 7 years, 74 of 103 treated patients (71.8%) experienced drug-free remission (incidence rate = 0.28/person-year [PY], 95% confidence interval [CI] 0.22-0.35/PY). Most patients (80/103, 77.7%) received cyclophosphamide therapy. Thirteen of the 74 patients (17.6%) had disease relapse after remission: 4 with ocular disease only, 4 with extraocular disease only, and 5 with both. The rate relapse of ocular MMP was 0.020/PY (95% CI 0.009-0.038/PY), and the rate of relapse of MMP at any site (ocular or extraocular site) was 0.029/PY (95% CI 0.015-0.050/PY). The use of cyclophosphamide was associated with a greater chance of remission (hazard ratio [HR] = 3.84, P < .0001) and a lower risk of relapse (HR = 0.32, P = .05) compared with other immunosuppressive drugs except for rituximab. Five patients experienced drug-free remission after rituximab therapy and none of them had relapse (median follow-up after remission = 3.6 years). When use of cyclophosphamide or rituximab was compared with all other treatments, the risk of MMP relapse at any site (HR = 0.17, P = .02) and of ocular MMP (HR = 0.11, P = .007) were significantly lower. CONCLUSIONS: Rates of relapse of MMP after drug-free remission are low but not zero; therefore, monitoring of patients remains necessary. Relapses were not observed among those patients treated with rituximab who had remission; however, follow-up duration in those patients was shorter than the whole MMP cohort and the sample size was small.

Autoimmune bullous diseases with skin and eye involvement: Cicatricial pemphigoid, pemphigus vulgaris, and pemphigus paraneoplastica.

Autoimmune blistering diseases are a heterogeneous group of disorders that mostly affect the skin and mucous membranes. Occasionally, other organ systems may be involved, depending on the unique pathophysiology of each disease. Cicatricial pemphigoid, pemphigus vulgaris, and paraneoplastic pemphigus are distinct entities, but all have the potential to have cutaneous and ocular involvement. Awareness and early recognition of ocular involvement in these diseases is important given the increased risk for vision loss and blindness with delay in management. Several skin diseases may be associated with involvement of the external eye. The most common autoimmune diseases are cicatricial pemphigoid, pemphigus vulgaris, and paraneoplastic pemphigus.

Autoimmune Blistering Diseases in the Elderly: Clinical Presentations and Management.

Elderly patients are more susceptible to the development of autoimmune blistering disorders such as bullous pemphigoid, mucous membrane pemphigoid, epidermolysis bullosa acquisita, and paraneoplastic pemphigus. This article focuses on the clinical aspects of the aforementioned autoimmune blistering diseases and highlights the important factors involved in treating elderly patients. It is essential for clinicians to offer individualized treatment plans for these patients to optimize outcomes, as elderly patients often have multiple co-morbidities, polypharmacy, and suboptimal socioeconomic status that can adversely influence adequate compliance.

Cicatricial pemphigoid and dry eye.

Cicatricial pemphigoid is the most common of the immunobullous disorders causing conjunctival cicatrization and is an autoimmune disease in which the ocular component of the immunopathology is directed at the conjunctival basement membrane. The disease is usually bilateral and more common in females, with most cases occurring between 30-90 years, and most often in the seventh decade. The disease occasionally occurs in children. Tear deficiency is a major cause of symptoms, although loss of vision is usually due to surface failure before the onset of aqueous tear deficiency, which occurs late in the progression of the disease. Management of the dry eye must be integrated with the management of the other components of both the ocular surface disease and inflammation. Management requires plastic surgery for the lid and lash malposition, tetracyclines and lid hygiene for the accompanying blepharitis. For the dry eye, the use of lubricants without preservatives is important, to avoid toxicity, and lubricant ointment is helpful for the relief of symptoms in terminally dry eyes without the capacity for surface wetting. Contact lenses, either large limbal diameter rigid gas permeable or gas permeable scleral lenses, are useful for treating dry eye and improving vision in some patients. Control of the conjunctival inflammation is mandatory to prevent disease progression and usually requires systemic immunosuppressive therapy.

Characteristics of patients with ocular cicatricial pemphigoid referred to major tertiary hospital.

OBJECTIVE: To evaluate the demographic and clinical characteristics of patients referred to a tertiary care hospital cornea clinic for ocular cicatricial pemphigoid (OCP) assessment. DESIGN: Retrospective, nonrandomized, consecutive case series. PARTICIPANTS: Thirty three patients with OCP who were treated at the corneal clinic of Toronto Western Hospital from 2003 to 2012. METHODS: Database search of patients from 2003 to 2012 with a referral request or diagnosis of OCP was conducted at a tertiary care hospital cornea clinic. Charts of 33 patients (64 eyes) were reviewed. Outcome measures included patient demographics, methods of diagnosis, visual acuity, ocular features, and disease staging using Foster's staging system, systemic modes of treatment, disease progression, and presence of systemic involvement. RESULTS: Mean patient age at presentation was 69.8 years (range 40-91), and 81% (27/33) were female. At presentation, disease staging consisted of stage I (subepithelial fibrosis) 7.8% (5/64), stage II (shortened fornices) 21.8% (14/64), stage III (symblepharon formation) 65.6% (42/64), and stage IV (keratinization with or without globe immobility) 4.6% (3/64). At the final follow-up visit, the proportions of the involved eyes for stages I to IV were 1.5% (1/64), 10.9% (7/64), 76.5% (49/64), and 10.9% (7/64), respectively. Conjunctival biopsies were obtained from 81% (27/33) of patients and reported as positive in 30% (8/27), negative in 63% (17/27), and inconclusive in 7% (2/27) of patients. Mean duration of follow-up was 6.8 ± 5.6 years (range 0.5-22), and 66.6% (22/33) of patients had progressive disease. Systemic mucocutaneous involvement was noted in 36.3% (12/33) of patients. CONCLUSIONS: The high rate of disease progression suggests the need for improved therapeutic options. Additional modalities are needed in addition to conjunctival biopsy to confirm a diagnosis of OCP in patients with clinical signs of the disease.

Contemporary issues in the diagnosis of oral pemphigoid: a selective review of the literature.

Pemphigoid is a group of bullous diseases that have a diversified morphologic presentation and affect the skin, oral mucosa, and other mucosal membranes, alone or in combination. In the literature, the condition has been subclassified into bullous pemphigoid and cicatricial pemphigoid (mucous membrane pemphigoid) on the basis of the primary organ of involvement. In addition to the clinical presentation and a subepithelial vesicle or bullae on routine histologic analysis, the diagnosis is based on direct and indirect immunofluorescence studies. Recent investigations indicate that different clinical groups of patients with pemphigoid produce autoantibodies to different molecules within the basement membrane zone. Based on these recent observations and a review of the literature, a viewpoint is presented that not all patients with cicatricial pemphigoid should be grouped together. Rather, they should be classified into subgroups-ocular, oral, etc-on the basis of the clinical phenotype and long-term follow-up. Such a division will facilitate the provision of appropriate and relevant treatment plans; if the clinical course changes, the diagnosis can be adjusted. This strategy will prevent patients with disease limited to the oral cavity from receiving systemic drugs or agents that may be more harmful than beneficial.

Relative incidence of intraoral pemphigus vulgaris, mucus membrane pemphigoid and lichen planus.

A retrospective analysis of patients was conducted in order to determine the relative incidence of oral pemphigus vulgaris, mucus membrane pemphigoid and lichen planus. The analysis yielded a relative incidence of 1:2:15 of pemphigus vulgaris, mucus membrane pemphigoid and lichen planus patients. The dangers of comparing and relating incidence statistics from one study to other studies were demonstrated.