Ocular Mucous Membrane Pemphigoid Research Articles

Ocular Mucous Membrane Pemphigoid: The Effect of Risk Factors at Presentation on Treatment Outcomes

PurposeAnalyze the influence of risk factors at presentation in the long-term immunosuppressive therapy (IMT) outcomes of ocular mucous membrane pemphigoid (OMMP). DesignRetrospective multicenter study. ParticipantsOMMP patients seen at Duke Eye Center, Tecnologico de Monterrey, and Hospital Clinic of Barcelona from 1990–2022. MethodsData at presentation on demographics, direct immunofluorescence and ocular findings, extraocular sites of involvement (EOM) and prior treatments, in patients with a clinical and/or laboratory diagnosis of OMMP, were analyzed with multivariable analysis and Kaplan-Meier plots to identify factors associated with adverse outcomes. Main outcome measures(1) inflammatory control (no conjunctival inflammation in both eyes at three months on IMT); (2) relapse (new-onset inflammation after absolute control in either eye); (3) progression (≥1 cicatrizing stage progression in either eye); and (4) vision loss (>2 Snellen lines). Results117 patients (234 eyes), 61% (71/117) women, with a mean age of 66.6 (standard deviation (SD) 12.4, range: 37–97) years and a median follow-up of 34 (interquartile range Q1 16, Q3 66; range: 3–265) months. Inflammatory control was achieved in 57% (67/117) patients, with high-risk EOM (HR-EOM), including esophageal, nasopharyngeal, and/or genital [adjusted odds ratio (aOR) 12.51; 95% confidence interval (CI), 2.61–59.99; P=0.002] and corneal scarring (aOR 3.06; 95% CI, 1.15–8.14; P=0.025) as significant risk factors for persistent inflammation. Disease relapse, progression, and vision loss occurred in 20% (23/117), 12% (14/117), and 27% (32/117) of patients, respectively. Baseline corneal scarring was a risk factor for relapse [adjusted hazard ratio 4.14; 95% CI, 1.61–10.62; P=0.003], progression (aOR 11.46; 95% CI, 1.78–73.75; P=0.010), and vision loss (aOR 3.51; 95% CI, 1.35–9.10, P=0.010). HR-EOM was associated with stage progression (aOR 34.57; 95% CI, 6.57–181.89; P<0.001) and vision loss (aOR 8.42; 95% CI, 2.50–28.42, P=0.001). There were no significant differences between IMT regimes and relapse (P=0.169). ConclusionsOMMP presenting with HR-EOMs and corneal scarring has an increased risk of stage progression and vision loss. Corneal scarring and severe inflammation at baseline were associated with an increased risk of relapse. A disease progression staging system incorporating both the HR-EOMs and corneal involvement is required to predict the visual outcome of OMMP better.

Diagnostic and prognostic values of conjunctival and oral biopsies analyzed by direct immunofluorescence in patients with mucous membrane pemphigoid.

Mucous membrane pemphigoid (MMP) is diagnosed on the basis of a characteristic clinical picture (a predilection for mucosal involvement and scarring in the affected tissues) and a positive direct immunofluorescence (DIF) result. In this study, we compare the diagnostic and prognostic values of conjunctival and oral biopsies analyzed by DIF in patients with MMP. Sixteen patients with MMP and mucosal involvement as a predominant symptom were classified into three groups based on the clinical picture. Oral and conjunctival DIF were performed on all patients. Our study showed that patients with simultaneous oral and conjunctival involvement had a positive oral DIF in 83% and a positive ocular DIF in 100% of the examined cases, respectively. Patients with isolated ocular MMP had a positive oral DIF in 50% and a positive ocular DIF in 66% of the examined cases, respectively. Patients with only oral involvement with MMP had a positive oral DIF in 100% and a positive ocular DIF in 50% of the examined cases, respectively. Oral biopsy should be performed first and is usually sufficient for the diagnosis, even in patients with exclusively ocular MMP, whereas in patients without clinical ocular involvement, ocular DIF is positive in half of the cases and may be a predictive factor for ocular lesions in the future.

Direct Immunofluorescence Findings and Factors Affecting Conjunctival Biopsy Positivity in Ocular Mucous Membrane Pemphigoid.

The aim of this study was to describe the direct immunofluorescence (DIF) findings and factors affecting conjunctival biopsy positivity in patients clinically diagnosed with ocular mucous membrane pemphigoid (OMMP). This retrospective observational case series included patients with clinical OMMP who underwent conjunctival biopsy for DIF in at least 1 eye between 2018 and 2021 in an institutional setting. The primary outcome measures were association of age and chronic ocular complications with biopsy positivity. Of 61 patients, DIF positivity was seen in 33 (54.1%) clinically suspected cases of OMMP. Of 39 patients who underwent bilateral biopsy, 23 (59%) were positive, of which 12 (52%) were positive in both eyes while 11 (48%) were positive in 1 eye. Of 22 patients who underwent unilateral biopsy, 10 (45%) were positive. Of the 100 biopsied eyes, 45 (45%) were DIF positive. Among the immunoreactants studied, linear deposition of C3 was seen in all 45 positive eyes (100%). Increasing age was significantly associated with higher likelihood of biopsy negativity ( P = 0.032), whereas a greater Sotozono chronic ocular complication score, indicative of disease severity, was associated with low likelihood of biopsy positivity ( P = 0.0042) and lower overall expression of immunoreactants on DIF ( P = 0.0007). Older patients and patients with more severe ocular surface disease sequelae are likely to have negative DIF results. To optimize the chances of confirming the diagnosis of OMMP by DIF, both eyes should be biopsied early in the disease course. If 1 eye is being biopsied, the less affected eye must be chosen.

[Diagnostics of ocular mucous membrane pemphigoid].

The diagnosis of ocular mucous membrane pemphigoid (MMP) remains achallenge as the timing and choice of diagnostic methods have adecisive influence on its quality. Asystematic approach is required that includes acomprehensive medical history, critical evaluation of the clinical findings and targeted laboratory testing. The diagnosis is complicated by the fact that some patients present purely clinically the symptoms of MMP without fulfilling the required immunohistochemical and laboratory criteria. Basically, the diagnosis of ocular MMP is based on three pillars: 1) medical history and clinical findings, 2) positive immunohistological (direct immunofluorescence) tissue sample and 3) specific serological autoantibodies. As the diagnosis of ocular MMP often implies prolonged systemic immunomodulatory treatment in predominantly older patients, the accurate diagnosis and approach are of critical relevance. The aim of this article is to present the recently updated diagnostic procedure.

Long-term outcomes of fornix reconstruction and cicatricial entropion repair in ocular mucous membrane pemphigoid and drug-related secondary pemphigoid

ObjectiveTo investigate the long-term outcomes of fornix reconstruction and cicatricial entropion repair in patients with ocular mucous membrane pemphigoid (MMP) and secondary MMP. MethodsRetrospective chart review of patients with MMP undergoing either fornix reconstruction (with amniotic membrane or buccal mucosal graft) or Wies cicatricial entropion repair between January 1, 2000, and September 1, 2020. Patients had a positive mucosal biopsy and (or) clinical features of MMP or secondary MMP. The primary outcome was overall success of fornix reconstruction based on fornix depth maintenance at latest follow-up. Secondary outcomes included resolution of trichiasis, visual acuity, and improvement of subjective symptoms. ResultsEight patients (10 eyes) with a diagnosis of MMP (3 males and 5 females; median age, 71 years) and 4 patients (4 eyes) with a diagnosis of secondary MMP (2 females and 2 male; median age, 87 years) were enrolled. Mean follow-up was 22.7 months (range, 0.3–87.5 months) for MMP patients and 15.4 months (range, 3.0–43.9 months) for secondary MMP patients. For MMP eyes, 30.0% underwent fornix reconstruction, 60.0% underwent entropion repair, and 10.0% received both. Re-formation of symblepharon and loss of fornix depth occurred in all MMP eyes at an average of 6.4 ± 7.0 months postoperatively, and trichiasis recurred in all patients at the last follow-up visit. In secondary MMP patients, 75.0% of the eyes showed recurrence of symblepharon, and 66.7% re-formed trichiasis. Both MMP and secondary MMP patients had short-term symptom improvements. ConclusionsFornix reconstruction and cicatricial entropion repair in our cohort of MMP and secondary MMP patients resulted in short-term symptomatic improvement, but recurrence was seen, on average, at 6 months postoperatively.

Keratoprosthesis in dry eye disease.

Bilateral corneal blindness with severe dry eye disease (DED), total limbal stem cell deficiency with underlying corneal stromal scarring and vascularization, combined with adnexal complications secondary to chronic cicatrizing conjunctivitis is a highly complex situation to treat. In such eyes, procedures such as penetrating keratoplasty alone or combined with limbal stem cell transplantation are doomed to fail. In these eyes, keratoprosthesis (Kpro) or an artificial cornea is the most viable option, eliminating corneal blindness even in eyes with autoimmune disorders such as Stevens-Johnson syndrome, ocular mucous membrane pemphigoid, Sjogren's syndrome, and nonautoimmune disorders such as chemical/thermal ocular burns, all of which are complex pathologies. Performing a Kpro in these eyes also eliminates the need for systemic immunosuppression and may provide relatively early visual recovery. In such eyes, the donor cornea around the central cylinder of the Kpro needs to be covered with a second layer of protection to avoid desiccation and progressive stromal melt of the underlying cornea, which is a common complication in eyes with severe DED. In this review, we will focus on Kpro designs that have been developed to survive in eyes with the hostile environment of severe DED. Their outcomes in such eyes will be discussed.

Repeatability of quantitative measurements of anterior segment analysis with swept‐source AS‐OCT in dry eye, ocular surface disease and healthy eyes

AbstractPurpose: Dry eye and ocular surface disease (OSD) are the most common causes of eye discomfort with up to 50%1 of the global population affected. Anterior segment optical coherence tomography (AS‐OCT) is essential to diagnose and track ocular surface changes. This study aims at assessing the precision of a modern swept source AS‐OCT in OSD vs healthy control.Methods: Five clinical groups were included: G1 = Sjögren's syndrome (n = 46); G2 = Ocular Mucous Membrane Pemphigoid, Graft‐versus‐Host Disease, etc. (n = 58); G3 = Meibomian Gland Disease (n = 47); G4 = Miscellaneous (Neurotrophic, Exposure, Transplant, etc.) (n = 36); G5 healthy controls (n = 41). Three consecutive measurements using a radial scan mode were collected using the AS‐OCT Casia2 (Tomey, Japan) and the repeatability limits (RLs) were calculated. The following parameters were obtained: anterior chamber depth (ACD), AC width (ACW), angle opening distance (AOD) and angle recess area (ARA) both at 250, 500 and 750 μm, angle to angle (ATA), central thickness apex (CTapex), lens vault (LV), trabecular iris angle (TIA) and trabecular iris‐space area (TISA) both at 250, 500 and 750 μm. Dry eye metrics such as OSDI® questionnaire, fluorescein break‐up time (FBUT), tear meniscus height (TMH), conjunctival inflammation (INFLCONJ) and ocular surface staining (OSS) were considered.Results: The higher RLs values were observed within the G4 cohort considering AOD (0.28, 0.29, 0.36, 0.35, 0.43 vs G5 0.18, 0.21, 0.18, 0.20, 0.26 mm),ARA (0.08, 0.10, 0.16, 0.18, 0.25, 0.27 vs. G5 0.06, 0.06, 0.09, 0.10, 0.14, 0.15 mm2), CTapex (66.12 vs. G5 13.55 μm), TIA (33.90, 22.57, 14.55, 20.02 vs. G5 30.94, 18.31, 9.44, 14.76 degrees) and TISA (0.06, 0.07, 0.14, 0.15, 0.23, 0.24 vs. G5 0.04, 0.05, 0.08, 0.09, 0.12, 0.14 mm2). G1 cohort reported the worst dry eye metrics (OSDI 52.90 ± 20.58 score, FBUT 3.51 ± 2.36 s, TMH 0.10 ± 0.07 mm, INFLCONJ 1.07 ± 1.78 score, OSS 4.27 ± 2.35 score).Conclusions: This is the first study to consider anterior segment analysis repeatability limits in OSD vs healthy cohorts with the AS‐OCT Casia2. Despite G1 cohort reported the worse dry eye metrics, the higher repeatability limits were observed in the G4 Miscellaneous group.Reference1. Stapleton, F. et al. TFOS DEWS II Epidemiology Report. Ocular Surface 15, 334–365, doi:10.1016/j.jtos.2017.05.003 (2017).

Rituximab in Mucous Membrane Pemphigoid: A Monocentric Retrospective Study in 10 Patients with Severe/Refractory Disease.

Rituximab (RTX) is a monoclonal antibody directed against CD20 antigen indicated in an increasing number of immune-mediated diseases. While its efficacy in pemphigus vulgaris has been widely investigated, only a few data about its possible role in pemphigoid diseases have been reported in the literature. Accordingly, herein we evaluated a case series of patients with mucous membrane pemphigoid (MMP) treated with RTX. We included patients with a history of severe/refractory MMP who received at least one cycle of intravenous RTX between May 2018 and December 2021 and had 6 months of follow-up time. Disease control (DC) was our early endpoint, while complete remission (CR) and partial remission (PR) were late endpoints. CR off-therapy, relapses, and adverse events were evaluated as well. Our population included 10 MMP patients. Eight out of ten patients (80%) achieved DC in a mean of 8 weeks, while two patients with ocular MMP were non-responders. Among the eight patients who achieved DC, two reached CR off therapy, two CR on minimal therapy, and two achieved PR on minimal therapy. In our case series, the addition of RTX to conventional therapies was demonstrated to be safe and effective in reaching rapid disease control in the majority of refractory MMP patients.

A 10-Year Review of the Management of Ocular Mucous Membrane Pemphigoid: A Private Practice Experience.

Ocular mucous membrane pemphigoid (OcMMP) is a rare and potentially blinding condition for which consensus treatment guidelines do not exist. The purpose of this study was to assess the effectiveness and safety of various immunomodulatory agents in the treatment of OcMMP in a private practice setting. We conducted a 10-year retrospective chart review of patients managed with OcMMP (n = 22). The median age at diagnosis was 73 (range: 35-91) years, and 59% (13/22) of patients were female. Visual acuity, Foster stage, and adverse effects (AEs) were documented. Treatment outcomes for each treatment episode were qualified at 3 months as complete response (CR), response (R), or failure (F). After 3 months, CR was then further subqualified as sustained CR, reactivation after initial CR, or AE after initial CR. The Fisher exact test P values were calculated for each outcome in comparison with mycophenolate. Twenty patients were treated with an immunomodulatory agent for a total of 55 treatment episodes. In comparison to dapsone, mycophenolate was more likely to achieve sustained CR (50% vs. 0%, P = 0.022) and R (100% vs. 50%, P = 0.007), and less likely to fail (0% vs. 50%, P = 0.007). Dapsone was also more likely to be discontinued because of AEs than mycophenolate (40% vs. 6%, P = 0.041). Mycophenolate is a superior first-line agent to dapsone in the treatment of OcMMP. Although not statistically significant, mycophenolate trends toward superiority over methotrexate as well. Mycophenolate is very effective when used in combination with rituximab. Azathioprine remains a reasonable second-line agent.

Utility of Direct Immunofluorescence Using Buccal Mucosal Biopsies in Those with Suspected Isolated Ocular Mucous Membrane Pemphigoid

To determine the rate of positivity of immunofluorescence studies in buccal biopsies in patients with cicatrizing conjunctivitis undergoing workup for ocular mucous membrane pemphigoid (MMP)/ocular cicatricial pemphigoid (OCP). Retrospective cohort review. Forty-one patients with cicatrizing conjunctivitis undergoing workup for OCP. A retrospective chart review of direct immunofluorescence (DIF) studies in buccal mucosal biopsies was performed. The primary outcome measure was the rate of positivity of direct and indirect immunofluorescence studies on buccal mucosal biopsies. Twenty-two patients (54%) had a positive buccal mucosal biopsy; 64% of patients (14/22) demonstrated+DIF on initial biopsy and an additional 36% of patients (8/22) on the second biopsy. Eighteen patients underwent conjunctival biopsy. In the 6 patients with a negative conjunctival biopsy, 4 (67%) had a positive buccal biopsy. Buccal mucosal immunofluorescence studies may be positive in patients with OCP even in the absence of extraocular disease. Buccal mucosal biopsy may be considered as an alternative to or attempted before conjunctival biopsy for the diagnosis of OCP, particularly in patients in whom conjunctival biopsy may be difficult or imminently visually threatening.

On the Current Care Situation and Treatment of Ocular Mucous Membrane Pemphigoid in Germany.

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. 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. 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 741patients. 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%). 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.

OP-10 Gut microbiota dysbiosis as a driver of inflammation in Ocular Mucous Membrane Pemphigoid.

Gut microbiome profiles between OcMMP patients (n=49) and healthy controls (n=40) were compared by extracting DNA from faecal samples and amplified for the V4 region of the 16S rRNA gene followed by Illumina Miseq platform sequencing. Sequencing reads were processed using the bioinformatics pipeline available in the mothur v.1.44.1 software. Using multivariable model and adjustment for participant factors, OcMMP cohort was found to be associated with lower number of operational taxonomic units (OTUs) and Shannon Diversity Index when compared to healthy controls. OcMMP OTUs were found to be significantly correlated with both the bulbar conjunctival inflammation score (p=0.03) and the current use of systemic immunotherapy (p=0.02). Linear discriminant analysis effect size scores found Streptococcus and Lachnoclostridium enriched in OcMMP. By contrast, healthy controls were enriched with Oxalobacter, Clostridia uncultured genus-level group (UCG) 014, Christensenellaceae R-7 group and butyrate-producing bacteria such as Ruminococcus, Lachnospiraceae, Coprococcus, Roseburia, Oscillospiraceae UCG 003, 005, NK4A214 group (Log10 LDA score <2, FDR-adjusted p<0.05). In conclusion, OcMMP patients have gut dysbiosis that correlated with bulbar conjunctival inflammation and the use of systemic immunotherapies. This provides a framework for future longitudinal deep phenotyping studies on the role of the gut microbiome in the pathogenesis of OcMMP. Low L, Suleiman K, Shamdas M, Bassilious K, Poonit N, Rossiter AE, Acharjee A, Loman N, Murray PI, Wallace GR, Rauz S. Gut dysbiosis in ocular mucous membrane pemphigoid. Front. Cell. Infect. Microbiol. 2022;12:780354. https://doi.org/10.3389/fcimb.2022.780354.

Use of Systemic Mycophenolate Mofetil Therapy in Ocular Surface Inflammatory Pathologies at the Initiative and Responsibility of the Ophthalmologist.

The purpose of the study was to evaluate the efficacy and safety of systemic mycophenolate mofetil (MMF) treatment in ocular surface inflammatory diseases. For this retrospective study, patients who were treated with systemic MMF for ocular surface inflammatory diseases between March 2020 and March 2022 were evaluated. Apart from demographic data, examination notes including MMF treatment indication and systemic side effect interrogation and routine laboratory examinations during drug treatment were extracted from the patient records. Detailed staging scores were performed according to the diagnosis including Foster and Mondino for ocular mucous membrane pemphigoid (MMP) and limbal stem cell deficiency scoring for limbal transplantation. For thorough evaluation, anterior segment pictures were used. Fourteen patients were enrolled to the study, with a mean age of 58 ± 12. MMP (6, 42.8%) and limbal allograft transplantation (6, 42.8%) constituted the main indications for the MMF treatment, followed by keratitis-ichthyosis-deafness (KID) syndrome (1, 7.2%) and Mooren's ulcer (1, 7.2%). Five of six patients with MMP regressed according to both staging systems. Only one remained stable which was evaluated as Stage 3. Furthermore, while all limbal transplant groups (6) stabilized and showed regression according to the individualized limbal stem cell deficiency staging system with no rejection during follow-up. Furthermore, patients with Mooren's ulcer and KID syndrome showed control of the inflammation and stabilization after MMF treatment. No significant systemic side effects apart from constipation and nausea (3) were observed in patients whose routine laboratory tests were stable throughout the follow-up. MMF has the potential to be a valuable and safe systemic agent of first choice in the control of ocular surface inflammatory disorders, especially when topical treatment is not effective. With such studies, it is predicted that MMF may reach wider usage areas with the increase in its effectiveness and safety in its use for ocular surface inflammatory pathologies.

European Guidelines (S3) on diagnosis and management of mucous membrane pemphigoid, initiated by the European Academy of Dermatology and Venereology - Part II.

This guideline has been initiated by the task force Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology, including physicians from all relevant disciplines and patient organizations. It is a S3 consensus‐based guideline that systematically reviewed the literature on mucous membrane pemphigoid (MMP) in the MEDLINE and EMBASE databases until June 2019, with no limitations on language. While the first part of this guideline addressed methodology, as well as epidemiology, terminology, aetiology, clinical presentation and outcome measures in MMP, the second part presents the diagnostics and management of MMP. MMP should be suspected in cases with predominant mucosal lesions. Direct immunofluorescence microscopy to detect tissue‐bound IgG, IgA and/or complement C3, combined with serological testing for circulating autoantibodies are recommended. In most patients, serum autoantibodies are present only in low levels and in variable proportions, depending on the clinical sites involved. Circulating autoantibodies are determined by indirect IF assays using tissue substrates, or ELISA using different recombinant forms of the target antigens or immunoblotting using different substrates. The major target antigen in MMP is type XVII collagen (BP180), although in 10–25% of patients laminin 332 is recognized. In 25–30% of MMP patients with anti‐laminin 332 reactivity, malignancies have been associated. As first‐line treatment of mild/moderate MMP, dapsone, methotrexate or tetracyclines and/or topical corticosteroids are recommended. For severe MMP, dapsone and oral or intravenous cyclophosphamide and/or oral corticosteroids are recommended as first‐line regimens. Additional recommendations are given, tailored to treatment of single‐site MMP such as oral, ocular, laryngeal, oesophageal and genital MMP, as well as the diagnosis of ocular MMP. Treatment recommendations are limited by the complete lack of high‐quality randomized controlled trials.

Ocular mucous membrane pemphigoid: novel treatment strategies.

To describe current treatments of ocular mucous membrane pemphigoid (OMMP), including conventional systemic immunosuppression (CIST) and novel biologic agents. CIST remains the main stay therapy for the management of OMMP. The choice of agents is tailored to disease severity - mild disease is treated with dapsone, whereas moderately severe cases are often treated with mycophenolate mofetil or sulfa-based drugs and severe cases are treated with cyclophosphamide. In recalcitrant disease newer biologics such as Rituximab, intravenous immunoglobins and tumour necrosis alpha antagonists have proven to be effective in disease control. Control of inflammation with topical therapy and halting conjunctival fibrosis remain as areas of unmet clinical needs. OMMP is largely treated with CIST. The recent introduction of new biologic agents could shape the way the disease is treated in the near future.

Repository Corticotropin Injection as an Alternative Treatment for Refractory Ocular Mucous Membrane Pemphigoid.

The purpose of this study was to report the clinical course and outcome of patients with refractory ocular mucous membrane pemphigoid (MMP) treated by repository corticotropin injection (RCI). Patients with biopsy-proven ocular MMP treated with RCI from 3 tertiary medical centers were evaluated. Medical records between January 2013 and January 2021 were reviewed and deidentified to retrieve relevant disease-related data. Primary outcome measures included conjunctival inflammatory activity, change in Foster clinical conjunctival scarring staging after RCI treatment, and the development of ocular and systemic complications. Included were 15 patients (10 women and 5 men; 36-95 yrs of age) with a mean follow-up of 4.5 years. Most of the patients (80%) had Foster stage 3 at presentation, and all patients had active MMP. Each patient had failed to respond to at least 1 immunomodulatory drug during the follow-up, and 9 (60%) patients had treatment failure of at least 2 other agents before the use of RCI. The mean duration of RCI treatment was 21 months (range, 3-54 mo). Foster stage did not change in any of the 15 patients at the last follow-up. Nine patients continued RCI therapy at the last follow-up, and in all of them, the disease activity of MMP was well controlled. No serious adverse events because of RCI were documented during the follow-up in any treated patient. RCI may serve as an alternative or an adjunctive treatment in patients with severe and refractory ocular MMP. Treatment with RCI seems to be safe and well-tolerated.

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

To quantitate the risk of relapse of ocular and extraocular disease among patients with mucous membrane pemphigoid (MMP) who had undergone drug-free remission. Retrospective, comparative, interventional case series. 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. 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. 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.

Single Center Retrospective Study of Patients with Ocular Mucous Membrane Pemphigoid (MMP)

ABSTRACT Purpose Mucous membrane pemphigoid (MMP) with ocular involvement often leads to devastating vision loss from ocular surface disease. This study sought to better characterize presenting symptoms, clinical characteristics, important factors in clinical progression, and visual acuity over time. Methods A retrospective chart review was performed on 88 patients seen at the Emory Eye Center between January 1, 2012 and July 1, 2017 for ocular MMP. Results A large percentage of patients with MMP presented at later stages. Partial or complete loss of the fornices and symblepharon were the most common initial disease complications. The time to clinical stabilization usually occurred 1 year after initial presentation. Conclusions Ocular MMP is a devastating disease that often presents to tertiary care hospitals at late stages and leads to numerous eyelid and ocular surface changes. This study demonstrated that presenting clinical signs are broad and that stabilization of visual acuity takes months.

Autoantibody Detection for Diagnosis in Direct Immunofluorescence-Negative Mucous Membrane Pemphigoid: Ocular and Other Sites Compared

To assess whether a panel of serum pemphigoid autoantibody tests could be used to confirm an immunopathologic diagnosis of mucous membrane pemphigoid (MMP) in direct immunofluorescent negative (DIF-) MMP patients. Prospective cross-sectional study. Seventy-six patients with multisite MMP with 45 matched control participants. Enzyme-linked immunosorbent assays (ELISAs) for BP180 and BP230 (MBL International), immunoglobulin A (IgA) A and immunoglobulin G indirect immunofluorescence (IIF) on human salt-split skin and the keratinocyte footprint assay for anti-laminin 332 antibodies. Sensitivity and specificity of autoantibody detection and significant differences for individual tests and test combinations for MMP involving different sites. All DIF- patients (24/73 [31.8%]) had either ocular-only disease or ocular involvement in multisite disease. Serum pemphigoid autoantibodies were detected in 29 of 76 MMP patients (38.2%) compared with 3 of 45 control participants (6.7%). Autoantibody reactivity detected by any 1 or more of the tests was present in 6 of 24 DIF- patients (25%) compared with 22 of 49 DIF positive (DIF+) patients (44.9%). Ocular-only MMP serum reactivity was not significantly different for any test or test combination compared with control participants, whereas DIF- multisite ocular MMP differed for 1 ELISA and 3 of 7 test combinations. By contrast, for DIF+ nonocular MMP patients, all the individual tests, apart from IgA IIF, and all test combinations were significantly different compared with those for control participants. For the entire MMP cohort, the sensitivity of all individual tests was low, having a maximum of 21.05% for BP180 reactivity but increasing to 38.16% for an optimal test combination. Disease activity was associated strongly with positive serologic findings. Pemphigoid serum autoantibody tests did not provide immunopathologic evidence of MMP in ocular-only MMP patients but showed limited value in DIF- multisite ocular MMP patients. The requirement for immunopathologic confirmation of MMP by autoantibody detection is inappropriate for DIF- ocular-only MMP patients, resulting in missed diagnoses, delayed therapy, and poor outcomes. Alternative diagnostic criteria for ocular-only MMP are required to exclude the other causes of scarring conjunctivitis until more sensitive and specific immunopathologic tests become available.

Plasma Rich in Growth Factors for the Treatment of Cicatrizing Conjunctivitis.

PurposeThe objective was to evaluate the clinical results obtained from the use of immunosafe plasma rich in growth factors (isPRGF) in the treatment of patients with cicatrizing conjunctivitis (CC) who had not responded to the usual therapy.Patients and MethodsThis is a retrospective study that included patients diagnosed with CC, in whom isPRGF was used in different phases (I: eye drops; II: eye drops and injectable; III: eye drops, injectable and surgical treatment) to achieve control of the inflammation. As a clinical follow-up of the patients, the better corrected visual acuity (BCVA), degree of inflammation (measured from 1 to 4), the severity of the CC, Schirmer I test, IOP and TBUT were analyzed. The adverse events were also evaluated.ResultsTen eyes (6 patients) were evaluated, 50% corresponded to Stevens–Johnson Syndrome and 50% to ocular mucous membrane pemphigoid. The mean age was 59.7 ± 16.5 (39–80) years, and 50% were women. Fifty per cent of the cases were initially considered severe CC, and 10% of the cases (one eye of one patient) were considered severe CC at the end of the treatment (p = 0.046). The initial degree of inflammation was 2 in 4 eyes, 3 in two eyes, and 4 in 4 eyes, and final inflammation degree was 1 in all cases (p = 0.004). Twenty per cent of the cases achieved stability in Phase I of the treatment with immunosafe PRGF, 70% with both Phases I and II, and only one case underwent Phase III to achieve stability. The IOP improved significantly (p = 0.027) though the BCVA, TBUT and Schirmer I test showed no significant changes. The follow-up time was 23.1 ± 6.7 (13.6–30.3) months. No adverse effects were reported.ConclusionTreatment with PRGF technology in its injectable and topical immunosafe formulations may be a novel alternative for the treatment of patients with CC, given its complement activity modulating effect, as well as its anti-inflammatory, antifibrotic and regenerative properties.