Tofacitinib for refractory ocular mucous membrane pemphigoid.
Ontology highlight
ABSTRACT: Purpose
To report the successful use of tofacitinib in the treatment of refractory ocular mucous membrane pemphigoid (MMP).Observations
Two patients with ocular MMP presented with refractory disease after failure of multiple therapies. Treatment with tofacitinib led to durable control of conjunctival inflammation within 8 weeks and no apparent progression of sub-conjunctival fibrosis. One patient maintained absence of apparent disease activity over 16 months of follow-up. Cessation of tofacitinib in the other patient led to disease relapse which was reversed by re-initiation of therapy.Conclusions and importance
Small molecule inhibitors of Janus kinases, such as tofacitinib, may offer an effective treatment option for refractory ocular MMP.
SUBMITTER: James H
PROVIDER: S-EPMC8111584 | biostudies-literature | 2021 Jun
REPOSITORIES: biostudies-literature
Publications
Tofacitinib for refractory ocular mucous membrane pemphigoid.
James Hayley H Paley Grace L GL Brasington Richard R Custer Philip L PL Margolis Todd P TP Paley Michael A MA
American journal of ophthalmology case reports 20210421
<h4>Purpose</h4>To report the successful use of tofacitinib in the treatment of refractory ocular mucous membrane pemphigoid (MMP).<h4>Observations</h4>Two patients with ocular MMP presented with refractory disease after failure of multiple therapies. Treatment with tofacitinib led to durable control of conjunctival inflammation within 8 weeks and no apparent progression of sub-conjunctival fibrosis. One patient maintained absence of apparent disease activity over 16 months of follow-up. Cessati ...[more]
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Project description:Mucous Membrane Pemphigoid is an orphan multi-system autoimmune scarring disease involving mucosal sites, including the ocular surface (OcMMP) and gut. Loss of tolerance to epithelial basement membrane proteins and generation of autoreactive T cell and/or autoantibodies are central to the disease process. The gut microbiome plays a critical role in the development of the immune system. Alteration in the gut microbiome (gut dysbiosis) affects the generation of autoreactive T cells and B cell autoantibody repertoire in several autoimmune conditions. This study examines the relationship between gut microbiome diversity and ocular inflammation in patients with OcMMP by comparing OcMMP gut microbiome profiles with healthy controls. DNA was extracted from faecal samples (49 OcMMP patients, 40 healthy controls), amplified for the V4 region of the 16S rRNA gene and sequenced using Illumina Miseq platform. Sequencing reads were processed using the bioinformatics pipeline available in the mothur v.1.44.1 software. After adjusting for participant factors in the multivariable model (age, gender, BMI, diet, proton pump inhibitor use), OcMMP cohort was found to be associated with lower number of operational taxonomic units (OTUs) and Shannon Diversity Index when compared to healthy controls. Within the OcMMP cohort, the number of 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). The linear discriminant analysis effect size scores indicated that Streptococcus and Lachnoclostridium were enriched in OcMMP patients whilst 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 were enriched in healthy controls (Log10 LDA score < 2, FDR-adjusted p <0.05). In conclusion, OcMMP patients have gut dysbiosis correlating 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.
| S-EPMC9046938 | biostudies-literature
Project description:PurposeOcular mucous membrane pemphigoid (OcMMP) is a rare eye disease characterized by relapsing-remitting or persisting long-lasting inflammatory events associated with progressive scarring. Despite long-term immunomodulating therapy, abnormal fibrosis keeps worsening in patients with OcMMP. This study investigates the fibrotic process in patients with OcMMP, as well as the critical role of the epithelium in modulating the local fibrosis.MethodsIn this prospective, observational pilot study, patients affected by long-lasting OcMMP were compared with age- and gender-matched healthy controls. Clinical grading was assessed, and conjunctival biopsy and impression cytology were performed. Conjunctival samples were used for quantifying the expression of transcripts regulating the inflammatory and fibrogenic processes.ResultsOcular surface clinical and functional markers worsened in patients with OcMMP with fibrotic disease progression. In more advanced disease stages, both impression cytologies and conjunctival biopsies revealed increased tissue remodeling and profibrotic markers (α-SMA and TGF-β), and decreased levels of inflammatory markers (I-CAM1, IL-10, and IL-17). Increased epithelial expression of profibrotic markers and histological changes were detected.ConclusionsChronic OcMMP is characterized by a progressive, aberrant self-sustaining fibrotic process that worsens clinical signs and symptoms. Conjunctival epithelial cells may transdifferentiate into myofibroblast-like phenotypes when chronically exposed to high levels of inflammation, as in the case of OcMMP. Tissue remodeling markers in OcMMP could be used as early diagnostic, prognostic, and therapeutic biomarkers, harvested in a non-invasive and painless procedure such as impression cytologies.
| S-EPMC10723221 | biostudies-literature
Project description:PurposeOcular mucous membrane pemphigoid (OcMMP) is a rare autoimmune disorder resulting in progressive conjunctival fibrosis and ocular surface failure leading to sight loss in up to 50%. This study was designed to optimize an ocular surface sampling technique for identification of novel biomarkers associated with disease activity and/or progressive fibrosis.MethodsFifty-seven patients with OcMMP underwent detailed examination of conjunctival inflammation and fibrosis using fornix depth measurement. Ocular surface impression cytology (OSIC) to sample superior bulbar conjunctiva combined with flow cytometry (OSIC-flow) profiled infiltrating leukocytes. Profiles were compared with healthy controls (HC) and disease controls (primary Sjögren's syndrome, pSS). Thirty-five OcMMP patients were followed every 3 months for 12 months.ResultsOverall neutrophils were elevated in OcMMP eyes when compared to pSS or HC (109 [18%] neutrophils/impression [NPI]; 2 [0.2%]; 6 [0.8%], respectively [P < 0.0001]) and in OcMMP patients with no visible inflammation when compared with HC (44.3 [7.9%]; 5.8 [0.8%]; P < 0.05). At 12 months follow-up, 53% of OcMMP eyes progressed, and this was associated with baseline conjunctival neutrophilia (P = 0.004). As a potential biomarker, a value of 44 NPI had sensitivity, specificity, and positive predictive values of 75%, 70%, and 73%, respectively. Notably, eyes with no visible inflammation and raised conjunctival neutrophils were more likely to progress and have a greater degree of conjunctival shrinkage compared to those without raised neutrophils.ConclusionsThese data suggest that OSIC-flow cytometric analyses may facilitate repeated patient sampling. Neutrophils may act as a biomarker for monitoring disease activity, progressive fibrosis, and response to therapy in OcMMP even when the eye appears clinically uninflamed.
| S-EPMC5072540 | biostudies-literature
Project description:ImportanceAn accurate diagnosis of mucous membrane pemphigoid (MMP) is essential to reduce diagnostic and therapeutic delay.ObjectiveTo assess the diagnostic accuracy of direct immunofluorescence microscopy on mucosal biopsy specimens and immunoserology in a large cohort of patients with suspected MMP.Design, setting, and participantsThis retrospective cohort study was carried out in a single tertiary care center for blistering diseases between January 2002 and March 2019. Eligible participants were patients with suspected MMP and paired data on at least a mucosal biopsy specimen for direct immunofluorescence microscopy (DIF) and indirect immunofluorescence microscopy (IIF) on a human salt-split skin substrate (SSS). In addition, an optional DIF test on a skin biopsy specimen and one or more performed routine immunoserologic tests were analyzed. Data analysis was conducted from April 2019, to June 2020.Main outcomes and measuresDiagnostic accuracy of DIF, IIF SSS, and immunoblot for BP180 and BP230.ResultsOf the 787 participants, 121 (15.4%) received the diagnosis of MMP (50 men [41.3%], 71 women [58.7%]; mean [SD] age at diagnosis, 60.1 [17.7] years). Sixty-seven of the patients with MMP (55.4%) had monosite involvement, of which oral site was the most frequently affected (51 [42.1%]). No significant difference was found between the sensitivity of DIF on a perilesional buccal biopsy and a normal buccal biopsy (89.3% vs 76.7%). Three patients with solitary ocular involvement showed a positive DIF of only the oral mucosa. In 6 patients with a negative mucosal DIF, a skin biopsy confirmed diagnosis of MMP. Overall, IIF SSS was less sensitive (44.6%), but highly specific (98.9%). The sensitivity of immunoblot (66.1%) was higher compared to SSS, but with lower specificity (91.3%).Conclusions and relevanceThis comparative diagnostic accuracy study of a cohort of 787 patients found a high sensitivity of a mucosal DIF biopsy for diagnosis of MMP, and lower sensitivity of serologic analysis. A biopsy can be taken from either perilesional or normal buccal mucosa. An additional DIF biopsy of another mucosal site or of affected or unaffected skin may increase the diagnostic yield and is recommended in patients with negative DIF results and high clinical suspicion.
| S-EPMC8082433 | biostudies-literature
Project description:ImportanceMucous membrane pemphigoid (MMP) is a rare and heterogeneous subepithelial autoimmune bullous disease with predominant mucosal involvement. Characteristics associated with the disease course and complications are yet to be delineated.ObjectivesTo evaluate characteristics associated with refractory disease course and blindness among patients with MMP and to estimate the association of different treatment strategies with the prognostic outcome.Design, setting, and participantsA retrospective cohort study of consecutive patients diagnosed with MMP and followed up for more than 1 year from 2007 to 2020 in 2 tertiary referral centers. Data were analyzed from January 1, 2009, to June 30, 2020.Main outcomes and measuresCharacteristics associated with refractory disease course and blindness were evaluated using multivariable logistic regression model.ResultsThe study encompassed 121 patients with MMP (mean [SD] age, 66.0 [14.0] years; 78 (64.5%) were women), of whom 56 (46.3%) followed a refractory course and 13 (10.7%) developed blindness. Anti-LAD-1 IgA (odds ratio [OR], 3.42; 95% CI, 1.11-10.52; P = .03) and anti-dermal-epidermal/epithelial junction (DEJ) IgG (by indirect immunofluorescence on human salt-split skin; OR, 2.92; 95% CI, 1.26-6.78; P = .01) were significantly associated with refractory course. Development of blindness was associated with older age (≥68 years; OR, 6.38; 95% CI, 1.35-30.16; P = .009), initial presentation with bilateral ocular involvement (OR, 7.92; 95% CI, 2.04-30.68; P = .001), and scarring ocular lesions (OR, 5.11; 95% CI, 1.47-17.79; P = .006). However, 4 (30.8%) and 2 (15.4%) of those experiencing blindness had no ocular scarring lesions and unilateral ocular involvement at the onset of their disease, respectively. Patients progressing to blindness were more likely to be treated by 3 or more immunosuppressive/immunomodulatory drugs (OR, 4.07; 95% CI, 1.17-14.14; P = .02) and by cyclophosphamide (OR, 7.64; 95% CI, 2.24-26.09; P < .001). Patients developing blindness and refractory course were more frequently managed by intravenous immunoglobulin (OR, 7.64; 95% CI, 2.24-26.09; P < .001 and OR, 3.47; 95% CI, 1.42-8.45; P = .005, respectively).Conclusions and relevanceFindings of this cohort study support that patients with MMP with anti-LAD-1 IgA and anti-DEJ IgG reactivity should be carefully monitored. While initial bilateral ocular disease and scarring ocular lesions were associated with blindness, patients initially presenting with unilateral and nonscarring ocular disease may still develop severe vision impairment.
| S-EPMC9857489 | biostudies-literature
Project description: Not available
| S-EPMC6137197 | biostudies-literature
Project description:BackgroundMucous membrane pemphigoid is a group of chronic subepithelial autoimmune blistering diseases that mainly affect mucous membranes. Laminin 332-specific autoantibodies are present in approximately 1/3 of the patients, being associated with an increased risk of malignancy. Because of the severe complications, an early recognition of the disease allowing a timely therapy is essential. The gold standard methods for detection of laminin 332-specific autoantibodies, including the immunoprecipitation and immunoblotting are non-quantitative, laborious and restricted to a few specialized laboratories worldwide. In addition, the use of radioimmunoassays, although highly sensitive and specific, are laborious, expensive and tightly regulated. Therefore, there is a stringent need for a quantitative immunoassay for the routine detection of laminin 332-specific autoantibodies more broadly available to diagnostic laboratories. The aim of this study was to compare different antigenic substrates, including native, recombinant laminin 332 and laminin 332-rich keratinocyte extracellular matrix, for development of an ELISA to detect autoantibodies in mucous membrane pemphigoid.ResultsUsing a relatively large number of sera from MMP patients with well-characterized autoantibody reactivity we show the suitability of ELISA systems using laminin 332 preparations as adjunct diagnostic tools in MMP. While glycosylation of laminin 332 does not appear to influence its recognition by MMP autoantibodies, ELISA systems using both purified, native and recombinant laminin 332 demonstrated a high sensitivity and good correlation with the detection of autoantibodies by immunoblotting. ELISA systems using different laminin 332 preparations represent a feasible and more accessible alternative for a broad range of laboratories.ConclusionsOur findings qualify the use of immunoassays with the laminin 332-rich preparations as an ancillary diagnostic tool in mucous membrane pemphigoid.
| S-EPMC6035451 | biostudies-literature
Project description:ImportanceMucous membrane pemphigoid (MMP) is a rare, heterogeneous subepithelial autoimmune bullous disease. The association between its clinical and immunological features is yet to be fully evaluated.ObjectivesTo characterize the clinical, immunoserological, and immunopathological characteristics of patients with MMP and to identify site- and autoantigen-specific characteristics.Design, setting, and participantsA retrospective cohort study encompassing all consecutive patients diagnosed with MMP from January 2007 through February 2020 in 2 tertiary referral centers in Germany.Main outcomes and measuresThe clinical, immunoserological, and immunopathological features of eligible patients were evaluated. Associations of different anatomical sites and autoantigens were assessed using a multivariable logistic regression model.ResultsThe study encompassed 154 patients (96 [62.3%] women and 58 [37.7%] men; mean [SD] age at diagnosis, 66.2 [13.8] years) with MMP, of whom 125 (81.2%), 61 (39.6%), 34 (22.1%), and 16 (10.4%) presented with lesions involving the oral, ocular, nasal, and genital mucosae, respectively, and 35 (22.7%) presented with cutaneous involvement. Among the 154 patients, the most frequently targeted antigen was BP180 (90 patients [58.4%]), followed by laminin 332 (13 patients [8.4%]) and BP230 (3 patients [1.9%]). Ocular disease was inversely associated with oral (adjusted odds ratio [aOR], 0.02; 95% CI, 0.01-0.13) and nasal (aOR, 0.20; 95% CI, 0.04-0.91) involvement and was associated with a 13-fold increased risk of malignant neoplasm (aOR, 13.07; 95% CI, 1.56-109.36). Anti-laminin 332 reactivity was associated with malignant neoplasm (aOR, 23.27; 95% CI, 1.83-296.68), whereas anti-BP180 NC16A immunoglobulin G seropositivity was associated with absence of ocular lesions (aOR, 0.09; 95% CI, 0.01-0.99).Conclusions and relevanceIn this cohort study of patients with MMP, malignant neoplasms were associated with ocular disease and anti-laminin 332 reactivity, suggesting potential benefit of malignant neoplasm screening in these patients.
| S-EPMC8771290 | biostudies-literature
Project description:BackgroundBullous pemphigoid (BP) and mucous membrane pemphigoid (MMP) are rare autoimmune blistering disorders characterized by autoantibodies (autoAbs) targeting dermo-epidermal junction components such as BP180 and BP230. The differential diagnosis, based on both the time of appearance and the extension of cutaneous and/or mucosal lesions, is crucial to distinguish these diseases for improving therapy outcomes and delineating the correct prognosis; however, in some cases, it can be challenging. In addition, negative results obtained by commercially available enzyme-linked immunosorbent assays (ELISAs) with BP and MMP sera, especially from patients with ocular involvement, often delay diagnosis and treatment, leading to a greater risk of poor outcomes.ObjectivesOur aim was to find potentially different reactivity profiles in BP and MMP and improve available approaches for diagnosis with focus on ocular MMP.MethodsTwo cohorts of 90 BP and 90 MMP, recruited from different Italian clinical centers, were characterized also employing a novel ELISA based on the BP180 extracellular domain (ECD-BP180).ResultsImmunoglobulin G (IgG) reactivity to BP180 and BP230 in MMP sera was significantly reduced in comparison with BP, mostly affecting BP230 and E-1080 (53% and 36% in BP vs. 11% and 3% in MMP, respectively, p < 0.0001). The combined sensitivity of BP180-NC16A and ECD-BP180 ELISAs was greater compared to BP180-NC16A and BP230 ELISAs both in BP (97% and 92%, respectively) and in MMP (42% and 31%, respectively). The present study shows that MMP patients with ocular involvement rarely reacted to BP180 by IgG in contrast with patients with oral and/or cutaneous involvement (p = 0.0245 and p = 0.0377, respectively), suggesting that an oral and/or cutaneous MMP positive to BP180 hardly evolves to ocular MMP. Of note, one-third of ocular MMP showed immunoglobulin A (IgA) reactivity to ECD-BP180 by immunoblotting.ConclusionsThe present study provides several hints to perform a correct and timely diagnosis in BP and MMP, which is crucial for improving therapy outcomes and delineating the correct prognosis.
| S-EPMC11638032 | biostudies-literature
Project description:Anti-laminin 332 mucous membrane pemphigoid (MMP) is an autoimmune blistering disease characterized by predominant mucosal lesions and autoantibodies against laminin 332. The exact diagnosis of anti-laminin 332 MMP is important since nearly 30% of patients develop solid cancers. This study compared two independently developed diagnostic indirect immunofluorescence (IF) tests based on recombinant laminin 332 expressed in HEK239 cells (biochip mosaic assay) and the migration trails of cultured keratinocytes rich in laminin 332 (footprint assay). The sera of 54 anti-laminin 332 MMP, 35 non-anti-laminin 332 MMP, and 30 pemphigus vulgaris patients as well as 20 healthy blood donors were analyzed blindly and independently. Fifty-two of 54 and 54/54 anti-laminin 332 MMP sera were positive in the biochip mosaic and the footprint assay, respectively. In the 35 non-anti-laminin 332 MMP sera, 3 were positive in both tests and 4 others showed weak reactivity in the footprint assay. In conclusion, both assays are easy to perform, highly sensitive, and specific, which will further facilitate the diagnosis of anti-laminin 332 MMP.
| S-EPMC8657402 | biostudies-literature