Conjunctival Neutrophils Predict Progressive Scarring in Ocular Mucous Membrane Pemphigoid

Abstract

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.

Evaluation of IL8 pathway on the ocular surface: new insights in patients with ocular mucous membrane pemphigoid

“…In fact, IL‐8 plays an important role in acute inflammation by recruiting inflammatory cells, including neutrophils, and inducing fibrotic processes (Williams et al. ). In addition, IL‐8 exerts angiogenic effect (Yoshida et al.…”

“…Since neutrophils’ infiltration has been observed in patients with oMMP associated with progression of conjunctival scarring, also in the absence of active inflammation (Williams et al. ), a major role of this cytokine may be hypothesized also in oMMP.…”

“…It has been showed that IL8 plays a key role in stimulating fibrogenic inflammatory reaction through neutrophils recruitment (Murphy 1997;Yang et al 2018). Since neutrophils' infiltration has been observed in patients with oMMP associated with progression of conjunctival scarring, also in the absence of active inflammation (Williams et al 2016), a major role of this cytokine may be hypothesized also in oMMP.…”

The 2016 Bowman Lecture Conjunctival curses: scarring conjunctivitis 30 years on

“…96 However, despite the absence of clinical signs of inflammation, there may still be significant cellular infiltrate on histological evaluation ('white inflammation'). 67,97,98 Further systemic immunosuppression with potential systemic toxicity may not necessarily be helpful in these cases, for whom more specific local therapy targeting the cellular infiltrate or fibrogenic process would be ideal. There is evidence for both ongoing residual subclinical inflammation 68,69 and transformed profibrotic fibroblasts 77 as the putative drivers of scarring which progresses, despite apparent clinical control of inflammation with systemic immunosuppression.…”

“…Some progress has been made using neutrophils and their products for this. 97,114 Expression of genes that are upand downregulated in inflammation and scarring may also be worth investigating for this purpose.…”