Treatment of recalcitrant recurrent corneal erosions with inhibitors of matrix metalloproteinase-9, doxycycline and corticosteroids

Dursun, Dilek; Kim, Michael C.; Solomon, Abraham; Pflugfelder, Stephen C.

doi:10.1016/s0002-9394(01)00913-8

Cited by 209 publications

(126 citation statements)

References 25 publications

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“…Corticosteroids and doxycycline, two agents that have been observed to decrease the severity of human keratitis sicca 30 -32 have been reported to decrease the level of MMP-9 in conditioned media from primary human cornea epithelial cultures. 22,33 It is likely that other more specific inhibitors of MMP-9 will become available in the future.…”

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase-9 Knockout Confers Resistance to Corneal Epithelial Barrier Disruption in Experimental Dry Eye

Pflugfelder

Farley

Luo

et al. 2005

The American Journal of Pathology

277

239

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Altered corneal epithelial barrier function is the cause for ocular irritation and visual morbidity in dry eye disease. Increased matrix metalloproteinase (MMP)-9 activity has been observed in the tear fluid of dry eye patients. To determine the pathogenic role of MMP-9 in the corneal epithelial disease of dry eye, the effects of experimentally induced dry eye on corneal epithelial morphology and barrier function were compared in MMP-9 knockout mice and their wild-type littermates. Dry eye was created through cholinergic blockade and exposure to a desiccating environment. The tear fluid MMP-9 concentration increased in response to dryness in wild-type mice. Corneal epithelial permeability to three different-sized molecules increased in dry eye wild-type mice, but not in MMP-9 knockout mice. Topical administration of active MMP-9 to dry eye MMP-9 knockout mice significantly increased corneal epithelial permeability. Compared to MMP-9 knockout mice, wild-type mice showed greater desquamation of differentiated apical corneal epithelial cells that expressed the tight junction protein occludin in response to dryness. This was accompanied by an increase in lower sized (50 kd) occludin in the corneal epithelia of wild-type mice. These findings could be replicated in cultured human corneal epithelial cells that were treated with active MMP-9. These studies indicate that increased MMP-9 activity on the ocular surface in response to dryness disrupts corneal epithelial barrier function. This appears to be because Corneal epithelial disease, termed keratitis sicca, is a severe and sight-threatening complication of dry eye. 1 A key clinical feature of keratitis sicca is disruption of corneal epithelial barrier function. [2][3][4] This results in eye irritation, corneal surface irregularity, blurred and fluctuating vision, and increased risk for corneal ulceration. 4 -8 Ocular surface inflammation has been implicated in the pathogenesis of keratitis sicca. Elevated levels of proinflammatory cytokines, such as interleukin (IL)-1, have been detected in the tear fluid of patients with this condition. 9 -11 Furthermore, the concentration and activity of matrix metalloproteinase (MMP)-9 in the tear fluid was found to be significantly increased in these eyes, with the highest concentrations observed in eyes with the severe corneal epithelial disease or sterile corneal ulcers. 10 -12 We hypothesize that MMP-9 plays an important role in the disruption of corneal epithelial barrier function in dry eye. We previously reported an experimental murine model of dry eye that disrupts corneal epithelial barrier function similar to human dry eye disease. 13 The purpose of this study was to compare the effects of experimentally induced dry eye (EIDE) on corneal epithelial morphology and barrier function in MMP-9 knockout mice and their wild-type (WT) littermates. Materials and Methods MiceThis research protocol was approved by the Baylor College of Medicine Center for Comparative Medicine and it conformed to the standards in the Association...

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Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase-9 Knockout Confers Resistance to Corneal Epithelial Barrier Disruption in Experimental Dry Eye

Pflugfelder

Farley

Luo

et al. 2005

The American Journal of Pathology

277

239

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“…43 This approach is based on biochemical evidence implicating increased levels of MMP activity in the pathogenesis of this condition. 31,38,44 Doxycycline has been shown to produce a 70% decrease in the activity of metalloproteinase-9 in unstimulated human corneal epithelial cultures.…”

Section: Inhibitors Of Mmpmentioning

confidence: 99%

“…These findings suggest that MMPs may be responsible for the breakdown of the anchoring molecules in the basement membrane during epithelial healing, and this is the basis for the use of inhibitors of MMP in the treatment of RCE. 43 The therapeutic effects of doxycycline and corticosteroids may also be due to their antiinflammatory properties. Doxycycline decreases the synthesis and bioactivity of interleukin-1 produced by cultured human epithelial cells.…”

Section: Inhibitors Of Mmpmentioning

confidence: 99%

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Pathogenesis, clinical features and management of recurrent corneal erosions

Ramamurthi

Rahman

Dutton

et al. 2005

Eye

111

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Recurrent corneal erosions (RCE) are common. They are characterised by repeated episodes of pain, difficulty in opening the eyes, watering, and photophobia resulting from poor epithelial adhesion. In the majority of patients with RCE, trauma is the initiating factor. Epithelial, stromal, and endothelial corneal dystrophies have all been described in association with RCE. Other causes that may lead to RCE include chemical and thermal injuries, previous herpetic keratitis, meibomian gland dysfunction, ocular rosacea, diabetes mellitus, Salzmann's nodular degeneration, band keratopathy, previous bacterial ulceration, kerato-conjunctivitis sicca, and epidermolysis bullosa. The conditions that are associated with RCE can be either primary or secondary depending on whether the basement membrane complex abnormality is intrinsic or acquired. Primary types tend to be bilateral, symmetrical and develop in multiple corneal locations. The pathogenetic mechanism of this disorder is related to poor adhesion of the corneal epithelium to the underlying stroma. Excessive matrix metalloproteinase (MMP) activity may play a role in the pathogenesis. Although the majority of patients will respond to simple measures such as padding and antibiotic ointment, RCE resistant to simple measures require approaches that are more elaborate. The common goal of these approaches is to encourage proper formation of adhesion complexes between the epithelium and the stroma. The use of longterm contact lenses, autologous serum eye drops, botulinum toxin, induced ptosis, oral MMP inhibitors, diamond burr polishing of Bowman's membrane have been reported with varying degree of success in treating RCE. Anterior stromal puncture with insulin needles or Neodymium : aluminium-yttriumgarnet may enhance the epithelial adhesion to the basement membrane by scar formation and success rates of up to 80% have been reported in the treatment of recalcitrant RCE. Excimer laser photo-therapeutic keratectomy (PTK) is now a well-established treatment modality for RCE and is being used both safely and effectively. Partial ablation of Bowman's layer with PTK gives a smooth surface for the newly generating epithelium to migrate and form adhesion complexes. The pathogenesis, clinical features, and management options of this common disorder are discussed in this review article.

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“…Furthermore, these eye drops reduce the activity level of matrix metalloproteinases. [25] Although the overall safety of topical glucocorticoids in clinical trials in pSS and keratoconjunctivitis sicca was considered satisfactory, prolonged use of topical glucocorticoids in pSS patients is restricted by their ability to induce glaucoma, cataract, decreased wound healing, increased risk of secondary infections, and epithelial defects. [26][27][28][29] Therefore, topical glucocorticoids are only recommended for short-term use when treatment with artificial tears is insufficient, and rapid reduction of inflammation should be achieved.…”

Section: Topical Glucocorticoidsmentioning

confidence: 99%

Safety of treatments for primary Sjögren’s syndrome

Nimwegen

Moerman

Smitt

et al. 2016

Expert Opinion on Drug Safety

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Introduction: Primary Sjögren's syndrome (pSS) is a disabling auto-immune disease, affecting exocrine glands and several organs. Areas covered:In this review we analyze the safety of therapies used in pSS. Symptomatic treatment is widely applied due to the good supportive effect and good safety profile. Systemic stimulation of tears and saliva can be successful in pSS. However, cumbersome adverse events can influence the tolerability of this therapy. Evidence for the effectiveness of synthetic DMARDs therapies in pSS is limited, while there is a risk of adverse events. Several studies on biologic DMARD treatment of pSS patients have shown promising efficacy and safety results. Expert opinion: The safety of symptomatic treatment of pSS is very good. However, systemic therapy is necessary to achieve long-term relieve and prevention of organ-damage. Synthetic DMARDs have not shown much efficacy in earlier studies, and their benefits do not weigh up to the possible harms, while biologic DMARDs show promising results regarding efficacy and cause mostly mild adverse events. Many questions remain unanswered regarding safety of DMARDs in pSS. There is a need for well designed studies, in which safety should be evaluated in a uniform manner to be able to compare the results between studies.ARTICLE HISTORY

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Treatment of recalcitrant recurrent corneal erosions with inhibitors of matrix metalloproteinase-9, doxycycline and corticosteroids

Cited by 209 publications

References 25 publications

Matrix Metalloproteinase-9 Knockout Confers Resistance to Corneal Epithelial Barrier Disruption in Experimental Dry Eye

Matrix Metalloproteinase-9 Knockout Confers Resistance to Corneal Epithelial Barrier Disruption in Experimental Dry Eye

Pathogenesis, clinical features and management of recurrent corneal erosions

Safety of treatments for primary Sjögren’s syndrome

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