Treatment of Vernal Keratoconjunctivitis Using Upadacitinib.

This case report presents a case of improvement of vernal keratoconjunctivitis associated with initiation of an oral Janus kinase inhibitor upadacitinib.

Staphylococcus aureus-derived virulent phenol-soluble modulin α triggers alarmin release to drive IL-36-dependent corneal inflammation.

Methicillin-resistant Staphylococcus aureus (MRSA) isolated from patients with keratitis produces substantial amounts of phenol-soluble modulin α (PSMα). However, the role of PSMα in S. aureus keratitis remains unclear. We observed that PSMα-producing and PSMα-deficient strains could infect the cornea in our experimental mouse keratitis model; however, only the PSMα-producing strain delayed epithelial wound healing and induced stromal inflammation. PSMα induced damage to the epithelium, the release of alarmins IL-1α and IL-36α, and the expression of inflammatory chemokines by resident corneal cells in the mouse corneal organ culture. The IL-36 (but not IL-1) receptor antagonist attenuated mouse keratitis induced by PSMα-containing bacterial culture supernatants, as well as by infection with PSMα-producing S. aureus, suggesting that the corneal inflammations were dependent on IL-36. Recombinant PSMα elicited IL-36-dependent corneal inflammation in mice. Thus, PSMα and the subsequently released IL-36 are critical factors triggering inflammation during S. aureus keratitis.

Biologics for allergy: therapeutic potential for ocular allergic diseases and adverse effects on the eye.

Biologics applying antibodies against IgE, IL-5, IL-5 receptor α, IL-4 receptor α, and IL-13 have dramatically improved recent treatment outcomes in allergic diseases including asthma, rhinitis, and atopic dermatitis. However, these drugs have not been approved for ocular allergic diseases such as allergic conjunctivitis, vernal keratoconjunctivitis, and atopic keratoconjunctivitis. Although the putative mechanisms suggest that these drugs should have beneficial effects in patients with ocular allergies and some studies have reported such beneficial effects, various adverse ocular symptoms have also been observed in clinical trials and off-label use studies. Since ocular allergic diseases have distinct pathogeneses, each biologic drug must be examined regarding specific effects on each ocular allergy. For example, IgE-mediated type 1 hypersensitivity plays a critical role in allergic conjunctivitis. By contrast, T cells and eosinophilic and non-IgE-mediated type 2 inflammation play important roles in vernal keratoconjunctivitis. Allergists must fully understand the effects of each drug on the eye. This review outlines both potential therapeutic and adverse effects of various biologics on allergic diseases of the eye.

Aqueous-Deficient Dry Eye Exacerbates Signs and Symptoms of Allergic Conjunctivitis in Mice.

Dry eye disease (DED) and allergic conjunctivitis affect a large number of patients, and many patients usually have both symptoms. We investigated the interactions between DED and allergic conjunctivitis in mice. Four experimental groups were compared: control, DED, allergy, and allergy with DED. DED was induced by removing the extraorbital lacrimal glands of the mice. Allergic conjunctivitis was induced by intraperitoneal administration of ovalbumin and antigen eye drops. The early phase reaction of the allergy was evaluated using the clinical score, scratching behavior, and vascular permeability in the conjunctiva. Epithelial barrier function was assessed by an LC-biotin assay. Tear fluid volume and corneal fluorescein staining decreased in the DED and allergy with DED groups. LC-biotin penetrated the entire epithelium of both the cornea and conjunctiva in DED mice. The clinical score of the early phase reaction was higher in allergy-induced mice than in non-allergy mice. Edema of the eyelid and conjunctiva were aggravated in mice with DED. The number of scratching episodes and leakage of Evans blue into the conjunctiva were higher in allergy-induced DED mice than in control mice. The presence of aqueous-deficient dry eye caused ocular surface epithelial damage and exacerbated allergic signs and symptoms.

Intracameral Bacteriophage Injection as Postoperative Prophylaxis for Enterococcus faecalis-Induced Endophthalmitis After Cataract Surgery in Rabbits.

Purpose: Post-cataract surgery bacterial endophthalmitis is a serious postoperative complication, and Enterococcus spp.-induced endophthalmitis reportedly has a particularly poor visual prognosis. This study aimed to demonstrate the prophylactic effect of postoperative intracameral phage administration in Enterococcus faecalis-induced endophthalmitis after cataract surgery in rabbits. Methods: Endophthalmitis was induced in rabbits by injecting E. faecalis into the anterior chamber just after lensectomy while simultaneously administering either phage phiEF24C-P2 or vehicle. Retinal function was evaluated using electroretinography. The number of viable bacteria and myeloperoxidase (MPO) activity in the eye and histopathologic examinations were analyzed 48 hours after infection. Results: In the vehicle-treated group, retinal function at 24 hours after infection was impaired, and the number of viable bacteria and MPO activity in the eye increased 48 hours later. In the phage-administered group, retinal function was maintained; the number of viable bacteria and MPO activity were significantly suppressed. Histopathologic examinations showed disruption of the retinal layers and the presence of numerous E. faecalis in the lens capsule and vitreous cavity in vehicle-treated eyes. In contrast, retinal structures were intact, and no E. faecalis staining was observed in phage-treated eyes. No retinal dysfunction was observed in the group that received phage only without lensectomy; almost no phage was detected in the eyes after 14 days of treatment. Conclusions: Phage administration in the anterior chamber did not cause retinal dysfunction and suppressed postoperative endophthalmitis in rabbits. Translational Relevance: In vivo results of intracameral phage administration suggest that phages are a promising prophylactic candidate for postoperative endophthalmitis.

Role of Damage-Associated Molecular Patterns (DAMPs/Alarmins) in Severe Ocular Allergic Diseases.

Severe ocular allergic diseases, such as atopic keratoconjunctivitis and vernal keratoconjunctivitis, cause severe allergic inflammation in the conjunctiva and corneal epithelial damage, resulting in visual disturbances. The involvement of damage (danger)-associated molecular patterns (DAMPs/alarmins) in the pathogenesis of these diseases has been recognized. Alarmins released from damaged corneal epithelial cells or eosinophils play a critical role in the induction of corneal lesions, vicious loop of corneal injury, and exacerbation of conjunctival allergic inflammation. Alarmins in the conjunctiva also play an essential role in the development of both allergic inflammation, based on the acquired immune system, and type 2 inflammation by innate immune responses in the ocular surface. Therefore, alarmins may be a potentially important therapeutic target in severe refractory ocular allergic diseases.

Promotion of conjunctival fibroblast-mediated collagen gel contraction by mast cells through up-regulation of matrix metalloproteinase release and activation.

Mast cells and conjunctival fibroblasts contribute to conjunctival wound healing and allergic ocular inflammation. The number of mast cells in the conjunctiva is increased in individuals with cicatricial fibrosis-causing ocular surface diseases and after glaucoma filtering surgery, suggesting that these cells may contribute to the scarring observed after such surgery. We studied the potential mechanism of fibroblast-mast cell interaction in the healing of conjunctival wounds using a three-dimensional collagen gel culture system. We found that mast cells derived from the bone marrow of mice embedded in a collagen gel did not induce gel contraction. However, an increase in mast cells was associated with increased collagen gel contraction mediated by mouse conjunctival fibroblasts. The extent of collagen degradation was not affected by the co-culture of mast cells and conjunctival fibroblasts. Gelatin zymography disclosed that mast cells increased the amounts of both the pro form of matrix metalloproteinase (MMP)-9 and the active form of MMP-2 in supernatants of conjunctival fibroblast cultures. Furthermore, the potentiating effect of mast cells on contraction of the collagen gel through conjunctival fibroblasts was attenuated by the addition of a synthetic MMP inhibitor. Thus, current results suggest that mast cells accelerate the conjunctival fibroblast-dependent contraction of collagen gel by increasing the release as well as activation of MMPs. Therefore, the interaction between mast cells and conjunctival fibroblasts may contribute to conjunctival scar formation after glaucoma filtering surgery.

Optic Neuropathy with Headache and Palpable Temporal Arteries Due to Hypertrophic Pachymeningitis Rather than Giant Cell Arteritis.

Purpose: To report a case of optic neuropathy diagnosed by color Doppler ultrasonography and Gadolinium-enhanced cerebral magnetic resonance imaging (MRI).Case report: A 79-year-old woman presented with headache and vision loss in her left eye. Although her bilateral temporal arteries were palpable and rope-like, color Doppler ultrasonography showed normal flow in both arteries with no signs of arteritis. MRI revealed increased enhancement of the pachymeninges enveloping both cerebral hemispheres, suggestive of hypertrophic pachymeningitis.Conclusion: Symptoms and laboratory data are similar for both hypertrophic pachymeningitis and giant cell arteritis (GCA). The present case suggests the utility of ultrasonography and MRI as rapid, convenient, and noninvasive tools for differential diagnosis of optic neuropathy.

Prophylactic and Therapeutic Effects of Oral Immunotherapy on Birch Pollen-Induced Allergic Conjunctivitis in Mice with a Rice-Based Edible Vaccine Expressing a Hypoallergenic Birch Pollen Allergen.

We investigated the prophylactic and therapeutic effects of the oral administration of transgenic rice seeds expressing a hypoallergenic Bet v 1 derivative of allergic birch pollen conjunctivitis in mice. Transgenic rice seed depositing a chimeric molecule called TPC7 (tree pollen chimera 7) created by DNA shuffling of Bet v 1 family sequences from birch, alder and hazel in protein bodies of endosperm was generated. BALB/c mice were sensitized to birch pollen in alum and challenged with pollen in eyedrops. They were fed TPC7 transgenic or non-transgenic (control) rice seeds for 14 d before sensitization (prophylactic protocol) or 17 d after sensitization (therapeutic protocol). The clinical score and number of conjunctival eosinophils were significantly lower in TPC7-fed mice than in the control mice based on both the prophylactic and therapeutic protocols. Serum concentration of allergen-specific IgE did not differ between TPC7-fed and control groups in either protocol. Prophylactic administration of TPC7 downregulated the production of IL-4 and IFN-γ, whereas therapeutic administration of TPC7 upregulated the production of IFN-γ by allergen-stimulated splenocytes. Prophylactic or therapeutic oral administration of transgenic rice expressing TPC7 suppressed birch pollen-induced allergic conjunctivitis in mice. Feeding transgenic rice is a potentially effective approach as an allergen-specific immunotherapy for allergic conjunctivitis.

Ocular Involvement in Relapsing Polychondritis.

Relapsing polychondritis (RPC) is a rare systemic immune-mediated disease characterized by recurrent inflammation of cartilaginous and proteoglycan-rich tissues throughout the body. Auricular, nasal, tracheal, and articular chondritis and arthritis are common systemic symptoms in patients with RPC. Ocular tissues are also targets of inflammation in RPC, and a variety of ocular symptoms are observed in approximately half of the patients with RPC. Scleritis/episcleritis, uveitis, and conjunctivitis are common symptoms associated with RPC. Less frequently, keratitis, retinopathy, optic neuropathy, muscle palsy, and orbital inflammation are also observed. Ocular inflammation could also be the first manifestation of RPC. Although RPC is a potentially fatal and sight-threatening disease, the rarity of the disease and its protean clinical presentation may lead to delayed diagnosis or misdiagnosis. Given the high prevalence of ocular involvement in RPC, to avoid misdiagnosis, physicians should be suspicious of RPC when they see patients with recurrent ocular inflammatory conditions and various systemic symptoms. In this article, we provide a comprehensive review of ocular manifestations associated with RPC.

Clinical profile and visual outcome of intraocular inflammation associated with cat-scratch disease in Japanese patients.

PURPOSE: To evaluate intraocular inflammation in Japanese patients with cat-scratch disease (CSD). STUDY DESIGN: Retrospective clinical chart review. PATIENTS AND METHODS: The cases of 15 consecutive patients (19 affected eyes) in Kochi Prefecture, Japan who were serologically positive for Bartonella henselae or Bartonella quintana infection in association with intraocular inflammation were reviewed. The clinical manifestations, ocular complications, and treatment modalities were recorded. The clinical charts and photographic records were also reviewed for evidence of optic disc lesions, macular star, foci of chorioretinitis, and other findings. RESULTS: Thirteen patients reported fever before or at the time of the initial presentation. Ten of 11 patients with decreased visual acuity manifested neuroretinitis, and the remaining patient showed retinochoroiditis with macular involvement. One patient with a visual field defect manifested branch retinal artery occlusion. Three patients without visual disturbance presented with fever of unknown cause. Discrete white retinal or retinochoroidal lesions were the most common findings (84% of eyes, 87% of patients), followed by retinal hemorrhage (63% of eyes, 80% of patients), optic disc lesions (63% of eyes, 73% of patients), serous retinal detachment (53% of eyes, 67% of patients), and macular star (47% of eyes, 60% of patients). CONCLUSION: White retinal or retinochoroidal foci were the most common ocular posterior segment manifestations of CSD in this patient population. A diagnosis of CSD should be suspected in patients with fever and chorioretinal white spots, and the absence of neuroretinitis or macular star does not exclude the possibility of intraocular inflammation in CSD.

In Vitro and In Vivo Evaluation of Three Newly Isolated Bacteriophage Candidates, phiEF7H, phiEF14H1, phiEF19G, for Treatment of Enterococcus faecalis Endophthalmitis.

Post-operative endophthalmitis caused by Enterococcus spp. progresses rapidly and often results in substantial and irreversible vision loss. Therefore, novel alternative treatments that are effective against enterococcal endophthalmitis are required. Bacteriophage therapy has the potential to be an optional therapy for infectious diseases. Therefore, we investigated the therapeutic potential of three newly isolated enterococcal phages, phiEF7H, phiEF14H1, and phiEF19G, in E. faecalis-induced endophthalmitis. These phages could lyse the broad-range E. faecalis, including strains derived from endophthalmitis and vancomycin-resistant E. faecalis in vitro, as determined by the streak test. Morphological and genomic analyses revealed that these phages were classified into the Herelleviridae genus Kochikohdavirus. The whole genomes of these phages contained 143,399, 143,280, and 143,400 bp, respectively. Endophthalmitis was induced in mice by injection of three strains of E. faecalis derived from post-operative endophthalmitis or vancomycin-resistant strains into the vitreous body. The number of viable bacteria and infiltration of neutrophils in the eye were both decreased by intravitreous injection of phiEF7H, phiEF14H1, and phiEF19G 6 h after injection of all E. faecalis strains. Thus, these results suggest that these newly isolated phages may serve as promising candidates for phage therapy against endophthalmitis.

Miscellaneous Ocular Symptoms in a Case of Relapsing Polychondritis.

PURPOSE: To report a case of miscellaneous ocular symptoms associated with relapsing polychondritis (RP). CASE REPORT: A 58-year-old man presented with multiple ocular symptoms including both anterior and posterior scleritis, conjunctivitis, eyelid edema, eye movement disorder, keratitis, and retinopathy. Miscellaneous systemic inflammation in the right auricle as well as nasal and laryngeal cartilage was also evident together with vestibular and auditory nerve disorders. According to his clinical signs and the results of color Doppler ultrasonography, positron emission tomography and computed tomography, and a biopsy of the right auricle, we made a diagnosis of RP. CONCLUSION: Given that RP is potentially fatal, it is important that the condition be diagnosed early and treated promptly. Ophthalmologists should be aware that RP is a potential cause of recurrent and refractory multiple ocular inflammatory disorders associated with systemic symptoms.

Therapeutic Effects of Intravitreously Administered Bacteriophage in a Mouse Model of Endophthalmitis Caused by Vancomycin-Sensitive or -Resistant Enterococcus faecalis.

Endophthalmitis due to infection with Enterococcus spp. progresses rapidly and often results in substantial and irreversible vision loss. Given that the frequency of this condition caused by vancomycin-resistant Enterococcus faecalis has been increasing, the development of novel therapeutics is urgently required. We have demonstrated the therapeutic potential of bacteriophage ΦEF24C-P2 in a mouse model of endophthalmitis caused by vancomycin-sensitive (EF24) or vancomycin-resistant (VRE2) strains of E. faecalis Phage ΦEF24C-P2 induced rapid and pronounced bacterial lysis in turbidity reduction assays with EF24, VRE2, and clinical isolates derived from patients with E. faecalis-related postoperative endophthalmitis. Endophthalmitis was induced in mice by injection of EF24 or VRE2 (1 × 104 cells) into the vitreous. The number of viable bacteria in the eye increased to >1 × 107 CFU, and neutrophil infiltration into the eye was detected as an increase in myeloperoxidase activity at 24 h after infection. A clinical score based on loss of visibility of the fundus as well as the number of viable bacteria and the level of myeloperoxidase activity in the eye were all significantly decreased by intravitreous injection of ΦEF24C-P2 6 h after injection of EF24 or VRE2. Whereas histopathologic analysis revealed massive infiltration of inflammatory cells and retinal detachment in vehicle-treated eyes, the number of these cells was greatly reduced and retinal structural integrity was preserved in phage-treated eyes. Our results thus suggest that intravitreous phage therapy is a potential treatment for endophthalmitis caused by vancomycin-sensitive or -resistant strains of E. faecalis.

Unilateral serous retinal detachment with choroidal thickening as a first presenting sign of acute myeloid leukemia.

PURPOSE: Serous retinal detachment is rare in leukemia, but bilateral or unilateral cases have been reported as the presenting sign of acute leukemia or the first sign of relapsing leukemia. We here report a case of unilateral serous retinal detachment with choroidal thickening before the detection of atypical lymphocytes or myeloblasts as the initial manifestation of subsequently diagnosed acute myeloid leukemia. OBSERVATIONS: A 43-year-old woman presented with serous retinal detachment in her left eye. Choroidal thickening was also revealed by B-scan ultrasonography and optical coherence tomography. Atypical lymphocytes or myeloblasts were not apparent on hematologic analysis at initial presentation, but an increased leukocyte count and the presence of 40% blasts in a peripheral smear were detected 1 month later. A bone marrow biopsy led to a diagnosis of acute promyelocytic leukemia. The retinal detachment and choroidal thickening showed amelioration 4 days after the onset of chemotherapy and had resolved 2 months later. CONCLUSIONS AND IMPORTANCE: The present findings suggest that, although retinal detachment is not a common manifestation in patients with leukemia, unilateral serous retinal detachment with choroidal thickening may be a presenting sign of acute myeloid leukemia.

Evaluation of offset of conjunctival hyperemia induced by a Rho-kinase inhibitor; 0.4% Ripasudil ophthalmic solution clinical trial.

Glaucoma leads to irreversible blindness. Numerous anti-glaucoma eye drops have been developed. Unfortunately, many patients with glaucoma still suffer from progressive visual disorders. Recently, ripasudil hydrochloride hydrate, a selective Rho-associated protein kinase inhibitor, was launched for the treatment of glaucoma. However, adverse events, such as conjunctival hyperemia, are often noted in clinical trials using healthy subjects. Therefore, we investigated the onset, offset, and kinetic changes of conjunctival hyperemia induced by ripasudil ophthalmic solution in patients with open-angle glaucoma or ocular hypertension who had already been treated with anti-glaucoma eye drops other than ripasudil. Conjunctival hyperemia was evaluated by both clinical grading by 3 ophthalmic physicians and pixel coverage of conjunctival blood vessels determined by conjunctival hyperemia-analyzing software. Conjunctival hyperemia appeared within 10 min post-instillation in most of the participants. Clinical grade and pixel coverage increased significantly 10 min post-instillation and then decreased. In most of the participants, hyperemia resolved within 2 h. Median conjunctival hyperemia offset was 90 min. A tendency of monotonic increase was observed between clinical grade and pixel coverage. Taken altogether, hyperemia induced by ripasudil was transient in glaucoma patients who had already been treated with anti-glaucoma eye drops other than ripasudil.

In vitro and in vivo performance of epinastine hydrochloride-releasing contact lenses.

A number of drug-releasing contact lenses are currently being studied to address issues inherent in eye drops as a drug delivery method. In this study, we developed epinastine hydrochloride-releasing daily soft contact lenses for treatment of allergic conjunctivitis and examined their in vitro and in vivo performance. Preformed soft contact lenses with/without ionic functional groups were soaked in a solution of epinastine hydrochloride in phosphate-buffered saline to prepare epinastine hydrochloride-releasing soft contact lenses. Among these contact lenses with different ionicities, anionic lenses demonstrated the maximum, relatively linear epinastine hydrochloride release, in vitro. The amount of epinastine hydrochloride release was directly proportional to the concentration of the epinastine hydrochloride solution used to prepare the contact lens. The epinastine hydrochloride-releasing anionic soft contact lens also demonstrated prolonged drug release and significantly greater efficacy compared with epinastine hydrochloride eye drops 12 h after treatment, in vivo. Further studies are required to determine the appropriate amount of epinastine hydrochloride to be contained in the anionic soft contact lenses.

Cytokine expression and barrier disruption in human corneal epithelial cells induced by alarmin released from necrotic cells.

PURPOSE: Dying cells release endogenous molecules known as alarmins that signal danger to surrounding tissue. We investigated the effects of necrotic cell-derived alarmins on cytokine expression and barrier function in human corneal epithelial cells. METHODS: The release of interleukin (IL)-6 and IL-8 from immortalized human corneal epithelial (HCE) cells in culture was measured with enzyme-linked immunosorbent assays. The abundance of IL-6 and 8 mRNAs was quantitated by reverse transcription and real-time polymerase chain reaction analysis. Barrier function of HCE cells was evaluated by measurement of transepithelial electrical resistance (TER). The subcellular localization of the p65 subunit of the transcription factor NF-κB was determined by immunofluorescence analysis, and phosphorylation of the endogenous NF-κB inhibitor IκBα was examined by immunoblot analysis. RESULTS: A necrotic cell supernatant prepared from HCE cells induced the up-regulation of IL-6 and 8 expression at both mRNA and protein levels as well as reduced TER in intact HCE cells. Among alarmins tested, only IL-1α (not IL-33 or HMGB1) mimicked these effects of the necrotic cell supernatant. Furthermore, IL-1 receptor antagonist (IL-1RA) and neutralizing antibodies to IL-1α (but not those to IL-1ß) each attenuated the effects of the necrotic cell supernatant. Exposure of HCE cells to the necrotic cell supernatant also induced the phosphorylation and degradation of IκBα as well as translocation of the p65 subunit of NF-κB to the nucleus. CONCLUSION: IL-1α released from necrotic corneal epithelial cells may trigger inflammatory responses at the ocular surface, including cytokine production and barrier disruption.