RARE DISEASE
Atopic keratoconjunctivitis
Atopic keratoconjunctivitis
Atopic keratoconjunctivitis
Drug discovery
2
drugs
With orphan designations
Overview
Atopic keratoconjunctivitis (AKC) is a chronic, sight-threatening ocular inflammatory disease strongly associated with systemic atopy, particularly atopic dermatitis. It primarily affects adults aged 30-50, presenting with severe itching, conjunctival hyperemia, papillary hypertrophy, and risk of corneal complications such as ulcers, neovascularization, and keratoconus. Chronic inflammation often leads to structural changes like symblepharon formation, cataracts, and vision loss without proper management [1][4][12].
Burden
60% develop corneal involvement; 2.5× increased risk of keratoconus compared to general population [4][12]
Vision-threatening complications in 20-30%: corneal perforation, limbal stem cell deficiency, secondary infections [8][12]
Significantly impacts quality of life due to persistent symptoms, frequent treatments, and high healthcare utilization [5][8]
Therapies
First-line: Topical mast cell stabilizers (olopatadine), antihistamines (azelastine), and short-term corticosteroids for flares [1][3]
Steroid-sparing agents: Tacrolimus ointment (0.03-0.1%) or cyclosporine drops (0.05%) for chronic management [1][7][13]
Severe cases: Systemic immunosuppressants (cyclosporine 5mg/kg/day) and multidisciplinary care with allergists/dermatologists [2][5]
Categories: rare ophthalmic disorders
Research Papers
308 drug discovery papers about Atopic keratoconjunctivitis, with 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
308 drug discovery papers about Atopic keratoconjunctivitis, with 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-30 | S2k-Guideline - Standardized application of the nasal and conjunctival provocation test on allergic diseases of the upper airways : of the German Society for Allergology and Clinical Immunology (DGAKI), German Society of Oto-Rhino-Laryngology, Head and Neck Surgery (DGHNO-KHC), German Dermatological Society (DDG), German Society of Pediatrics and Adolescent Medicine (DGKJ), German Society of Ophthalmology (DOG), German Respiratory Society (DGP), German Society for Occupational and Environmental Medicine (DGAUM), German Society for Pediatric Allergology and Environmental Medicine (GPA), German Society for Pediatric Pulmonology (GPP), Ärzteverband Deutscher Allergologen (AeDA), and German Professional Association of Otorhinolaryngologists (BVHNO).
Broad evidence confirms that AR (ICD J30.3) is a chronic disease with high prevalence among children and adults worldwide. Its consequences, both from a public health perspective and at the level of the individual patient, are often underestimated, and the condition is inadequately treated. In addition, AR is often related to comorbidities with additional impact on diseases-severity. Allergen provocation of the easily accessible nasal (nasal allergen provocation test: NPT) or conjunctival mucosa (conjunctival allergen provocation test: CPT) reproduces the allergen-dependent, IgE-mediated allergic reaction under controlled and standardized conditions. These measures are regarded as the diagnostic gold standard, particularly in cases of unclear results in primary allergological tests, enabling clinically relevant identification of the causative allergen. Approved test allergens are critical for ensuring the methodological quality of the NPT. However, their availability is increasingly limited, although adequate quantities of allergen solutions remain indispensable for high-quality nasal allergen testing. Unilateral allergen provocation has been established in the clinical routine for decades in Germany. However, scientific evidence for unilateral application of the test allergen is pending. International position papers differ from this recommendation. The CPT is a simple, safe, and well-tolerated measure. It is primarily used in perennial and, in selected cases, seasonal allergic conjunctivitis. This method is less commonly applied for vernal keratoconjunctivitis and atopic keratoconjunctivitis. It is primarily used to confirm the underlying allergen, particularly when establishing the indication for allergen immunotherapy (AIT). It can also be employed to monitor treatment effects such as e.g., AIT or pharmacotherapy. Although highly sensitive, the procedure of nasal ASA provocation remains a time-consuming procedure. While challenging in children, NPT provides clinically relevant additional diagnostic information on the causes of the allergic symptoms. Allergological diagnostic work-up also includes pulmonary assessment, particularly in patients with established asthma or symptoms suggestive of asthma. Both AAR and PNIF are applied as standard procedures for assessing the outcome of NPT in Germany. In individual cases, other rhinometric methods may also be used.
2026-06-17 | An update on our understanding of host defense mechanisms at the ocular surface; innate immune dysregulation at the ocular surface: lessons from Stevens-Johnson syndrome and related inflammatory disorders.
The ocular surface is a frontline mucosal immune barrier that protects the eye from pathogens while preserving immune tolerance essential for vision. Breakdown of this innate immune homeostasis can trigger chronic ocular surface inflammation, exemplified by Stevens-Johnson syndrome/toxic epidermal necrolysis with severe ocular complications (SJS/TEN with SOC) and atopic keratoconjunctivitis (AKC). The review summarizes current knowledge of ocular surface innate immunity, focusing on pattern-recognition receptors (TLR3, RIG-I, MDA5) and downstream interferon-stimulated genes (e.g. IFI44L, CXCL10, IFIT2) and their regulation. The influence of host genetic predispositions and microRNA regulatory networks on these pathways is highlighted, and innate immune profiles are compared among SJS/TEN with SOC, AKC, and healthy ocular surfaces. Dysregulation of mucosal innate immunity - shaped by host genetic factors, abnormal epithelial responses, and microRNA-mediated feedback loops - underlies the persistence and severity of chronic ocular surface disorders such as SJS/TEN with SOC and AKC. A deeper understanding of these mechanisms may inform the development of novel diagnostic biomarkers (e.g. microRNA signatures) and immune-modulating therapies to restore immune homeostasis and prevent vision-threatening inflammation. PubMed was used as the literature search methodology.
2026-06-04 | Allergic eye disease in clinical practice: essential updates for eye care professionals.
Allergic eye disease affects 15-40% of people worldwide, particularly children and adolescents, and often coexists with atopic dermatitis, allergic asthma, and allergic rhinitis. To capture the latest insights into its causes, presentation and management, the authors performed a comprehensive PubMed/MEDLINE literature review through April 2025 using multiple search terms such as 'ocular allergy', 'allergic conjunctivitis', 'Seasonal Allergic Conjunctivitis', 'Perennial Allergic Conjunctivitis', 'Atopic Keratoconjunctivitis', 'Giant Papillary Conjunctivitis', "Contact Blepharoconjunctivitis, 'Vernal Keratoconjunctivitis', 'Shield Ulcers', 'immunology', 'allergic rhinitis', and related terminologies. The current review review integrates epidemiological data, mechanistic studies and clinical guidelines to offer a cohesive overview of this condition. Allergic eye disease arises when environmental allergens trigger an IgE-mediated immune response in the eye, leading to inflammation that ranges from mild seasonal redness and itching to severe forms with tissue changes and corneal involvement. Diagnosis depends on the history and eye examination of a patient, with ancillary tests used only when the presentation is unclear. Management begins with allergen avoidance, lubricating drops and cold compresses, progressing to topical antihistamines or mast-cell stabilisers and short-course corticosteroids for flares. Looking ahead, newer treatments such as calcineurin inhibitors, monoclonal antibodies against key inflammatory cytokines and targeted small-molecule drugs are expanding the ability to control symptoms without long-term steroid use. Given its chronic, relapsing nature and potential to cause ocular surface damage, corneal complications, and visual morbidity, early recognition and stage-appropriate management of allergic eye disease are essential in routine clinical practice to preserve ocular surface integrity, maintain visual function, and improve patient quality of life.
2026-04-27 | Systemic Immune Dysregulation in Neurofibromatosis Type 1: Translational Validation of Atopic Multimorbidity.
Neurofibromin deficiency drives a pro-inflammatory tumor microenvironment via neuro-immune crosstalk. However, whether this local dysregulation translates into a clinically relevant systemic inflammatory phenotype remains unclear. Using the TriNetX global network, we identified 23,218 individuals with NF1 and propensity score-matched them 1:1 with controls. The primary outcomes were new diagnoses of atopic multimorbidity, including atopic dermatitis (AD), asthma, allergic rhinitis (AR), urticaria, and atopic keratoconjunctivitis (AKC). Cox proportional hazard regression models were used to estimate adjusted hazard ratios (aHRs). Our analysis revealed that NF1 patients exhibited profoundly elevated risks of AD (aHR 7.45; 95% CI 4.18 - 13.28), asthma (aHR 4.68; 95% CI 3.72 - 5.90), AR (aHR 7.15; 95% CI 5.52 - 9.25), urticaria (aHR 3.54; 95% CI 2.28 - 5.48), and notably, AKC (aHR 17.35; 95% CI 6.92 - 43.50) (all p < 0.0001). Subgroup analyses indicated that these associations were generally more pronounced in adults, females, and non-White individuals. These findings provide epidemiological validation that the neuro-inflammatory drive in NF1 is not confined to tumorigenesis but manifests as a pervasive systemic neuro-immune dysregulation. This implies that targeting shared pathways could offer dual benefits for tumor control and systemic inflammation.
2026-03-08 | Progressive Keratoconus as a Complication of Atopic Keratoconjunctivitis: A Case Report.
Presentation of a case report demonstrating the complexity of care for a patient with atopic keratoconjunctivitis (AKC), including the management of complications such as corneal ulceration, development of keratoconus, corticosteroid-induced intraocular pressure elevation, and cataract formation. We describe a case of a 52-year-old male with a marginal corneal ulcer within the context of atopic blepharokeratoconjunctivitis, focusing on complications and the need for intensive local and systemic therapy to stabilize the disease. Intensive therapy led to a gradual improvement of the disease. Corneal cross-linking stabilized keratoconus, intraocular pressure elevation was successfully managed with anti-glaucoma medication, and cataract surgery resulted in a significant improvement of visual function. This case report highlights the importance of early diagnosis and the need for long-term, multidisciplinary care in patients with AKC. Regular follow-up examinations, patient education, and a combination of local, systemic, and surgical therapy are essential in order to prevent complications and stabilize the disease.
antibodies
2026-08-03 | An interdisciplinary framework for management of ocular allergy: Integrating the allergist in clinical practice.
Ocular allergy represents one of the most frequent yet under-recognized manifestations of pediatric allergic disorders, affecting up to 30% of children worldwide. The disease encompasses a spectrum ranging from mild, intermittent seasonal or perennial allergic conjunctivitis to severe, vision-threatening forms such as vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC). Despite its high prevalence and the strong association with systemic allergic diseases-including asthma, allergic rhinitis, and atopic dermatitis-the involvement of pediatric allergists in routine ocular allergy care remains limited. This review proposes an interdisciplinary framework that integrates allergists more centrally into ocular allergy management. A structured approach to diagnosis highlights the allergist's essential role in identifying systemic triggers, performing allergy testing, and differentiating ocular allergy from mimics such as viral conjunctivitis, blepharitis, and autoimmune ocular surface disease. Management, as a stepwise, collaborative strategy beginning with allergen avoidance and topical dual-acting antihistamine/mast-cell stabilizers, progressing to steroid-sparing immunomodulators, systemic therapy, and advanced options such as allergen immunotherapy, emerging biologic treatments, including omalizumab and dupilumab, is discussed in the context of severe VKC and AKC, along with benefits, limitations, and need for ophthalmic oversight. This framework underscores the importance of timely referral from ophthalmologists to pediatric allergists, co-management of complex cases, and early integration of systemic allergy care. Through interdisciplinary collaboration, long-term visual outcomes can be improved and inappropriate steroid use minimized. A practical interdisciplinary care pathway and treatment escalation algorithm are proposed to facilitate real-world collaborative management.
2026-05-15 | Delayed-Onset Unilateral Hyperemia and Foreign-Body Sensation Following Dupliumab Therapy for Atopic Dermatitis
Purpose: We present a case of dupilumab-associated ocular surface disease presenting as atypical superior filamentary keratitis and describe our treatment approach.Case summary: A 20-year-old male receiving dupilumab for atopic dermatitis was referred for bilateral ocular discomfort 2 months after treatment initiation. Examination revealed follicular hyperplasia of the left superior palpebral conjunctiva, limbal elevation and hyperemia, corneal infiltration, and superficial neovascularization, consistent with severe atopic keratoconjunctivitis. Considering the inflammation was refractory to prior long-term therapy, the patient was treated with topical corticosteroids, antibiotics, and a sub-Tenon triamcinolone injection; however, the clinical course fluctuated with repeated improvement and deterioration. Despite subsequent tacrolimus therapy, characteristic filaments developed in the superior cornea of both eyes with significant exacerbation following dupilumab administration. Subjective symptoms improved after the patient voluntarily discontinued dupilumab. Subsequently, the condition stabilized after extending the dupilumab dosing interval and the patient remains under observation with ongoing medication adjustments.Conclusions: Dupilumab treatment can induce corneal filament formation, particularly in the superior area. Patients with a history of ocular disease or those receiving ophthalmic medications should be monitored closely during therapy.
2026-05-08 | Proteomic profiling of tear fluid in patients with atopic keratoconjunctivitis.
Atopic keratoconjunctivitis (AKC) is a chronic, severe ocular surface disease associated with atopic dermatitis, which may impair vision and ultimately lead to blindness. In this study, discovery-based proteomic analysis was performed on tear samples from patients with AKC to elucidate molecular characteristics and identify proteins of interest. All patients underwent thorough ophthalmological examination and were divided into four subgroups: healthy controls (n = 17), atopic dermatitis without ocular surface disease (n = 11), mild (n = 65), and moderate-severe AKC (n = 32). Tear film samples collected with Schirmer's filtration paper were analyzed with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Proteins were considered significantly regulated if they demonstrated a p-value lower than 0.05, following correction for multiple hypothesis testing, and if they exhibited a fold change greater than 2. A total of 2503 proteins were identified. Compared with controls, mild AKC and moderate-severe AKC showed 14 and 29 significantly regulated proteins, respectively. Mild vs moderate-severe AKC yielded 21 significantly regulated proteins. Four proteins overlapped in both mild AKC and moderate-severe AKC compared to healthy controls: Short-chain specific acyl-CoA dehydrogenase, serpin B13, non-secretory ribonuclease, and probable E3 ubiquitin-protein ligase HERC4. Regulated proteins were involved in immune-related, metabolic, and epithelial processes. This exploratory proteomic study suggests that AKC is associated with changes in immune-related pathways, including mucosal innate immunity, eosinophil migration, and cytokine signaling, as well as metabolic processes, and epithelial differentiation and barrier function.
2026-04-16 | Pediatric Ocular Surface Disorders
Ocular surface disorders in the pediatric population constitute a clinically demanding group of conditions that differ substantially from their adult counterparts, both in their underlying mechanisms and in the way they present. The immature corneal innervation, the evolving tear film composition, and the immunologically active conjunctiva-associated lymphoid tissue of the developing eye collectively create a milieu in which inflammatory and hypersensitivity responses can be intense, yet symptoms may remain subtle or absent. Children frequently cannot articulate their discomfort, and the clinician must rely on behavioral cues — persistent eye rubbing, photophobia, recurrent redness — as well as objective findings to reach a timely diagnosis. Delay carries a real cost: amblyopia, irreversible corneal scarring, and the compounding effects of chronic illness during critical windows of visual development. This chapter covers the full spectrum of pediatric ocular surface disease, from allergic conditions including vernal keratoconjunctivitis, atopic keratoconjunctivitis, and giant papillary conjunctivitis, to infectious keratoconjunctivitis, pediatric blepharokeratoconjunctivitis, phlyctenular keratoconjunctivitis, ocular rosacea, and dry eye disease, as well as the severe, sight-threatening sequelae of Stevens-Johnson syndrome and ocular graft-versus-host disease. Current management strategies are discussed with an emphasis on early immunomodulation, steroid-sparing regimens, and the emerging role of biologic therapies and regenerative medicine in children who do not respond to conventional treatment. Pediatrik popülasyonda oküler yüzey hastalıkları, hem altta yatan mekanizmalar hem de klinik prezentasyon açısından erişkin hastalıktan belirgin biçimde ayrılan, tanısal ve terapötik güçlükler sunan geniş bir hastalık grubunu oluşturmaktadır. Gelişmekte olan gözde immatür korneal innervasyon, olgunlaşma sürecindeki gözyaşı filmi bileşimi ve immünolojik açıdan aktif konjonktiva ilişkili lenfoid doku bir arada, inflamatuar ve aşırı duyarlılık yanıtlarının şiddetli seyredebildiği ancak semptomların zaman zaman silik ya da hiç olmadığı özgün bir ortam oluşturur. Çocuklar şikayetlerini çoğunlukla ifade edemediğinden klinisyen, tanıya ulaşmak için ısrarcı göz ovma, fotofobi ve tekrarlayan kızarıklık gibi davranışsal ipuçlarına ve nesnel bulgulara dayanmak durumundadır. Tanının gecikmesi; görsel gelişimin kritik dönemlerinde ambliopi, geri dönüşü olmayan korneal skar ve kronik hastalığın biriken etkileri şeklinde somut maliyetler doğurmaktadır. Bu bölüm, vernal keratokonjonktivit, atopik keratokonjonktivit ve dev papiller konjonktivit dahil alerjik hastalıklar ile enfeksiyöz keratokonjonktivit, pediatrik blefarokeratokonjonktivit, flikteniüler keratokonjonktivit, oküler rozasea ve kuru göz hastalığının yanı sıra Stevens-Johnson sendromu ve oküler graft-versus-host hastalığının ciddi, görme tehdidi oluşturan sekellerini kapsayan pediatrik oküler yüzey hastalıklarının tüm spektrumunu ele almaktadır. Güncel tedavi stratejileri; konvansiyonel tedaviye yanıtsız çocuklarda erken immünomodülasyon, steroid koruyucu rejimler ve biyolojik ajanlar ile rejeneratif tıbbın gelişen rolüne vurgu yapılarak tartışılmaktadır.
2026-03-20 | Atopic keratoconjunctivitis: From molecular mechanisms to clinical implications.
Atopic keratoconjunctivitis (AKC) is a chronic, bilateral inflammatory disease of the ocular surface that primarily affects young adults with a history of atopic dermatitis, asthma, or allergic rhinitis. AKC is considered the most severe form of ocular surface allergy and can result in serious complications that threaten vision, such as corneal ulceration, neovascularization, and scarring. Genetic predisposition, through regulatory genes that impact skin barrier function, immune system regulation, and allergic responses, plays a crucial role in the development and severity of AKC. Recent research has highlighted the roles of epithelial barrier dysfunction, gastrointestinal and eyelid/conjunctival dysbiosis, Th2-driven cytokines, and eosinophilic inflammation in disease perpetuation. Diagnosing AKC requires a high level of suspicion, careful integration of clinical signs, and a thorough assessment of coexisting atopic conditions. Management is often challenging and involves a stepwise approach, beginning with topical antihistamines and mast cell stabilizers, progressing to corticosteroids, calcineurin inhibitors, and, in severe or refractory cases, systemic immunosuppressive therapy or surgical intervention. Novel therapies, including biologics targeting IL-4 and IL-13, show promise in selected patients. A multidisciplinary approach and long-term follow-up are crucial for minimizing complications and preserving visual function. We provide a comprehensive update on the epidemiology, clinical manifestations, immunopathogenesis, diagnostic approach, and therapeutic strategies for AKC.
proteins
2024-11-06 | Traumatic Corneal Perforation as a Complication of Neurotrophic Keratitis in the setting of Atopic Keratoconjunctivitis and Rheumatoid Arthritis
Purpose: To report a case of traumatic corneal perforation secondary to neurotrophic keratitis associated with atopic keratoconjunctivitis and rheumatoid arthritis.Methods: Case report.Results: We present the case of a 34-year-old woman with untreated rheumatoid arthritis (RA), atopic keratoconjunctivitis (AKC) and neurotrophic keratitis (NK) who developed severe bilateral cor-neal ulceration and unilateral perforation as a result of traumatic eye drop application.The patient responded favorably to a multifaceted treatment approach including the application of corneal fibrin glue and bandage contact lens bilaterally, oral steroids, doxycycline and vitamin C. Addi-tional conservative measures to improve the ocular surface were employed, including frequent application of preservative free artificial tears and warm saltwater soaks.Proper technique for eye drop application was discussed and demonstrated to the patient.Lastly, identifying and treating the patient's underlying RA significantly improved the conjunctival inflammation.Conclusion: Corneal esthesiometry should be performed routinely in patients with AKC or RA to identify patients with an increased risk factor for severe NKrelated complications.A multifaceted ap-proach to treatment including topical and systemic medication is recommended for patients who present with complications of NK associated with AKC or RA.Identifying and treating underly-ing autoimmune disease such as RA can aid tremendously in the treatment of ocular inflamma-tion and prevention of further complications.Despite corneal perforation, no surgical intervention was required and the patient's visual acuity was preserved.
2020-07-30 | Neurotrophic factors and nerve growth factor in ocular allergy.
During allergic reaction, nervous and immune systems mutually interact through release of mediators, including neurotrophic factors and nerve growth factor (NGF). These mediators modulate allergic reaction through binding their receptors expressed by immune and structural cells and by stimulating neuropeptide release by nerves. The role of neuropeptides and NGF has been demonstrated in allergic asthma and rhinitis, and, to a lesser extent, in allergic conjunctivitis. The aim of this review are to elucidate the evidence of the role of NGF and neuropeptides in the pathogenesis of allergic conjunctivitis. NGF modulates allergic reaction by stimulating release of cytokines, inflammatory mediators and neuropeptides by immune and structural cells and nerve endings at the site of inflammation. Evidence showed that local and systemic NGF levels increase in patients with allergic conjunctivitis, including allergic rhinoconjuncivitis, vernal keratoconjunctivitis and atopic keratoconjunctivitis. We recently described an increase of conjunctival p75NTR expression in patients with allergic rhinoconjuncivitis, and an increase of tear levels of NGF after conjunctival provocation test with allergen. NGF modulates ocular allergic reaction. Increasing understanding of the role of neuropeptides in allergic conjunctivitis may pave the way to the development of novel therapeutic approaches and improvement of patients' management.
2020-07-23 | Why Chain Length of Hyaluronan in Eye Drops Matters
The chain length of hyaluronan (HA) determines its physical as well as its physiological properties. Results of clinical research on HA eye drops are not comparable without this parameter. In this article methods for the assessment of the average molecular weight of HA in eye drops and a terminology for molecular weight ranges are proposed. The classification of HA eye drops according to their zero shear viscosity and viscosity at 1000 s-1 shear rate is presented. Based on the gradient of mucin MUC5AC concentration within the mucoaqueous layer of the tear film a hypothesis on the consequences of this gradient on the rheological properties of the tear film is provided. The mucoadhesive properties of HA and their dependence on chain length are explained. The ability of HA to bind to receptors on the ocular epithelial cells, and in particular the potential consequences of the interaction between HA and the receptor HARE, responsible for HA endocytosis by corneal epithelial cells is discussed. The physiological function of HA in the framework of ocular surface homeostasis and wound healing are outlined, and the influence of the chain length of HA on the clinical performance of HA eye drops is illustrated. The use of very high molecular weight HA (hylan A) eye drops as drug vehicle for the next generation of ophthalmic drugs with minimized side effects is proposed and its advantages elucidated. Consequences of the diagnosis and treatment of ocular surface disease are discussed.
2019-04-01 | Management of advanced ocular surface disease in patients with severe atopic keratoconjunctivitis
Severe ocular surface disease, including limbal stem cell deficiency (LSCD) can occur as a consequence of severe atopic keratoconjunctivitis (AKC) that has been inadequately treated. Our goal was to describe the management and outcomes of severe ocular surface disease in AKC patients.We performed a retrospective analysis of a case series of 13 eyes of 8 patients with advanced ocular surface disease associated with severe AKC. The clinical presentation, medical and surgical management, and visual and anatomic outcomes were analyzed.Five eyes were treated with medical interventions alone, which included topical or systemic immunomodulatory therapy (IMT) for all eyes. These eyes had a decline in mean visual acuity from LogMAR 0.96 to 2.04 between the initial and final visits related to recurrent epithelial defects or corneal ulceration. Eight eyes were treated with surgical approaches in addition to medical treatment. Initial surgical treatments included limbal stem cell transplantation (n = 5), Boston keratoprosthesis (n = 2), and superficial keratectomy (n = 1). Both eyes that underwent primary keratoprosthesis had severe post-operative complications and became no light perception. In the remainder of the surgically treated eyes, there was an improvement visual acuity from LogMAR 1.43 to 0.6 between the pre-operative and final post-operative visit.Visual rehabilitation in eyes severe ocular surface disease due to prolonged AKC is challenging. While some patients did experience improved vision, most eyes did not improve or experienced severe complications with vision loss. Early intervention with immunomodulatory therapy may prevent progression of the disease to advanced stages.
2017-09-11 | Resolvin D1 Increases Mucin Secretion in Cultured Rat Conjunctival Goblet Cells via Multiple Signaling Pathways
Goblet cells in the conjunctiva secrete mucin into the tear film protecting the ocular surface. The proresolution mediator resolvin D1 (RvD1) regulates mucin secretion to maintain homeostasis during physiological conditions and in addition, actively terminates inflammation. We determined the signaling mechanisms used by RvD1 in cultured rat conjunctival goblet cells to increase intracellular [Ca2+] ([Ca2+]i) and induce glycoconjugate secretion.Increase in [Ca2+]i were measured using fura 2/AM and glycoconjugate secretion determined using an enzyme-linked lectin assay with the lectin Ulex Europaeus Agglutinin 1. Signaling pathways activated by RvD1 were studied after goblet cells were pretreated with signaling pathway inhibitors before stimulation with RvD1. The results were compared with results when goblet cells were stimulated with RvD1 alone and percent inhibition calculated.The increase in [Ca2+]i stimulated by RvD1 was blocked by inhibitors to phospholipases (PL-) -D, -C, -A2, protein kinase C (PKC), extracellular signal-regulated kinases (ERK)1/2 and Ca2+/calmodulin-dependent kinase (Ca2+/CamK). Glycoconjugate secretion was significantly inhibited by PLD, -C, -A2, ERK1/2 and Ca2+/CamK, but not PKC.We conclude that RvD1 increases glycoconjugate secretion from goblet cells via multiple signaling pathways including PLC, PLD, and PLA2, as well as their signaling components ERK1/2 and Ca2+/CamK to preserve the mucous layer and maintain homeostasis by protecting the eye from desiccating stress, allergens, and pathogens.
cell therapies
2025-08-06 | Emerging concepts in atopic dermatitis and atopic keratoconjunctivitis.
Atopic dermatitis (AD) is a chronic inflammatory skin disease involving Th2 cytokine-driven inflammation. AD patients are at risk of developing conjunctivitis, including atopic keratoconjunctivitis (AKC), a sight-threatening chronic allergic eye disease involving both Th2 and Th1/17 cytokine-driven inflammation.In AD, dupilumab is highly effective by inhibiting interleukin (IL)-4 and IL-13. However, some AD patients develop dupilumab-associated ocular surface disease (DAOSD), an AKC-like disease. There are no biomarkers to predict who will develop DAOSD. The purpose of this review is to highlight recent findings in AD and AKC suggesting different immunopathogenic mechanisms are involved. A recent proteomics study of tear fluids identified raised inflammatory markers ( n = 31) in AD patients with DAOSD ( n = 22) and a shift towards a Th1/17 profile. Alternative biologics have been investigated for treating moderate-to-severe AD which have fewer ocular side-effects. The inhibitory effects of dupilumab cause an associated upregulation of IL-33 which could lead to an AKC-like disease. A recent therapeutic approach in AD via regulatory T cells suggests a novel treatment for those at risk of DAOSD. Ocular side-effects of dupilumab suggest that the immunopathogenic pathways in moderate-to-severe AD and AKC are not the same and, for DAOSD, might require different treatment approaches.
2025-07-25 | Shield ulcer in keratoconus in the absence of atopic or vernal kerato-conjunctivitis.
Corneal shield ulcer is a severe complication of atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC). This condition is caused by the mechanical irritation of the corneal epithelium due to giant papillae and toxic epitheliopathy resulting from inflammatory mediators. To date, there have been no reported cases of corneal shield ulcers in the literature without AKC or VKC. However, the authors have reported a unique case of shield ulcer in a patient with keratoconus but no history of AKC or VKC. The cause is hypothesised to be due to mechanical friction between the corneal steep apex and palpebral conjunctiva. Additionally, a new technique, the use of a dry amniotic membrane, is described to manage the persistent epithelial defect in shield ulcers.
2023-10-02 | Subconjunctival injection of human umbilical cord mesenchymal stem cells alleviates experimental allergic conjunctivitis via regulating T cell response
T helper 2 (Th2) cells are thought to play critical roles in allergic conjunctivitis (AC). They release inflammatory cytokines to promote an allergic response in AC. Due to individual heterogeneity and long-term chronic management, current therapies do not always effectively control AC. Mesenchymal stem cells (MSCs) have been shown to be effective in treating allergy-related disorders, but it is unclear how exactly the Th2-mediated allergic response is attenuated. This study aims to elucidate the therapeutic effect and mechanism of the human umbilical cord MSCs (hUCMSCs) in a mouse model of experimental AC (EAC).A mouse EAC model was established by inoculating short ragweed (SRW) pollen. After the SRW pollen challenge, the mice received a single subconjunctival or tail vein injection of 2 × 106 hUCMSCs, or subconjunctival injection of hUCMSCs conditioned medium (hUCMSC-CM), and dexamethasone eye drops was used as positive control; subsequent scratching behavior and clinical symptoms were assessed. Immunostaining and flow cytometry were carried out to show allergic reactions and the activation of CD4 + T cell subsets in the conjunctiva and cervical lymph nodes (CLNs). Gene expression was determined by RNA-seq and further verified by qRT-PCR and Western blot. Co-culture assays were performed to explore the regulatory role of hUCMSCs in the differentiation of CD4 + naive T cells (Th0) into Th2 cells.Subconjunctival administration of hUCMSCs resulted in fewer instances of scratching and lower inflammation scores in EAC mice compared to the tail vein delivery, hUCMSC-CM and control groups. Subconjunctival administration of hUCMSCs reduced the number of activated mast cells and infiltrated eosinophils in the conjunctiva, as well as decreased the number of Th2 cells in CLNs. After pretreatment with EAC mouse serum in vitro to mimic the in vivo milieu, hUCMSCs were able to inhibit the differentiation of Th0 into Th2 cells. Further evidence demonstrated that repression of Th2 cell differentiation by hUCMSCs is mediated by CRISPLD2 through downregulation of STAT6 phosphorylation. Additionally, hUMCSCs were able to promote the differentiation of Th0 cells into regulatory T cells in CLNs of EAC mice.Subconjunctival injection of hUCMSCs suppressed the Th2-allergic response and alleviated clinical symptoms. This study provides not only a potential therapeutic target for the treatment of AC but also other T cell-mediated diseases.
2015-08-08 | Linking immune responses with fibrosis in allergic eye disease
Purpose of review Here, we explore an emerging theme in the literature, which is the role of dendritic cells in the causation of fibrosis. To fully appreciate this pathway to disease, we also review the most recent literature regarding dendritic cell biology as it pertains to ocular surface tissues. On the basis of this information, we propose a unifying hypothesis for how dendritic cells may cause conjunctival fibrosis in the allergy setting. Recent findings Work in models of airway remodeling and liver fibrosis has pointed to a potentially central role for dendritic cells in the pathobiology of fibrosis. Indeed, these cells are recognized as the most potent antigen-presenting cells, and as such activate T lymphocytes that are profibrotic under certain conditions. However, recent findings suggest a more direct role for dendritic cells, which opens up the possibility that a similar pathway may be relevant in the causation of conjunctival fibrosis, particularly in allergic eye disease. Summary Conjunctival fibrosis is a serious clinical concern and is associated with chronic inflammation of the ocular surface tissue, such as in allergic eye disease. Dendritic cells are required in mediating allergic disease by activating pathologic T lymphocytes. Recent findings pointing to a central role for dendritic cell in fibrosis may, however, mean that these cells could also be contributing directly to conjunctival fibrosis. If so, furthering our understanding of dendritic cells could lead to the identification of novel and more effective therapeutic strategies to treat this disease.
2015-08-01 | Culture medium from TNF-α–stimulated mesenchymal stem cells attenuates allergic conjunctivitis through multiple antiallergic mechanisms
BackgroundThe immunomodulatory and anti-inflammatory functions of mesenchymal stem cells (MSCs) have been demonstrated in several autoimmune/inflammatory diseases, but their contribution to allergic conjunctivitis and underlying antiallergic mechanisms remain elusive.ObjectiveWe sought to explore the clinical application of MSCs to experimental allergic conjunctivitis (EAC) and its underlying antiallergic mechanisms.MethodsCulture medium from TNF-α–stimulated, bone marrow–derived MSCs (MSC-CMT) was administered topically to mice with EAC, and the related allergic symptoms and biological changes were evaluated. Murine spleen-derived B cells, bone marrow–derived mast cells (MCs), and lung vascular endothelial cells were cultured in vitro to investigate the antiallergic MSC-CMT mechanisms.ResultsTopical instillation of MSC-CMT significantly attenuated the clinical symptoms of short ragweed pollen–induced EAC, with a significant decrease in inflammatory cell frequency, nuclear factor κB p65 expression, and TNF-α and IL-4 production. In vitro MSC-CMT significantly inhibited the activation of MCs and B-cell IgE release and reduced histamine-induced vascular hyperpermeability. During EAC, MSC-CMT treatment also decreased IgE production, histamine release, enrichment and activation of MCs, and conjunctival vascular hyperpermeability. The MSC-CMT–mediated inhibition of B cells, MCs, and histamine and its antiallergic effects during EAC were abrogated when MSCs were pretreated with COX2 small interfering RNA.ConclusionsOur findings provide compelling evidence that MSC-CMT inhibits EAC through COX2-dependent multiple antiallergic mechanisms and support the use of MSC-CMT as a novel strategy for treating allergic conjunctivitis. The immunomodulatory and anti-inflammatory functions of mesenchymal stem cells (MSCs) have been demonstrated in several autoimmune/inflammatory diseases, but their contribution to allergic conjunctivitis and underlying antiallergic mechanisms remain elusive. We sought to explore the clinical application of MSCs to experimental allergic conjunctivitis (EAC) and its underlying antiallergic mechanisms. Culture medium from TNF-α–stimulated, bone marrow–derived MSCs (MSC-CMT) was administered topically to mice with EAC, and the related allergic symptoms and biological changes were evaluated. Murine spleen-derived B cells, bone marrow–derived mast cells (MCs), and lung vascular endothelial cells were cultured in vitro to investigate the antiallergic MSC-CMT mechanisms. Topical instillation of MSC-CMT significantly attenuated the clinical symptoms of short ragweed pollen–induced EAC, with a significant decrease in inflammatory cell frequency, nuclear factor κB p65 expression, and TNF-α and IL-4 production. In vitro MSC-CMT significantly inhibited the activation of MCs and B-cell IgE release and reduced histamine-induced vascular hyperpermeability. During EAC, MSC-CMT treatment also decreased IgE production, histamine release, enrichment and activation of MCs, and conjunctival vascular hyperpermeability. The MSC-CMT–mediated inhibition of B cells, MCs, and histamine and its antiallergic effects during EAC were abrogated when MSCs were pretreated with COX2 small interfering RNA. Our findings provide compelling evidence that MSC-CMT inhibits EAC through COX2-dependent multiple antiallergic mechanisms and support the use of MSC-CMT as a novel strategy for treating allergic conjunctivitis.
small molecules
2026-09-30 | S2k-Guideline - Standardized application of the nasal and conjunctival provocation test on allergic diseases of the upper airways : of the German Society for Allergology and Clinical Immunology (DGAKI), German Society of Oto-Rhino-Laryngology, Head and Neck Surgery (DGHNO-KHC), German Dermatological Society (DDG), German Society of Pediatrics and Adolescent Medicine (DGKJ), German Society of Ophthalmology (DOG), German Respiratory Society (DGP), German Society for Occupational and Environmental Medicine (DGAUM), German Society for Pediatric Allergology and Environmental Medicine (GPA), German Society for Pediatric Pulmonology (GPP), Ärzteverband Deutscher Allergologen (AeDA), and German Professional Association of Otorhinolaryngologists (BVHNO).
Broad evidence confirms that AR (ICD J30.3) is a chronic disease with high prevalence among children and adults worldwide. Its consequences, both from a public health perspective and at the level of the individual patient, are often underestimated, and the condition is inadequately treated. In addition, AR is often related to comorbidities with additional impact on diseases-severity. Allergen provocation of the easily accessible nasal (nasal allergen provocation test: NPT) or conjunctival mucosa (conjunctival allergen provocation test: CPT) reproduces the allergen-dependent, IgE-mediated allergic reaction under controlled and standardized conditions. These measures are regarded as the diagnostic gold standard, particularly in cases of unclear results in primary allergological tests, enabling clinically relevant identification of the causative allergen. Approved test allergens are critical for ensuring the methodological quality of the NPT. However, their availability is increasingly limited, although adequate quantities of allergen solutions remain indispensable for high-quality nasal allergen testing. Unilateral allergen provocation has been established in the clinical routine for decades in Germany. However, scientific evidence for unilateral application of the test allergen is pending. International position papers differ from this recommendation. The CPT is a simple, safe, and well-tolerated measure. It is primarily used in perennial and, in selected cases, seasonal allergic conjunctivitis. This method is less commonly applied for vernal keratoconjunctivitis and atopic keratoconjunctivitis. It is primarily used to confirm the underlying allergen, particularly when establishing the indication for allergen immunotherapy (AIT). It can also be employed to monitor treatment effects such as e.g., AIT or pharmacotherapy. Although highly sensitive, the procedure of nasal ASA provocation remains a time-consuming procedure. While challenging in children, NPT provides clinically relevant additional diagnostic information on the causes of the allergic symptoms. Allergological diagnostic work-up also includes pulmonary assessment, particularly in patients with established asthma or symptoms suggestive of asthma. Both AAR and PNIF are applied as standard procedures for assessing the outcome of NPT in Germany. In individual cases, other rhinometric methods may also be used.
2026-06-17 | An update on our understanding of host defense mechanisms at the ocular surface; innate immune dysregulation at the ocular surface: lessons from Stevens-Johnson syndrome and related inflammatory disorders.
The ocular surface is a frontline mucosal immune barrier that protects the eye from pathogens while preserving immune tolerance essential for vision. Breakdown of this innate immune homeostasis can trigger chronic ocular surface inflammation, exemplified by Stevens-Johnson syndrome/toxic epidermal necrolysis with severe ocular complications (SJS/TEN with SOC) and atopic keratoconjunctivitis (AKC). The review summarizes current knowledge of ocular surface innate immunity, focusing on pattern-recognition receptors (TLR3, RIG-I, MDA5) and downstream interferon-stimulated genes (e.g. IFI44L, CXCL10, IFIT2) and their regulation. The influence of host genetic predispositions and microRNA regulatory networks on these pathways is highlighted, and innate immune profiles are compared among SJS/TEN with SOC, AKC, and healthy ocular surfaces. Dysregulation of mucosal innate immunity - shaped by host genetic factors, abnormal epithelial responses, and microRNA-mediated feedback loops - underlies the persistence and severity of chronic ocular surface disorders such as SJS/TEN with SOC and AKC. A deeper understanding of these mechanisms may inform the development of novel diagnostic biomarkers (e.g. microRNA signatures) and immune-modulating therapies to restore immune homeostasis and prevent vision-threatening inflammation. PubMed was used as the literature search methodology.
2026-06-04 | Allergic eye disease in clinical practice: essential updates for eye care professionals.
Allergic eye disease affects 15-40% of people worldwide, particularly children and adolescents, and often coexists with atopic dermatitis, allergic asthma, and allergic rhinitis. To capture the latest insights into its causes, presentation and management, the authors performed a comprehensive PubMed/MEDLINE literature review through April 2025 using multiple search terms such as 'ocular allergy', 'allergic conjunctivitis', 'Seasonal Allergic Conjunctivitis', 'Perennial Allergic Conjunctivitis', 'Atopic Keratoconjunctivitis', 'Giant Papillary Conjunctivitis', "Contact Blepharoconjunctivitis, 'Vernal Keratoconjunctivitis', 'Shield Ulcers', 'immunology', 'allergic rhinitis', and related terminologies. The current review review integrates epidemiological data, mechanistic studies and clinical guidelines to offer a cohesive overview of this condition. Allergic eye disease arises when environmental allergens trigger an IgE-mediated immune response in the eye, leading to inflammation that ranges from mild seasonal redness and itching to severe forms with tissue changes and corneal involvement. Diagnosis depends on the history and eye examination of a patient, with ancillary tests used only when the presentation is unclear. Management begins with allergen avoidance, lubricating drops and cold compresses, progressing to topical antihistamines or mast-cell stabilisers and short-course corticosteroids for flares. Looking ahead, newer treatments such as calcineurin inhibitors, monoclonal antibodies against key inflammatory cytokines and targeted small-molecule drugs are expanding the ability to control symptoms without long-term steroid use. Given its chronic, relapsing nature and potential to cause ocular surface damage, corneal complications, and visual morbidity, early recognition and stage-appropriate management of allergic eye disease are essential in routine clinical practice to preserve ocular surface integrity, maintain visual function, and improve patient quality of life.
2026-04-27 | Systemic Immune Dysregulation in Neurofibromatosis Type 1: Translational Validation of Atopic Multimorbidity.
Neurofibromin deficiency drives a pro-inflammatory tumor microenvironment via neuro-immune crosstalk. However, whether this local dysregulation translates into a clinically relevant systemic inflammatory phenotype remains unclear. Using the TriNetX global network, we identified 23,218 individuals with NF1 and propensity score-matched them 1:1 with controls. The primary outcomes were new diagnoses of atopic multimorbidity, including atopic dermatitis (AD), asthma, allergic rhinitis (AR), urticaria, and atopic keratoconjunctivitis (AKC). Cox proportional hazard regression models were used to estimate adjusted hazard ratios (aHRs). Our analysis revealed that NF1 patients exhibited profoundly elevated risks of AD (aHR 7.45; 95% CI 4.18 - 13.28), asthma (aHR 4.68; 95% CI 3.72 - 5.90), AR (aHR 7.15; 95% CI 5.52 - 9.25), urticaria (aHR 3.54; 95% CI 2.28 - 5.48), and notably, AKC (aHR 17.35; 95% CI 6.92 - 43.50) (all p < 0.0001). Subgroup analyses indicated that these associations were generally more pronounced in adults, females, and non-White individuals. These findings provide epidemiological validation that the neuro-inflammatory drive in NF1 is not confined to tumorigenesis but manifests as a pervasive systemic neuro-immune dysregulation. This implies that targeting shared pathways could offer dual benefits for tumor control and systemic inflammation.
2026-03-08 | Progressive Keratoconus as a Complication of Atopic Keratoconjunctivitis: A Case Report.
Presentation of a case report demonstrating the complexity of care for a patient with atopic keratoconjunctivitis (AKC), including the management of complications such as corneal ulceration, development of keratoconus, corticosteroid-induced intraocular pressure elevation, and cataract formation. We describe a case of a 52-year-old male with a marginal corneal ulcer within the context of atopic blepharokeratoconjunctivitis, focusing on complications and the need for intensive local and systemic therapy to stabilize the disease. Intensive therapy led to a gradual improvement of the disease. Corneal cross-linking stabilized keratoconus, intraocular pressure elevation was successfully managed with anti-glaucoma medication, and cataract surgery resulted in a significant improvement of visual function. This case report highlights the importance of early diagnosis and the need for long-term, multidisciplinary care in patients with AKC. Regular follow-up examinations, patient education, and a combination of local, systemic, and surgical therapy are essential in order to prevent complications and stabilize the disease.
antibodies
2026-08-03 | An interdisciplinary framework for management of ocular allergy: Integrating the allergist in clinical practice.
Ocular allergy represents one of the most frequent yet under-recognized manifestations of pediatric allergic disorders, affecting up to 30% of children worldwide. The disease encompasses a spectrum ranging from mild, intermittent seasonal or perennial allergic conjunctivitis to severe, vision-threatening forms such as vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC). Despite its high prevalence and the strong association with systemic allergic diseases-including asthma, allergic rhinitis, and atopic dermatitis-the involvement of pediatric allergists in routine ocular allergy care remains limited. This review proposes an interdisciplinary framework that integrates allergists more centrally into ocular allergy management. A structured approach to diagnosis highlights the allergist's essential role in identifying systemic triggers, performing allergy testing, and differentiating ocular allergy from mimics such as viral conjunctivitis, blepharitis, and autoimmune ocular surface disease. Management, as a stepwise, collaborative strategy beginning with allergen avoidance and topical dual-acting antihistamine/mast-cell stabilizers, progressing to steroid-sparing immunomodulators, systemic therapy, and advanced options such as allergen immunotherapy, emerging biologic treatments, including omalizumab and dupilumab, is discussed in the context of severe VKC and AKC, along with benefits, limitations, and need for ophthalmic oversight. This framework underscores the importance of timely referral from ophthalmologists to pediatric allergists, co-management of complex cases, and early integration of systemic allergy care. Through interdisciplinary collaboration, long-term visual outcomes can be improved and inappropriate steroid use minimized. A practical interdisciplinary care pathway and treatment escalation algorithm are proposed to facilitate real-world collaborative management.
2026-05-15 | Delayed-Onset Unilateral Hyperemia and Foreign-Body Sensation Following Dupliumab Therapy for Atopic Dermatitis
Purpose: We present a case of dupilumab-associated ocular surface disease presenting as atypical superior filamentary keratitis and describe our treatment approach.Case summary: A 20-year-old male receiving dupilumab for atopic dermatitis was referred for bilateral ocular discomfort 2 months after treatment initiation. Examination revealed follicular hyperplasia of the left superior palpebral conjunctiva, limbal elevation and hyperemia, corneal infiltration, and superficial neovascularization, consistent with severe atopic keratoconjunctivitis. Considering the inflammation was refractory to prior long-term therapy, the patient was treated with topical corticosteroids, antibiotics, and a sub-Tenon triamcinolone injection; however, the clinical course fluctuated with repeated improvement and deterioration. Despite subsequent tacrolimus therapy, characteristic filaments developed in the superior cornea of both eyes with significant exacerbation following dupilumab administration. Subjective symptoms improved after the patient voluntarily discontinued dupilumab. Subsequently, the condition stabilized after extending the dupilumab dosing interval and the patient remains under observation with ongoing medication adjustments.Conclusions: Dupilumab treatment can induce corneal filament formation, particularly in the superior area. Patients with a history of ocular disease or those receiving ophthalmic medications should be monitored closely during therapy.
2026-05-08 | Proteomic profiling of tear fluid in patients with atopic keratoconjunctivitis.
Atopic keratoconjunctivitis (AKC) is a chronic, severe ocular surface disease associated with atopic dermatitis, which may impair vision and ultimately lead to blindness. In this study, discovery-based proteomic analysis was performed on tear samples from patients with AKC to elucidate molecular characteristics and identify proteins of interest. All patients underwent thorough ophthalmological examination and were divided into four subgroups: healthy controls (n = 17), atopic dermatitis without ocular surface disease (n = 11), mild (n = 65), and moderate-severe AKC (n = 32). Tear film samples collected with Schirmer's filtration paper were analyzed with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Proteins were considered significantly regulated if they demonstrated a p-value lower than 0.05, following correction for multiple hypothesis testing, and if they exhibited a fold change greater than 2. A total of 2503 proteins were identified. Compared with controls, mild AKC and moderate-severe AKC showed 14 and 29 significantly regulated proteins, respectively. Mild vs moderate-severe AKC yielded 21 significantly regulated proteins. Four proteins overlapped in both mild AKC and moderate-severe AKC compared to healthy controls: Short-chain specific acyl-CoA dehydrogenase, serpin B13, non-secretory ribonuclease, and probable E3 ubiquitin-protein ligase HERC4. Regulated proteins were involved in immune-related, metabolic, and epithelial processes. This exploratory proteomic study suggests that AKC is associated with changes in immune-related pathways, including mucosal innate immunity, eosinophil migration, and cytokine signaling, as well as metabolic processes, and epithelial differentiation and barrier function.
2026-04-16 | Pediatric Ocular Surface Disorders
Ocular surface disorders in the pediatric population constitute a clinically demanding group of conditions that differ substantially from their adult counterparts, both in their underlying mechanisms and in the way they present. The immature corneal innervation, the evolving tear film composition, and the immunologically active conjunctiva-associated lymphoid tissue of the developing eye collectively create a milieu in which inflammatory and hypersensitivity responses can be intense, yet symptoms may remain subtle or absent. Children frequently cannot articulate their discomfort, and the clinician must rely on behavioral cues — persistent eye rubbing, photophobia, recurrent redness — as well as objective findings to reach a timely diagnosis. Delay carries a real cost: amblyopia, irreversible corneal scarring, and the compounding effects of chronic illness during critical windows of visual development. This chapter covers the full spectrum of pediatric ocular surface disease, from allergic conditions including vernal keratoconjunctivitis, atopic keratoconjunctivitis, and giant papillary conjunctivitis, to infectious keratoconjunctivitis, pediatric blepharokeratoconjunctivitis, phlyctenular keratoconjunctivitis, ocular rosacea, and dry eye disease, as well as the severe, sight-threatening sequelae of Stevens-Johnson syndrome and ocular graft-versus-host disease. Current management strategies are discussed with an emphasis on early immunomodulation, steroid-sparing regimens, and the emerging role of biologic therapies and regenerative medicine in children who do not respond to conventional treatment. Pediatrik popülasyonda oküler yüzey hastalıkları, hem altta yatan mekanizmalar hem de klinik prezentasyon açısından erişkin hastalıktan belirgin biçimde ayrılan, tanısal ve terapötik güçlükler sunan geniş bir hastalık grubunu oluşturmaktadır. Gelişmekte olan gözde immatür korneal innervasyon, olgunlaşma sürecindeki gözyaşı filmi bileşimi ve immünolojik açıdan aktif konjonktiva ilişkili lenfoid doku bir arada, inflamatuar ve aşırı duyarlılık yanıtlarının şiddetli seyredebildiği ancak semptomların zaman zaman silik ya da hiç olmadığı özgün bir ortam oluşturur. Çocuklar şikayetlerini çoğunlukla ifade edemediğinden klinisyen, tanıya ulaşmak için ısrarcı göz ovma, fotofobi ve tekrarlayan kızarıklık gibi davranışsal ipuçlarına ve nesnel bulgulara dayanmak durumundadır. Tanının gecikmesi; görsel gelişimin kritik dönemlerinde ambliopi, geri dönüşü olmayan korneal skar ve kronik hastalığın biriken etkileri şeklinde somut maliyetler doğurmaktadır. Bu bölüm, vernal keratokonjonktivit, atopik keratokonjonktivit ve dev papiller konjonktivit dahil alerjik hastalıklar ile enfeksiyöz keratokonjonktivit, pediatrik blefarokeratokonjonktivit, flikteniüler keratokonjonktivit, oküler rozasea ve kuru göz hastalığının yanı sıra Stevens-Johnson sendromu ve oküler graft-versus-host hastalığının ciddi, görme tehdidi oluşturan sekellerini kapsayan pediatrik oküler yüzey hastalıklarının tüm spektrumunu ele almaktadır. Güncel tedavi stratejileri; konvansiyonel tedaviye yanıtsız çocuklarda erken immünomodülasyon, steroid koruyucu rejimler ve biyolojik ajanlar ile rejeneratif tıbbın gelişen rolüne vurgu yapılarak tartışılmaktadır.
2026-03-20 | Atopic keratoconjunctivitis: From molecular mechanisms to clinical implications.
Atopic keratoconjunctivitis (AKC) is a chronic, bilateral inflammatory disease of the ocular surface that primarily affects young adults with a history of atopic dermatitis, asthma, or allergic rhinitis. AKC is considered the most severe form of ocular surface allergy and can result in serious complications that threaten vision, such as corneal ulceration, neovascularization, and scarring. Genetic predisposition, through regulatory genes that impact skin barrier function, immune system regulation, and allergic responses, plays a crucial role in the development and severity of AKC. Recent research has highlighted the roles of epithelial barrier dysfunction, gastrointestinal and eyelid/conjunctival dysbiosis, Th2-driven cytokines, and eosinophilic inflammation in disease perpetuation. Diagnosing AKC requires a high level of suspicion, careful integration of clinical signs, and a thorough assessment of coexisting atopic conditions. Management is often challenging and involves a stepwise approach, beginning with topical antihistamines and mast cell stabilizers, progressing to corticosteroids, calcineurin inhibitors, and, in severe or refractory cases, systemic immunosuppressive therapy or surgical intervention. Novel therapies, including biologics targeting IL-4 and IL-13, show promise in selected patients. A multidisciplinary approach and long-term follow-up are crucial for minimizing complications and preserving visual function. We provide a comprehensive update on the epidemiology, clinical manifestations, immunopathogenesis, diagnostic approach, and therapeutic strategies for AKC.
proteins
2024-11-06 | Traumatic Corneal Perforation as a Complication of Neurotrophic Keratitis in the setting of Atopic Keratoconjunctivitis and Rheumatoid Arthritis
Purpose: To report a case of traumatic corneal perforation secondary to neurotrophic keratitis associated with atopic keratoconjunctivitis and rheumatoid arthritis.Methods: Case report.Results: We present the case of a 34-year-old woman with untreated rheumatoid arthritis (RA), atopic keratoconjunctivitis (AKC) and neurotrophic keratitis (NK) who developed severe bilateral cor-neal ulceration and unilateral perforation as a result of traumatic eye drop application.The patient responded favorably to a multifaceted treatment approach including the application of corneal fibrin glue and bandage contact lens bilaterally, oral steroids, doxycycline and vitamin C. Addi-tional conservative measures to improve the ocular surface were employed, including frequent application of preservative free artificial tears and warm saltwater soaks.Proper technique for eye drop application was discussed and demonstrated to the patient.Lastly, identifying and treating the patient's underlying RA significantly improved the conjunctival inflammation.Conclusion: Corneal esthesiometry should be performed routinely in patients with AKC or RA to identify patients with an increased risk factor for severe NKrelated complications.A multifaceted ap-proach to treatment including topical and systemic medication is recommended for patients who present with complications of NK associated with AKC or RA.Identifying and treating underly-ing autoimmune disease such as RA can aid tremendously in the treatment of ocular inflamma-tion and prevention of further complications.Despite corneal perforation, no surgical intervention was required and the patient's visual acuity was preserved.
2020-07-30 | Neurotrophic factors and nerve growth factor in ocular allergy.
During allergic reaction, nervous and immune systems mutually interact through release of mediators, including neurotrophic factors and nerve growth factor (NGF). These mediators modulate allergic reaction through binding their receptors expressed by immune and structural cells and by stimulating neuropeptide release by nerves. The role of neuropeptides and NGF has been demonstrated in allergic asthma and rhinitis, and, to a lesser extent, in allergic conjunctivitis. The aim of this review are to elucidate the evidence of the role of NGF and neuropeptides in the pathogenesis of allergic conjunctivitis. NGF modulates allergic reaction by stimulating release of cytokines, inflammatory mediators and neuropeptides by immune and structural cells and nerve endings at the site of inflammation. Evidence showed that local and systemic NGF levels increase in patients with allergic conjunctivitis, including allergic rhinoconjuncivitis, vernal keratoconjunctivitis and atopic keratoconjunctivitis. We recently described an increase of conjunctival p75NTR expression in patients with allergic rhinoconjuncivitis, and an increase of tear levels of NGF after conjunctival provocation test with allergen. NGF modulates ocular allergic reaction. Increasing understanding of the role of neuropeptides in allergic conjunctivitis may pave the way to the development of novel therapeutic approaches and improvement of patients' management.
2020-07-23 | Why Chain Length of Hyaluronan in Eye Drops Matters
The chain length of hyaluronan (HA) determines its physical as well as its physiological properties. Results of clinical research on HA eye drops are not comparable without this parameter. In this article methods for the assessment of the average molecular weight of HA in eye drops and a terminology for molecular weight ranges are proposed. The classification of HA eye drops according to their zero shear viscosity and viscosity at 1000 s-1 shear rate is presented. Based on the gradient of mucin MUC5AC concentration within the mucoaqueous layer of the tear film a hypothesis on the consequences of this gradient on the rheological properties of the tear film is provided. The mucoadhesive properties of HA and their dependence on chain length are explained. The ability of HA to bind to receptors on the ocular epithelial cells, and in particular the potential consequences of the interaction between HA and the receptor HARE, responsible for HA endocytosis by corneal epithelial cells is discussed. The physiological function of HA in the framework of ocular surface homeostasis and wound healing are outlined, and the influence of the chain length of HA on the clinical performance of HA eye drops is illustrated. The use of very high molecular weight HA (hylan A) eye drops as drug vehicle for the next generation of ophthalmic drugs with minimized side effects is proposed and its advantages elucidated. Consequences of the diagnosis and treatment of ocular surface disease are discussed.
2019-04-01 | Management of advanced ocular surface disease in patients with severe atopic keratoconjunctivitis
Severe ocular surface disease, including limbal stem cell deficiency (LSCD) can occur as a consequence of severe atopic keratoconjunctivitis (AKC) that has been inadequately treated. Our goal was to describe the management and outcomes of severe ocular surface disease in AKC patients.We performed a retrospective analysis of a case series of 13 eyes of 8 patients with advanced ocular surface disease associated with severe AKC. The clinical presentation, medical and surgical management, and visual and anatomic outcomes were analyzed.Five eyes were treated with medical interventions alone, which included topical or systemic immunomodulatory therapy (IMT) for all eyes. These eyes had a decline in mean visual acuity from LogMAR 0.96 to 2.04 between the initial and final visits related to recurrent epithelial defects or corneal ulceration. Eight eyes were treated with surgical approaches in addition to medical treatment. Initial surgical treatments included limbal stem cell transplantation (n = 5), Boston keratoprosthesis (n = 2), and superficial keratectomy (n = 1). Both eyes that underwent primary keratoprosthesis had severe post-operative complications and became no light perception. In the remainder of the surgically treated eyes, there was an improvement visual acuity from LogMAR 1.43 to 0.6 between the pre-operative and final post-operative visit.Visual rehabilitation in eyes severe ocular surface disease due to prolonged AKC is challenging. While some patients did experience improved vision, most eyes did not improve or experienced severe complications with vision loss. Early intervention with immunomodulatory therapy may prevent progression of the disease to advanced stages.
2017-09-11 | Resolvin D1 Increases Mucin Secretion in Cultured Rat Conjunctival Goblet Cells via Multiple Signaling Pathways
Goblet cells in the conjunctiva secrete mucin into the tear film protecting the ocular surface. The proresolution mediator resolvin D1 (RvD1) regulates mucin secretion to maintain homeostasis during physiological conditions and in addition, actively terminates inflammation. We determined the signaling mechanisms used by RvD1 in cultured rat conjunctival goblet cells to increase intracellular [Ca2+] ([Ca2+]i) and induce glycoconjugate secretion.Increase in [Ca2+]i were measured using fura 2/AM and glycoconjugate secretion determined using an enzyme-linked lectin assay with the lectin Ulex Europaeus Agglutinin 1. Signaling pathways activated by RvD1 were studied after goblet cells were pretreated with signaling pathway inhibitors before stimulation with RvD1. The results were compared with results when goblet cells were stimulated with RvD1 alone and percent inhibition calculated.The increase in [Ca2+]i stimulated by RvD1 was blocked by inhibitors to phospholipases (PL-) -D, -C, -A2, protein kinase C (PKC), extracellular signal-regulated kinases (ERK)1/2 and Ca2+/calmodulin-dependent kinase (Ca2+/CamK). Glycoconjugate secretion was significantly inhibited by PLD, -C, -A2, ERK1/2 and Ca2+/CamK, but not PKC.We conclude that RvD1 increases glycoconjugate secretion from goblet cells via multiple signaling pathways including PLC, PLD, and PLA2, as well as their signaling components ERK1/2 and Ca2+/CamK to preserve the mucous layer and maintain homeostasis by protecting the eye from desiccating stress, allergens, and pathogens.
cell therapies
2025-08-06 | Emerging concepts in atopic dermatitis and atopic keratoconjunctivitis.
Atopic dermatitis (AD) is a chronic inflammatory skin disease involving Th2 cytokine-driven inflammation. AD patients are at risk of developing conjunctivitis, including atopic keratoconjunctivitis (AKC), a sight-threatening chronic allergic eye disease involving both Th2 and Th1/17 cytokine-driven inflammation.In AD, dupilumab is highly effective by inhibiting interleukin (IL)-4 and IL-13. However, some AD patients develop dupilumab-associated ocular surface disease (DAOSD), an AKC-like disease. There are no biomarkers to predict who will develop DAOSD. The purpose of this review is to highlight recent findings in AD and AKC suggesting different immunopathogenic mechanisms are involved. A recent proteomics study of tear fluids identified raised inflammatory markers ( n = 31) in AD patients with DAOSD ( n = 22) and a shift towards a Th1/17 profile. Alternative biologics have been investigated for treating moderate-to-severe AD which have fewer ocular side-effects. The inhibitory effects of dupilumab cause an associated upregulation of IL-33 which could lead to an AKC-like disease. A recent therapeutic approach in AD via regulatory T cells suggests a novel treatment for those at risk of DAOSD. Ocular side-effects of dupilumab suggest that the immunopathogenic pathways in moderate-to-severe AD and AKC are not the same and, for DAOSD, might require different treatment approaches.
2025-07-25 | Shield ulcer in keratoconus in the absence of atopic or vernal kerato-conjunctivitis.
Corneal shield ulcer is a severe complication of atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC). This condition is caused by the mechanical irritation of the corneal epithelium due to giant papillae and toxic epitheliopathy resulting from inflammatory mediators. To date, there have been no reported cases of corneal shield ulcers in the literature without AKC or VKC. However, the authors have reported a unique case of shield ulcer in a patient with keratoconus but no history of AKC or VKC. The cause is hypothesised to be due to mechanical friction between the corneal steep apex and palpebral conjunctiva. Additionally, a new technique, the use of a dry amniotic membrane, is described to manage the persistent epithelial defect in shield ulcers.
2023-10-02 | Subconjunctival injection of human umbilical cord mesenchymal stem cells alleviates experimental allergic conjunctivitis via regulating T cell response
T helper 2 (Th2) cells are thought to play critical roles in allergic conjunctivitis (AC). They release inflammatory cytokines to promote an allergic response in AC. Due to individual heterogeneity and long-term chronic management, current therapies do not always effectively control AC. Mesenchymal stem cells (MSCs) have been shown to be effective in treating allergy-related disorders, but it is unclear how exactly the Th2-mediated allergic response is attenuated. This study aims to elucidate the therapeutic effect and mechanism of the human umbilical cord MSCs (hUCMSCs) in a mouse model of experimental AC (EAC).A mouse EAC model was established by inoculating short ragweed (SRW) pollen. After the SRW pollen challenge, the mice received a single subconjunctival or tail vein injection of 2 × 106 hUCMSCs, or subconjunctival injection of hUCMSCs conditioned medium (hUCMSC-CM), and dexamethasone eye drops was used as positive control; subsequent scratching behavior and clinical symptoms were assessed. Immunostaining and flow cytometry were carried out to show allergic reactions and the activation of CD4 + T cell subsets in the conjunctiva and cervical lymph nodes (CLNs). Gene expression was determined by RNA-seq and further verified by qRT-PCR and Western blot. Co-culture assays were performed to explore the regulatory role of hUCMSCs in the differentiation of CD4 + naive T cells (Th0) into Th2 cells.Subconjunctival administration of hUCMSCs resulted in fewer instances of scratching and lower inflammation scores in EAC mice compared to the tail vein delivery, hUCMSC-CM and control groups. Subconjunctival administration of hUCMSCs reduced the number of activated mast cells and infiltrated eosinophils in the conjunctiva, as well as decreased the number of Th2 cells in CLNs. After pretreatment with EAC mouse serum in vitro to mimic the in vivo milieu, hUCMSCs were able to inhibit the differentiation of Th0 into Th2 cells. Further evidence demonstrated that repression of Th2 cell differentiation by hUCMSCs is mediated by CRISPLD2 through downregulation of STAT6 phosphorylation. Additionally, hUMCSCs were able to promote the differentiation of Th0 cells into regulatory T cells in CLNs of EAC mice.Subconjunctival injection of hUCMSCs suppressed the Th2-allergic response and alleviated clinical symptoms. This study provides not only a potential therapeutic target for the treatment of AC but also other T cell-mediated diseases.
2015-08-08 | Linking immune responses with fibrosis in allergic eye disease
Purpose of review Here, we explore an emerging theme in the literature, which is the role of dendritic cells in the causation of fibrosis. To fully appreciate this pathway to disease, we also review the most recent literature regarding dendritic cell biology as it pertains to ocular surface tissues. On the basis of this information, we propose a unifying hypothesis for how dendritic cells may cause conjunctival fibrosis in the allergy setting. Recent findings Work in models of airway remodeling and liver fibrosis has pointed to a potentially central role for dendritic cells in the pathobiology of fibrosis. Indeed, these cells are recognized as the most potent antigen-presenting cells, and as such activate T lymphocytes that are profibrotic under certain conditions. However, recent findings suggest a more direct role for dendritic cells, which opens up the possibility that a similar pathway may be relevant in the causation of conjunctival fibrosis, particularly in allergic eye disease. Summary Conjunctival fibrosis is a serious clinical concern and is associated with chronic inflammation of the ocular surface tissue, such as in allergic eye disease. Dendritic cells are required in mediating allergic disease by activating pathologic T lymphocytes. Recent findings pointing to a central role for dendritic cell in fibrosis may, however, mean that these cells could also be contributing directly to conjunctival fibrosis. If so, furthering our understanding of dendritic cells could lead to the identification of novel and more effective therapeutic strategies to treat this disease.
2015-08-01 | Culture medium from TNF-α–stimulated mesenchymal stem cells attenuates allergic conjunctivitis through multiple antiallergic mechanisms
BackgroundThe immunomodulatory and anti-inflammatory functions of mesenchymal stem cells (MSCs) have been demonstrated in several autoimmune/inflammatory diseases, but their contribution to allergic conjunctivitis and underlying antiallergic mechanisms remain elusive.ObjectiveWe sought to explore the clinical application of MSCs to experimental allergic conjunctivitis (EAC) and its underlying antiallergic mechanisms.MethodsCulture medium from TNF-α–stimulated, bone marrow–derived MSCs (MSC-CMT) was administered topically to mice with EAC, and the related allergic symptoms and biological changes were evaluated. Murine spleen-derived B cells, bone marrow–derived mast cells (MCs), and lung vascular endothelial cells were cultured in vitro to investigate the antiallergic MSC-CMT mechanisms.ResultsTopical instillation of MSC-CMT significantly attenuated the clinical symptoms of short ragweed pollen–induced EAC, with a significant decrease in inflammatory cell frequency, nuclear factor κB p65 expression, and TNF-α and IL-4 production. In vitro MSC-CMT significantly inhibited the activation of MCs and B-cell IgE release and reduced histamine-induced vascular hyperpermeability. During EAC, MSC-CMT treatment also decreased IgE production, histamine release, enrichment and activation of MCs, and conjunctival vascular hyperpermeability. The MSC-CMT–mediated inhibition of B cells, MCs, and histamine and its antiallergic effects during EAC were abrogated when MSCs were pretreated with COX2 small interfering RNA.ConclusionsOur findings provide compelling evidence that MSC-CMT inhibits EAC through COX2-dependent multiple antiallergic mechanisms and support the use of MSC-CMT as a novel strategy for treating allergic conjunctivitis. The immunomodulatory and anti-inflammatory functions of mesenchymal stem cells (MSCs) have been demonstrated in several autoimmune/inflammatory diseases, but their contribution to allergic conjunctivitis and underlying antiallergic mechanisms remain elusive. We sought to explore the clinical application of MSCs to experimental allergic conjunctivitis (EAC) and its underlying antiallergic mechanisms. Culture medium from TNF-α–stimulated, bone marrow–derived MSCs (MSC-CMT) was administered topically to mice with EAC, and the related allergic symptoms and biological changes were evaluated. Murine spleen-derived B cells, bone marrow–derived mast cells (MCs), and lung vascular endothelial cells were cultured in vitro to investigate the antiallergic MSC-CMT mechanisms. Topical instillation of MSC-CMT significantly attenuated the clinical symptoms of short ragweed pollen–induced EAC, with a significant decrease in inflammatory cell frequency, nuclear factor κB p65 expression, and TNF-α and IL-4 production. In vitro MSC-CMT significantly inhibited the activation of MCs and B-cell IgE release and reduced histamine-induced vascular hyperpermeability. During EAC, MSC-CMT treatment also decreased IgE production, histamine release, enrichment and activation of MCs, and conjunctival vascular hyperpermeability. The MSC-CMT–mediated inhibition of B cells, MCs, and histamine and its antiallergic effects during EAC were abrogated when MSCs were pretreated with COX2 small interfering RNA. Our findings provide compelling evidence that MSC-CMT inhibits EAC through COX2-dependent multiple antiallergic mechanisms and support the use of MSC-CMT as a novel strategy for treating allergic conjunctivitis.
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Drug Discovery Landscape
2 orphan drug designations for Atopic keratoconjunctivitis.
2 orphan drug designations for Atopic keratoconjunctivitis.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Ciclosporin (eye drops, solution) | small molecules | EMA | Allergan Pharmaceuticals Ireland | |
Ciclosporin [Restasis] | small molecules | EMA | Allergan Pharmaceuticals Ireland |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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