Treatment of Idiopathic Inflammatory Orbital Syndrome (IOIS) With Prominent Lacrimal Gland Involvement Using Oral Non-Steroidal Anti-Inflammatory Drugs (NSAIDs).

Idiopathic orbital inflammatory syndrome (IOIS) is a chronic inflammatory process of unknown etiology, which can either be localized or diffuse. In cases where there is isolated inflammation of the lacrimal gland, it is known as dacryoadenitis. This study focuses on the treatment of a patient with IOIS with prominent lacrimal gland involvement. The mainstay of treatment for idiopathic isolated dacryoadenitis is oral corticosteroids, but non-steroidal anti-inflammatory drug (NSAIDs) is known to be effective in treating idiopathic dacryoadenitis as well. There is no formal study yet to evaluate the use of NSAIDs in treating idiopathic dacryoadenitis. Here, we report a case of idiopathic isolated dacryoadenitis which was successfully treated with NSAIDs.

Immune checkpoint inhibitors and the orbit; two cases of reactive dacryoadenitis.

Immune checkpoints refer to mechanisms entrusted with the modulation of immune responses in peripheral tissues and are required for minimising collateral damage. Immune checkpoint inhibitors (ICPi) work through numerous pathways, including the anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), anti-PD-1 (programmed cell death protein 1) and the PD-L1 (protein cell death protein-ligand-1) pathways. They are proving to be an exciting therapeutic avenue in the attempt to activate anti-tumour activity. Ipilimumab is a fully human monoclonal antibody working on the anti-CTLA-4 pathway, while nivolumab and pembrolizumab are humanised monoclonal IgG4 antibodies that work on the PD-1 pathway. Despite a growing body of research pertinent to these novel therapies, early indications show that they are limited by their side effect profile. Furthermore, their efficacy appears to be greater in cancers with a high mutational burden. We present two female patients with bilateral reactive dacryoadenitis secondary to ICPi therapy, a finding that to the best of our knowledge was not previously described in the literature.

Dacryoadenitis: do not forget ANCA vasculitis.

Objective: This paper aimed to describe another form of aggressive limited Granulomatosis with polyangiitis (GPA) revealed by dacryoadenitis. Methods and results: We report an unusually limited GPA in a 48-year-old man presenting with bilateral proptosis. She had never presented kidney or pulmonary manifestations, but her disease was persistently active including oto-rhino-laryngological manifestations, dacryoadenitis, and neurological manifestations unresponsive to corticosteroids and immunosuppressors. Discussion: Granulomatosis with polyangiitis (GPA) is an auto-immune inflammatory vasculitis. Involvement of lacrimal glands as the first presentation is uncommon. It is characterized by the development of granulomas. Patients with orbital mass without lacrimal gland involvement have a higher rate of systemic disease, a severe clinical course, and a higher rate of recurrences. A patient with dacryoadenitis seems to be with a good prognosis. Eye manifestations were significantly more common in patients with pachymeningitis. MPO-ANCA-positive pachymeningitis was more frequent in older female patients. PR3-ANCA-positive pachymeningitis had more severe neurological damage. Induction treatment consists of intravenous methylprednisolone (IV) associated with cyclophosphamide. Conclusion: Faced with dacryoadenitis, it is important to screen for ANCA-associated vasculitis. Abbreviations: GPA = Granulomatosis with polyangiitis, ANCA = Antineutrophil Cytoplasmic Antibodies.

Treatment Outcomes of Patients with Orbital Inflammatory Diseases: Should Steroids Still Be the First Choice?

Objective: To clarify the therapy response in orbital inflammatory diseases (OID), we analyzed the treatment effects of steroid therapy, the use of disease-modifying antirheumatic drugs (DMARDS), and biologicals in our tertiary referral center cohort. Methods: We collected the clinical and demographic data of all patients treated for non-specific orbital inflammation (NSOI) (n = 111) and IgG4-ROD (n = 13), respectively at our center from 2008 to 2020 and analyzed them with descriptive statistics. NSOI were sub-grouped according to the location into either idiopathic dacryoadenitis (DAs) (n = 78) or typical idiopathic orbital myositis (n = 32). Results: Mean age at first clinical manifestation was significantly different between subgroups (IOI: 49.5 ± 18, IgG4-ROD: 63.2 ± 14, p = 0.0171). Among all examined OID, 63 patients (50%) achieved full remission (FR) with corticosteroids (NSOI 53%/IgG4-ROD 31%). In contrast, classic myositis showed a significantly higher response (76%). Disease-modifying drugs (DMARDS) for myositis accomplished only 33% FR (NSOI 57%) and 66% did not respond sufficiently (NSOI 43%). The biologic agent (Rituximab) was significantly more efficient: 19 of 23 patients (82%) achieved full remission and only 4 (17%) did not respond fully and needed orbital irradiation or orbital decompressive surgery.

AS101 regulates the Teff/Treg balance to alleviate rabbit autoimmune dacryoadenitis through modulating NFATc2.

Sjögren's syndrome (SS) dry eye can cause ocular surface inflammation and lacrimal gland (LG) damage, leading to discomfort and potential vision problems. The existing treatment options for SS dry eye are currently constrained. We investigated the possible therapeutic effect and the underlying mechanism of AS101 in autoimmune dry eye. AS101 was injected subconjunctivally into a rabbit model of autoimmune dacryoadenitis and its therapeutic effects were determined by evaluating clinical and histological scores. The expressions of effector T cells (Teff)/regulatory T cells (Treg)-related transcription factors and cytokines, inflammation mediators, and transcription factor NFATc2 were measured by quantitative real-time PCR and/or Western blot both in vivo and in vitro. Additionally, the role of NFATc2 in the immunomodulatory effects of AS101 on T cells was explored by co-culturing activated peripheral blood lymphocytes (PBLs) transfected with NFATc2 overexpression lentiviral plasmid with AS101. AS101 treatment potently ameliorated the clinical severity and reduced the inflammation of LG. Further investigation revealed that AS101 treatment led to decreased expression of Th1-related genes (T-bet and IFN-γ) and Th17-related genes (RORC, IL-17A, IL-17F, and GM-CSF) and increased expression of Treg-related gene Foxp3 in vivo and in vitro. Meanwhile, AS101 suppressed the expression of TNF-α, IL-1ß, IL-23, IL-6, MMP-2, and MMP-9. Mechanistically, AS101 downregulated the expression of NFATc2 in inflamed LGs. Overexpression of NFATc2 in activated PBLs partially blunted the effect of AS101 on Teff suppression and Treg promotion. In conclusion, AS101 is a potential regulator of Teff/Treg cell balance and could be an effective treatment agent for SS dry eye.

Gonococcal dacryoadenitis complicated by orbital cellulitis: a case report.

Gonococcal dacryoadenitis is uncommon, and its diagnosis may be delayed especially if there is a low index of clinical suspicion. Making an early diagnosis is extremely important because in some cases the organism may spread contiguously, leading to vision-threatening sequelae such as corneal perforation. The authors present a case report of a patient diagnosed with gonococcal dacryoadenitis complicated by orbital cellulitis. Our case demonstrates that in all cases of purulent dacryoadenitis, urgent evaluation, cultures and treatment is crucial, and it is prudent to consider gonococcal dacryoadenitis as a rare but possible differential in patients who are sexually active with an unexplained cause for dacryoadenitis.

[Cell technologies as a basis for the development of regenerative principles for the treatment of lacrimal gland diseases]. / Kletochnye tekhnologii kak osnova razrabotki regeneratornykh printsipov lecheniya zabolevanii sleznoi zhelezy.

The lacrimal gland (LG) is a tubuloacinar exocrine gland composed of acinar, ductal, and myoepithelial cells. Three-dimensional distribution of acinar lobules, ducts, and myoepithelial cells is necessary for the effective functioning of the organ. LG is the main organ of immune surveillance of the ocular surface system. The embryogenesis of the gland is regulated by the interaction of genetic mechanisms, internal epigenetic (enzyme systems, hormones) and exogenous factors. There is no doubt that there is a clear genetic program for the implementation of the complex process of embryonic development. The mechanisms regulating LG organogenesis initiate the work of a huge number of structural oncogenes, transcription and growth factors, etc. Studying the expression and selective activity of regulatory genes during organ development, their participation in the differentiation of different cell types is a current trend at the nexus of clinical genetics, molecular biology, embryology and immunocytochemistry. Due to its relatively simple structure and accessibility, human LG is a suitable object for potential application in regenerative medicine. Development of a universal protocol for obtaining functional differentiated secretory epithelium of LG capable of expressing tissue-specific markers is an urgent task. Determining the nature and origin of stem cells and progenitor cells will allow the isolation and multiplication of these cells in culture. After obtaining a functionally active culture of LG cells, it is possible to create a model of autoimmune diseases.

Medication-associated orbital inflammation: A systematic review.

We performed a comprehensive systematic review to identify medication-associated orbital inflammation and to characterize its clinico-radiological features. We reviewed English-language articles describing medication-associated orbital inflammation (i.e., orbital myositis, dacryoadenitis and orbital fat) published to June, 2023. Isolated inflammation of the intraocular structures or globe alone (i.e. uveitis, scleritis, optic neuritis and perineuritis) were excluded. In medication-associated orbital inflammation, the extraocular muscles are preferentially affected, occurring in isolation or in combination with other orbital and/or intraocular structures. Clinico-radiological manifestations may be non-specific; however, certain medications may be distinguished according to the presence of systemic prodrome, laterality, associated intraocular inflammation, and predisposition to involve certain orbital structures. Rapid identification, discontinuation of the provoking medication, and systemic corticosteroid therapy (if appropriate) typically achieves a favorable visual prognosis. As new medications become adopted by clinicians, rare adverse effects will be further delineated.Medication-associated orbital inflammation is an important diagnostic consideration in orbital inflammatory disease. A careful medication history and clinical assessment may be revealing, permitting timely discontinuation of the offending agent and initiation of appropriate management.

IgG4-related disease: an update on pathology and diagnostic criteria with a focus on salivary gland manifestations.

Immunoglobulin G4-related disease (IgG4-RD) is a multi-organ disorder characterized by a highly variable clinical presentation depending on the affected organ/s, extent of tumefactive fibroinflammatory lesions, and associated functional impairment. The disease pursues a chronic, relapsing, often asymptomatic course and hence may pose a significant diagnostic challenge. Diagnostic delay can lead to progressive fibrosis and irreversible organ damage resulting into significant morbidity and even mortality. Given its broad clinical spectrum, physicians of all specialties may be the first clinicians facing this diagnostic challenge. Outside the pancreatobiliary system, the head and neck represents the major site of IgG4-RD with variable organ-specific diffuse or mass-forming lesions. In up to 75% of cases, elevated serum IgG4 levels are observed, but this figure possibly underestimates the fraction of seronegative cases, as the disease manifestations may present metachronously with significant intervals. Together with negative serology, this can lead to misdiagnosis of seronegative cases. A standardized nomenclature and diagnostic criteria for IgG4-RD were established in 2012 and revised in 2020 facilitating scientific research and expanding the range of diseases associated with IgG4 abnormalities. In addition to orbital pseudotumor, dacryoadenitis, Riedel thyroiditis, sinonasal manifestations, and rare miscellaneous conditions, IgG4-related sialadenitis is one of the most frequent presentations in the head and neck region. However, controversy still exists regarding the relationship between sialadenitis and IgG4-RD. This review focuses on the clinicopathological features of IgG4-related sialadenitis and its contemporary diagnostic criteria.

Immunoglobulin G4-related Dacryoadenitis Successfully Treated with Baricitinib.

A 48-year-old woman visited our hospital because of bilateral lacrimal gland enlargement. Her serum immunoglobulin G4 (IgG4) level was high, and positron emission tomography-computed tomography showed significant positive findings in the bilateral lacrimal gland. A biopsy revealed a considerable increase in IgG4/CD138, leading to a diagnosis of IgG4-related dacryoadenitis. The disease did not respond to steroid therapy, so treatment was started with baricitinib because of exacerbation of the original atopic dermatitis and dacryoadenitis after the second dose of the coronavirus disease 2019 (COVID-19) vaccine. Baricitinib was effective for resolving both dermatitis and dacryoadenitis, and steroids were able to be discontinued. The IgG4 level also improved.

Bilateral Dacryoadenitis As the First Presentation in an Undiagnosed Sarcoidosis Patient.

Sarcoidosis is an idiopathic multisystem disorder associated with hilar lymphadenopathy and noncaseating granulomas that can affect any organ. Ocular involvement is less common; however, sarcoidosis is a known cause of uveitis, dry eye, and conjunctival nodules. We report a case of a 36-year-old male with an occupational history of dust exposure presenting to the ophthalmology clinic with bilateral painless upper eyelid swelling of one-week duration. The diagnosis of sarcoidosis was suspected based on clinical examination, laboratory analysis, and imaging showing mediastinal lymphadenopathy, further confirmed by pathologic examination showing noncaseating granulomas with the presence of some asteroid and Schaumann bodies. A treatment plan consisting of prednisone, folic acid, and azathioprine was effective for the patient, though azathioprine was eventually changed to methotrexate due to an allergic reaction. The patient is on a maintenance dose of methotrexate and is asymptomatic after a year of careful management and follow-up. This case emphasizes the significance of considering sarcoidosis as a differential diagnosis in patients presenting with bilateral dacryoadenitis.

Chronic bilateral dacryoadenitis caused by SARS-CoV-2 infection: a case report.

BACKGROUND: Dacryoadenitis is inflammation of the lacrimal gland, mainly caused by viral infection. It can also be caused by bacterial pathogens and non-infectious processes such as auto-immune diseases and malignancy. Chronic dacryoadenitis is rarely linked to SARS-CoV-2 infection, with only five reports in the literature. REPORT: A 26-year-old Arab woman experienced chronic inflammatory dacryoadenitis after a mild SARS-CoV-2 infection, which was successfully treated with oral prednisone. CONCLUSIONS: Dacryoadenitis can occur due to inflammation caused by either SARS-CoV-2 exposure. The treatment typically involves the administration of steroids, with duration to be decided based on clinical response.

Marginal Zone B (MZB) Cells: Comparison of the Initial Identification of Immune Activity Leading to Dacryoadenitis and Sialadenitis in Experimental Sjögren's Syndrome.

Although multiple mouse strains have been advanced as models for Sjögren's syndrome (SS), which is a human systemic autoimmune disease characterized primarily as the loss of lacrimal and salivary gland functions, the C57BL/6.NOD-Aec1Aec2 recombinant inbred (RI) mouse derived from the NOD/ShiLtJ line is considered one of the more appropriate models exhibiting virtually all the characteristics of the human disease. This mouse model, as well as other mouse models of SS, have shown that B lymphocytes are essential for the onset and development of observed clinical manifestations. Recently, studies carried out in the C57BL/6.IL14α transgenic mouse have provided clear evidence that the marginal zone B (MZB) cell population is directly involved in the early pathological events initiating the development of the clinical SS disease, as well as late-stage lymphomagenesis resulting in B-cell lymphomas. Since MZB cells are difficult to study in vivo and in vitro, we carried out a series of ex vivo investigations that utilize temporal global RNA transcriptomic analyses to profile differentially expressed genes exhibiting temporal upregulation during the initial onset and subsequent development of pathophysiological events within the lacrimal and salivary gland tissues per se or associated with the leukocyte cell migrations into these glands. The initial transcriptomic analyses revealed that while the upregulated gene expression profiles obtained from lacrimal and salivary glands overlap, multiple genetic differences exist between the defined activated pathways. In the current study, we present a concept suggesting that the initial pathological events differ between the two glands, yet the subsequent upregulated TLR4/TLR3 signal transduction pathway that activates the type-1 interferon signature appears to be identical in the two glands and indicates an autoimmune response against dsRNA, possibly a virus. Here, we attempt to put these findings into perspective and determine how they can impact the design of future therapeutic protocols.

Dacryoadenitis post COVID-19 infection and immunization.

Dacryoadenitis can be a rare presentation following COVID-19 infection or can be an immunological response post COVID-19 vaccination. Herein we report two cases of lacrimal gland involvement, one post COVID-19 infection, and the other post COVID-19 vaccination. A definitive causal relationship, however, remains uncertain.

Eyelid Edema May Be as a Sign of Dacryoadenitis in the Course of Epstein-Barr Virus Infectious Mononucleosis.

Epstein-Barr virus (EBV) is a widespread virus that causes frequent, in many cases asymptomatic, infections. Mononucleosis is the most frequent clinical syndrome encountered during EBV infection. In rare cases, the disease can present at the onset with atypical signs that make an immediate diagnostic classification difficult. An example in this sense is the onset of dacryoadenitis with consequent eyelid edema. In these cases, it is difficult to immediately recognize this sign as referable to mononucleosis and it appears necessary to carry out a series of analyses aimed at excluding any other edematous causes. We describe below a clinical case of dacryoadenitis in the course of infectious mononucleosis and a review of similar cases described in the literature starting from 1952 (the year in which this sign was described for the first time). We counted 28 cases before ours, thus confirming the exceptional nature of this event.

Bilateral Eyelid Edema in a Pediatric Patient With COVID-19: A Case Report and Literature Review.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is primarily transmitted through the eyes, nose, or mouth. Ophthalmic complications, such as conjunctivitis and dacryoadenitis, have been reported in patients with coronavirus disease 19 (COVID-19). We report the case of an early adolescent girl who presented with bilateral urticarial rashes, eyelid edema, fever, and cough. She was diagnosed with acute dacryoadenitis with SARS-CoV-2 infection confirmed by a nasopharyngeal polymerase chain reaction and clinical investigations. The patient was treated with dexamethasone (3 mg daily) for three days, which resulted in the resolution of fever and urticarial rash, and improvement of eyelid edema. While bilateral upper eyelid edema and acute dacryoadenitis commonly occur in pediatric patients due to Epstein-Barr virus (EBV) infection and Kawasaki disease, they are rarely associated with other diseases. However, ocular symptoms have been reported in 11.4% of patients with COVID-19. In addition, eyelid edema and acute dacryoadenitis have also been reported after COVID-19 messenger RNA (mRNA) vaccination. The underlying mechanisms of these complications are not yet completely understood. Our case highlights the possibility of bilateral eyelid edema in children with COVID-19, which can occur in addition to other viral infections such as EBV.

[The role of miRNA in the pathogenesis of diseases associated with functional dysregulation of the lacrimal gland]. / Rol' mikroRNK v patogeneze zabolevanii, svyazannykh s narusheniem funktsii sleznoi zhelezy.

At this time, the mechanism causing lacrimal gland dysfunction is not understood completely. In diseases associated with lacrimal gland involvement (Sjogren's syndrome, sarcoidosis, IgG4-associated disease, etc.) patients have been observed to experience elevated cellular apoptosis, active production of autoantibodies to glandular tissue, increased level of pro-inflammatory cytokines, functional disruption of signaling molecules leading to changes in tear production. Difficulties in differential diagnosis of lacrimal gland dysfunction in above-listed diseases are associated, on the one hand, with similarity of the clinical picture of ophthalmological manifestations, and on the other hand - with complicated morphological interpretation of changes in the glandular tissues. In this view, miRNA is a promising diagnostic and prognostic marker that would help with differential diagnosis as well as with choosing the treatment tactics. Methods of molecular profiling and identification of "molecular phenotypes" of lacrimal gland and ocular surface damage will allow the use of miRNA as biomarkers and prognostic factors for personalized treatment.

A Case of Herpes Zoster Ophthalmicus With Multiple Delayed Ocular Complications.

Herpes zoster ophthalmicus (HZO) presents a variety of ocular complications, most of which occur simultaneously as skin lesions. We report a case of HZO with delayed onset of multiple ocular complications. A 72-year-old man developed HZO, blepharitis, iritis, and conjunctivitis in the left eye, which resolved after topical ocular treatment and systemic acyclovir administration. However, six weeks after the first onset of the rash, the patient came to our hospital because of recurrent blepharitis, iritis, scleritis, conjunctivitis, eye pain, ptosis, and blurred vision in the left eye. Best corrected visual acuity (BCVA) in the left eye had decreased to hand motion, and the Goldmann visual field test showed only mild residual peripheral vision on the lateral side. Intraocular pressure showed 25 mmHg in the left eye and inflammation in the anterior chamber with paralytic mydriasis. Orbital magnetic resonance imaging (MRI) showed the contrast effects with the lacrimal gland, superior ophthalmic vein, supraorbital nerve, optic nerve, and around optic nerve sheath. The patient was diagnosed with optic neuritis, optic perineuritis, ptosis, paralytic mydriasis, trigeminal neuralgia, lacrimal gland inflammation, blepharitis, iritis, scleritis, and ocular hypertension after HZO, and three courses of steroid pulse therapy were administered. Thereafter, BCVA improved to 0.3 in the left eye, with improvement in central vision, and MRI lesions and other symptoms also improved. The patient has had no complications or recurrence of HZO. HZO can cause a variety of ocular complications. Since autoimmune mechanisms might be involved, combined immunotherapy should be considered.