The 2023 revised diagnostic criteria for IgG4-related ophthalmic disease.

Immunoglobulin G4 (IgG4)-related disease is a clinical entity characterized by elevated serum IgG4 concentrations and infiltration of IgG4-immunopositive plasmacytes in various organs, including ophthalmic lesions. Diagnostic criteria for IgG4-related ophthalmic disease (IgG4-ROD) were established in 2014 and describe the most affected ocular adnexal tissues such as lacrimal glands, trigeminal nerves and extraocular muscles, but do not mention optic neuropathy, the most severe indication of ophthalmic lesions. We reviewed published case reports of optic neuropathy in IgG4-related disease (n = 44), and in many cases, decreased visual acuities recovered well following treatment such as systemic corticosteroids, rituximab, and orbital surgery. However, some patients did not recover, especially when pretreatment visual acuities were as low as light perception or less. Herein, we propose a 2023 revised diagnostic criteria for IgG4-ROD, which include a reminder not to overlook optic neuropathy. The 2014 diagnostic criteria specify mucosa-associated lymphoid tissue (MALT) lymphoma as an important differential diagnosis for the relationship between IgG4-ROD and orbital lymphoma. The 2023 revision directs physicians' attention toward lymphomas other than MALT lymphoma, considering that the 2014 criteria might have placed too much emphasis on MALT lymphoma.

Artificial intelligence-based differential diagnosis of orbital MALT lymphoma and IgG4 related ophthalmic disease using hematoxylin-eosin images.

PURPOSE: To investigate the possibility of distinguishing between IgG4-related ophthalmic disease (IgG4-ROD) and orbital MALT lymphoma using artificial intelligence (AI) and hematoxylin-eosin (HE) images. METHODS: After identifying a total of 127 patients from whom we were able to procure tissue blocks with IgG4-ROD and orbital MALT lymphoma, we performed histological and molecular genetic analyses, such as gene rearrangement. Subsequently, pathological HE images were collected from these patients followed by the cutting out of 10 different image patches from the HE image of each patient. A total of 970 image patches from the 97 patients were used to construct nine different models of deep learning, and the 300 image patches from the remaining 30 patients were used to evaluate the diagnostic performance of the models. Area under the curve (AUC) and accuracy (ACC) were used for the performance evaluation of the deep learning models. In addition, four ophthalmologists performed the binary classification between IgG4-ROD and orbital MALT lymphoma. RESULTS: EVA, which is a vision-centric foundation model to explore the limits of visual representation, was the best deep learning model among the nine models. The results of EVA were ACC = 73.3% and AUC = 0.807. The ACC of the four ophthalmologists ranged from 40 to 60%. CONCLUSIONS: It was possible to construct an AI software based on deep learning that was able to distinguish between IgG4-ROD and orbital MALT. This AI model may be useful as an initial screening tool to direct further ancillary investigations.

Stromal area differences with epithelial-mesenchymal transition gene changes in conjunctival and orbital mucosa-associated lymphoid tissue lymphoma.

Purpose: To examine the molecular biological differences between conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma and orbital MALT lymphoma in ocular adnexa lymphoma. Methods: Observational case series. A total of 129 consecutive, randomized cases of ocular adnexa MALT lymphoma diagnosed histopathologically between 2008 and 2020.Total RNA was extracted from formalin-fixed paraffin-embedded tissue from ocular adnexa MALT lymphoma, and RNA-sequencing was performed. Orbital MALT lymphoma gene expression was compared with that of conjunctival MALT lymphoma. Gene set (GS) analysis detecting for gene set cluster was performed in RNA-sequence. Related proteins were further examined by immunohistochemical staining. In addition, artificial segmentation image used to count stromal area in HE images. Results: GS analysis showed differences in expression in 29 GS types in primary orbital MALT lymphoma (N=5,5, FDR q-value <0.25). The GS with the greatest difference in expression was the GS of epithelial-mesenchymal transition (EMT). Based on this GS change, immunohistochemical staining was added using E-cadherin as an epithelial marker and vimentin as a mesenchymal marker for EMT. There was significant staining of vimentin in orbital lymphoma (P<0.01, N=129) and of E-cadherin in conjunctival lesions (P=0.023, N=129). Vimentin staining correlated with Ann Arbor staging (1 versus >1) independent of age and sex on multivariate analysis (P=0.004). Stroma area in tumor were significant difference(P<0.01). Conclusion: GS changes including EMT and stromal area in tumor were used to demonstrate the molecular biological differences between conjunctival MALT lymphoma and orbital MALT lymphoma in ocular adnexa lymphomas.

Machine Learning Model with Texture Analysis for Automatic Classification of Histopathological Images of Ocular Adnexal Mucosa-associated Lymphoid Tissue Lymphoma of Two Different Origins.

PURPOSE: The purpose of this study was to develop artificial intelligence algorithms that can distinguish between orbital and conjunctival mucosa-associated lymphoid tissue (MALT) lymphomas in pathological images. METHODS: Tissue blocks with residual MALT lymphoma and data from histological and flow cytometric studies and molecular genetic analyses such as gene rearrangement were procured for 129 patients treated between April 2008 and April 2020. We collected pathological hematoxylin and eosin-stained (HE) images of lymphoma from these patients and cropped 10 different image patches at a resolution of 2048 × 2048 from pathological images from each patient. A total of 990 images from 99 patients were used to create and evaluate machine-learning models. Each image patch of three different magnification rates at ×4, ×20, and ×40 underwent texture analysis to extract features, and then seven different machine-learning algorithms were applied to the results to create models. Cross-validation on a patient-by-patient basis was used to create and evaluate models, and then 300 images from the remaining 30 cases were used to evaluate the average accuracy rate. RESULTS: Ten-fold cross-validation using the support vector machine with linear kernel algorithm was identified as the best algorithm for discriminating between conjunctival mucosa-associated lymphoid tissue and orbital MALT lymphomas, with an average accuracy rate under cross-validation of 85%. There were ×20 magnification HE images that were more accurate in distinguishing orbital and conjunctival MALT lymphomas among ×4, ×20, and ×40. CONCLUSION: Artificial intelligence algorithms can successfully distinguish HE images between orbital and conjunctival MALT lymphomas.

Relationship between Vitreous IL-6 Levels, Gender Differences and C-Reactive Protein (CRP) in a Blood Sample of Posterior Uveitis.

This study retrospectively determined the relationship between vitreous IL-6 levels and clinical and laboratory data collected from uveitis patients. We examined an unknown cause of posterior uveitis, collecting vitreous fluid to investigate vitreous IL-6 levels. The samples were analyzed in consideration of clinical and laboratory factors, such as the male/female ratio. The present study included 82 eyes from 77 patients with a mean age of 66.20 ± 15.41 years. The IL-6 concentrations of the vitreous specimens were 6255.0 ± 14,108.3 pg/mL in males and 277.6 ± 746.3 pg/mL in females, which was found to be a statistically significant difference (p = 0.048) (n = 82). There was also a statistically significant correlation between vitreous IL-6 concentrations, serum C-reactive protein (CRP) value and white blood cell counts (WBCs) (n = 82). In multivariate analysis, vitreous IL-6 levels were significantly correlated with gender and CRP in all cases (p = 0.048 and p < 0.01, respectively) and were also significantly correlated with CRP in non-infectious uveitis (p < 0.01). In infectious uveitis, there were no significant differences between IL-6 level and several variables. Vitreous IL-6 concentrations were higher in males than in females in all cases. In non-infectious uveitis, vitreous IL-6 levels were correlated with serum CRP. These results might suggest that intraocular IL-6 levels depend on gender differences in posterior uveitis, and intraocular IL-6 levels in non-infectious uveitis may reflect systemic inflammations, including increased serum CRP.

FOXP3 and CXCR4-positive regulatory T cells in the tumor stroma as indicators of tumor immunity in the conjunctival squamous cell carcinoma microenvironment.

Conjunctival squamous cell carcinoma (SCC) is the most common ocular surface neoplasia. The purpose of this retrospective study was to examine the role of regulatory T cell (Treg) activity in tumor immunity and investigate the tumor microenvironment as a new treatment focus in conjunctival SCC. Cancer progression gene array and immunohistochemical analyses of FOXP3 as a Treg marker, CD8 as a tumor-infiltrating lymphocyte marker, and CXCR4 expression on activated Tregs were conducted in a series of 31 conjunctival SCC cases. The objective was to investigate the immunoreactive response in tumor cells and stromal cells in the cancer microenvironment. The stroma ratio in tumor cells was investigated by monitoring α-smooth muscle actine (SMA) expression between carcinoma in situ (Tis) and advanced carcinoma (Tadv) (P<0.01). No significant change in PD-L1 expression was observed in this study (P = 0.15). Staining patterns of FOXP3, CD8, and CXCR4 were examined separately between tumor cells and stromal cells in SCC tumors. Differences in staining of FOXP3 in Tregs and CD8 in tumor-infiltrating lymphocytes in tumor stroma in the Tis group were observed compared with the Tadv group (each P<0.01). In addition, double immunostaining of CXCR4/FOXP3 was correlated with progression-free survival (P = 0.049). Double immunostaining of CXCR4/FOXP3 correlated with American Joint Committee on Cancer T-stage, independent of age or Ki67 index (P<0.01). Our results show that FOXP3 and the CXCR4/FOXP3 axis are important pathologic and prognostic factors of ocular surface neoplasia, including SCC. The tumor microenvironment of conjunctival SCC should be considered in the future development of treatment options.

Insights into Current Management Strategies for Dysthyroid Optic Neuropathy: A Review.

Dysthyroid optic neuropathy (DON) is a potentially sight-threatening eye disease associated with Graves' orbitopathy (GO). DON is not common in GO patients, reportedly occurring in only about 5% of patients. The pathogenesis of severe DON is considered to involve both muscular nerve strangulation and impaired blood flow. There is some objective grading of physical examination findings and the severity of GO, including a clinical activity score (CAS) and EUropean Group On Graves' Orbitopathy (EUGOGO), but no specialized protocol completely characterizes DON. Most clinicians have decided that the combination of clinical activity findings, including visual acuity, color vision, and central critical fusion frequency, and radiological findings, including magnetic resonance imaging (MRI), can be used to diagnose DON. MRI has the most useful findings, with T2-weighted and fat-suppressed images using short-tau inversion recovery (STIR) sequences enabling detection of extraocular changes including muscle and/orbital fat tissue swelling and inflammation and, therefore, disease activity. The first-choice treatment for DON is intravenous administration of steroids, with or without radiotherapy. Unfortunately, refractoriness to this medical treatment may indicate the need for immediate orbital decompression within 2 weeks. Especially in the acute phase of DON, thyroid function is often unstable, and the surgeon must always assume the risk of general anesthesia and intra- and post-operative management. In addition, there are currently many possible therapeutic options, including molecular-targeted drugs. The early introduction and combination of these immunomodulators, including Janus kinase inhibitors and insulin-like growth factor-1 receptor antibody (teprotumumab), may be effective for GO with DON. However, this is still under investigation, and the number of case reports is small. It is possible that these options could reduce systemic adverse events due to unfocused glucocorticoid administration. The pathophysiology of DON is not yet fully understood, and further studies of its treatment and long-term visual function prognosis are needed.

Multicenter, retrospective, observational study for the Treatment Pattern of systemic corticoSTERoids for relapse of non-infectious uveitis accompanying Vogt-Koyanagi-Harada disease or sarcoidosis.

PURPOSE: Non-infectious uveitis associated with Vogt-Koyanagi-Harada (VKH) disease or sarcoidosis is commonly treated with systemic corticosteroids (SCS). We assessed the use of SCS for non-infectious uveitis relapses in Japanese clinical practice. STUDY DESIGN: Multicenter, retrospective chart review (UMIN Clinical Trial Registry; UMIN000032390). METHODS: One hundred fifty-seven patients (15- ≤ 75 years; 103 VKH disease, 54 sarcoidosis) given SCS to treat a relapse of non-infectious intermediate, posterior, or panuveitis accompanying VKH disease or sarcoidosis were studied (August 2011-December 2018). SCS dose and duration, concomitant medications, subsequent relapses, and steroid-related adverse drug reactions (ADRs) were analyzed for 12 months after target relapse treatment. Relationships between background factors and total SCS dose were analyzed (logistic regression). RESULTS: Mean (± SD) total SCS dose over 12 months after target relapse treatment was 3874 ± 2775 mg, and was higher in patients with immunosuppressants than in those without (4575 mg vs 3496 mg). Immunosuppressant use was the only factor significantly associated with higher total SCS dose (p = 0.0196). Mean duration of SCS treatment for relapse was 318.7 ± 89.3 days. Only 29.3% of patients were steroid-free after 12 months; the percentage was higher in patients without immunosuppressants (36.3% vs 16.4%). Subsequent relapse was experienced by 39.5% of patients, and 13.4% had a steroid-related ADR (mostly glaucoma or diabetes). CONCLUSION: In Japanese clinical practice, many patients with recurrent uveitis accompanying VKH disease or sarcoidosis received SCS for relapse for ≥ 300 days, suggesting that reducing corticosteroids is challenging in patients with difficulty suppressing inflammation.

Clinical features and symptoms of IgG4-related ophthalmic disease: a multicenter study.

PURPOSE: The aim of this study was to elucidate the clinical features and symptoms of IgG4-related ophthalmic disease (IgG4-ROD). STUDY DESIGN: Retrospective, multicenter study. METHODS: The medical charts of 378 patients with IgG4-ROD diagnosed at 9 hospitals in Japan were reviewed. The demographic profiles, clinical findings, and ocular symptoms of the patients were analyzed. RESULTS: On the basis of the diagnostic criteria for IgG4-ROD, the diagnosis was definite in 261 patients (69%), probable in 45 patients (12%), and possible in 72 patients (19%). The patients' mean age at the time of diagnosis was 60.6 ± 13.9 years; 195 (52%) were male. The mean IgG4 serum level at the time of the initial diagnosis was 578.9 mg/dL. Imaging studies showed pathologic lesions as follows: lesions in the lacrimal glands (86%), extraocular muscles (21%), trigeminal nerve (20%), and eyelids (12%); isolated orbital mass (11%); diffuse orbital lesion (8%); lesion in the perioptic nerve (8%); and lesion in the sclera (1%). The ophthalmic symptoms included dry eye (22%), diplopia (20%), decreased vision (8%), and visual field defects (5%). IgG4-ROD with extraocular lesions was observed in 182 patients (48%). CONCLUSION: Although the lacrimal glands are well known to be the major pathologic site of IgG4-ROD, various ocular tissues can be affected and cause ophthalmic symptoms including visual loss.

Expression of thrombospondin-1 in conjunctival squamous cell carcinoma is correlated to the Ki67 index and associated with progression-free survival.

PURPOSE: Conjunctival squamous cell carcinoma (SCC) is primarily treated with surgical resection. SCC has various stages, and local recurrence is common. The purpose of this study was to investigate thrombospondin-1 expression and its association with prognosis. METHODS: In this retrospective study, a gene expression array along with immunohistochemistry were performed for the evaluation of thrombospondin-1 expression, localization, as well as Ki67 labeling cell indices in carcinoma in situ (Tis) and advanced conjunctival SCC (Tadv). The presence or absence and intensity of cytoplasmic and nuclear staining in tumor cells were also divided into groups with a score of 0-3 and semi-quantitatively analyzed to investigate intracellular staining patterns. The association between thrombospondin-1 expression and tumor progression in a series of 31 conjunctival SCCs was further investigated. RESULTS: All 31 patients in the cohort (100%) were East Asian. A simple comparison between Tis and Tadv demonstrated significant differences in expressions of 45 genes, including thrombospondin-1 (p < 0.01). In this cohort, 30/31 tumors were positive (96%) for thrombospondin-1. Furthermore, thrombospondin-1 intracellular staining pattern analysis scores were 2.12 and 0.96 for nuclear and cytoplasmic staining, respectively, with a significant difference observed between Tis and Tadv (p < 0.01). Alteration of the Ki67 labeling index was significantly correlated with that of the thrombospondin-1 cytoplasmic score (p = 0.030). Furthermore, univariate Cox regression analysis showed a significant correlation between thrombospondin-1 staining and progression-free survival (p = 0.026) and final orbital exenteration (p = 0.019). CONCLUSIONS: The present results demonstrated that thrombospondin-1 is a potential molecular target in the pathology of conjunctival SCC, in addition to serving as a prognostic factor.

Sub-Tenon Injection of Triamcinolone Acetonide for Choroidal Mass in Sarcoidosis: A Case Report.

PURPOSE: To report the clinical course of a sub-tenon injection of triamcinolone acetonide for treatment of an asymptomatic choroidal mass in sarcoidosis. METHODS: This was a retrospective, non-comparative interventional case study. RESULTS: A 36-year-old Japanese man with sarcoidosis presented with an asymptomatic choroidal mass lesion associated with subretinal fluid accumulation in his left eye, but without any other sign of intraocular inflammation in either of his eyes. He had started systemic steroid administration for thrombocytopenia 2 days prior to being examined. After a single sub-tenon injection of triamcinolone acetonide (20 mg) the subretinal fluid was completely absorbed and the choroidal granuloma began to shrink in size. After the injection, the granuloma became a scar without any complication or recurrence over the next 34 months. CONCLUSION: Sub-tenon injection of triamcinolone acetonide might be an effective treatment for choroidal granuloma in sarcoidosis.

Expression, intracellular localization, and mutation of EGFR in conjunctival squamous cell carcinoma and the association with prognosis and treatment.

PURPOSE: Conjunctival squamous cell carcinoma (SCC) is primarily treated with surgical resection. SCC has various stages, and local recurrence is common. The purpose of this study was to determine molecular localization of epidermal growth factor receptor (EGFR) and the possibility of EGFR as a biomarker for the management of conjunctival SCC. METHODS: In this retrospective study, we performed immunohistochemistry to evaluate EGFR expression and localization in tumor cells, EGFR mutation-specific expression (E746-A750del and L858R), and human papillomavirus expression in a series of 29 conjunctival SCCs. RESULTS: All 29 tumors in our cohort were EGFR positive (100%). Twenty-one of 29 tumors (72%) showed focal EGFR staining, and seven (28%) showed diffuse EGFR staining. In addition, we calculated the percentages of the two most important mutations in EGFR (exon 19 746-A750del (8/29, 27.5%), exon 21 (L858R mutant (2/29, 6.8%)) in conjunctival SCCs. We observed that the translocation of EGFR from the membrane into the cytoplasm was related to clinical prognosis, as we detected correlations between EGFR cytoplasmic staining and final orbital exenteration and between decreased EGFR membrane staining and progression-free survival. CONCLUSIONS: EGFR is important in the pathology of ocular surface squamous neoplasia including SCC and is a prognostic factor. Increased understanding of EGFR mutations may have important implications for future treatment options.

Frontal sinusitis associated with orbital decompression for Graves' orbitopathy.

Orbital decompression (OD) for Graves' orbitopathy usually includes removal of orbital medial wall. While OD occasionally cause or worsen chronic sinusitis because of the obstructed sinus drainage by prolapsed orbital fat, to date few reports have been published on the management or prevention of sinusitis associated with OD. Here, we present two patients (three sides) with newly developed and one patient (one side) with worsening obstructive frontal sinusitis following OD. These three patients had OD including the removal of the superior attachment of uncinated process to lamina papyracea. Endoscopic modified Lothrop procedure (EMLP) was useful to relieve symptoms and keep an enough access to frontal sinuses for all cases. We also performed EMLP for another two patients (four sides) with pre-existing sinusitis before OD. Worsening of sinusitis could be avoided by EMLP before OD. EMLP was useful approach for both treatment and prevention of sinusitis related to OD. The superior attachment site of uncinated process and the pattern of frontal sinus drainage might predict the occurrence of obstructive frontal sinusitis following OD.

Bilateral retinitis after influenza virus infection in a case report.

PURPOSE: To report 2 years' longitudinal retinal changes using spectral domain optical coherence tomography (SD-OCT) images in a case of retinitis after influenza virus infection. OBSERVATIONS: A 48-year-old female complained of scotoma in the central visual field after influenza virus infection. Her best visual acuity was 20/16, her fundus examination was normal, and fluorescein angiography demonstrated no evident leakage in either the retina or the optic disc. However, SD-OCT images showed a disrupted, blurred inner-segment ellipsoid zone in the macula of both eyes. Two steroid pulse therapy sessions in the first 3 months showed temporary improvement of the central scotoma. However, atrophy of the photoreceptor layer at the juxta fovea gradually progressed in OCT images during the follow-up period. In contrast, the fovea itself was mostly intact and visual acuity was maintained in the 2-year period. CONCLUSIONS AND IMPORTANCE: We experienced a unique case of retinitis after influenza infection, in whom progressive atrophy of the photoreceptor layer was observed in SD-OCT images.

Preoperative clinical factors and visual outcomes following orbital decompression with dysthyroid optic neuropathy.

BACKGROUND: To investigate preoperative clinical factors and visual outcomes of Japanese patients with dysthyroid optic neuropathy (DON) after urgent orbital decompression. METHODS: This retrospective, observational case series study investigated 44 patients who exhibited several preoperative clinical factors that might be associated with the need for urgent orbital decompression due to DON. Additionally, the visual acuity of DON patients was compared between the patients preoperatively and at 1 and 6 months postoperatively. RESULTS: All 44 patients received steroid and with or without radiation therapy, with 27 patients able to avoid undergoing urgent surgery. However, the remaining 17 patients required urgent orbital decompression following a lack of response to the therapy. None of the patients who initially avoided surgery required additional surgery for DON. Factors significantly associated with the need for urgent orbital decompression surgery included: female gender, older age, long disease duration, unilateral significant DON, history of resistance to pulsed steroid therapy, unstable thyroid function, high TRAb (Thyrotrophin receptor antibody)value, poor visual acuity, presence of central diplopia, and presence of corneal problems (P < 0.05 each). The results also showed that postoperative visual outcomes of surgery for DON were acceptable. CONCLUSION: This study revealed several preoperative clinical factors for DON that appear to be associated with the need for urgent orbital decompression surgery in Japanese patients.

Impact of Early Vitrectomy for Dense Vitreous Hemorrhage of Unknown Etiology.

BACKGROUND: Surgical intervention for dense vitreous hemorrhage (DVH) with unclear etiology is often delayed in favor of conservative follow-up despite possible disease progression and the availability of safe minimally invasive vitrectomy. OBJECTIVES: The aim of this study is to investigate the efficacy of early surgical intervention for DVH with unknown etiology. METHODS: Eighty-eight cases (88 eyes) of DVH with unknown origin were retrospectively reviewed. Inclusion criteria were as follows: (1) measured visual acuity (VA) of 20/200 or worse and (2) fundus invisibility requiring B-scan ultrasonography. Eyes with a history of diabetic retinopathy, recent trauma, or likely retinal detachment (RD) as revealed by B-scan ultrasonography were excluded. Outcome measures were a cause of vitreous hemorrhage and final VA following early (≤2 weeks after symptom onset) or delayed vitrectomy. RESULTS: The most frequently occurring causes of DVH were central or branch retinal vein occlusion (30 eyes, 34%) and retinal tear or RD (29 eyes, 33%). logMAR VA significantly improved after treatment (p < 0.001). Final VA was significantly higher for eyes treated within 2 weeks compared with eyes treated later than 2 weeks after symptom onset (p = 0.020). CONCLUSIONS: Surgical intervention within 2 weeks after symptom onset may prevent a lower visual outcome.

Long-term efficacy and safety of infliximab and cyclosporine combination therapy for refractory uveoretinitis in Behçet's disease.

PURPOSE: This study aimed to evaluate the long-term efficacy and safety of infliximab (IFX) and cyclosporine (CsA) combination therapy for refractory uveoretinitis in Behçet's disease (BD). PATIENTS AND METHODS: The study involved a retrospective review of the medical records of 11 patients with Behçet's uveoretinitis refractory to conventional treatment who had been treated with IFX+CsA combination therapy. The frequency of ocular inflammatory attacks and a Behçet's disease ocular attack score 24 (BOS24) were used as indices for the evaluation of efficacy during each 6-month period prior to and following initiation of therapy. For the assessment of safety, adverse events (AEs) were recorded throughout the treatment period. RESULTS: The patients had received IFX+CsA combination therapy for 5.6±2.3 years. The frequency of ocular attacks per 6-month period decreased markedly from 2.9±1.6 during the baseline period to 0.6±0.9 during months 1-6, 0.5±0.9 during months 7-12, 0.3±0.5 during months 13-18, 0.3±0.7 during months 19-24, and 0.0±0.0 thereafter (P=0.003). The BOS24 score per ocular attack significantly decreased from 5.2±2.4 during the baseline period to 1.5±2.1 during months 1-6, 1.7±3.1 during months 7-12, 1.6±2.9 during months 13-18, and 0.4±1.0 during months 19-24 (P=0.002). No serious AEs were observed, with the exception of urinary tract infection and cataract progression. Two patients exhibited transient elevation of the serum creatinine level, which was normalized following a reduction in the dose of CsA. CONCLUSION: For refractory Behçet's uveoretinitis, IFX+CsA combination therapy offers a promising treatment option as it appears to have an acceptable safety profile and can reduce the frequency and severity of ocular inflammatory attacks over a long period of time.

IgG4-related disease in the Japanese population: a genome-wide association study.

BACKGROUND: IgG4-related disease is a newly recognised immunopathological entity that includes autoimmune pancreatitis, IgG4-related sialadenitis, and IgG4-related kidney disease. To understand the genetic landscape of IgG4-related disease, we did a genome-wide association study. METHODS: We did a genome-wide association study of Japanese individuals, initially screening 857 patients with IgG4-related disease at 50 Japanese research institutions and DNA samples from 2082 healthy control participants from the Nagahama Prospective Genome Cohort for the Comprehensive Human Bioscience. From Oct 27, 2008, to July 22, 2014, we enrolled 835 patients and used data from 1789 healthy participants. Only patients with confirmed diagnosis of IgG4-related disease according to the international diagnostic criteria were included. Genotyping was done with the Infinium HumanOmni5Exome, HumanOmni2.5Exome, or HumanOmni2.5 Illumina arrays, and genomic distributions were compared between case and control samples for 958 440 single nucleotide polymorphisms. The HLA region was extensively analysed using imputation of HLA alleles and aminoacid residues. Fine mapping of the FCGR2B region was also done. Associations between clinical manifestations of disease and the genetic variations identified in these two genes were examined. FINDINGS: We identified the HLA-DRB1 (p=1·1×10-11) and FCGR2B (p=2·0×10-8) regions as susceptibility loci for IgG4-related disease. We also identified crucial aminoacid residues in the ß domain of the peptide-binding groove of HLA-DRB1, in which the seventh aminoacid residue showed the strongest association signal with IgG4-related disease (p=1·7×10-14), as has been reported with other autoimmune diseases. rs1340976 in FCGR2B showed an association with increased FCGR2B expression (p=2·7×10-10) and was in weak linkage disequilibrium with rs1050501, a missense variant of FCGR2B previously associated with systemic lupus erythematosus. Furthermore, rs1340976 was associated with the number of swollen organs at diagnosis (p=0·011) and IgG4 concentration at diagnosis (p=0·035). INTERPRETATION: Two susceptibility loci for IgG4-related disease were identified. Both FCGR2B and HLA loci might have important roles in IgG4-related disease development. Common molecular mechanisms might underlie IgG4-related disease and other immune-related disorders FUNDING: The Japanese Ministry of Health, Labour, and Welfare, the Japanese Agency of Medical Research and Development, and Kyoto University Grant for Top Global University Japan Project.

Vasculitis with superior ophthalmic vein thrombosis compatible with neuro-neutrophilic disease.

PURPOSE: To present a unique case of neuro-neutrophilic disease with inflammation and thrombosis of the superior ophthalmic vein (SOV). OBSERVATIONS: A 43-year-old Japanese man with past histories of oculomotor paralysis, auditory disorder, ischemic enteritis, and recurrent oral ulceration was referred to our hospital because of blurred vision in his right eye. Ophthalmic examination revealed decreased best corrected visual acuity and central scotoma in his right eye. Orbit magnetic resonance imaging (MRI) revealed an enlarged SOV in the right eye, with Gadolinium (Gd) enhancement in the wall of the vein but not inside the vein, indicating thrombosis. Multiple Gd-enhanced hyperintense lesions were also observed in the juxtacortical area of the brain. We diagnosed the patient with vasculitis in the right SOV that was adversely affecting the optic nerve. We ruled out systemic thrombophilia, infections, and malignancy by systemic examinations. The human leukocyte antigen (HLA) typing was Cw1-, B54-, B61-, A2-, A24-, and DR4-positive and B51-negative. We treated the patient with systemic steroid and anticoagulant therapy. After three courses of steroid pulse therapy, his symptoms and the MRI findings of the right SOV and brain improved; therefore, we decided to discontinue the anticoagulant therapy. One month after anticoagulant cessation, MRI revealed recurrence of the thrombus and enlargement of the right SOV despite the lack of vision worsening. We restarted the anticoagulant therapy while continuing the oral prednisolone treatment. At the final visit, 14 months after the onset of the disease, the patient was still receiving oral anticoagulation with warfarin potassium and prednisolone (5 mg/day). His symptoms and the right eye's visual function remained normal with a mildly enlarged SOV; there was less Gd enhancement and no brain lesions on MRI. CONCLUSIONS AND IMPORTANCE: We treated a unique case of possible neuro-neutrophilic disease that presented visual disturbances due to right SOV inflammation and thrombosis. Anticoagulation and systemic steroid therapies were required to reduce the inflammation and to prevent the recurrence of thrombosis.

A case of bilateral vasculitis associated with pineal germinoma.

PURPOSE: To report a rare case of bilateral periphlebitis associated with a pineal germinoma. OBSERVATIONS: A 17-year-old male teenager presented at a local clinic complaining of blurred vision in both eyes. The treating physician identified bilateral uveitis, and prescribed the patient with a local steroid treatment. However, the inflammatory findings did not improve with the treatment, and the patient was referred to our hospital for further examination. At the first visit, his best-corrected visual acuities were 0.3 for the right eye and 0.06 for the left eye; we found no inflammation in the anterior ocular segment, but observed bilateral retinal periphlebitis and a proliferative membrane from the papilla to the macula in the ocular fundus. In addition, we found a tractional serous retinal detachment in the macula. We suspected tuberculous uveitis clinically and initiated treatment with an antituberculous drug. However, the condition of the patient did not improve. Two months after our initial examination, left optic neuritis appeared, and we initiated a steroid pulse therapy. Although the periphlebitis remained, the left optic nerve findings and the visual acuity of both eyes improved. Thus, we reduced the oral steroid dose gradually. However, two months after initiating the dose reduction, the patient suffered a consciousness disturbance, and we detected a pineal tumor by magnetic resonance imaging (MRI). The patient was diagnosed as having a germ cell tumor by pathological examination and underwent radiation and chemotherapy. We noted marked improvements in both the periphlebitis findings and in the visual acuity following the treatment for the pineal tumor. CONCLUSIONS AND IMPORTANCE: Cases of pineal tumor accompanied with retinal periphlebitis have been reported rarely. Because juvenile retinal vasculitis cases of unknown cause can be associated with pineal germinomas, we recommend brain MRI examinations for such cases.