Koju Kamoi

Comparison of infliximab versus ciclosporin during the initial 6-month treatment period in Behçet disease

Aim To compare the efficacy and safety of infliximab versus ciclosporin A (CsA) in refractory uveoretinitis in Behçet disease. Methods In this retrospective clinical chart review of patients with Behçet disease who were treated with CsA or infliximab, we collected information on the number of uveitis attacks, visual acuity and adverse side effects that occurred during the 6 months prior to and after the initiation of CsA (n=20) or infliximab (n=17). Results The number of acute episodes of uveitis during the 6 months before and after initiation of CsA were 3.3±2.4 and 1.2±1.2, and those of infliximab were 3.1±2.7 and 0.4±1.0, respectively (p<0.005). The number of episodes after infliximab administration was significantly lower than that seen for CsA (p<0.05). During the 6-month treatment period, there were no significant differences noted in the improvement of the visual acuity between the two therapies. After CsA administration, neurological symptoms and renal toxicity were seen in one patient each, while after the infliximab administration, an infusion reaction and leucopenia were seen in one patient each. Conclusion During the initial 6 months of treatment, infliximab proved to be more effective in reducing acute episodes of uveitis in Behçet disease.

Immunological homeostasis of the eye.

Uveitis is a sight-threatening disease caused by autoimmune or infection-related immune responses. Studies in experimental autoimmune uveitis and in human diseases imply that activated CD4(+) T cells, Th1 and Th17 cells, play an effector role in ocular inflammation. The eye has a unique regional immune system to protect vision-related cells and tissues from these effector T cells. The immunological balance between the pathogenic CD4(+) T cells and regional immune system in the eye contributes to the maintenance of ocular homeostasis and good vision. Current studies have demonstrated that ocular parenchymal cells at the inner surface of the blood-ocular barrier, i.e. corneal endothelial (CE) cells, iris pigment epithelial (PE) cells, ciliary body PE cells, and retinal PE cells, contribute to the regional immune system of the eye. Murine ocular resident cells directly suppress activation of bystander T cells and production of inflammatory cytokines. The ocular resident cells possess distinct properties of immunoregulation that are related to disparate anatomical location. CE cells and iris PE cells, which are located at the anterior segment of the eye and face the aqueous humor, suppress activation of T cells via cell-to-cell contact mechanisms, whereas retinal PE cells suppress the activation of T cells via soluble factors. In addition to direct immune suppression, the ocular resident cells have another unique immunosuppressive property, the induction of CD25(+)Foxp3(+) Treg cells that also suppress the activation of bystander T cells. Iris PE cells convert CD8(+) T cells into Treg cells, while retinal PE cells convert CD4(+) T cells greatly and CD8(+) T cells moderately into Treg cells. CE cells also convert both CD4(+) T cells and CD8(+) T cells into Treg cells. The immunomodulation by ocular resident cells is mediated by various soluble or membrane-bound molecules that include TGF-β TSP-1, B7-2 (CD86), CTLA-2α, PD-L1 (B7-H1), galectin 1, pigment epithelial-derived factor PEDF), GIRTL, and retinoic acid. Human retinal PE cells also possess similar immune properties to induce Treg cells. Although there are many issues to be answered, human Treg cells induced by ocular resident cells such as retinal PE cells and related immunosuppressive molecules can be applied as immune therapy for refractive autoimmune uveitis in humans in the future.

Timing of recurrent uveitis in patients with Behçet's disease receiving infliximab treatment

Aim To investigate the relationship between recurrence of uveitis and timing of infliximab in patients with Behçets disease. Methods Charts were retrospectively reviewed for 23 patients with refractory uveoretinitis associated with Behçets disease treated using infliximab at our hospital. Infliximab was administered by intravenous infusion at weeks 0, 2 and 6, and every 8 weeks thereafter. The relationship between recurrence of uveitis and infliximab infusion was analysed. Results Mean duration of infliximab treatment for the 23 patients was 20 months, and the mean number of infliximab infusions was 12. Recurrent uveitis was seen during treatment in 13 of 23 patients, with no recurrences in the remaining 10 patients. Two patients developed recurrence soon after starting treatment—for example, first recurrence after starting infliximab was on day 19 or day 29, but the other 11 patients experienced recurrences after 5–6 months of infliximab treatment. As regards the timing of recurrences following infliximab infusion, 10 of the 13 patients developed recurrences ∼5 weeks after infliximab infusion. Recurrent uveitis in these patients most often occurred during weeks 7–8 after infusion. However, three of the patients developed recurrent uveitis at various times, for example in weeks 1, 4, 7 and 8 after infliximab infusion. Conclusion Infliximab is effective for suppressing recurrence of uveitis in Behçets disease, but responses to infliximab differ among patients. Careful observation following infliximab infusion is necessary to manage the recurrence of uveitis during treatment.

Comparison of the ocular characteristics of anterior uveitis caused by herpes simplex virus, varicella-zoster virus, and cytomegalovirus

PurposeTo compare the clinical characteristics of anterior uveitis (AU) caused by herpes simplex virus (HSV), varicella-zoster virus (VZV), or cytomegalovirus (CMV).MethodsThe medical records were reviewed of 46 patients whose diagnoses were based on their clinical characteristics [e.g., unilateral involvement, presence of keratic precipitates (KPs), and elevation of intraocular pressure (IOP)] and on PCR detection of herpes virus DNA in the aqueous humor. The demographics, chief complaints, and clinical characteristics of the three types of herpetic AU were compared.ResultsOf the 46 patients with AU, eight had HSV-AU, 20 had VZV-AU, and 18 had CMV-AU. HSV-AU and VZV-AU shared common features, i.e., a relatively acute disease process and the presence of large KPs. Among the three groups of patients, the characteristic features of those with VZV-AU were severe intraocular inflammation, as shown by severe aqueous flare, highest viral load in the aqueous humor, and presence of segmental iris atrophy. In comparison, patients with CMV-AU had the mildest intraocular inflammation, lowest corneal endothelial cell density, and highest IOP.ConclusionsAlthough the AU caused by each of the three types of herpes viruses has a number of common features, each disease also has distinct features that should facilitate an accurate diagnosis.

Detection of Candida and Aspergillus species DNA using broad-range real-time PCR for fungal endophthalmitis

BackgroundThe goal of this work is to establish a broad-range real-time polymerase chain reaction (PCR) diagnostic system for ocular fungal infection and to measure Candida and Aspergillus DNA in the ocular fluids obtained from unknown uveitis/endophthalmitis patients.MethodsAfter obtaining informed consent, intraocular fluids (aqueous humor and vitreous fluid samples) were collected from 54 patients with idiopathic uveitis or endophthalmitis. Samples were assayed for Candida or Aspergillus DNA using broad-range (18S rRNA sequences) quantitative real-time PCR.ResultsCandida or Aspergillus DNA was detected in seven out of 54 patient ocular samples (13%). These PCR-positive samples showed significantly high copy numbers of Candida or Aspergillus DNA. On the other hand, fungal DNA was not detected in any of the other 46 samples collected from these idiopathic uveitis or endophthalmitis patients. In the one PCR-negative case, PCR did not detect any fungal genome in the sample, even though this patient was clinically suspected of having Candida endophthalmitis. Real-time PCR results were negative for fungal DNA in the bacterial endophthalmitis patients and in various uveitis patients. In addition, fungal DNA was also not detected in patients without ocular inflammation (controls).ConclusionsAnalysis of ocular samples by this broad-range real-time PCR method can be utilized for rapid diagnosis of patients suffering from unknown intraocular disorders such as idiopathic uveitis/endophthalmitis.

HTLV-1 Uveitis

Human T cell lymphotropic virus type 1 (HTLV-1) is the first retrovirus described as a causative agent of human disease. Following adult T cell leukemia/lymphoma and HLTV-1-associated myelopathy/tropical spastic paraparesis, HTLV-1 uveitis (HU) has been established as a distinct clinical entity caused by HTLV-1 based on seroepidemiological, clinical, and virological studies. HU is one of the most common causes of uveitis in endemic areas of Japan and can be a problematic clinical entity all over the world. HU occurs with a sudden onset of floaters and foggy vision, and is classified as an intermediate uveitis. Analysis of infiltrating cells in eyes with HU revealed that the majority of infiltrating cells were CD3+ T cells, but not malignant cells or leukemic cells based on their T cell receptor usage. HTLV-1 proviral DNA, HTLV-1 protein, and viral particles were detected from infiltrating cells in eyes with HU. HTLV-1-infected CD4+ T cell clones established from infiltrating cells in eyes with HU produced large amounts of various inflammatory cytokines, such as IL-1, IL-6, IL-8, TNF-α, and interferon-γ. Taken together, HU is considered to be caused by inflammatory cytokines produced by HTLV-1-infected CD4+ T cells that significantly accumulate in eyes; therefore, topical and/or oral corticosteroid treatment is effective to treat intraocular inflammation in patients with HU. Further investigation is needed to establish a specific treatment for HU.

HTLV infection and the eye.

Purpose of review Human T-cell lymphotropic virus (HTLV) is the first discovered retrovirus causing malignancy in human. HTLV infection affects hosts ocular tolerance and causes various diseases in the eye. Here we discuss the manifestations, mechanisms, treatments, and future directions of HTLV-related ocular diseases. Recent finings Recent serological researches showed that the number of HTLV-1 carriers in metropolitan area was increasing, although seroprevalence of HTLV-1 in general population was decreased after screening serological tests in blood donors started. The most common clinical entity of uveitis was still HTLV-1 uveitis in HTLV-1 highly endemic area, but prevalence of HTLV-1 uveitis varies in different parts of the world. As for treatment of inflammation, tacrolimus and 5-azacytidine were reported to be effective for autoimmune manifestations in HTLV-1-related overlap syndrome (deratomyositis/Sjogrens syndrome) and HTLV-1-related myelodysplastic syndrome. Interleukin-2 receptor targeted therapies improved scleritis in patients with adult T-cell leukemia/lymphoma caused by HTLV-1. Basic researches identified that HTLV-1 tax and HTLV-1 basic leucine zipper factor play critical roles in the HTLV-1-related disease and are now being investigated as targeted therapies. Summary Development of modern molecular biology makes it possible to reveal deep insights of HTLV-1-related ocular diseases. Although effective therapies based on basic researches have been reported, further endeavor is necessary to establish much more specific treatments of the ocular diseases.

A new era of uveitis: impact of polymerase chain reaction in intraocular inflammatory diseases

Uveitis is a sight-threatening intraocular inflammatory disorder which may occur from both infectious and non-infectious or autoimmune causes. The frequency of infectious uveitis and autoimmune uveitis varies depending on countries and regions. According to a nationwide survey conducted by the Japanese Ocular Inflammation Society, infectious and non-infectious uveitis accounted for 16.4 and 50.1% of new patients, respectively while the remaining 33.5% of new uveitis cases were not classified or were idiopathic uveitis. Infectious uveitis is particularly important because it causes tissue damage to the eye and may result in blindness unless treated. However, it can be treated if the pathogenic microorganisms are identified promptly and accurately. Remarkable advancements in molecular and immunological technologies have been made in the last decade, and the diagnosis of infectious uveitis has been greatly improved by the application of molecular and immunological investigations, particularly polymerase chain reaction (PCR). PCR performed on a small amount of ocular samples provides a prompt, sensitive, and specific molecular diagnosis of pathogenic microorganisms in the eye. This technology has opened a new era in the diagnosis and treatment of uveitis, enabling physicians to establish new clinical entities of uveitis caused by infectious microorganisms, identify pathogens in the eyes of many patients with uveitis, and determine prompt diagnosis and appropriate therapy. Here we review the PCR process, new PCR tests specialized for ocular diseases, microorganisms detected by the PCR tests, diseases in the eye caused by these microorganisms, and the clinical characteristics, diagnosis, and therapy of uveitis.

Human iris pigment epithelium suppresses activation of bystander T cells via TGFβ–TGFβ receptor interaction

Iris pigment epithelial (IPE) cells from the anterior segment in the eye are able to suppress activation of bystander responder T cells in vitro. The cultured IPE cells fully suppress proliferation and cytokine production by responder T cells via direct cell-to-cell contact. We have now investigated whether primary cultured human iris pigment epithelial (h-IPE) cells that were established from fresh iris tissues can also inhibit the activation of T cells in vitro. We found that cultured h-IPE cells significantly inhibited T cell proliferation and the IFN-gamma production by the target T cells from both the allogeneic and autogeneic peripheral blood mononuclear cells (PBMCs). The h-IPE cells also inhibited the activation of CD4(+) T cells from patients with active uveitis. The suppression by h-IPE occurred in a completely contact-dependent manner. The h-IPE constitutively expressed transforming growth factor beta (TGFbeta) and the receptors, and the T cells exposed to h-IPE greatly expressed Smad transcripts. In addition, TGFbeta2-siRNA transfected h-IPE failed to inhibit activation of responder T cells. Similarly, h-IPE cells in the presence of anti-TGFbeta neutralizing antibodies or recombinant TGFbeta receptor blocking proteins failed to inhibit the T-cell activation. In conclusion, cultured human iris pigment epithelium fully inhibits T cell activation in vitro. Our data support the hypothesis that the ocular resident cells play a critical role in immunosuppression in the eye.

Phaco forward-chop technique for managing posterior nuclear plate of hard cataract

&NA; Surgical management of hard cataracts can be problematic despite improvements in phacoemulsification devices. Phaco chop, considered one of the best techniques for dealing with hard cataracts, cannot always divide the hard cataract completely. We have devised a phaco forward‐chop technique that can be implemented safely and efficiently following incomplete phaco chop in a hard cataract. Financial Disclosure: Neither author has a financial or proprietary interest in any material or method mentioned.