RESUMO
PURPOSE: To report two cases of ibrutinib-related uveitis and review the literature to date. METHODS: We report two cases of ibrutinib-related uveitis using CARE guidelines and review the cases reported in the literature. RESULTS: Case 1) A 55-year-old female with recurrent primary central nervous system lymphoma presented with bilateral decreased visual acuity, photophobia, and floaters that started one month after initiating oral treatment with ibrutinib. Chronic non-granulomatous bilateral anterior-intermediate uveitis with macular edema was identified. Secondary causes were ruled out, and a presumptive diagnosis of ibrutinib-related uveitis was made. Case 2) A 57-year-old female with Waldenström macroglobulinemia who was treated with ibrutinib for two years presented with bilateral blurred vision, photophobia, red eyes, and floaters. A diagnosis of non-granulomatous, noninfectious panuveitis with bilateral cystoid macular edema was made. Secondary causes were ruled out, and ibrutinib toxicity was the most likely cause. CONCLUSION: Ibrutinib-related uveitis is a novel and under-diagnosed clinical entity. The most frequent clinical presentation in the literature is bilateral, non-granulomatous, anterior, and intermediate uveitis. Macular edema is a frequent complication. Uveitis usually requires topical treatment and the suspension of ibrutinib. Switching to second-generation Bruton tyrosine kinase inhibitors is proposed as a potential therapeutic alternative.
Assuntos
Adenina , Piperidinas , Humanos , Feminino , Adenina/análogos & derivados , Adenina/efeitos adversos , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Tomografia de Coerência Óptica , Acuidade Visual , Inibidores de Proteínas Quinases/efeitos adversos , Uveíte/induzido quimicamente , Uveíte/diagnóstico , Uveíte/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/diagnóstico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Edema Macular/induzido quimicamente , Edema Macular/diagnóstico , Edema Macular/tratamento farmacológico , Angiofluoresceinografia , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/diagnósticoRESUMO
The effect of fine particulate matter (PM2.5) on the development of uveitis remains unclear. Therefore, this study was designed to investigate the role of PM2.5 in experimental autoimmune uveitis (EAU) and its potential mechanism. Our results showed that PM2.5 could exacerbate the activity of EAU, as evidenced by severer clinical and pathological changes, correlated with elevated Th17 cells frequency and IL-17A expression. Proteomic analysis revealed ferroptosis was the most significant pathway. In vivo, the levels of Fe2+, ROS, lipid ROS, and malondialdehyde, as well as the expression of TFRC, HMOX1, FTH1, and FTL1 in CD4+ T cells were increased, while GSH/GSSG ratio and the expression of ACSL1 and GPX4 were decreased after PM2.5 exposure. In vitro, the expression of TFRC and HMOX1 were increased, while the expression FTH1, FTL1, ACSL1, and GPX4 were decreased after PM2.5 exposure. Ferrostatin-1 effectively alleviated PM2.5-induced intraocular inflammation and suppressed the frequency of Th17 cells. These results suggest that PM2.5 could aggravate intraocular inflammation and immune response in EAU mice through ferroptosis. Ferroptosis could be a potential marker for the prevention and treatment of uveitis.
Assuntos
Ferroptose , Material Particulado , Células Th17 , Uveíte , Ferroptose/efeitos dos fármacos , Animais , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Uveíte/induzido quimicamente , Uveíte/imunologia , Material Particulado/toxicidade , Camundongos , Doenças Autoimunes/induzido quimicamente , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , FemininoRESUMO
Immune checkpoint inhibitors (ICI) such as Programmed cell Death 1 (PD-1) inhibitors have improved cancer treatment by enhancing the immune system's ability to target malignant cells. Their use is associated with immune-related adverse events (irAEs), including uveitis. The profile of pro-inflammatory cytokines underlying Anti-PD-1-induced uveitis shares significant overlap with that of non-infectious uveitis. Current corticosteroid treatments for uveitis while effective are fraught with vision threatening side effects. The cytokine profile in ICI-related uveitis has a large overlap with that of noninfectious uveitis, this overlap strongly supports the potential for therapy that activates the PD-1 axis in the eye to treat uveitis. Indeed, ICI related uveitis often resolves with cessation of the ICI, restoring the endogenous PD-1 axis. The potential benefit of targeting many pro-inflammatory cytokines via local PD-1 axis activation is mitigating ocular inflammation while minimizing adverse effects.
Assuntos
Citocinas , Inibidores de Checkpoint Imunológico , Receptor de Morte Celular Programada 1 , Uveíte , Humanos , Uveíte/induzido quimicamente , Uveíte/tratamento farmacológico , Uveíte/imunologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Citocinas/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidoresRESUMO
Uveitis is a group of inflammatory ocular pathologies. Endotoxin-Induced Uveitis (EIU) model represent a well-known model induced by administration of Lipopolysaccharide (LPS). The aim is to characterize two models of EIU through two routes of administration with novel noninvasive imaging techniques. 29 rats underwent Intraocular Pressure (IOP) measurements, Optical Coherence Tomography (OCT), proteomic analysis, and Positron Emission Tomography and Computed Tomography (PET/CT). Groups included healthy controls (C), BSS administered controls (Ci), systemically induced EIU with LPS (LPSs), and intravitreally induced EIU with LPS (LPSi) for IOP, OCT, and proteomic studies. For 18F-FDG PET/CT study, animals were divided into FDG-C, FDG-LPSs and FDG-LPSi groups and scanned using a preclinical PET/CT system. LPSi animals exhibited higher IOP post-induction compared to C and LPSs groups. LPSi showed increased cellular infiltrate, fibrotic membranes, and iris inflammation. Proinflammatory proteins were more expressed in EIU models, especially LPSi. PET/CT indicated higher eye uptake in induced models compared to FDG-C. FDG-LPSi showed higher eye uptake than FDG-LPSs but systemic uptake was higher in FDG-LPSs due to generalized inflammation. OCT is valuable for anterior segment assessment in experimental models. 18F-FDG PET/CT shows promise as a noninvasive biomarker for ocular inflammatory diseases. Intravitreal induction leads to higher ocular inflammation. These findings offer insights for future inflammatory disease research and drug studies.
Assuntos
Modelos Animais de Doenças , Pressão Intraocular , Lipopolissacarídeos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Proteômica , Tomografia de Coerência Óptica , Uveíte , Animais , Uveíte/induzido quimicamente , Uveíte/diagnóstico por imagem , Uveíte/metabolismo , Tomografia de Coerência Óptica/métodos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Proteômica/métodos , Lipopolissacarídeos/toxicidade , Pressão Intraocular/efeitos dos fármacos , Ratos , Masculino , Fluordesoxiglucose F18/administração & dosagem , Endotoxinas/toxicidade , Ratos Sprague-DawleyRESUMO
Biological disease-modifying antirheumatic drugs (bDMARDs) can have different effects on various clinical manifestations of ankylosing spondylitis (AS). Data on the effects of interleukin 17 inhibitors (IL17-i) on uveitis in AS continue to accumulate. Objective: to evaluate the effect of IL17-i therapy on the course of uveitis in AS. The study involved 73 patients with AS (New York criteria, 1984), who received IL17-i (57-secukinumab (SEC), 22-netakimab (NTK)) for at least 1 year. The average age of patients at the time of inclusion in the study was 41.93 ± 8.95 years, the average duration of AS was 10.75 ± 6.22 years. There were 40 men (56.7%) and 33 women (43.3%) among the patients. HLA-B27 was detected in 62/73 (85%), coxitis in 58 (79%), enthesitis in 63 (86.3%), peripheral arthritis in 57 (78%), psoriasis in 7 (9.5%), and inflammatory bowel disease (IBD) in 3 (4.1%) patients; in 6 (8.2%) patients, the disease started before the age of 16; 19 (26%) patients had at least one episode of uveitis during the course of the disease. The rates of uveitis was estimated by comparing the number of incidences per 100 patient-years before the start of bDMARDs therapy and during IL17-i using. The incidence rate of uveitis before the start of bDMARDs therapy for all patients was 8.3 per 100 pt-years (95% CI 0.065-0.107), during IL17-i therapy- 9.2 per 100 pt-years (95% CI 0.06-0.15), p = 0.72. The incidence rate of uveitis among patients who used SEC was 10.1 per 100 pt-years (95% CI 0.079-0.13) before the start of bDMARDs therapy and 9.4 per 100 pt-years (95% CI 0.05-0.15), p = 0.74 during SEC therapy. The incidence rate of uveitis among patients who used NTK was 4.8 per 100 pt-years (95% CI 0.028-0.08) before the start of bDMARDs therapy and 7.1 per 100 pt-years (95% CI 0.019-022), p = 0.3 during the NTK therapy. For patients with a history of uveitis, the incidence rate of uveitis was 22.5 per 100 pt-years (95% CI 0.18-0.28) before the start of therapy with bDMARDs and 29.1 per 100 pt-years (95% CI 0.18-0.43), p = 0.29 during IL17-i therapy. Occurrences of uveitis were observed in 4 of 57 patients (7%) during SEC therapy and in 1 of 25 (4%) patients during the NTK therapy. One case of new-onset uveitis was recorded during the using of SEC. There were no significant differences in the incidence rates of uveitis during IL17-i therapy compared with non-biological therapy. IL17-i therapy have not demonstrated a significant effect on the course of uveitis in AS in the study group.
Assuntos
Interleucina-17 , Espondilite Anquilosante , Uveíte , Humanos , Espondilite Anquilosante/tratamento farmacológico , Uveíte/induzido quimicamente , Uveíte/tratamento farmacológico , Masculino , Interleucina-17/antagonistas & inibidores , Feminino , Adulto , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Antirreumáticos/uso terapêutico , Antirreumáticos/efeitos adversosRESUMO
BACKGROUND: Several immune checkpoint inhibitors (ICIs) have been linked to the occurrence of Vogt-Koyanagi-Harada disease (VKHD)-like uveitis. Among the ICIs, there has been no report of immune-related adverse events (irAEs) caused by a new programmed death protein-1(PD-1) monoclonal antibody (Toripalimab). CASE PRESENTATION: This paper presents a case of VKHD-like uveitis that arose following Toripalimab therapy for urothelial cancer of the bladder, and the patient experienced symptoms 10 days after the final dosage of 20 months of medication treatment. This patient with bladder uroepithelial carcinoma had severe binocular acute panuveitis with exudative retinal detachment after receiving Toripalimab therapy. Binocular VKHD-like uveitis was suggested as a diagnosis. Both eyes recovered after discontinuing immune checkpoint inhibitors and local and systemic corticosteroid treatment. CONCLUSIONS: This report suggests that VKHD-like uveitis can also occur in patients receiving novel PD-1 antibodies and the importance of paying attention to eye complications in patients receiving treatment over a long period.
Assuntos
Inibidores de Checkpoint Imunológico , Síndrome Uveomeningoencefálica , Humanos , Síndrome Uveomeningoencefálica/induzido quimicamente , Síndrome Uveomeningoencefálica/diagnóstico , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Uveíte/induzido quimicamente , Uveíte/diagnóstico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Feminino , Pessoa de Meia-Idade , Idoso , Antineoplásicos Imunológicos/efeitos adversosRESUMO
Importance: Fluoroquinolone use has been associated with increased risk of uveitis and retinal detachment in noninterventional studies, but the findings have been conflicting and causality is unclear. Objective: To estimate the association of systemic fluoroquinolone use with acute uveitis or retinal detachment, using multiple analyses and multiple databases to increase the robustness of results. Design, Setting, and Participants: This cohort study used data from the Clinical Practice Research Datalink Aurum and GOLD UK primary care records databases, which were linked to hospital admissions data. Adults prescribed a fluoroquinolone or a comparator antibiotic, cephalosporin, between April 1997 and December 2019 were included. Adults with uveitis or retinal detachment were analyzed in a separate self-controlled case series. Data analysis was performed from May 2022 to May 2023. Exposures: Systemic fluoroquinolone or comparator antibiotic. Main Outcomes and Measures: The primary outcome was a diagnosis of acute uveitis or retinal detachment. Hazard ratios (HRs) were estimated in the cohort study for the association of fluoroquinolone prescription with either uveitis or retinal detachment, using stabilized inverse probability of treatment weighted Cox regression. Rate ratios (RRs) were estimated in the self-controlled case series, using conditional Poisson regression. Estimates were pooled across databases using fixed-effects meta-analysis. Results: In total, 3â¯001â¯256 individuals in Aurum (1â¯893â¯561 women [63.1%]; median [IQR] age, 51 [35-68] years) and 434â¯754 in GOLD (276â¯259 women [63.5%]; median [IQR] age, 53 [37-70] years) were included in the cohort study. For uveitis, the pooled adjusted HRs (aHRs) for use of fluoroquinolone vs cephalosporin were 0.91 (95% CI, 0.72-1.14) at first treatment episode and 1.07 (95% CI, 0.92-1.25) over all treatment episodes. For retinal detachment, the pooled aHRs were 1.37 (95% CI, 0.80-2.36) at first treatment episode and 1.18 (95% CI, 0.84-1.65) over all treatment episodes. In the self-controlled case series, for uveitis, the pooled adjusted RRs (aRRs) for fluoroquinolone use vs nonuse were 1.13 (95% CI, 0.97-1.31) for 1 to 29 days of exposure, 1.16 (95% CI, 1.00-1.34) for 30 to 59 days, and 0.98 (95% CI, 0.74-1.31) for 60 days for longer. For retinal detachment, pooled aRRs for fluoroquinolone use vs nonuse were 1.15 (95% CI, 0.86-1.54) for 1 to 29 days of exposure, 0.94 (95% CI, 0.69-1.30) for 30 to 59 days, and 1.03 (95% CI, 0.59-1.78) for 60 days or longer. Conclusions and Relevance: These findings do not support an association of systemic fluoroquinolone use with substantively increased risk of uveitis or retinal detachment. Although an association cannot be completely ruled out, these findings indicate that any absolute increase in risk would be small and, hence, of limited clinical importance.
Assuntos
Antibacterianos , Fluoroquinolonas , Descolamento Retiniano , Uveíte , Humanos , Fluoroquinolonas/efeitos adversos , Descolamento Retiniano/induzido quimicamente , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/epidemiologia , Feminino , Masculino , Pessoa de Meia-Idade , Uveíte/induzido quimicamente , Uveíte/tratamento farmacológico , Uveíte/diagnóstico , Antibacterianos/efeitos adversos , Adulto , Fatores de Risco , Idoso , Estudos Retrospectivos , Reino Unido/epidemiologia , Bases de Dados Factuais , IncidênciaRESUMO
INTRODUCTION: Anti-tumor necrosis factor α (anti-TNF α) agents are an effective treatment for a variety of inflammatory and autoimmune diseases. In ophthalmology anti-TNF α began to emerge as a possible therapy for non-infectious uveitis, paradoxically their administration may result in the onset or recurrence of inflammatory eye disease such as uveitis. We reported a case of new onset of bilateral anterior and intermediate uveitis in a patient with rheumatoid arthritis (RA) while being treated with infliximab and we performed a review of literature. OBSERVATION: A 25-year-old female with RA under infliximab, presented with bilateral blurred vision. Anterior segment examination demonstrated retrodescmetic fine precipates, 1+ cells in the anterior chamber on both eyes. The fundus examination was difficult because of the vitritis. Fluorescein angiography demonstrated mild optic disc edema, and bilateral diffuse peripheral fern leaf cappilaritis. Optical coherence tomography showed severe cystoid macular edema bilaterally. The diagnosis of bilateral anterior and intermediate uveitis caused by infliximab was retained after exclusion of infectious and autoimmune aetiologies. She was treated with corticosteroid with good visual outcome. CONCLUSION: In our case, new onset of uveitis may be considered as paradoxical effect of anti-TNF α therapy. Rheumatologists and ophthalmologists should be aware of this effect. Careful monitoring of patients under infliximab is necessary for appropriate diagnosis and early treatment.
Assuntos
Artrite Reumatoide , Uveíte Intermediária , Uveíte , Feminino , Humanos , Adulto , Infliximab/efeitos adversos , Inibidores do Fator de Necrose Tumoral , Uveíte/induzido quimicamente , Uveíte/diagnóstico , Uveíte/tratamento farmacológico , Fator de Necrose Tumoral alfa , Uveíte Intermediária/complicações , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/complicaçõesAssuntos
Inibidores de Checkpoint Imunológico , Uveíte , Humanos , Uveíte/induzido quimicamente , Uveíte/tratamento farmacológico , Uveíte/diagnóstico , Inibidores de Checkpoint Imunológico/efeitos adversos , Incidência , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Fatores de Risco , Estudos Retrospectivos , Melanoma/tratamento farmacológico , AdultoAssuntos
Inibidores de Janus Quinases , Uso Off-Label , Tatuagem , Uveíte , Humanos , Uveíte/tratamento farmacológico , Uveíte/induzido quimicamente , Inibidores de Janus Quinases/uso terapêutico , Tatuagem/efeitos adversos , Adulto , Masculino , Feminino , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversos , Granuloma/induzido quimicamente , Granuloma/tratamento farmacológico , Granuloma de Corpo Estranho/induzido quimicamente , Granuloma de Corpo Estranho/tratamento farmacológico , Granuloma de Corpo Estranho/etiologiaRESUMO
OBJECTIVE: Uveitis is a common manifestation of various autoimmune diseases and can lead to severe visual impairment. Hydroxychloroquine (HCQ) is an antimalarial drug that is also used to treat autoimmune diseases. The aim of this study was to investigate the association between HCQ use and the incidence of uveitis in patients with autoimmune diseases, as well as to identify potential risk factors for the development of uveitis in this study. METHODS: We conducted a population-based cohort study using a nationwide database to investigate the incidence of uveitis in patients with autoimmune diseases who received HCQ treatment. We selected non-HCQ comparison cohort at a 1:1 ratio by propensity score matching on age, sex, index date, urbanization, income, comorbidities, and medications. The data were analyzed using Cox proportional hazards models, and propensity score matching (PSM) was used to reduce selection bias. RESULTS: Our study included 15 822 patients with autoimmune diseases. After 1:1 PSM, there were 4555 individuals in both the HCQ group (n = 4555) and the non-HCQ group (n = 4555). The multiple Cox proportional hazard regression analysis was used for the estimation of adjusted hazard ratios on uveitis. After PSM, the adjusted hazard ratio for the HCQ group was 0.74 (95% CI = 0.58-0.95). These findings suggest that HCQ may play a protective role in reducing the risk of uveitis in patients with autoimmune diseases, including rheumatoid arthritis, Sjogren's syndrome, and systemic lupus erythematosus groups. The Kaplan-Meier survival curves also showed a significantly lower incidence of uveitis in the HCQ group (log-rank = 0.0229) after PSM. CONCLUSION: HCQ use is associated with a lower incidence of uveitis in patients with autoimmune diseases. Further studies are needed to confirm this association and to investigate the underlying mechanisms.
Assuntos
Doenças Autoimunes , Uveíte , Humanos , Hidroxicloroquina/efeitos adversos , Estudos de Coortes , Estudos Retrospectivos , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/epidemiologia , Uveíte/induzido quimicamente , Uveíte/diagnóstico , Uveíte/tratamento farmacológicoAssuntos
Melanoma , Neoplasias Cutâneas , Uveíte , Humanos , Melanoma/tratamento farmacológico , Nivolumabe/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Uveíte/induzido quimicamente , Uveíte/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologiaRESUMO
Purpose: The purpose of this study was to compare the efficacy, and ocular pharmacokinetics of a new 0.04% w/v bis in die means twice a day (BID) ophthalmic solution and marketed 0.05% w/v quater in die means four times a day (QID) ophthalmic emulsion of difluprednate in New Zealand white (NZW) rabbits. Methods: The preclinical proof of concept was established in paracentesis-induced acute inflammation, endotoxin-induced acute uveitis, and bovine serum albumin-induced chronic uveitis in NZW rabbit animal models. A comparison of clinical score, total cell count, and total protein was performed to determine efficacy. An ocular pharmacokinetic study was conducted to study the influence of the vehicle on the ocular absorption of the drug. Results: In both uveitis models, the new solution formulation and marketed emulsion formulation inhibited total clinical score, total cell count, PGE2, and total protein significantly more than the placebo and lipopolysaccharide (disease control) groups and were comparable. In an ocular pharmacokinetic study, the Cmax and AUC0-t of difluoroprednisolone 17-butyrate in humor were â¼2-fold higher after 14 days' instillation of new solution formulation (0.04% w/v, BID) compared with 14 days' instillation of marketed emulsion (0.05% w/v, QID). Conclusions: The study demonstrated that the efficacy of the solution formulation at a lower dose and reduced dosing regimen were comparable to that of the emulsion formulation. The reduction in strength and regimen may result in improved patient adherence and outcomes.
Assuntos
Fluprednisolona , Uveíte , Animais , Coelhos , Emulsões , Fluprednisolona/análogos & derivados , Soluções Oftálmicas , Uveíte/induzido quimicamente , Uveíte/tratamento farmacológicoRESUMO
PURPOSE: Faricimab, a novel pharmaceutical agent targeting both angiopoietin-2 and vascular endothelial growth factor-A pathways, has gained approval for treating neovascular age-related macular degeneration and diabetic macular oedema. While clinical trials have demonstrated its favorable safety profile, this research presents two cases of hypertensive uveitis following intravitreal Faricimab injections. METHODS: Medical history, clinical findings and multimodal images were retrospectively collected. RESULTS: The patients experienced elevated intraocular pressure, mutton-fat keratic precipitates, anterior and posterior segment inflammation shortly after faricimab administration. CONCLUSIONS: These cases prompt further investigation into the potential risk of uveitis associated with faricimab and underscore the importance of continued monitoring and research to elucidate its real-world safety profile.
Assuntos
Inibidores da Angiogênese , Injeções Intravítreas , Uveíte , Humanos , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/administração & dosagem , Uveíte/induzido quimicamente , Uveíte/diagnóstico , Uveíte/tratamento farmacológico , Feminino , Idoso , Masculino , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Tomografia de Coerência Óptica , Acuidade Visual , Pressão Intraocular/efeitos dos fármacos , Estudos Retrospectivos , Angiopoietina-2 , Angiofluoresceinografia , Idoso de 80 Anos ou maisRESUMO
The combination of BRAF kinase inhibitors (BRAFis) and MEK kinase inhibitors (MEKis) is one of the most promising chemotherapy regimens in the treatment of BRAF-mutant melanoma. Although BRAFi plus MEKi combined therapy is widely used for the treatment of BRAFV600-mutated melanoma, the incidence of uveitis caused by BRAFi plus MEKi is limited. In this report, we described five cases (two men and three women) of Vogt-Koyanagi-Harada (VKH) disease-like uveitis in melanoma patients who received BRAFi plus MEKi combined therapy. Of note, all the patients had the HLA-DRB1*04 haplotype, which is frequently detected in VKH-like non-infectious uveitis. On the other hand, among BRAFi plus MEKi-treated patients who did not develop VKH disease-like uveitis, only one of five (20%) patients had the HLA-DRB1*04 haplotype. Collectively, BRAFi/MEKi might induce severe VKH disease-like uveitis in melanoma patients with the HLA-DRB1*04 haplotype.
Assuntos
Cadeias HLA-DRB1 , Melanoma , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas B-raf , Síndrome Uveomeningoencefálica , Humanos , Cadeias HLA-DRB1/genética , Melanoma/tratamento farmacológico , Melanoma/genética , Masculino , Síndrome Uveomeningoencefálica/induzido quimicamente , Síndrome Uveomeningoencefálica/diagnóstico , Síndrome Uveomeningoencefálica/genética , Feminino , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adulto , Sulfonamidas/efeitos adversos , Sulfonamidas/administração & dosagem , Vemurafenib/efeitos adversos , Vemurafenib/administração & dosagem , Uveíte/induzido quimicamente , Uveíte/diagnóstico , Uveíte/genética , HaplótiposRESUMO
PURPOSE: To investigate the roles of sphingosine kinases (SphKs) and sphingosine-1-phosphate receptors (S1PRs) in endotoxin-induced uveitis (EIU) mice. METHODS: EIU model was induced using an intraperitoneal injection of lipopolysaccharide (LPS). The expression of SphKs and S1PRs in the retina was assessed using quantitative polymerase chain reaction (qPCR) and immunofluorescence. The effects of S1PR antagonists on the expression of inflammatory cytokines in the retina were evaluated using qPCR and western blotting. Effects of leukocyte infiltration of the retinal vessels were evaluated to determine the effects of the S1PR2 antagonist and genetic deletion of S1PR2 on retinal inflammation. RESULTS: Retinal SphK1 expression was significantly upregulated in EIU. SphK1 was expressed in the GCL, IPL, and OPL and S1PR2 was expressed in the GCL, INL, and OPL. Positive cells in IPL and OPL of EIU retina were identified as endothelial cells. S1PR2 antagonist and genetic deletion of S1PR2 significantly suppressed the expression of IL-1α, IL-6, TNF-α, and ICAM-1, whereas S1PR1/3 antagonist did not. Use of S1PR2 antagonist and S1PR2 knockout in mice significantly ameliorated leukocyte adhesion induced by LPS. CONCLUSION: SphK1/S1P/S1PR2 signaling was upregulated in EIU and S1PR2 inhibition suppressed inflammatory response. Targeting this signaling pathway has potential for treating retinal inflammatory diseases.
Assuntos
Lipopolissacarídeos , Fosfotransferases (Aceptor do Grupo Álcool) , Receptores de Esfingosina-1-Fosfato , Animais , Masculino , Camundongos , Western Blotting , Citocinas/metabolismo , Citocinas/genética , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Lisoesfingolipídeo/metabolismo , Receptores de Lisoesfingolipídeo/genética , Retina/metabolismo , Retina/patologia , Retinite/metabolismo , Retinite/induzido quimicamente , Receptores de Esfingosina-1-Fosfato/metabolismo , Receptores de Esfingosina-1-Fosfato/genética , Uveíte/metabolismo , Uveíte/induzido quimicamenteRESUMO
Tubulointerstitial nephritis is a common cause of acute renal failure, in two thirds of cases it is associated with drugs (mostly antimicrobials and NSAIDs), in 5-10% of cases it is associated with infections (bacterial/viral/parasitic), in 5-10% of cases it is idiopathic (this is the case of the TINU syndrome characterized by interstitial nephritis and bilateral uveitis, and the anti-glomerular basal membrane antibody syndrome), and finally in 10% of cases it is associated with systemic diseases (sarcoidosis, by Sjogren, LES). The pathogenesis is based on a cell-mediated immune response and in most cases removing the causative agent is the gold standard of therapy. However, a percentage of patients, in a variable range from 30% to 70% of cases, do not fully recover renal function, due to the rapid transformation of the interstitial cell infiltrate into vast areas of fibrosis. Clozapine is a second generation atypical antipsycothic usually used for the treatment of schizophrenia resistant to other types of treatment; it can cause severe adverse effects among which the best known is a severe and potentially fatal neutropenia, furthermore a series of uncommon adverse events are recognized including hepatitis, pancreatitis, vasculitis. Cases of acute interstitial tubular nephritis associated with the use of clozapine have been described in the literature, although this complication is rare. Medical personnel using this drug need to be aware of this potential and serious side effect. We describe the case of a 48-year-old man who developed acute renal failure after initiation of clozapine.