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The uveal tract constitutes the middle layer of the eye and is formed by the iris and ciliary body in the anterior part and the choroid in the posterior part.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Uveitis possibly encompasses the most heterogeneous group of clinical pathologies. Currently, more than 100 subtypes are described.</p><p id="par0010" class="elsevierStylePara elsevierViewall">In our country, an annual incidence of 51.91 cases/100,000 inhabitants and a prevalence of 144.85/100,000 inhabitants is estimated.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The most frequent type is anterior uveitis and its aetiology differs slightly between regions.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">This provides a diagnostic perplexity for ophthalmologists and non-ophthalmologists dedicated to this challenging pathology. And this is of no small importance since, as is well known, uveitis is one of the main causes of vision loss and 10% of blindness cases in developed countries.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Uveitis generally begins at a young age and therefore the disease burden throughout life is possibly greater than that of other age-associated eye diseases such as glaucoma or age-related macular degeneration.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In the last 30 years there has been tremendous progress in the field of ocular inflammation. At the end of the last century, most ophthalmologists attributed uveitis to non-specific immune mechanisms, and used glucocorticoids almost exclusively as the principal treatment. Currently, uveitis has come to be defined as a subspecialty within ophthalmology.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Progress has been made in leaps and bounds and there has been a paradigm shift in the diagnosis and treatment of uveitis. The use of sophisticated immunological biomarkers, molecular and genetic diagnostic methods, advances in imaging techniques, and the development of biological therapies and immunotherapies<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> have revolutionised the field of uveitis.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Although its exact pathogenesis is still unclear, it is recognised to be multifactorial, encompassing genetics, immune dysregulation, gut microbiota abnormalities, and environmental factors.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">It has been hypothesised that the combination of certain genetic or epigenetic factors with an immune response regulation imbalance leads to the development of this disease.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Genetic predisposition is a major factor in the development of uveitis. Both major histocompatibility complex (MHC) and non-MHC genes have been identified as participants in the pathogenesis of various subtypes of uveitis. The TH17 immune response is key in the pathogenesis of non-infectious uveitis.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">In multiple ethnic populations it has been shown that HLA genes such as the HLA-DR4 and DRB1/DQA1 show a strong association with Vogt-Koyanagi-Harada disease, and the HLA-B51 gene is strongly linked with Behçet’s disease (BD).<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> But the most powerful association of a uveitic aetiology with an HLA gene is the association between Birdshot chorioretinopathy with the HLA-A29 gene. This association has been verified to such an extent that it has even been stated that Birdshot uveitis would only affect individuals who are HLA-A29 positive.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Other uveitis genetic research studies have identified genes such as SUMO4, MCP-1, and CTLA4 associated with Vogt-Koyanagi-Harada disease or BD.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">The Genome-Wide Association Studies (GWAS) have provided a powerful tool to investigate genetic predisposition to uveitis, and this has revealed several associated genes such as IL23R/C1orf141, STAT4, and ADO/ZNF365/EGR2.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">However, the genes identified to date only account for a small fraction of the genetic basis of uveitis and most of the pathogenic genes have yet to be discovered.</p><p id="par0070" class="elsevierStylePara elsevierViewall">Furthermore, epigenetic factors such as DNA methylation and non-coding RNA (ncRNA) play an important role in the development of uveitis. The application of new technologies such as whole exome and whole genome sequencing and epigenetic modifications such as mRNA modification with N6-methyl-adenosine (m6A) will be helpful to discover new pathogenic genes for uveitis.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">The understanding of the genetic and epigenetic mechanisms of uveitis may provide a foundation for the development of new, more precise and personalised strategies in its treatment in the future.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Continuing with the pathogenesis of uveitis, another of the fundamental pathogenic mechanisms in its development is molecular or antigenic mimicry. Molecular mimicry is a term that defines the similarity of different antigens that can be confused by the immune system<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> and it has been put forward as the initiating event of most autoimmune diseases.</p><p id="par0085" class="elsevierStylePara elsevierViewall">The immune system is usually tolerant of autoantigens, especially in immune privileged sites such as the eye.</p><p id="par0090" class="elsevierStylePara elsevierViewall">This ocular immune privilege is usually maintained by a number of mechanisms including anterior chamber-associated immune deviation, protective surfaces of intraocular cells, suppressive factors, and the blood–retinal barrier (BRB).</p><p id="par0095" class="elsevierStylePara elsevierViewall">The BRB is impermeable for large molecules such as antibodies and non-activated lymphocytes. Only previously activated lymphocytes are able to pass the tissue barriers to detect potential hidden pathogens and tumor cells. In other words: T cells that are activated by mimotopes outside of the eye can cross the BRB and enter ocular tissues.</p><p id="par0100" class="elsevierStylePara elsevierViewall">Therefore, autoimmunity to intraocular antigens must be initiated by activated T cells, which have their primary antigen outside of the eye. This antigen is not intraocular, but rather a cross-reaction to an extraocular or similar environmental antigen. This is the phenomenon known as “antigenic mimicry”. A long series of molecules and epitopes from pathogens (bacteria, viruses, fungi, parasites) and nutritional molecules such as bovine milk casein have been described as possible antigens or primary activators that could induce uveitis.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">The microbiota is assuming an important role in the pathogenesis of uveitis. There is increasing scientific evidence on the so-called “ocular microbiota”. The term refers to all types of commensal and pathogenic microorganisms present in the eye.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Commensal microbes have been demonstrated to play a fundamental role in regulating host physiology, the induction and development of the immune system, as well as the host's defense against pathogen invasion, although dysbiosis (unbalanced microbiota) could lead to microbial overgrowth and cause local or systemic inflammation.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Common bacteria isolated from the eye are gram-positive bacteria, including <span class="elsevierStyleItalic">Coagulase-negative staphylococcus</span>, <span class="elsevierStyleItalic">Streptococcus</span>, <span class="elsevierStyleItalic">Propionibacterium</span>, Diphtheroids and <span class="elsevierStyleItalic">Micrococcus.</span></p><p id="par0120" class="elsevierStylePara elsevierViewall">There are still many unanswered questions, for example: how the intraocular microbiota and intraocular immunity interact with the environment to modulate inflammatory eye diseases? In addition, there are many difficulties in carrying out studies of the ocular microbiota, since most of the microorganisms that constitute the intraocular microbiome are sparse in number, anaerobic, and extremely difficult to culture.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Therapies manipulating commensal microbiome and that prime the host immune system to counteract inflammatory processes and diseases, such as inflammatory bowel disease, graft-versus-host disease, HIV infection, and psychological-stress-induced inflammation have emerged as a novel therapeutic strategy. Nonetheless, it remains to be determined whether the clinical intervention targeting gut microbiome is effective in improving uveitis in humans.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Of particular interest are recent advances in obtaining images of each layer of the uveal tract, including enhanced depth imaging using optical coherence tomography (EDI-OCT), swept-source OCT technology for deeper visualization of the choroid, fundus autofluorescence, indocyanine green angiography with confocal scanning, laser imaging for sharper images, and wide-field and ultra wide-field imaging techniques.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> OCT angiography (OCTA) provides retinal and choroidal vascularization indices higher than conventional angiography and is a technique that is revolutionizing the clinical practice of uveitis. This powerful technique is giving us more information about many enigmatic diseases, such as white dot syndromes and Vogt-Koyanagi-Harada disease.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Current treatment for noninfectious uveitis includes corticosteroids, nonbiologic immunosuppressive agents, and anticytokine biologic therapies.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Although corticosteroids continue to be the most potent and effective treatment for the treatment of intraocular inflammation, the results of their use are not optimal and in some cases the control of flares is not achieved.</p><p id="par0145" class="elsevierStylePara elsevierViewall">Patients diagnosed with uveitis sometimes require periocular or intravitreal corticosteroid injections which generally lead to many intraocular adverse effects such as increased intraocular pressure and cataracts, although newer dexamethasone intraocular implants approved for use in uveitis have shown less risk of complications compared with other locally applied corticosteroids.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> The use of systemic glucocorticoids, either orally or intravenously, produce known adverse events such as hyperglycemia and bone metabolism disorders.</p><p id="par0150" class="elsevierStylePara elsevierViewall">The drugs most commonly used to replace corticosteroids are nonbiologic immunosuppressive agents including azathioprine, methotrexate, mycophenolate, cyclosporine, and tacrolimus, which can potentially produce significant side effects.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">More recently, anticytokine biologic therapies have led to a breakthrough in therapeutic options for non-infectious uveitis.</p><p id="par0160" class="elsevierStylePara elsevierViewall">In 2016, adalimumab was the first anti-TNF biologic drug approved by the FDA for the treatment of non-infectious intermediate uveitis, posterior uveitis, and panuveitis, and marked a before and after in the management of non-infectious uveitis.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Real-life studies have shown that the use of adalimumab as second line (or further) biotherapy could be predictive for discontinuation due to inefficacy of this therapy.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> In addition, undifferentiated uveitis is the most prone to premature discontinuation of adalimumab due to adverse events.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">Certolizumab and golimumab<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> are other anti-TNF therapies, which, although they have not yet obtained approval for the treatment of uveitis, they have shown efficacy in reducing flares and improving visual acuity, with the additional advantage that certolizumab can be used during pregnancy due to its minimal maternal-fetal placental transfer.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">Subsequently, other biological therapies such as tocilizumab, an interleukin-6 receptor inhibitor, have shown improvement in macular edema in cases of refractory uveitis with minimal adverse effects.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> IL-1 inhibitors such as anakinra and canakinumab have shown efficacy in the treatment of refractory uveitis secondary to BD.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Rituximab,<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> an inhibitor of the CD-20 protein found on the surface of lymphocytes, and abatacept, a soluble protein that blocks the CD-28 molecule, have shown promising results in the treatment of refractory uveitis in juvenile idiopathic arthritis.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">In the diagnosis of uveitis it is important to know the incidence, as well as the prevalence of certain infectious diseases and their endemic nature. The resurgence of infections such as mosquito-borne diseases, dengue, West Nile virus, Chikungunya virus, and other diseases play an important role in the proper diagnosis of infectious uveitis in certain endemic regions and in non-endemic countries. Migration flows and globalization have promoted the reactivation of certain infectious diseases such as tuberculosis in non-endemic countries and an increase in tuberculous uveitis in immigrants living in non-endemic areas.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> In recent years, due to a relaxation of prevention measures, an upturn in sexually transmitted infections has been detected and therefore an increase in uveitis secondary to syphilis is also being observed.</p><p id="par0180" class="elsevierStylePara elsevierViewall">During the COVID-19 pandemic, ocular complications were described in acute SARS-CoV-2 infection, such as conjunctivitis, episcleritis, and anterior uveitis, among others. But above all, it has been the COVID-19 vaccines that have produced various ocular adverse effects, including facial nerve palsy, abducens nerve palsy, acute macular neuroretinopathy, central serous retinopathy, thrombosis, uveitis, multiple evanescent white dot syndrome, Vogt-Koyanagi-Harada disease reactivation, and new-onset Graves’ disease.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">The COVID-19 pandemic has also had a special impact on patients with uveitis, as they had to be monitored through remote consultations by means of videoconference or telephone call.</p><p id="par0190" class="elsevierStylePara elsevierViewall">Finally, after reading this editorial on ocular immunology, inflammation and uveitis, you will realize that determining the aetiology of uveitis is often guesswork and sometimes the diagnosis is conjectured. The investigation must include possible systemic causes and additionally, given the therapies used, its management requires the participation of non-ophthalmologist specialists such as internists, rheumatologists, infectologists or immunologists.</p><p id="par0195" class="elsevierStylePara elsevierViewall">Therefore, a multidisciplinary approach<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> with the use of uveitis units is becoming more and more necessary, for any specialty; in addition, these non-ophthalmic specialists must not only be astute observers of clinical signs and symptoms, but they must also be adept at interpreting complex laboratory tests, genetics, imaging, polymerase chain reaction (PCR) results of ocular fluids, ophthalmic pathology and its clinical-pathological correlation.</p><p id="par0200" class="elsevierStylePara elsevierViewall">In conclusion, the management of uveitis has progressed far beyond the simple administration of steroids. It now involves a methodical search for the underlying aetiology of the disease, including microbiology, immunology, genetics, molecular diagnosis, and biomarkers.</p><p id="par0205" class="elsevierStylePara elsevierViewall">We hope you enjoy reading the articles referenced in this editorial and that this article may help improve the management and care of patients with uveitis.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Financing</span><p id="par0210" class="elsevierStylePara elsevierViewall">No funding of any kind has been received for the production of this article.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflict of interests</span><p id="par0215" class="elsevierStylePara elsevierViewall">The author declares that she has no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Financing" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflict of interests" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:21 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The eyeball" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "R.S. 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Journal Information
Vol. 160. Issue 6.
Pages 258-260 (March 2023)
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Vol. 160. Issue 6.
Pages 258-260 (March 2023)
Editorial
Uveitis
Uveítis
Patricia Fanlo Mateo
Unidad de Enfermedades Autoinmunes y Minoritarias, Servicio de Medicina Interna, Hospital Universitario de Navarra, Pamplona, Spain
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