Noninfectious Uveitis

**3**

**Chapter 1**

**1. Introduction**

Introductory Chapter: Current and

Uveitis represents a significant burden of visual loss causing around 10–15% of all cases of blindness in the United States, and it is the fifth cause of visual loss in the developed world, accounting for up to 20% of legal blindness [1]. Visual loss due to uveitis currently has a significant impact on the productivity and quality of life of many patients worldwide. Therefore, advances in research and development of diagnostic techniques and therapeutic strategies are crucial for patients suffering

One of the main obstacles that ophthalmologists face on diagnosis and treatment of eye disease is the unique complexity of the physical and physiological barriers, as well as the delicate anatomical structures of the human eye. This biologic scenario, particularly in highly destructive tissue disorders like infectious and autoimmune uveitis, represents a challenge for early and accurate diagnosis and effective therapy. Even today, with all possible diagnostic resources available in tertiary eye care facilities, more than 30% of patients suffering from uveitis do not have a definitive etiologic diagnosis [2]. The same is true for current therapeutic methods which suffer from lack of specificity, and are limited to availability at the site of inflammation due to the complex anatomical and physiological characteristics of the eye [3]. Therefore, the development of improved diagnostic methods and therapeutic modalities for inflammatory ocular disorders has recently received special and

In the past decades, scientific research at the molecular level and technological development have revolutionized medicine like never before. Such advances, particularly those related to detection technology are significant since early, and accurate diagnosis allows prompt and adequate treatment. Molecular biology has revolutionized medicine with the promise of improving our understanding of the pathogenic mechanisms that produce disease. The human plasma proteome has become the primary target for molecular analysis directed to improve the diagnosis and monitor the therapeutic response of many systemic and ocular disorders. There are at least eight different classes of plasma proteins classified by designed and functional basis. Two such groups are: the "tissue leakage products," which are intracellular proteins that are released into the plasma due to cell damage or death; and the "foreign proteins," which come from infectious microorganisms or parasites

from many forms of infectious and autoimmune intraocular inflammation.

intense attention by the uveitis research community.

**2. Advances in diagnosis of uveitis**

Future Trends in the Diagnosis

and Management of Uveitis

*Alejandro Rodriguez-Garcia and C. Stephen Foster*

#### **Chapter 1**

## Introductory Chapter: Current and Future Trends in the Diagnosis and Management of Uveitis

*Alejandro Rodriguez-Garcia and C. Stephen Foster* 

#### **1.Introduction**

Uveitis represents a significant burden of visual loss causing around 10–15% of all cases of blindness in the United States, and it is the fifth cause of visual loss in the developed world, accounting for up to 20% of legal blindness [1]. Visual loss due to uveitis currently has a significant impact on the productivity and quality of life of many patients worldwide. Therefore, advances in research and development of diagnostic techniques and therapeutic strategies are crucial for patients suffering from many forms of infectious and autoimmune intraocular inflammation.

 One of the main obstacles that ophthalmologists face on diagnosis and treatment of eye disease is the unique complexity of the physical and physiological barriers, as well as the delicate anatomical structures of the human eye. This biologic scenario, particularly in highly destructive tissue disorders like infectious and autoimmune uveitis, represents a challenge for early and accurate diagnosis and effective therapy. Even today, with all possible diagnostic resources available in tertiary eye care facilities, more than 30% of patients suffering from uveitis do not have a definitive etiologic diagnosis [2]. The same is true for current therapeutic methods which suffer from lack of specificity, and are limited to availability at the site of inflammation due to the complex anatomical and physiological characteristics of the eye [3]. Therefore, the development of improved diagnostic methods and therapeutic modalities for inflammatory ocular disorders has recently received special and intense attention by the uveitis research community.

#### **2. Advances in diagnosis of uveitis**

In the past decades, scientific research at the molecular level and technological development have revolutionized medicine like never before. Such advances, particularly those related to detection technology are significant since early, and accurate diagnosis allows prompt and adequate treatment. Molecular biology has revolutionized medicine with the promise of improving our understanding of the pathogenic mechanisms that produce disease. The human plasma proteome has become the primary target for molecular analysis directed to improve the diagnosis and monitor the therapeutic response of many systemic and ocular disorders. There are at least eight different classes of plasma proteins classified by designed and functional basis. Two such groups are: the "tissue leakage products," which are intracellular proteins that are released into the plasma due to cell damage or death; and the "foreign proteins," which come from infectious microorganisms or parasites and are released or exposed to the plasma are the main, but not the only source for diagnostic assays. The plasma proteome has been typically analyzed by electrophoresis combined with chromatography and mass spectrometry [4]. However, many new diagnostic methods have emerged, like DNA microarrays, which may be used for disease diagnosis by detecting biomarkers (genotyping, post-translational modifications, multi-SNPs marker screening, and determination of disease-relevant genes); detecting infectious agents (bacteria, virus, and fungal detection); and genetic disorders (detection of chromosome abnormalities, mutation analysis, and screening of SNPs) [5]. This methodology may interact with other molecular detection methods to study different disease biomarkers from blood, saliva, and other body tissues and fluids like aqueous and vitreous humors. For example, the ability to measure a wide range of molecular components in saliva and compare them to the plasma proteome has become a feasible way to study immunologic markers and microbes for autoimmune and infectious diseases, respectively [6]. Another application of molecular tools like polymerase chain reaction (PCR) has improved the timing for confirmatory diagnosis of infectious uveitis and endophthalmitis [7]. However, the number and type of microorganisms that may be studied in a given sample is limited due to differences in amplification techniques, as well as primers and fluorescent labels availability on multiplex detection systems. More recently, the use of next-generation sequencing (NGS) has proven to be a promising diagnostic strategy for multiple detections of common and rare microorganisms, including virus associated with infectious uveitis and endophthalmitis present in single vitreous samples. An important contribution of NGS so far is related to the improvement of pathogen detection in cases of negative culture endophthalmitis [8].

 Despite these promising advances, the development and implementation of many new diagnostic techniques still need to be assessed for their effectiveness regarding precision and accuracy; sensitivity and specificity; predictive value, and cost-benefit balance convenience to be standardized and used widely on a clinical basis.

Imaging diagnostic methods have also suffered significant improvement. The development of the ocular coherence tomography (OCT) which provides noncontact, *in vivo*, cross-sectional, high-speed, and high-resolution images of different ocular structures including the cornea, anterior segment, retina, and optic nerve has evolved from low resolution time-domain image acquisition technology, to spectral domain and swept-source high-definition OCT with en-face, more in-depth, and extended image acquisition modalities [9]. Another significant advancement in diagnostic imaging technology is the development of multimodal devices, which allow the use of different complementary imaging techniques like fluorescein and indocyanine green digital angiography, wide-field angiography, autofluorescence, OCT, and OCT-Angiography all-in-one single machine [10]. Such multimodal equipment has permitted saving costs, time, office space, and less personal rotation when performing multiple studies to a single patient.

Another innovative and very exciting development in ocular image analysis has to do with artificial intelligence (AI), a new field of computer science research that will dramatically change the diagnostic and therapeutic pathways of many chronic degenerative ocular conditions including uveitis. Artificial intelligence already permits early identification of diabetic retinopathy, glaucoma, age-related macular degeneration, retinopathy of prematurity, refractive errors, and cardiovascular risk factors based on color fundus photographs through deep learning algorithms [11]. Very soon, patients will routinely be taken a non-mydriatic fundus photograph at the pre-exam room by an ophthalmic technician allowing the accurate recognition of many systemic associated and primary ocular disorders. Image pattern recognition is the basis of this technology, which requires

*Introductory Chapter: Current and Future Trends in the Diagnosis and Management of Uveitis DOI: http://dx.doi.org/10.5772/intechopen.86377* 

 a large number of fundus photographs to learn from (training dataset) as well as a separate database for validation (validation dataset) [12]. This technology may be coupled with imaging diagnostic devices, such as a fundus camera with fluorescein, indocyanine green, and autofluorescence capabilities; SD-OCT, swept soured OCT, OCT-A, corneal topography, visual system aberrometry and wavefront imaging, anterior segment tomography, and ultrasound, among others, for the detection of specific diagnoses. Soon, this technology will be applied to patients with different forms of uveitis with specific and characteristic clinical appearance analyzed by different image diagnostic devices that will permit the accurate computerized diagnosis in a routine exam.

#### **3. Advances in therapy of uveitis**

 Topical therapy with eye drops makes up more than 90% of ophthalmic formulations including different corticosteroids and non-steroidal anti-inflammatory eye drops. However, their intraocular bioavailability is limited by tear clearance, nasolacrimal drainage, and limited penetration related to the anterior biological barriers including the corneal epithelium and the hemato-aqueous barrier. Moreover, protein binding and enzymatic degradation also account for the limited absorption into target tissues [13]. Many different drug delivery strategies, including prodrugs, chemical permeability enhancers, stimuli-responsive *in situ* gels, and drug delivery carriers like liposomes are being developed to counter the elimination mechanisms mentioned before [14]. The emergence of nanotechnology has impulse the development of such therapeutic strategies for many ocular diseases including uveitis. Different active drugs have been coupled with nanocarriers to overcome the ocular anatomic barriers for direct interaction with specific intraocular tissues, increasing their therapeutic efficiency. Drugs loaded into nanoparticles improve their pharmacodynamics and pharmacokinetics and at the same time, reduce their immunogenicity, biorecognition, and toxicity [15]. One of the most developed fields in ophthalmic pharmacology is the sustained-release intraocular drug delivery devices. Polymeric-controlled release microparticle injections and implants, cyclodextrin-based nanospheres, nanocapsules, microencapsulated cells, liposomes, nano-micelles, and dendrimers are among the most used methods to deliver anti-inflammatory and immunomodulatory drugs into the eye [15, 16]. Such strategies are intended to avoid the side effects of prolonged systemic corticosteroids and immunosuppressive chemotherapy. An intraocular injection may provide a high-dose of medication directly into the site of inflammation with few or no systemic side effects. However, this therapeutic approach is not exempt from potential serious complications like endophthalmitis, vitreous hemorrhage, and retinal detachment, particularly when the administration needs to be repeated several times to achieve their purpose [17]. So far, several polymeric implants are already being used for the control of intraocular inflammation, including corticosteroid formulations [18]. Many other nanotechnology carriers mentioned before may be coupled with different drugs like cyclosporine-A, ganciclovir, non-steroidal anti-inflammatory drugs, anti-angiogenic, and anti-glaucoma medications to be delivered intraocularly. However, because nanoparticles are recently developed, they face several challenges including the need for extensive *in vivo* studies in animal models and then in humans to validate their efficacy and safety. Another essential task is the identification of specific ocular disease-related biomarkers and their cellular and molecular function to develop target-specific drugs that block the biomarker function.

More recently, transscleral iontophoresis has been employed to deliver sufficient dose medications into the eye in a non-invasive way, avoiding injections or the implantation of sustained-release drug devices with minimal side effects [19].

On the other hand, many specific, target-directed biologic molecules manufactured by recombinant DNA technology are used for treating joint systemic and ocular autoimmune inflammation. Such molecules consist of monoclonal antibodies, soluble receptors, cytokines, natural cytokine antagonists, and accessory molecules in antigen presentation. They play critical roles in the pathogenesis of inflammatory uveitis, like TNF-α, IL-1, IL-6; IL-17, T, and B-lymphocytes; and adhesion molecules like LFA-1 and ICAM-1 [20].

Future therapeutic strategies that may be exploited include immune tolerance, inducers of apoptosis, neuroprotective agents, gene therapy, gene transcription factors, and other modulating molecules that permit reprogramming of cells *in vivo*.

#### **Author details**

Alejandro Rodriguez-Garcia1 \* and C. Stephen Foster2

1 Tecnologico de Monterrey, School of Medicine and Health Sciences, Institute of Ophthalmology and Visual Sciences, Monterrey, Mexico

2 Massachusetts Eye Research and Surgery Institute, Ocular Immunology and Uveitis Foundation, Harvard Medical School, Boston, MA, USA

\*Address all correspondence to: arodri@tec.mx

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Introductory Chapter: Current and Future Trends in the Diagnosis and Management of Uveitis DOI: http://dx.doi.org/10.5772/intechopen.86377* 

#### **References**

[1] Durrani OM. Degree, duration, and causes of visual loss in uveitis. British Journal of Ophthalmology. 2004;**88**(9):1159-1162. DOI: 10.1136/ bjo.2003.037226

[2] Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. American Journal of Ophthalmology. 2005;**140**(3):509-516

[3] Loftsson T, Sigurdsson HH, Konradsdottir F, Gisladdottir S, Jansook P, Stefansson E. Topical drug delivery to the posterior segment of the eye: Anatomical and physiological considerations. Die Pharmazie - An International Journal of Pharmaceutical Sciences. 2008;**63**(3):171-179. DOI: 10.1691/ph.2008.7322

[4] Anderson NL, Anderson NG. The human plasma proteome. Molecular and Cellular Proteomics. 2002;**1**(11):845-867. DOI: 10.1074/mcp. R200007-MCP200

[5] Yoo SM, Choi JH, Lee SY, Yoo NC. Applications of DNA microarray in disease diagnostics. Journal of Microbiology and Biotechnology. 2008;**19**(7):635-646. DOI: 10.4014/ jmb.0803.226

[6] Streckfus CF, Bigler LR. Saliva as a diagnostic fluid. Oral Diseases. 2002;**8**:69-76

 [7] Chiquet C, Lina G, Benito Y, Cornut PL, Etienne J, Romanet JP, et al. Polymerase chain identification in aqueous humor of patients with postoperative endophthalmitis. Journal of Cataract and Refractive Surgery. 2007;**33**(4):635-641. DOI: 10.1016/j. jcrs.2006.12.017

[8] Deshmukh D, Joseph J, Chakrabarti M, Sharma S, Jayasudha R, Sama KC, et al. New insights into culture negative endophthalmitis by unbiased next generation sequencing. Scientific Reports. 2019;**9**(1):844. DOI: 10.1038/ s41598-018-37502-w

[9] Invernizzi A, Cozzi M, Staurenghi G. Optical coherence tomography and optical coherence tomography angiography in uveitis: A review. Clinical and Experimental Ophthalmology. 2019;**47**(3):357-371. DOI: 10.1111/ceo.13470

[10] Nagiel A, Lalane RA, Sadda SR, Schwartz SD. Ultra-widefield fundus imaging: A review of clinical applications and future trends. Retina. 2016;**36**(4):660-678. DOI: 10.1097/ IAE.0000000000000937

[11] Ting D, Cheung C, Lim G, Tan G, Jama NQ. Development and validation of a deep learning system for diabetic retinopathy and related eye diseases using retinal images from multiethnic populations. Journal of the American Medical Association. 2017;**318**(22):2211- 2223. DOI: 10.1001/jama.2017.18152

[12] Hogarty DT, Mackey DA, Hewitt AW. Current state and future prospects of artificial intelligence in ophthalmology: A review. Clinical and Experimental Ophthalmology. 2018;**47**(1):128-139. DOI: 10.1111/ ceo.13381

[13] Bisht R, Mandal A, Jaiswal JK, Rupenthal ID. Nanocarrier mediated retinal drug delivery: Overcoming ocular barriers to treat posterior eye diseases. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology. 2018;**10**(2):e1473. DOI: 10.1002/wnan.1473

[14] Ye T, Yuan K, Zhang W, Song S, Chen F, Yang X, et al. Prodrugs

incorporated into nanotechnologybased drug delivery systems for possible improvement in bioavailability of ocular drugs delivery. Asian Journal of Pharmaceutical Sciences. 2013;**8**(4):207- 217. DOI: 10.1016/j.ajps.2013.09.002

[15] Weng Y, Liu J, Jin S, Guo W, Liang X, Hu Z. Nanotechnology-based strategies for treatment of ocular disease. Acta Pharmaceutica Sinica B. 2017;**7**(3):281-291. DOI: 10.1016/j. apsb.2016.09.001

[16] Al-Halafi AM. Nanocarriers of nanotechnology in retinal diseases. Saudi Journal of Ophthalmology. 2014;**28**(4):304-309. DOI: 10.1016/j. sjopt.2014.02.009

[17] Avery RL, Bakri SJ, Blumenkranz MS, Brucker AJ, Cunningham ET Jr, D'Amico DJ, et al. Intravitreal injection technique and monitoring: Updated guidelines of an expert panel. Retina. 2014;**34**(Suppl. 12):S1-S18. DOI: 10.1097/IAE.0000000000000399

[18] Pavesio C, Zierhut M, Bairi K, Comstock TL, Usner DW, Group FAS. Evaluation of an intravitreal fluocinolone acetonide implant versus standard systemic therapy in noninfectious posterior uveitis. Ophthalmology. 2010;**117**(3):567.e1-575. e1. DOI: 10.1016/j.ophtha.2009.11.027

[19] Hastings MS, Li SK, Miller DJ, Bernstein PS, Mufson D. Visulex: Advancing iontophoresis for effective noninvasive back-to-the-eye therapeutics. Drug Delivery Technology. 2004;**4**:53-57

[20] Sharma SM, Fu DJ, Xue K. A review of the landscape of targeted immunomodulatory therapies for noninfectious uveitis. Ophthalmology and therapy. 2018;**7**(1):1-17. DOI: 10.1007/ s40123-017-0115-5

#### **Chapter 2**

## Vogt-Koyanagi-Harada Disease

*Cristhian A. Urzua* 

#### **Abstract**

Vogt-Koyanagi-Harada (VKH) disease is an autoimmune disorder characterized by bilateral intraocular inflammation, exudative retinal detachments, and extraocular manifestations in the auditory, integumentary, and central nervous systems (CNS). This condition is driven by T-cell-mediated autoimmunity directed against melanocytes present in the uveal tissue, in a specific genetic context. The diagnosis is based on clinical presentation, accounting with a set of standardized diagnostic criteria. Studies have reported that patients who have a significant delay in the diagnosis and/or clinical signs of the chronic stage of the disorder have a poorer prognosis and thus special efforts have to be performed in order to have an early diagnosis, together with an appropriate treatment. In that sense, the development of tools that allow us to detect this disease and its degree of severity is extremely important. In this line, novel candidate biomarkers—such as quantification of mRNA levels of NOD and glucocorticoid receptor—have been recently reported, and they represent significant advances that can help the clinician to improve patient categorization and outcomes.

**Keywords:** Vogt-Koyanagi-Harada disease, VKH, vitiligo, treatment response, biomarkers

#### **1.Introduction**

Vogt-Koyanagi-Harada (VKH) disease is an inflammatory and autoimmune condition characterized by intraocular inflammation, serous retinal detachments, and extraocular manifestations at the level of the auditory, integumentary, and central nervous systems (CNS) [1–3].

No epidemiological studies have been carried out on this condition. However, it has been related to certain geographical areas, such as Latin America and Asia, with a significant contribution of native origin. In this regard, its frequency has been reported up to 22.4% of uveitis causes in referral centers around the world [4–8].

Recently, significant advances have been reported regarding treatment options and novel approaches to evaluate and categorize this group of patients, in order to personalize follow-up and management in each subject and thus achieve better functional and anatomic outcomes [9].

#### **2. Pathogenesis**

 The main disease mechanism would be driven by cell-mediated autoimmunity directed against melanocyte-related proteins, which are located mainly in the uveal tissue, skin, and CNS. A significant body of evidence has been published regarding the role of genetic associations. The human leukocyte antigen (HLA) appears as a

risk factor for VKH, and particularly HLA-DR alleles have shown more consistent data [10, 11]. Moreover, several associations with certain polymorphisms have been reported in Chinese population. In this regard, important advances regarding the role of genetic background in VKH have been introduced by Yang et al. This group has been extensively studying different polymorphisms in VKH in Chinese population [12].

Regarding the role of the immune system in VKH pathogenesis, CD4 + lymphocytes and key cytokines—such as interleukin-2 and interferon gamma—appear to play central roles in the development of autoimmunity against melanocyteassociated proteins [13–15].

#### **3. Clinical findings**

A prodromal stage may precede the ocular involvement. This stage is characterized by tinnitus and meningismus, which may include nausea, vomiting, stiffness of the neck and back, as well as headache as a frequent symptom. However, despite its high frequency, headache cannot be considered as a sufficient criterion for the definition of meningismus. By this stage, if lumbar puncture is performed, it may be returned with pleocytosis [3, 16].

After this prodromal phase of neurological findings, the disease continues toward ocular involvement, presenting bilateral acute panuveitis, with a low grade of anterior chamber cells and vitreous haze, and diffuse choroiditis, associated with exudative retinal detachments and optic disc swelling [1, 16–18] (**Figure 1**).

Following this initial uveitic phase, a significant group of patients may develop chronic granulomatous inflammation, and progressive depigmentation of the fundus resulting in "sunset glow fundus" appearance and/or chorioretinal atrophy (**Figure 2**). These clinical findings frequently result from insufficiently treated or from a late diagnosis, and they have been associated with poorer functional outcomes [19–21].

 Experimental studies have reported choroidal infiltration of activated lymphocytes in patients with "sunset glow fundus," suggesting a persistent low grade of subclinical inflammation, which may be implicated in the mechanism of autoimmune-mediated ocular depigmentation and atrophy [22, 23].

 In addition, integumentary findings may be seen in some patients. In this regard, alopecia, poliosis, and vitiligo are classic signs related to pathological autoimmune response directed to pigmented tissues (**Figure 3**).

#### **Figure 1.**

*Color fundus photo showing extensive areas of subretinal fluid and bullous serous retinal detachment in a 37-year-old female with VKH.* 

#### **Figure 2.**

*Extensive fundus depigmentation in a VKH patient after 1 year of disease onset. Note the characteristic "sunset glow" appearance of the fundus.* 

#### **Figure 3.**

*Integumentary findings in VKH patients. (A) Areas of vitiligo in the perioral area and (B) poliosis in two adult patients with VKH.* 

#### **4. Diagnosis**

Diagnosis of VKH involves a comprehensive ophthalmic evaluation, in order to confirm the presentation of characteristic findings described above. Importantly, the bilateral nature of the condition and the presence of panuveitis, with areas of subretinal fluid and/or retinal detachments, as well as the inexistence of evidence of alternative diseases are hallmarks of the set of standardized diagnostic criteria previously published (**Table 1**) [3, 9, 24]. In that sense, the presence of integumentary and/or neurological findings defines the category of diagnosis (probable


placoid areas of hyperfluorescence, pooling within subretinal fluid, optic nerve staining) and diffuse

choroidal thickening without evidence of posterior scleritis on *ultrasonography* 


#### **Table 1.**

*Revised diagnostic criteria for Vogt-Koyanagi-Harada disease\*.* 

if only ocular findings are found, incomplete if at least an extraocular criteria is documented, and complete if all the extraocular criteria may be found) [3, 4, 25].

Despite these previously published diagnostic criteria, a moderate agreement among uveitis experts has been recently reported for the diagnosis of VKH, with a calculated kappa coefficient of 0.4 [25].

#### **5. Treatment**

The cornerstone of the therapy corresponds to the use of systemic corticosteroids (CS), based on the following principles: early treatment initiation, intensive (initial dose of prednisolone/prednisone of 1 mg/kg/day, with a maximum dose of 80 mg/day), and prolonged (at least 6 months) [27, 28].

Despite this aggressive therapy with systemic CS, a significant proportion of VKH patients present refractoriness, remaining with active inflammation and thus requiring immunomodulatory therapy (IMT) [9]. This subset of refractory patients has better functional outcomes if an earlier IMT is indicated [9].

Therefore, an early CS-response categorization should be carried out, in order to distinguish and to separate subjects with a potential benefit of early IMT initiation. In that sense, some clinical predictive factors of GC refractoriness have been described, such as baseline VA ≤ 20/200, fundus depigmentation at diagnosis, and chronic disease, which are important facts to be considered in the context of an appropriate VKH initial evaluation [9].

Currently, a trend to the use of IMT, as first-line therapy, has been observed, with no preference in terms of a specific immunosuppressant [29].

#### **6. Novel biomarkers of treatment response and disease activity**

As stated above, systemic CS play a significant role for the management of VKH patients. CS have been broadly used for autoimmune and inflammatory diseases. It is a family of lipophilic medications that has its main mechanism of action at the level of the cellular nucleus, interacting directly with the DNA, enhancing or repressing gene expression [30].

Some significant developments have been published regarding potential biomarkers of treatment response based on the glucocorticoid receptor (GR), which is a ligand-dependent transcriptional factor [30]. Urzua et al. have found a distinct expression profile of GR isoforms that allows to categorize GC response as early as 2 weeks [26]. This laboratory-based approach is based on the quantification of mRNA levels of GR isoforms in two time points and a ratio calculation between both measurements. Furthermore, an in vitro assay has been developed, using a similar strategy based on GR expression measurements after in vitro manipulation of immune cells of VKH patients. In that sense, a single blood sample is required, and patient compliance is not mandatory since sampling for a second time or a CS systemic therapy is not required to perform the experiments (Urzua et al., data not published).

As previously described VKH may present with episodes of subclinical inflammation in which, despite clinical examination may appear with no disease activity, there is evidence of inflammatory foci at the level of choroid, using ancillary testing [17]. Although there have been efforts to standardize clinical examination in patients with uveitis, some issues remain, mainly related to the accuracy of measurements and subjectivity, especially with the clinical quantification of flare and vitreous inflammation [31, 32]. In that sense, a novel laboratory-based tool to categorize disease activity in VKH patients has been recently initiated. Following previous reports regarding the utility of GR quantification to evaluate treatment response in VKH, a protein implicated in this pathway has been studied as a candidate biomarker. A phosphatase of the MAPK pathway has been evaluated in different in vitro experimental conditions, and it has been found to have an association between its expression profile and disease activity in VKH patients (Urzua et al., data not published).

 Significant evidence has been published regarding potential biomarkers for disease activity. In that sense, Yang et al. have reported a higher expression of NOD1/NOD2 and osteopontin (a matricellular protein) in patients with active VKH in comparison with healthy controls and inactive VKH [33, 34].

 These promising biomarkers may help clinicians to make decisions in an inflammatory condition, which can present with significant choroidal inflammation with the absence of clinical evidence of active inflammation, with a resulting worsening in prognosis, in terms of sunset glow fundus and visual outcomes [21].

#### **Author details**

Cristhian A. Urzua1,2

1 Facultad de Medicina, Clinica Alemana-Universidad del Desarrollo, Santiago, Chile

2 Laboratorio de Enfermedades Autoinmunes Oculares y Sistemicas, Facultad de Medicina, Universidad de Chil, Santiago, Chile

\*Address all correspondence to: cristhian.urzua@uchile.cl

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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 [22] Inomata H, Sakamoto T. Immunohistochemical studies of Vogt-Koyanagi-Harada disease with sunset sky fundus. Current Eye Research 9 Suppl:35-40, 1990

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[24] da Silva FT, Damico FM, Marin ML, et al. Revised diagnostic criteria

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[26] Urzua CA, Guerrero J, Gatica H, Velasquez V, Goecke A. Evaluation of the Glucocorticoid Receptor as a Biomarker of Treatment Response in Vogt-Koyanagi-Harada Disease. Investigative Ophthalmology & Visual Science. 2017;**58**:974-980

[27] Nazari H, Rao NA. Resolution of subretinal fluid with systemic corticosteroid treatment in acute Vogt-Koyanagi-Harada disease. The British Journal of Ophthalmology. 2012;**96**:1410-1414

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**19**

**Chapter 3**

**Abstract**

Behcet's Disease

still not well-understood severe uveitis.

immunosuppressants

**1. Introduction**

positive pathergy test.

(**Table 2**) [4, 5].

*Karina Julian and Bahram Bodaghi*

Defined as a systemic vasculitis developing in a particular genetic background, uveitis is one of the hallmarks to diagnose Behcet's disease and also one of the important clinical criteria to start systemic treatment. Isolated anterior non granulomatous uveitis with hypopyon, even though a classic clinical picture, actually develops in a minority of cases. In most patients, uveitis is posterior, associated to small vessel occlusive retinal vasculitis, carrying a high risk of permanent retinal damage and subsequent severe visual loss. The guarded natural prognosis of the disease has positively changed in the last decennials with the introduction of biologic immunosuppressant agents in the field of uveitis. Vision can be preserved in most cases provided a prompt early diagnosis and adequate therapy. The potential role of oral bacteria as a triggering factor for autoinflammation in predisposed hosts is interesting, opening the door to prevention in this

**Keywords:** hypopyon uveitis, occlusive vasculitis, retinitis, retinal atrophy,

prognosis guarded and usually urges to start proper treatment.

Named after the Turkish ophthalmologist, Hulusi Behcet (who described in 1937 the classic triad of oral aphthosis, genital ulcers, and hypopyon uveitis) [1], Behcet's disease (BD) is a systemic relapsing obliterative vasculitis, affecting arteries, veins, and mainly capillaries. Even though almost all organs can eventually be involved, the compromise of the central nervous system (CNS) and eye makes the disease's

There is no specific test to diagnose Behcet's disease: by definition, its diagnosis is a clinical one. In 1990, the International Study Group for Behcet's disease established a set of diagnostic criteria in an attempt to unify the five different ones used by that time [2]. They required the presence of oral ulcerations plus any two of genital ulcerations, typical defined eye lesions, typical defined skin lesions or a

Far from being solved, the debate on the diagnostic criteria is still active, and many other sets have been proposed. Among them, the Behcet's Disease Research Committee of Japan defines the diagnosis as complete or incomplete upon the presence of major and minor symptoms (**Table 1**) [3]. The Dilsen criteria (revised in 2000) seems more suitable to the European patients suffering from Behcet's disease

## **Chapter 3**  Behcet's Disease

*Karina Julian and Bahram Bodaghi* 

### **Abstract**

 Defined as a systemic vasculitis developing in a particular genetic background, uveitis is one of the hallmarks to diagnose Behcet's disease and also one of the important clinical criteria to start systemic treatment. Isolated anterior non granulomatous uveitis with hypopyon, even though a classic clinical picture, actually develops in a minority of cases. In most patients, uveitis is posterior, associated to small vessel occlusive retinal vasculitis, carrying a high risk of permanent retinal damage and subsequent severe visual loss. The guarded natural prognosis of the disease has positively changed in the last decennials with the introduction of biologic immunosuppressant agents in the field of uveitis. Vision can be preserved in most cases provided a prompt early diagnosis and adequate therapy. The potential role of oral bacteria as a triggering factor for autoinflammation in predisposed hosts is interesting, opening the door to prevention in this still not well-understood severe uveitis.

**Keywords:** hypopyon uveitis, occlusive vasculitis, retinitis, retinal atrophy, immunosuppressants

#### **1.Introduction**

Named after the Turkish ophthalmologist, Hulusi Behcet (who described in 1937 the classic triad of oral aphthosis, genital ulcers, and hypopyon uveitis) [1], Behcet's disease (BD) is a systemic relapsing obliterative vasculitis, affecting arteries, veins, and mainly capillaries. Even though almost all organs can eventually be involved, the compromise of the central nervous system (CNS) and eye makes the disease's prognosis guarded and usually urges to start proper treatment.

There is no specific test to diagnose Behcet's disease: by definition, its diagnosis is a clinical one. In 1990, the International Study Group for Behcet's disease established a set of diagnostic criteria in an attempt to unify the five different ones used by that time [2]. They required the presence of oral ulcerations plus any two of genital ulcerations, typical defined eye lesions, typical defined skin lesions or a positive pathergy test.

Far from being solved, the debate on the diagnostic criteria is still active, and many other sets have been proposed. Among them, the Behcet's Disease Research Committee of Japan defines the diagnosis as complete or incomplete upon the presence of major and minor symptoms (**Table 1**) [3]. The Dilsen criteria (revised in 2000) seems more suitable to the European patients suffering from Behcet's disease (**Table 2**) [4, 5].



#### **Table 2.**

*Behcet's disease: the Dilsen criteria.* 

#### **2. Clinical picture**

#### **2.1 Non-ocular disease**

Almost every organ and system can eventually be affected by this severe vasculitis. Painful, recurrent oral and genital ulcers are so frequent that their presence is part of the diagnostic criteria [6]. Other skin manifestations are papulopustules,

#### *Behcet's Disease DOI: http://dx.doi.org/10.5772/intechopen.85265*

acneiform dermatitis, and erythema nodosum [7]. Arthritis is also a common manifestation of the disease [8]. Gastrointestinal involvement affects around 3–30% of cases with symptoms overlapping inflammatory bowel disease [9]. Central nervous system (CNS) involvement can touch almost 31% of patients and makes the prognosis guarded [10]. Venous thrombosis and arterial aneurysms are present in around 25% of cases [11].

#### **2.2 Ocular disease**

The classic clinical picture is the one of recurrent, bilateral, non-granulomatous posterior or panuveitis with retinal vasculitis. This is the case for almost 80% of patients, while in around 10% disease manifests as anterior, non-granulomatous uveitis with hypopyon and eventually synechiae (**Figure 1**) [12].

Disease seems to be more severe in males, and ocular pain, redness, photophobia, and blurred vision are almost always present.

Retinitis is also a classic and sight-threatening manifestation of posterior segment involvement, leading most of the time to retinal atrophy. Indeed, Behcet's disease is one of the differential diagnoses of macular atrophy related to uveitis (**Figure 2**) [13].

Retinal vasculitis is the hallmark of the disease, it is obliterative in nature, it affects both arteries and veins, and, most importantly, it involves the capillaries [14].

Behcet's disease is mainly a capillaropathy, being fluorescein angiography (FA) essential to its proper diagnosis and management. FA will better delineate areas of non-perfusion (**Figure 3**), capillary leakage (**Figure 4**), and vascular remodeling. The "fern-leaf"-shaped leakage pattern from capillaries, even though not pathognomonic, is highly evocative of BD (**Figure 5**).

 Given the highly vascularized nature of choroidal tissue, it is not surprising to see choroidal involvement during active disease. Indocyanine green angiography (ICGA) shows irregular filling of the choriocapillaris, choroidal filling defects, and dye leakage from choroidal vessels [15]. Enhanced depth imaging optical coherence tomography (EDI-OCT) shows increased subfoveal choroidal thickness even in eyes without evident uveitis activity, making this finding a possible indicator of subclinical ocular inflammation in patients with BD [16].

Optic neuropathy (ON), although considered a rare manifestation of Behcet´s disease, might actually be overshadowed by uveitis' complications. It can appear during the course of already known BD (and should be considered as part of the neuro-BD disease spectrum), or it can even be the first manifestation of the disease (BD should then be kept in mind as a differential diagnosis of optic neuropathy

#### **Figure 1.**

*Hypopyon and nasal synechiae in the left eye of a young patient suffering from acute reactivation of anterior uveitis related to Behcet's disease.* 

#### **Figure 2.**

*Horizontal OCT scan from the right eye of a patient with advanced Behcet's disease posterior uveitis. Generalized retinal atrophy and retinal pigment hypertrophy are seen.* 

#### **Figure 3.**

*Late-frame fluorescein angiography showing extensive peripheral areas of retinal non-perfusion affecting the inferior temporal area of the right eye.* 

#### **Figure 4.**

*Early frame fluorescein angiography of the right eye of a patient suffering from Behcet's disease retinal vasculitis. Areas of capillary leakage are present as well as peripheral ischemia and optic disc hyperfluorescence.* 

#### **Figure 5.**

*Late-frame fluorescein angiography of the right and left eye from a patient suffering from Behcet's disease associated with retinal vasculitis. Typical "fern-leaf" pattern of capillary leakage is present.* 

in regions where its prevalence is high) [17]. The prognosis of BD-associated ON seems not to be as poor as the one of BD uveitis, with excellent response to the combination of corticosteroids and immunosuppressants and recovery as the rule [18, 19]. However, the use of cyclosporine should be avoided in these cases since it could promote the development of neurologic involvement [20].

#### **3. Etiology and pathogenesis**

 Despite years of research, BD remains idiopathic. Even though there are sporadic cases all around the world, disease is more prevalent along the ancient silk route and in countries located between 30 and 45 north latitude through the Mediterranean Basin, the Middle East, and Far East regions such as China and Japan [21]. This particular geographic distribution points toward a genetic predisposing factor. The high frequency of HLA-B51 among a wide range of affected ethnic populations highlights the importance of a special genetic background: even though not considered as part of the diagnostic criteria, the positivity of HLA-B51 increases the risk of BD in around six times [22].

Besides the classic and well-known predisposition to BD associated with HLA-B51 positivity, new insights on disease's pathogenesis came out from genome-wide association studies (GWAS). The disruption of different biological pathways might determine the intrinsic biological process in multifactorial diseases, as BD. Six biologic pathways have been recently identified as possible mechanisms in the pathogenesis of BD:focal adhesion pathway, MAPK (mitogen-activated protein kinase) signaling, TGF (transforming growth factor) beta signaling, ECM-receptor interaction, complement and coagulation cascades and proteasome pathways [23].

 Then, on this special genetic background, environmental factors might play a role as triggers for disease development. Infectious agents have been postulated as these triggering factors. Recently, a relationship between periodontal disease and specific polymorphisms of interleukin (IL)-1alpha and (IL)-1beta in Turkish patients with BD was reported, making periodontitis-induced autoinflammatory response a candidate for the development or severity of BD via IL-1 gene alteration [24]. Improvement of oral health among this high-risk population might affect BD course, leading to a better prognosis [25].

Neutrophils' activation plays a predominant role in BD; this is evidenced through the positivity of pathergy test, one of the diagnostic criteria for the disease [2, 26]. The activation of the innate immune system against environmental and/ or autoantigens in this particular genetic background is then perpetuated by the adaptive immune system [27].

#### **4. Diagnosis and differential diagnosis**

As it was already stated, diagnosis is clinical and based on the presence of different combinations of symptoms and signs. In the acute attack, patients usually show raised inflammatory acute reactants (sedimentation rate and C-reactive protein) and high levels of white blood cells, mainly neutrophils [28, 29].

HLA-B51 is positive in around 50–70% of cases even though not necessary for the diagnosis [22, 30].

Differential diagnosis of hypopyon uveitis encompasses HLA-B27 associated, endogenous/exogenous endophthalmitis, toxic anterior segment syndrome (TASS) after cataract surgery, and masquerade syndromes [31–35]. BD-associated retinal vasculitis is unique in its predilection for capillaries but a similar picture can eventually be found in cases of HLA-B27 posterior uveitis with retinal vasculitis [36–39].

#### **5. Treatment**

 Topical treatment is reserved for the minority of cases in which anterior uveitis is the only ocular disease manifestation. Prednisolone acetate with or without cyclopentolate is usually enough to stop episodes of anterior non-granulomatous uveitis. However, if these attacks are frequent or inflammatory quiescence requires more than three drops per day of prednisolone acetate for long periods, systemic treatment should be initiated.

The majority of cases presenting with posterior uveitis will require systemic treatment to control the sight-threatening manifestations of the disease.

High-dose systemic corticosteroids (1 g intravenous of Solu-Medrol or 1 mg/kg/ day of oral prednisone) are useful in severe acute inflammatory attacks. However, they should not be administered alone given the high risk of flare up while tapering and the side effect profile of high doses [40].

Azathioprine and cyclosporine have both shown to be effective in BD's uveitis in two different randomized clinical trials (RCT) [41–43]. In many cases, a single agent is not enough to control uveitis, and a combination of them is administered. Drugs are usually well tolerated in long term, providing the proper check of their own side effects' profile is performed (liver toxicity for azathioprine, renal toxicity for cyclosporine). The likelihood of patients on cyclosporine to develop CNS complications should be kept in mind, and the drug is not recommended in the management of BD's associated optic neuropathy [44].

High levels of tumor necrosis factor (TNF) alpha are present in BD's uveitis [45]. The blockage of this inflammatory pathway is therefore a very effective approach to disease control. Infliximab (a chimeric monoclonal antibody against TNF alpha) and adalimumab (a fully humanized monoclonal antibody) are both widely used in the treatment of BD-associated posterior uveitis with high rates of success [46]. Adalimumab has the advantage of subcutaneous administration, theoretically improving patients' quality of life [47].

Other anti-TNF alpha molecules, such as certolizumab pegol and golimumab, have also shown positive results in small case series of BD's uveitis [48, 49].

#### *Behcet's Disease DOI: http://dx.doi.org/10.5772/intechopen.85265*

Interferon alpha-2ª is a very effective biologic treatment for BD's associated posterior uveitis [50]. Subcutaneously administered, it has rapid positive effect and also long relapse-free period making prophylactic maintenance treatment unnecessary [51, 52]. Drug is administered as a monotherapy after discontinuation of all previous immunosuppressive drugs (including corticosteroids). However, the associated flu-like syndrome limits the use of this important agent in the management of BD's uveitis.

Cytotoxic agents (chlorambucil and cyclophosphamide) were in the past the drug of choice for this severe form of uveitis [53, 54]. Nowadays, however, given the more specific and less toxic agents available, they are only used in those settings

 Intravitreal steroids (either triamcinolone acetonide, fluocinolone, or dexamethasone implant) are adjuvant rescue treatment in recalcitrant cases not responding to systemic medication or whenever systemic medication is contraindicated [55]. Their effect is always transitory and associated with the risk of local complications (mainly cataract and glaucoma).

#### **6. Prognosis**

Visual prognosis is directly related to anatomical location of inflammation and rapid introduction of proper treatment. The minority of cases manifesting only by anterior uveitis usually shows excellent visual prognosis. Posterior uveitis, however, might be sight-threatening even if only one acute attack involves the macula. The development of modern biologic agents has positively changed the natural guarded prognosis of this disease even though there is still a low proportion of cases that will not respond to different combinations of treatment.

#### **Author details**

Karina Julian1,2\* and Bahram Bodaghi3

1 Eye Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates

2 Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, United States

3 IHU FOReSIGHT, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France

\*Address all correspondence to: karinajulian@hotmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Section 2

Infectious Uveitis
