LITHUANIAN UNIVERSITY OF HEALTH SCIENCES MEDICAL ACADEMY
FACULTY OF MEDICINE DEPARTMENT OF PAEDIATRICS
Ophthalmological changes caused by autoimmune
diseases in children
Student: Miriam Schmuck Supervisor: Lina Jankauskaitė MD, PhD Co-Supervisor: Ausra Snipaitiene, MD
SUMMARY ... 3
ACKNOWLEDGEMENTS………..4
CONFLICT OF INTEREST ... 4
ABBREVIATIONS ... 5
INTRODUCTION ... 8
AIMS AND OBJECTIVES ... 9
1. LITERATURE REVIEW ... 10
1.1 Anatomy of the eye………...………..9
1.2 Ocular immunity ... 10
1.3 Uveitis in children ... 11
1.4 Immunopathology of uveitis ... 14
1.5 Pathological changes during uveitis ... 16
1.6 Diagnostics………....16 1.7 Medication ... 18 1.8 Treatment guidelines ... 19 2. RESEARCH METHODOLOGY ... 21 3. RESULTS ... 22 4. DISCUSSION OF RESULTS ... 25 5. CONCLUSION ... 29 6. LIMITATIONS ... 29 REFERENCES ... 30
SUMMARY
Background:
Uveitis is the inflammation of the uveal parts of the eye which can lead to severe complications or blindness.
Aim and Objectives:
The aim of this review is to discuss the clinical features of uveitis related to rheumatological diseases in childhood and new treatment strategies. The objectives are to discuss:
1. Early identification of predictive signs for autoimmune uveitis development 2. Quality of life of an affected individual
3. New treatment options for autoimmune uveitis
Methods:
Literature search was conducted in Medline/Pubmed and Google scholar using a combination of the following terms “Ophthalmo*” OR “eye” OR “ocular” OR “uveitis” AND “Rheuma*” OR “Autoimmune” OR “Systemic” OR “Lupus” OR “Sarcoidosis” OR “Arthritis” AND “Child“ OR “Childhood” OR “Juvenile” OR “Pediatric”. Articles that were in English, not older than 5 years before the search date with free full text access, were manually sorted according to inclusion and exclusion criteria.
Results:
After the initial search and filter activation, 2947 articles were identified, of which 44 were further analyzed. Ten articles were finally included into this literature review. Diseases that were investigated, include Juvenile idiopathic arthritis (JIA), childhood-onset Systemic Lupus erythematosus (cSLE) and Sarcoidosis.
Conclusion:
1. Predictive factors for disease development are early-onset of disease, oligo-articular type of JIA, AHA (anti-histone antibody) presence in girls, ANA (antinuclear antibody) presence in both genders, and increased erythrocyte sedimentation rate (ESR)
2. Compared to the average individual age, children suffering from autoimmune uveitis will experience social marginalization, learning difficulties and depression at a higher level
3. New medications (tocilizumab) and new combinations of previously known medications have shown excellent results, treating childhood-onset autoimmune uveitis
ACKNOWLEDGEMENTS
I want to express my sincere gratitude to my supervisor, Lina Jankauskaite MD, PhD and to my co-supervisor, Ausra Snipatiene MD for their support.
CONFLICT OF INTEREST
ABBREVIATIONS
ABA: Abatacept AC: Anterior chamber
ACAID: Anterior chamber associated immune deviation ADA: Adalimumab
AHA: Antihistone antibody ANA: Antinuclear antibody APC: Antigen-presenting cell AqH: Aqueous humor ATT: Antitubercular therapy AU: Autoimmune uveitis
ß-TGF: beta Transformin growth factor CAU: Chronic autoimmune uveitis CD: Cluster of differentiation CMV: Cytomegalovirus
CpG: Unmethylated doesycytidine-phosphate-guanine cSLE: Childhood-onset systemic lupus erythematosus CTP: Consensus treatment plan
CTPs: Consensus treatment plans DC: Dendritic cell
DNA: Deoxyribonucleic acid
EAU: Experimental autoimmune uveitis ERA: Enthesitis associated arthritis ESR: Erythrocyte sedimentation rate ETA: Etanercept
FasL: Fas ligand
HLA: Human leukocyte antigen HRQoL: Health related quality of life HSV: Herpes simplex virus
HTLV-1: Human T-cell lymphotropic virus type-1 IFN: Interferon
IL: Interleukin INX: Infliximab
IRBP: Iron-responsive element binding protein IVIG: Intra-venous immunoglobulin
JIA: Juvenile idiopathic arthritis
JIA-U: Juvenile idiopathic arthritis associated uveitis LEF: Leflunomide
LPS: Lipopolysaccharide
MHC: Major histocompatibility complex MTB: Mycobacterium tuberculosis mTEC: Medullary thymic epithelial cells MTX: Methotrexate
NOD2: Nucleotide-binding oligomerization domain-containing protein 2 N Treg: natural regulatory T cell
OCT: Optical coherence tomography PMN: Polymorphonuclear leukocyte PTX: Pertussis toxin
QoL: Quality of life RA: Rheumatoid arthritis RF: Rheumatoid factor RNP: Ribonucleoprotein RTX: Rituximab
SLE: Systemic lupus erythematosus
SSA: Sjögren’s-syndrome-related antibody SSB: Sjögren’s-syndrome Typ B
SUN: Standardization of uveitis nomenclature TBC: Tuberculosis
TCR: T cell receptor TCZ: Tocilizumab
TGF: Transforming growth factor Th: T helper cell
TINU: Tubulointerstitial nephritis and uveitis TNF-α: Tumor necrosis factor α
T reg: Regulatory T cell VA: Visual Acuity
VEGF: Vascular endothelial growth factor VKH: Vogt-Koyanagi-Harada
INTRODUCTION
Rheumatic diseases in childhood can be associated with several pathological changes of the eye, as well as peri-orbita and the orbit. The ocular involvement varies from conjunctivitis, scleritis, keratitis, uveitis, retinal vasculitis to optic neuritis. Uveitis is the most common of the previously mentioned ocular manifestations [1]. The most disquieting outcome of ocular inflammation is legal blindness. It is the duty of the attending physician, albeit it is a rheumatologist, ophthalmologist, pediatrician or, all of them as a team to prevent this consequence. Therefore, the specific features and early warning signs for uveitis and other ophthalmic inflammatory conditions need to be made very clear for all doctors. The diagnosis of ocular inflammation is challenging, especially in patients of young age. It is often late due to difficulties taking complex anamnestic data, poor patient compliance, the concealed nature of the disease and the ability to mimic other conditions associated with ocular pathology [2]. Profound knowledge about the different phenotypes of ocular inflammation and its causes must be existing to shorten the diagnostic process and prevent treatment delay. Only if the know-how is present and close communication between doctors of all relevant specialties can be assured, dramatic clinical outcomes for still so young patients can be prevented.
The aim of this review is to discuss the clinical features of uveitis related to rheumatological diseases in childhood, to summarize most recent data with regard to early identification of predictive signs of autoimmune uveitis development, the quality of life of an affected individual and new treatment strategies.
AIMS AND OBJECTIVES
The aim of this review is to discuss the clinical features of uveitis related to rheumatological diseases in childhood and new treatment strategies.
Through thorough analyzation of recent studies these objectives have been discussed: 1. Early identification of predictive signs for autoimmune uveitis development 2. Quality of life of an affected individual
1. LITERATURE REVIEW
1.1 Anatomy of the eye
The human eye consists of six main parts: the sclera, which is the protective cover; the cornea, which transfers light rays to deeper layers of the eye; the choroid containing blood vessels and is responsible for nourishment. The retina, which contains photoreceptor cells; the lens and the iris which control the amount of light reaching the photoreceptor cells (Fig. 1) [3].
Fig. 1: Schematic diagram of the human eye shown in cross-section [4]
1.2 Ocular immunity
The eye has a unique and highly sophisticated set of immune properties which allow it to keep a low level of immune activity and a high level of tissue integrity (known as an immune privilege). It gives the right tools for the protection and prevention of inflammation. A physical barrier, the so-called blood-retinal barrier, and the absence of lymphatic drainage play a key role. Molecular mechanisms, like release of immunosuppressive factors, such as beta transferrin growth factor (ß-TGF)and Fas ligand (FasL), by ocular cells and low expression of major histocompatibility complex (MHC) class II molecules in antigen-presenting cells, are also part of the immune properties of the eye [5].
Simultaneously, these processes assist with the inactivation of the immune response of pigment epithelium cells. These cells resemble the functions of macrophages since they can secret anti-inflammatory cytokines. Experimental studies in vitro showed that these cells can inhibit T cell proliferation [6]. Peripheral immune tolerance is achieved of anterior chamber-associated immune deviation (ACAID). It elicits antigen specific CD8 and antigen-specific T regulatory cells (T reg) which in turn downgrade immune response. T regs prevent the evolution of autoimmune diseases by maintaining self-tolerance and protecting from pathogen-induced immune pathology [7]. Central immune tolerance is the elimination of self-reactive T cells in the thymus. This also applies to retinal antigens [8].
An immature T cell interacts with its allied tissue antigen through its peculiar T cell receptor (TCR). Tissue antigens are generated in the thymus by the ectopic expression, led by gene-regulatory protein autoimmune regulator (AIRE). Those specific to the eye are the retinal antigens iron-responsive element binding protein (IRBP) and arrestin [9]. AIRE mutations result in the absence or reduced expression of tissue antigens in the thymus, failure of auto-reactive T cells elimination, and hence in a progressive multi-organ failure [10]. Animal model studies have shown that IRBP levels are directly related to the amount of auto-reactive T cells capable of triggering uveitis [8]. Low levels of retinal antigens permit the escape of activated T cells from the elimination by the thymus. Under normal circumstances, the reactive T cells regulated by the peripheral immune tolerance, which makes T cells tolerant to their specific antigen when they encounter these antigens in healthy tissues. Retinal antigens are located in the eye, a somewhat unapproachable anatomical unit, allowing the activated T cell to confront a microbial antigen with a structural resemblance to their peculiar antigen [11]. Several studies by Xu et al. have shown that labored expression of a retinal antigen in the periphery leads to tolerance and thus, the prevention of autoimmunity [12]. This labored expression is transmitted via vaccination with naked deoxyribonucleic acid (DNA) or retroviral delivery. The immune privilege may trigger ocular autoimmunity by sealing off retinal antigens in the eye and interfering with the peripheral tolerance [13].
1.3 Uveitis in children
Uveitis is an inflammation of the uveal components of the eye, namely the iris, choroid and retina [14]. It causes 10-15% of visual impairment, and in 35% of affected people it leads to visual loss or legal blindness [15]. According to different studies, the incidence of uveitis is 17-52 per 100 000/year. The prevalence is 38–714 cases per 100 000/year. The uveitis prevalence, phenotype, and disease progression depend on patient demographic characteristics, such as age, gender and race.
Uveitis is classified according to different criteria, including anatomical location, clinical course, cause, histopathology or lateralism of the inflammation. Most often, it is classified according to the
anatomical site of infection, in anterior, intermediate, posterior and pan-uveitis. According to the clinical course, it can be acute, chronic or recurrent. If uveitis is classified according to etiology, it can be either infectious or non-infectious and granulomatous and non-granulomatous. Uveitis can be present bilaterally or only in one eye [7].
Table 1: Uveitis classification according to anatomical location [7]
Anterior uveitis Intermediate uveitis
Posterior uveitis Panuveitis
Clinical presentation Acute, unilateral uveal inflammation Bilateral vitreous inflammation Usually painless inflammation of retina, choroid, papilla or optic nerve Intermixture between the features of anterior and posters uveitis Clinical symptoms Blurred vision, photophobia and pain Blurred vision and floaters Floaters, scotomas and decreased visual acuity Intermixture between the features of anterior and posters uveitis Etiology Idiopathic or associated with rheumatological conditions (most often seronegative spondyloarthropa thies) Idiopathic or associated with rheumatological conditions (most often sarcoidosis or multiple sclerosis) Idiopathic or associated with rheumatological conditions (most often sarcoidosis) Idiopathic or associated with rheumatological conditions (most often sarcoidosis, Bechet disease and VKH) Complications Anterior or posterior synechiae Macular edema, retinal vasculitis and neovascularizatio n of the optic disk and retina
Glaucoma, cataract and retinal detachment Same as anterior and posterior uveitis Vogt-Koyanagi-Harada (VKH)
Uveitis is extremely rare in the pediatric population. It only accounts for 5-10% of all uveitis cases [16]. However, it can result in severe morbidity since children have a higher tendency to develop complications. Those may implicate lifelong disabilities or even blindness. The little patient’s inability to verbalize complaints, poor cooperation in eye examination or the possible asymptomatic nature of uveitis itself cause treatment challenges [17]. Pediatric uveitis has its peculiarities, caused by a special set of underlying conditions. Uveitis etiological aspects in children are the same as for adults. Usually, in children, the uveal inflammation is caused by a syndrome of autoimmune origin. The prevalence of autoimmune uveitis with childhood-onset depends on gender and age of the patient [19]. Pediatric uveitis
can be associated with many autoimmune diseases, such as Blau syndrome, Vogt-Koyanagi-Harada syndrome, lupus erythematosus, many vasculitides like Kawasaki disease, Sarcoidosis or Bechet disease [22]. The vast majority of cases are either idiopathic or derived from JIA [18,19]. JIA-U (Juvenile idiopathic arthritis associated uveitis) arthritis is typically antecedent to ocular manifestations. Only in 3-7% of cases, uveal inflammation appears first [20]. In 90% of instances, uveitis occurs within the first four years after the diagnosis of JIA [21]. There are plenty of risk factors for chronic autoimmune uveitis because of the multifactorial basis of the pathology. The risk factors to develop autoimmune uveitis form four main categories as follows: genetics, environmental impulses, mistakenly activation of the immune system and clinical risk factors. A genetic study in pediatric uveitis have illustrated an association with polymorphism of HLA (Human leukocyte antigen) class II genes. HLA-DR1 has a positive effect on uveitis development. Children who are carriers of the specific DR1*11 or DR1*13 or HLA-B27 alleles are related more often with uveitis. However, genetic testing for uveitis was performed only on non-Hispanic white children with JIA [23].
Uveitis is associated with HLA genes, especially HLA class I and class II have shown to be relevant, including sympathetic ophthalmia, VKH disease, birdshot retinochoroidopathy, Bechet disease, and intermediate uveitis. HLA molecules play a significant role in antigen presentation. They trigger recognition of particular antigens and epitopes. Sympathetic ophthalmia and VKH disease are associated with HLA-DR4. In these two conditions immune responses target melanin-related antigens that are present in the retina [24]. In birdshot retinochoroidopathy, Bechet disease, and intermediate uveitis, immune responses affect retinal arrestin [25].
Roughly 10-20% of children with JIA will develop uveitis in the course of their disease. Predictive factors are positivity for antinuclear antibodies (ANA), young at arthritis diagnosis, and oligo-articular, or poly-articular RF (Rheumatoid factor) negative JIA. The earlier these signs appear, the higher the risk [26]. Therefore, the importance of regular ophthalmologic check-ups in this period should be emphasized. Besides, biomarkers have been identified as valuable predictors of disease activity and as terms of reference for treatment selection. Most recent research findings on these biomarkers are summarized in chapter 4 “Discussion”. A different set of risk factors is used for severe uveitis. Sight-threatening conditions are accurately defined as severe uveitis. In this situation short time interval between JIA and the associated uveitis diagnosis, young age at diagnosis of uveitis, male gender, uveitis preceding arthritis, and visual loss, or detection of complications at first ophthalmological examination are considered as particular risk [27]. Discrepancies in the epidemiology of pediatric uveitis related to racial genetic diversity and changing environmental conditions are presumed to be huge [28]. A study by Adwani et al. carried out in Oman asserted that none of all the investigated children with JIA presented with uveitis [29]. JIA is the most common pediatric disease, with JIA-U being its most common extra-articular finding. The more often encountered type, chronic anterior uveitis, is most
frequently associated with oligo-articular and RF negative poly-articular types of JIA. On the contrary, acute anterior uveitis is symptomatic, unilateral, and episodic. This type of JIAU is rare and related to enthesitis-associated arthritis (ERA) [30].
Recent discoveries related to predisposing factors for autoimmune uveitis in children are mentioned in Section 4 “Discussion”.
1.4 Immunopathology of uveitis
A disturbance of the immune mechanisms of the eye, caused by either endogenous or exogenous factors, has to occur to result in uveitis. If this attack is successful, an imbalance between inflammatory mechanisms and regulatory mechanisms constitutes. Enhanced generation of pro-inflammatory cytokines (Interleukin (IL)-2, IL-12, Tumor necrosis factor (TNF-α), interferon (IFN)-γ), chemotactic factors, complement system activation, antigen-presenting cells, T- and B-lymphocytes, endothelial cells and in contrast down-regulation of anti-inflammatory cytokines (IL-4, IL-10, IFN-α) can be observed thereupon [31]. Most of the knowledge about the autoimmune uveitis process has come from animal models. T cells specific for retinal antigens are of particular importance in the pathogenesis of the experimental autoimmune uveitis (EAU) in animals. These cells have shown to be able to transmit the disease from immunized donors to genetically cognate naive recipients. The hypothesis that T cells play the chief part in the pathogenesis of human uveitis is backed up by the medical efficacy, remedies attacking T cells (macrolide antibiotics, cyclosporine, FK-506, and mycophenolic acid). These medications interrupt the IL-2 receptor pathway which is responsible for signal transmission. As a result of this, T cell activation and antibodies specific for the IL-2 receptor are malfunctioning [32]. Antibodies to retinal antigens are a factor supporting the disease progression, but do not inhibit the ability to initiate the EAU by themselves. Their increased molecular size makes them unfit to cross the blood-retinal barrier [33]. As stated before, defects in central and peripheral tolerance, caused by a malfunctioning thymus, create non-tolerant retinal antigen-specific T cells, with the higher affinity of their TCR for peculiar antigen. Mice lacking AIRE, and mice transgenic for an IRBP-specific TCR on most T cells had a greater incidence of uveitis [34]. In addition to T cell elimination, the thymus produces T regs as well which can inactivate other types of T cells. By inhibiting other T cells located in the same tissue, they magnify their effect and regulate several mechanisms of autoimmunity.
A decrease in the number of T regs, accomplished by monoclonal antibodies, results in a predisposition of EAU [8]. T cells learn to recognize retinal antigens, by encountering microbial components in the periphery that are genetically like their specific retinal antigen. This process is called molecular/antigenic mimicry [35]. Microbial integral parts interfere with innate pattern recognition receptors on APCs (Antigen presenting cells), triggering abnormal signals that induce inflammation
(Figure 2). In mice, inflammatory stimuli have led to the activation of retinal antigen-specific T cells, a small number of which invaded the eye after a few hours [36]. They bind with their peculiar antigen, causing ocular alterations and inflammation after a couple of days. Once the inflammation has reached its peak, dendritic cells in the retina serve as APCs with an increased expression of MHC class II molecules [37]. CD45+ cells, found in the circulation, can function as APCs [38]. Even ten APCs, gaining entrance to the eye, are sufficient to cause EAU [13]. Within four days, retinal antigen-specific T cells mature in the spleen, are released into the circulation, and invade the eye. Here they trigger inflammation, including the secretion of chemokine and cytokines, activation of the retinal vasculature, and the activation of leukocytes from the bloodstream. These activated leukocytes (neutrophils, monocytes, and “non-specific” polyclonal T cells) induce tissue damage. Every single cell type has its particular use in the inflammatory process. The lack of any one of them could reduce or end the inflammation and alleviate EAU [39].
Figure 2: Critical checkpoints in uveitis, as defined from studies with animal models [40]
Medullary thymic epithelial cells (mTEC), Dendritic cell (DC), Lipopolysaccharide (LPS), Unmethylated deoxycytidine-phosphate-guanine (CpG), Mycobacterium tuberculosis (MTB), Pertussis toxin (PTX), Polymorphonuclear leukocyte (PMN), Iron-responsive element binding protein (IRBP), Interleukin (IL), Transformin growth factor (TGF), natural regulatory T cell (nTreg) , T helper cell (Th)
Regulatory mechanisms are a positive factor regarding predisposition, as well as necessary for the completion of the disease. An antigen present in the anterior chamber is released into the circulation and carried to the spleen by ocular APCs. In the spleen, it generates the formation of antigen-specific CD4+ and CD8+ regulatory T cells [41]. Up to now, it could only be proven that ACAID mechanisms alleviate inflammatory processes caused by ocular trauma. In some types of AU (Autoimmune uveitis), including Bechet syndrome and VKH disease, the inflammation is enhanced by the pathologic reduction
in T cell number and function [42/43]. CD4+ T cells, but not CD8+ T cells, can act as ocular inflammation effector T cells. Whether the role of CD8+ T cells is pathologic or regulatory for EAU is not clear yet. CD4+ T cells, that prevailing secret the IL-17 (so-called Th17 cells), play a key role in uveal inflammation [44]. In mice, the inactivation of IL-17 alleviates and finalizes EAU, while the inactivation of IFN-γ enhances it. CD4+ Th1 cells predominantly secret IFN-γ [45]. This phenomenon has also been observed with experimental arthritis and allergic encephalomyelitis and has led to the conclusion, that only Th17 cells are the elicitors of tissue-specific autoimmunity [46]. However, both Th1 and Th17 cells inhibit the ability to deteriorate ocular autoimmunity [45]. In animal models, an antigen recognized by the APC in the presence of mycobacteria triggers a response driven by Th17 cells, meanwhile an antigen recognized by a dendritic cell grown in vitro triggers a response driven by Th1 cells. These first incidences of uveitis in humans are not known yet. According to the mentioned hypothesis, the setting around initial antigen presentation is crucial for the following pathology. Different mechanisms of autoimmunity can lead to full-blown ocular disease or manifestation. Human uveitis is not always homogenous, even though different forms of it can be treated with the same medication [47].
1.5 Pathological changes during uveitis
Routine ophthalmologic examination is necessary for patients with JIA, and early treatment is critical to prevent visual loss. Complications associated with poorly controlled or untreated uveitis include posterior synechiae, cataract, glaucoma, cystoid macular edema, and band keratopathy [48]. Uveitis can result in numerous complications, varying from mild changes to severe sight-threatening consequences. Synechiae typically occur with severe cases of anterior uveitis. The hallmark of these adverse events is an irregularly shaped pupil which is visible with the naked eye. Another complication is band-shaped keratopathy which is the deposition of calcium salts in the cornea. The more centrally they are located, the stronger the visual impairment. Cataract can not only result from uveitis, but also steroid therapy. Ocular hypertension is another possible consequence of uveitis. It can be caused either by enhanced secretion of aqueous humor or diminished drainage of inflammatory fluids from the angle between iris and cornea. Just like all variants of hypertension, ocular hypertension is a common side effect of long-term steroid therapy and not rarely results in a severe instant rise in IOP (intra-ocular pressure). A complication of uveitis is cystoid macular edema which in circumstances of delayed treatment may cause irreversible vision loss [14]. Posterior synechiae, band-shaped keratopathy, and cataract according to this sequence, are the most common complications of uveitis [49]. When looking at JIA-U, the frequency of complications is lower in the developed world [50]. Superior access to medical care allows for early diagnosis and immediate pharmaceutical intervention [51]. Several factors
have shown to be of great value for the prediction of the prospective progress of JIA-U. Indicators for a poor prognosis are male gender, young age at the onset of uveitis, short interval between onset of arthritis and associated uveitis, and detection of synechiae during the diagnostic ophthalmologic examination (Table 3) [52].
Table 2: Some major uveitis conditions and their characteristics [40]
Disease Clinical symptoms Causality
Idiopathic uveitis Can present as anterior,
posterior or panuveitis Unknown. Believed to be autoimmune Sympathetic ophthalmia Retinal vasculitis, multifocal
choroiditis, intermediate uveitis or panuveitis
Penetrating wound to one eye and autoimmunization to ocular antigens
Uveitis associated with VKH Granulomatous inflammation of the uvea. Depigmentation of iris and retinal pigment epithelium
Unknown. Associations with immunological responses to proteins in the melanin synthesis pathway Anterior uveitis associated
with JIA
Chronic bilateral iridocyclitis, frequent with this particular variety of arthritis
Unknown. Autoimmune causes suspected
Uveitis associated with
Bechet disease Inflammation of the iris, uvea and retina; vitritis; vasculitis Unknown. Infectious trigger suspected. Associations reported with polymorphism of NOD2 and IL-15
Ocular sarcoidosis Granulomatous or non-granulomatous uveitis, anterior or posterior with deposits of leukocytes in the form of “mutton fat” keratin precipitates
Unknown. Ocular
manifestations of sarcoidosis not associated with NOD2
Anterior uveitis associated
with spondyloarthropathy Recurrent inflammation of the anterior segment, usually unilateral
Unknown. Microbial trigger suspected. Antigenic
similarity of HLA-B27 molecule an arrestin reported Anterior uveitis associated
with Blau syndrome Granulomatous inflammation of the iris Unknown. Infectious trigger suspected. Associations with polymorphism in NOD2
Nucleotide-binding oligomerization domain-containing protein (NOD), Interleukin (IL), Vogt-Koyanagi-Harada (VKH), Human leukocyte antigen (HLA)
It is the ophthalmologist task to perform a proper assessment of visual acuity, disease activity, and possible complications in both eyes. Through slit-lamp examination, the amount and nature of cells is measured, and the disease severity is graded based on the Standardization of Uveitis Nomenclature (SUN) criteria (Table 2) [53]. Aqueous humor analysis shows disease activity, while flares indicate increased activity or damage to the eye. Also, intra-ocular pressure (IOP) and fundoscopy are executed to rule out complications. Specifically, for early detection of cystoid macular edema an Optical coherence tomography (OCT) should be mandated. Once signs of uveitis are present, the etiology has to be identified. A neat clinical history, observations, and laboratory tests can yet lead to an accurate diagnosis. At first, the joints should be inspected to rule out JIA, hence being the most probable cause. Blau syndrome, presenting with scaly or papular skin rash, or Vogt-Koyanagi-Harada (VKH) syndrome, accompanied by skin manifestations, such as vitiligo, can be excluded through a dermatologic examination. TINU (Tubulointerstitial nephritis and uveitis) syndrome goes hand in hand with interstitial tubular nephritis and deafness [14]. A complete review of all systems is indicated in any case since most often systemic immune-mediated diseases are to be found. In the pediatric clinical setting to obtain a thorough history, the parents or caregivers of the patient should be interviewed [54]. More attention should be given to the child’s point of view on the disease itself and the disease and treatment-related adverse effects [55].
Table 3: SUN working group grading scheme for anterior chamber cells [28]
Grade Cells in the field
0 <1 0.5 1-5 1 6-15 2 16-25 3 26-50 4 >50 1.7 Medication
Before starting the treatment, it has to be investigated, which parts of the eye are affected by the disease (anterior, intermediate, posterior or panuveitis). At the very beginning, corticosteroids are the drug of choice [56]. However, systemic immunosuppression is not often warranted in the setting of uveitis as sole disease manifestation. In certain circumstances, surgery is indicated. Complications, such as cataract, band-shaped keratopathy (if affecting vision due to central cornea affection) and glaucoma,
due not leave an alternative to surgical intervention [14]. JIA-U is an example in which surgery does not bring the desired success and topical corticosteroids cause cataract, raise the IOP and lead to irreversible optic nerve destruction. Topical corticosteroid therapy is only very efficient in the case of unilateral uveitis with macular edema. If topical corticosteroids fail, methotrexate, cyclosporine and biologic agents are used [57]. Anyhow the choice of steroid-sparing agent depends on patient factors and physician’s personal experience with immunosuppressive pharmaceuticals [58]. All of the currently used immunosuppressive agents have the potential to cause serious side effects. New therapies include tumor necrosis factor (TNF) inhibitors, monoclonal antibodies attacking lymphocyte surface antigens [59], intravenous immunoglobulins (IVIG) [60], interferon-alpha [61], and additional topical remedies [60]. Sulfasalazine is the drug of choice for the prevention of anterior uveitis relapses [62].
TNF inhibitors, including etanercept and infliximab, have shown to be of a great use in several
systemic inflammatory syndromes, such as ankylosing spondylitis or juvenile rheumatoid arthritis [63]. TNFs drive the inflammatory process in animal models. Admittedly this phenomenon could be different in humans [64]. Several studies tackling this question have had unequal outcomes. More extensive clinical trials are required to analyze this drug and find the forms of uveitis responding to it.
Interferon-alpha reduces ocular inflammation. The mechanism is still unknown. Anyhow it is
highly effective for uveitis associated with Bechet disease, for which recurrent attacks of florid bilateral panuveitis with an occlusive retinal vasculitis are typical. This leads to a gradual diminution of visual acuity. The representatives of this drug class show beneficial outcome in 90% of people with Bechet disease. A decline in intraocular inflammation and amelioration of the visual acuity occurred in open-label trials [61].
Monoclonal antibodies targeted against lymphocyte surface antigens are useful because T
cells play a main part in inflammatory processes of the eye. A very few trials exist with monoclonal antibodies, but they already show promising results for the future. Patients refractory to a combined immunosuppressive therapy had a significant decline in ocular inflammation and uveitis recurrence rate, without severe adverse effects [61].
IVIG therapy is beneficial for patients suffering from birdshot chorioretinopathy or a chronic
bilateral posterior uveitis. The mechanism of action is still unknown, but IVIG treatment could achieve enhanced visual acuity and reduced cystoid macular edema. The advocate for this drug is the spared immunosuppression and a successively decreased risk for opportunistic infections. The biggest limitation is IVIGs high cost, elevated risk for thrombosis, and the transmission of blood-borne infections [61].
A group of pediatric rheumatologists and ophthalmologists with expert knowledge regarding autoimmune uveitis, analyzed to date existing trials with regard to the clinical management of JIA-U [65]. They formulated arranged consensus treatment plans (CTPs) for immune-modulatory medications, to summarize up-to-date treatment methods for rheumatic ophthalmological conditions. According to their data collection, two different treatment plans are proposed. First aims for children susceptible to steroid therapy. The second one is a solution for the therapy insecurities regarding the drug of choice for children in need of biological therapy. The options of biological agents are either methotrexate, infliximab, or adalimumab. The initial pharmaceutical approach is topical steroids. Failure of corticosteroid or tolerance to it, make alternative immunosuppressive remedies necessary. The clinical management of JIA-U is complex and recalcitrant. Both consensus treatment plans apply to children with any of the following features: 1) ongoing uveitis activity despite the use of topical steroids, 2) worsening uveitis activity while on topical steroids, 3) recurrent uncontrolled disease (>1+ anterior chamber (AC) cells) with the taper of topical steroids to twice daily or less, 4) development of new ocular complications attributable to either inflammation or treatment during topical steroid therapy, and 5) intolerant or unable to adhere to the treatment with topical corticosteroid drops. Due to their questionnaire, the vast majority of attending physicians would avoid the use of systemic corticosteroids in the case of Chronic auto-immune uveitis (CAU) in children. The ophthalmological screening should be carried out at least every two to six weeks in case of relapsing uveitis flares. In general, methotrexate (MTX) showed to be the favored first-line treatment for children with CAU that are not taking steroids concomitantly. In the case the MTX treatment failed to have the desired effect, it was substituted with infliximab (INX) by most doctors. Adalimumab (ADA) could be an alternative. If the child developed tolerance to MTX, either ADA or INX is an appropriate replacement. The first approach for this situation is the addition of anti-emetics, folic acid/leucovorin, and MTX dose adjustment [65].
2. RESEARCH METHODOLOGY
Search strategy
Literature was identified by searching Medline (Pubmed), Google scholar and Cochrane databases with the combination of the following terms: “ophthalmo*” OR “eye” OR “ocular” OR “uveitis” AND “rheuma*” OR “autoimmune” OR “systemic” OR “Lupus” OR “Sarcoidosis” OR “Arthritis” AND “pediatric” OR “paediatric” OR “child” OR “childhood” OR “juvenile” (Table 4). Filters that were applied from the very beginning are date range, species and age (Table 5). The resulting papers were manually excluded or included by reading the title and abstract. Articles considering humans below 18 years of age, suffering from autoimmune diseases related to JIA or SLE, were included. Initially information regarding sarcoidosis associated uveitis was searched as well, but all of the traced papers had to be withdrawn due to inadmissible research conduction. The reason for exclusion showed to be, adult patients or disease onset in adulthood, ocular manifestations of rheumatic eye disease other than uveitis, literature, systemic review and metanalysis, and high risk for bias (Table 6).
Table 4: Search criteria by terms
Ophthalmo AND Rheuma AND Juvenile
Eye Autoimmune Pediatric
Ocular Systemic Child
Uveitis Childhood
Table 5: Search criteria
Date range: Within 5 years
Species: Human
Age: Birth up to 18 years
Table 6: Exclusion and inclusion criteria
Inclusion Exclusion
Age: Birth up to 18 years Adult
Uveitis Ocular manifestations of rheumatic eye disease other than uveitis
Rheumatic diseases Literature or systemic review
Suspicion of bias
3. RESULTS
The search was done combining the following terms: “ophthalmo*” OR “eye” OR “ocular” OR “uveitis” AND “rheuma*” OR “autoimmune” OR “systemic” AND “pediatric” OR “paediatric” OR “child” OR “childhood” OR “juvenile”. Three filters were added: date range, species and age. This quest resulted in 2947 articles, whose titles and abstracts were analyzed and sorted according to the inclusion and exclusion criteria. Of these only 44 showed to be suitable for further analysis. 10 articles were investigated in this thesis. The others (n=34) were excluded from investigation on different grounds (exclusion criteria).
The facts and figures of each of these articles were extracted and arranged into a table in the following order: Author, total number of authors, year, country, type of study and summary. The details of this information can be found in Table 7 below. The articles are shown in the same sequence as they are analyzed in the following section (“Discussion”).
Table 7: Critical summary of the articles that were filtered after the initial search
Author Year Country Type of study Number of
participants
Condition Summary
Nordal et al. 2017 Norway, Denmark and
Sweden
Long-term cohort study
500 JIA-U Significant predictors of
uveitis are young age at onset of arthritis and presence of AHA in girls
and ANA in boys Haasnot et al. 2015 Netherlands Retrospective
cohort study
358 JIA-U Elevated ESR appears to be
a predictor for the occurrence of uveitis in
patients with JIA Haasnot et al. 2018 Netherlands,
Belgium, Germany and
USA
Cohort study 522 JIA-U Identification of the amino
acid serine at position 11 in HLA-DRβ1 is associated to increased risk of uveitis and
specific to females Walscheid et
al. 2015 Germany and Switzerland Cohort study 79 JIA-U s100A12 levels are found in Increased S100A8/A9 and the serum and aqueous humor of patients with autoimmune uveitis. Serum
reflects the activity of joint and eye diseases
Sen et al. 2017 UK Cross-sectional
Interview study 10 CAU themes including “impact This study shows that on school”, “social factors”
and “emotional reactions” are important domains influencing health related
quality of life in children with chronic autoimmune
uveitis Simonini et
al. 2017 Italy Retrospective, multi-center cohort study
94 JIA-U Type of disease, time and
type of systemic therapy to achieve inactivity predict different duration of uveitis
remission after treatment withdrawal
Bichler et al. 2015 Canada Single-center, retrospective study
15 JIA-U Children with JIA had
significantly more uveitis flares on LEF compared to
MTX despite receiving antiTNF-alpha comedication more
frequently Ramanan et
al. 2017 UK double-blinded, Multi-center, randomized, placebo-controlled
study
114 JIA-U ADA therapy-controlled
inflammation and was associated with a lower rate
of treatment failure than placebo among children with active JIA associated uveitis who were taking a
stable dose of MTX. Patients who received ADA
had a much higher incidence of adverse events
than those who received placebo Miserocchi et
al. 2016 Italy Retrospective study 8 JIA-U effective treatment option RTX may be a promising for refractory JIA-U leading
to long-term quiescence of uveitis, particularly for
patients who have not responded to other biologic
therapies Tappeiner et al. 2016 Germany, Switzerland, Spain, UK, Netherlands and Finland Retrospective study
17 JIA-U TCZ appears to represent a
therapeutic option for severe JIA-U that has been refractory to MTX and TNF-alpha inhibitors in
selected patients
Antinuclear antibody (ANA), Antihistone antibody (AHA), Juvenile idiopathic arthritis associated uveitis (JIA-U), Chronic autoimmune uveitis (CAU), Erythrocyte sedimentation rate (ESR), Human leukocyte antigen (HLA), Methotrexate (MTX), Adalimumab (ADA), Leflunomide (LEF), Tumor necrosis factor (TNF), Tocilizumab (TCZ), Rituximab (RTX), United Kingdom (UK), United States of America (USA)
Ten articles (Table 7) with newly gathered information regarding predictors for autoimmune uveitis in children, the quality of life of an affected child and new treatment options for autoimmune uveitis, were identified by the advanced literature search.
4. DISCUSSION OF RESULTS
Predictors of uveitis development
A Nordic population-based cohort study, by Nordal et al., evaluated predictive factors of uveitis in JIA. They showed that young age at onset of arthritis in JIA-U and presence of anti-histone antibodies (AHA) in girls, and the presence of anti-nuclear antibodies (ANA) in both genders were of particular importance. These features correlate with a higher incidence of inflammatory eye damage in the future. AHA belong to the ANA subtypes that are present in children with JIA. Other ANA subtypes associated with autoimmune connective tissue diseases in children, such as anti-DNA (anti-deoxyribonucleic acid), anti-RNPribonucleoprotein), anti-SSA Sjögren’s-syndrome-related) and anti-SSB (anti-Sjögren’s-syndrome Type B) antibodies did not show to be specific for ocular manifestations. In conclusion, the presence of AHA in girls, ANA in both genders, oligo-arthritis, and early-onset of JIA are as predictors for prospective ocular involvement [66].
Several studies focused on the relationship between ESR and the occurrence of JIA-U. A retrospective cohort study by Haasnot et al., has proven a significant influence of elevated ESR values on uveitis development. Patients diagnosed with uveitis before the onset of JIA are not involved because the focus of this study was the immune-pathogenic evolution from JIA to uveitis. The concrete formation of JIA-U is still unknown. Elevated ESR values reveal higher activity of the autoimmune disease, so these indicate an activated state of the immune system. The immune activation might trigger an increased influx of inflammatory cells into the eye. Hence a disbalance of T-helper cells and T regs result in generating uveitis [67].
The detection of the exact pathogenetic relationship between JIA and the uveitis associated is still desperately anticipated. Yet, just a few minor links regarding an abnormal immune response are known yet. With the help of immunoassays, it is possible to identify immune mediators even in samples of a low volume of aqueous humor (AqH). This method makes it possible to measure and quantify immune molecules. Assessment of the presence of biomarkers in the aqueous humor of patients diagnosed with JIA-U had not been done. Studies regarding those biomarkers were lacking. Therefore, the research team of Haasnot et al. conducted another study to find the link between biomarkers in AqH of affected eyes and the disease pathogenesis. The number of biomarkers in ocular fluids of patients suffering from JIA-U and other types of uveal inflammation were investigated. They identified decreased levels of Interleukin 29 (IL-29) in the AqH of patients with autoimmune uveitis in comparison with other
forms of uveitis. IL-29 plays a crucial role in two defense mechanisms of the human body. First, it plays an important role in viral clearance and hence it is expressed in increased amounts during viral invasion into tissues. Tightening the blood-brain-barrier by decreasing permeability, which is achieved by the regulation of microvascular endothelial cells and, it leads to the prevention of viral infection. The same protective mechanism could exist in the eye at the retina-ocular barrier since IL-29 is also present there. The reduction of IL-29 expression in the eyes of children with autoimmune uveitis could result in insufficient antigen protection at the barrier site, leading to a higher susceptibility to viral infection in the anterior chamber [68].
The American Academy of pediatrics had launched a list of risk factors for vision loss and ocular complications, including male gender, short duration between arthritis and uveitis diagnoses, a uveitis diagnosis before arthritis diagnosis, young age at uveitis onset, an anterior chamber cell score ≥1+, initial visual acuity (VA) of 20/200 or worse, and presence of complications at first ophthalmology examination. In a recent study by Walscheid et al. all these risk factors were compared by their significance in JIA-U development and severity. Simply the oligo-articular JIA subtype and young age at arthritis diagnosis remained significant predictors after their results were analyzed. This study also showed that most children are diagnosed with JIA-U within the first four years after JIA diagnosis. According to these results, starting the regular ophthalmologic screening is crucial to prevent JIA-U development. No significant predictors for the severity of uveitis or disease progress appeared in this study [69].
Quality of life
Visual disability is underestimated in JIA. It appears to have a more severe impact on the quality of life of a young individual than it is suspected so far. According to a recent interview study by Sen et al., Health-related quality of life (HRQoL) in children depends on a complex interaction of physical, social and cultural factors. The HRQoL of children with visual impairment tends to be significantly decreased. The subjective experience of the disease, the treatment and, the complications of both play a significant role in the child’s perception of well-being. All gender and age ranges are equally affected. The treatment has the most substantial impact. Often the ocular changes lead to adverse emotional reactions and side effects. Many children try to avoid pharmaceutical therapy due to fear of adverse events. Often also scholarly achievements are afflicted by missed classes due to regular doctor appointments. Besides, difficulties reading the information, teachers forgetting about their condition and, frustration about lost time with fellow pupils lead to anxiety. They are creating challenges in personality development, as well [70].
Furthermore, higher rates of incidence of bullying and social exclusion, not being seen as a full member of school society, aggravates the situation. When it comes to complications of uveitis and treatment, two main points are concerning affected children and their parents the most: i.e. cataract removal and poor vision resulting from visual blurring.
Additionally, preoccupations are caused by topics regarding the requirements of adaptation to participate in activities. Negative emotions, distress, and sadness caused by fear, anger and, worry about the deterioration of the illness and going blind in the future. A condition with the ability to result in visual loss can be a heavy emotional burden for a child [70].
New discoveries on treatment options
Childhood autoimmune chronic uveitis tends to evolve into a severe and impeding disease from a previous mild asymptomatic condition. Therefore, a powerful, stepwise started and ended immunosuppressive therapy is necessary. However, there is no guideline advice regarding the precise duration of uveitis treatment. Primarily once disease inactivity is achieved, certain insecurity in terms of the most suitable medication exists. Several recent studies by Simonini et al. lead to the assumption that the longer the period of disease inactivity, the lower the probability of remission after the therapy ends. In contrast, the time needed to achieve inactivity than the length of inactivity itself seemed to predict uveitis remission after treatment withdrawal [71].
In case therapy with steroids turns out to be unsatisfactory, the second-line treatment low-dose Methotrexate (MTX). In the unusual event of intolerance or toxic side effects to MTX, Leflunomide (LEF) is next in line. LEF is an inhibitor of pyrimidine synthesis with similar effectiveness compared to MTX. It has been useful in this setting for the treatment of JIA related joint manifestations for many years. A study by Bichler et al. has brought to light that the incidences of anterior uveitis flare in children with JIA-U are more common under treatment with LEF in comparison to the treatment with MTX. In addition to this negative feature of LEF, it has also shown to be less efficient compared to MTX in treating concomitant uveitis in JIA patients. Even though LEF has the same properties as MTX regarding the therapy of JIA joint manifestations, on these grounds, LEF is the third-line treatment of JIA-U flares. It is a backup only in the rare cases MTX is inefficient. If LEF is the drug of choice for a patient experiencing JIA-U, close monitoring is required, and additional treatment is inevitable in the case of anterior uveitis flares [72].
As described previously, MTX is a commonly used drug for the treatment of JIA-U. In cases resistant to MTX, not only LEF can be used. There is also the possibility of adding certain medicines to pre-existing therapy with MTX. An example of an adjunct is Adalimumab (ADA), which is a fully human anti-tumor necrosis factor α monoclonal antibody. According to a study by Ramanan et al., in
combination with ADA, MTX treatment efficacy was drastically extended compared to the duration MTX used as a single agent. Hence, ADA causes a significant delay in MTX treatment failure. It can also be adjunctive to the first-line treatment, systemic steroids. With a daily, stable dose of glucocorticoids, many patients can reduce or even discontinue this medication [73].
Nevertheless, the adjunction of ADA has adverse events as well. Many patients experienced mild side effects, including gastrointestinal and respiratory infections. This research team suspects a correlation with the use of ADA and the genesis of cancer and demyelinating diseases. Anyhow, no trial for the evaluation of this possibility exists. The decision to add ADA to the pharmaceutical therapy of autoimmune uveitis should be well thought through and made individually considering all features of the specific patients [73].
A team of researchers, namely Miserocchi et al., carefully examined Rituximab (RTX) in a retrospective study. RTX is a specific anti-CD20 B cell monoclonal antibody. It has been used for JIA related joint manifestations and other rheumatic inflammatory conditions of long duration. It was able to effectuate complete remission in many cases. Also, the results of this experimental research by Miserocchi et al. are promising. A couple of months after the initiation of RTX injections, a significant reduction of intraocular inflammation in the anterior chamber and improved efficacy of corticosteroids occurred. A lot of patients were able to diminish their daily steroid dose or discontinue it entirely. Hence side effects of long-standing corticosteroid therapy could be avoided. Not only the steroid dose could be reduced by concomitant administration of RTX, but also other immunosuppressive agents could be tapered. Also, RTX exhibits an excellent tolerability and safety record. The only side effect that is worth mentioning is the slightly increased tendency to catch mild infections. Altogether this medication has shown to be an excellent choice in cases refractory to TNF- α blockers (ADA) [74].
A brand-new approach to the treatment of autoimmune uveitis is the so-called drug Tocilizumab (TCZ). It is a fully humanized anti-IL-6 antibody. Interleukin 6 (IL-6) is a proinflammatory cytokine, which is associated with the proliferation and differentiation of immune cells. In the context of rheumatologic diseases, IL-6 levels are indicators for the severity of the condition and predictors for the joint manifestation progression. Additionally, elevated IL-6 levels were present during the examination of ocular fluids of patients with ongoing uveitis. Tocilizumab had shown excellent outcomes for numerous rheumatic inflammatory ailments, including rheumatoid arthritis (RA), polyarticular JIA and, uveitis of another autoimmune origin. In a very recent study by Tappeiner et al. TCZ has shown a tremendous anti-inflammatory effect on autoimmune uveitis and additionally reduced macular edema in patients who suffered from it concomitantly. Abundant IL-6 promotes the genesis of vascular endothelial growth factor (VEGF), which subsequently triggers an increased vascular permeability, leading to an influx of blood plasma into the macular region. Thus, therapeutic IL-6 blockage results in decreased macular fluid accumulation. Anyhow, TCZ still has to be used with caution since only minimal research
exists in this field. So far, it is recommended only in exceptional cases of severe and refractory JIA-U with a high incidence of adverse events [75].
5. CONCLUSION
1. The yet biggest challenge is to promptly diagnose the condition and avoid an unnecessary delay of the treatment initiation. The research studies summarized in this thesis have yielded promising results. Predictive factors for disease development are early-onset of disease, oligo-articular type of JIA, AHA presence in girls, ANA presence in both genders, and increased laboratory parameters (ESR).
2. The present findings confirm that a higher level of awareness regarding these diseases is needed, since the quality of life of children being struck by uveitis associated with rheumatological diseases is significantly decreased. Compared to the average individual their age, they will experience social marginalization, learning difficulties and sadness at a higher rate.
3. New medications with promising results were identified and used successfully. LEF has shown to be an efficient third line treatment for autoimmune associated ocular inflammation. The adjunction of ADA to MTX or steroids, improves clinical status of the patient and in some cases allows withdrawal of steroids. RTX has been identified as an excellent alternative to TNF-α inhibitors. TCZ, a new drug on the market, significantly reduces ocular inflammation of autoimmune origin with concomitant macular edema.
6. LIMITATIONS
Data collection was done by one investigator. This could have had an impact on the articles that were selected. Unfortunately, no data regarding autoimmune ophthalmologic changes in children from Lithuania was available in English language. Therefore, only research from other countries could be evaluated. Autoimmune diseases are very rare in children, thus are the ocular manifestations associated with them. The amount of studies regarding this topic is very limited, for this reason the literature review part of this thesis is based mainly on articles being older than ten years.
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