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1.  Neutralization of IL-17 ameliorates uveitis but damages photoreceptors in a murine model of spondyloarthritis 
Introduction
Uveitis, or intraocular inflammatory disease, is a frequent extra-articular manifestation of several forms of arthritis. Despite the frequent co-occurrence of uveitis and arthritis, little is understood of the eye's predisposition to this disease. We recently described a previously unreported uveitis in a murine model of spondyloarthropathy triggered by autoimmunity to aggrecan, a prominent proteoglycan (PG) macromolecule in cartilage. In contrast to the joint and spine, wherein interferon-gamma (IFNγ) deficiency reduced disease, IFNγ deficiency worsened uveitis. Given the regulatory role of IFNγ on the Th17 response and the current focus of anti-interleukin-17 therapeutics in patients with uveitis and spondyloarthritis, we sought to determine the extent to which interleukin (IL)-17 mediates uveitis in the absence of IFNγ.
Methods
Antigen specific T cell cytokine production was measured in splenocyte cultures using multiplex-ELISA. Transgenic (Tg) mice expressing the T cell receptor (TCR) recognizing the dominant arthritogenic epitope in the G1 domain of PG (TCR-Tg), also lacking IFNγ, were immunized with PG. Mice were then systemically administered an anti-IL-17 neutralizing antibody. The onset and severity of peripheral arthritis was evaluated by clinical scoring criteria and histology. Uveitis was assessed using intravital videomicroscopy, which visualizes leukocyte trafficking within the vasculature and tissue of the iris, and by histology.
Results
TCR-Tg splenocytes stimulated in vitro with recombinant G1 peptide demonstrated exacerbated production of cytokines, such as macrophage inflammatory protein (MIP)-1α, MIP-1β, IL-1β, and most notably IL-17A as a consequence of IFNγ deficiency. In vivo, IL-17 inhibition prevented the component of PG-induced arthritis that occurs independently of IFNγ. Blockade of IL-17 ameliorated the ongoing leukocyte trafficking responses within the iris vasculature and tissue, which coincided with reduced infiltration of leukocytes within the anterior and posterior eye segments. However, the anti-IL-17 treatment resulted in unanticipated photoreceptor toxicity.
Conclusions
These data support a protective, regulatory role for IFNγ in suppression of IL-17-mediated intraocular disease and to a lesser extent, joint disease. The unanticipated photoreceptor toxicity raises some caution regarding the use of anti-IL-17 therapeutics until the mechanism of this potential effect is determined.
doi:10.1186/ar3697
PMCID: PMC3392808  PMID: 22269151
2.  IFNγ regulates discordant mechanisms of uveitis versus joint and axial disease in a murine model resembling spondyloarthritis 
Arthritis and Rheumatism  2012;64(3):762-771.
OBJECTIVE
The spondyloarthropathies (such as ankylosing spondylitis) are multi-system inflammatory diseases that frequently result in uveitis, or intra-ocular eye inflammation. Despite the common co-occurrence of uveitis with arthritis, there has been no explanation for the eye’s susceptibility to inflammation. Using an innovative intravital videomicroscopic approach, we discovered the co-existence of uveitis with axial and peripheral joint inflammation in mice immunized with cartilage proteoglycan (PG). Here, we elucidate the characteristics of uveitis and test the impact of IFNγ deficiency on the eye versus the joint and spine.
METHODS
Female, TCR-Tg or IFNγ knock-out crossed to TCR-Tg mice were immunized with PG. Uveitis was assessed by intravital videomicroscopy and histology. The clinical and histopathologic severity of arthritis and spondylitis were evaluated. Bone remodeling process within the spine was assessed by whole-body NIR imaging. Immunoblotting and immunofluorescence staining were used to examine expression of PG and ADAMTS-5 along with examination of the cellular composition of uveitic eyes.
RESULTS
PG neo-epitopes along with the aggrecanase, ADAMTS-5, are present in the eye as they are the joint. Anterior uveitis develops in response to PG immunization. The cellular infiltrate consists mainly of neutrophils and eosinophils. Unexpectedly, IFNγ deficiency markedly exacerbates uveitis while ameliorating joint and spine disease, indicating divergent mechanisms that drive diseases in the eye versus joints and spine.
CONCLUSIONS
This is the first detailed description of a murine disease model wherein uveitis coincides with arthritis and spondylitis. Our observations provide great opportunity to understand the pathogenesis of a relatively common but poorly understood disease.
doi:10.1002/art.33404
PMCID: PMC3271189  PMID: 21987263
3.  Investigation of the peptidoglycan sensing molecule, PGLYRP-2, in murine inflammatory uveitis 
Background/aim
Peptidoglycan (PGN) recognition proteins (PGLYRPs) are innate immune molecules that recognise bacterial cell wall PGN, and participate in several inflammatory diseases such as arthritis. We sought to elucidate the contribution of PGLYRPs in murine uveitis (intraocular inflammatory disease) elicited by PGN, and the extent to which systemically administered PGN alters uveitis compared with arthritis versus locally triggered ocular responses.
Methods
Mice deficient for PGLYRP-2, PGLYRP-3 or PGLYRP-4 were administered PGN by an intraperitoneal or intraocular injection. Arthritis was assessed by near-infrared imaging and histopathology, while uveitis was measured by intravital videomicroscopy and histopathology.
Results
Systemic PGN exposure predisposed to arthritis through a PGLYRP-2 dependent mechanism. By contrast, systemic PGN exposure did not predispose to uveitis, and PGLYRP-2 deficiency had no impact on the development the uveitis. When PGN was administered locally, a robust uveitis ensued, which occurred independently of PGLYRP-2. Regardless of whether PGN was administered systemically or locally, neither PGLYRP-3 nor PGLYRP-4 deficiency significantly altered ocular inflammation compared with wild-type control animals.
Conclusions
Our findings highlight the complexity of PGLYRPs and how PGLYRP-2 may use different molecular pathways in the joints versus eyes. Collectively, our results support a non-essential or redundant role for PGLYRPs-2, -3, -4 in uveitis.
doi:10.1136/bjophthalmol-2012-302650
PMCID: PMC4084548  PMID: 23361435
4.  Updates on the risk markers and outcomes of severe juvenile idiopathic arthritis-associated uveitis 
International journal of clinical rheumatology  2013;8(1):10.2217/ijr.12.83.
Uveitis is the most common extra-articular manifestation of juvenile idiopathic arthritis, which is the most common systemic cause of uveitis in children. Known risk factors for uveitis include antinuclear antibody seropositivity, young age of arthritis onset, specific juvenile idiopathic arthritis subtype and short duration of disease. Risk markers for severe ocular disease include gender, age and complications at initial visit. Due to the risk for vision-compromising sequelae such as cataracts, band keratopathy, glaucoma, vision loss and blindness, an understanding of the risk factors for uveitis development and severe ocular disease is crucial to help prevent serious visual disability and complications. This paper reviews the pathogenesis of uveitis, known risk factors for uveitis development and severe visual outcome, and addresses the need for additional biomarkers of uveitis risk, prognosis and remission.
doi:10.2217/ijr.12.83
PMCID: PMC3810987  PMID: 24187594
juvenile arthritis; juvenile idiopathic arthritis-associated uveitis; ocular disease; pediatric rheumatology; risk; uveitis
5.  Management and evaluation of extra-articular manifestations in spondyloarthritis 
Spondyloarthritis (SpA) is a chronic inflammatory disease with either predominantly axial symptoms of the spine and sacroiliac joints (axial SpA, including ankylosing spondylitis) or predominantly arthritis (peripheral SpA). Next to these spinal and articular symptoms, many patients with SpA also have extra-articular manifestations (EAMs). EAMs associated with SpA include anterior uveitis (25–30%), psoriasis (10–25%) or inflammatory bowel disease (IBD) (5–10%) and cardiovascular manifestations. Peripheral arthritis occurs in approximately 30% of patients, especially in large joints, and shows an asymmetrical, oligoarticular pattern. Other common joint complaints are due to enthesitis, which manifest as extra-articular bony tenderness in areas such as the Achilles tendon. Acute anterior uveitis presents with acute pain, loss of vision and redness in one eye that usually subsides spontaneously after several weeks. Rapid treatment by an ophthalmologist is required to prevent synechiae formation which could ultimately result in glaucoma and blindness. Although less common, organ involvement in SpA can also be located in the heart, lungs or kidneys. The risk of cardiovascular events is increased in SpA. Cardiac manifestations can involve the aortic valve (1–10%) or the atrioventricular node and the risk of atherosclerotic events is increased in this group. Treatment of SpA includes physical exercise and nonsteroidal anti-inflammatory drugs (NSAIDs), and in case of peripheral arthritis, sulphasalazine can be added. When there is insufficient response to NSAIDs, tumor necrosis factor blockers, especially infliximab, etanercept, adalimumab and golimumab, are very effective in treating axial manifestations, arthritis, enthesitis and psoriasis. Anterior uveitis in SpA can be treated adequately by the ophthalmologist and in the case of refractory uveitis, treatment with adalimumab and infliximab seems to be more effective compared with etanercept. When IBD occurs with SpA, the use of NSAIDs should be minimized, except for celecoxib, and infliximab or adalimumab are preferred to etanercept. The incidence of atherosclerotic events or SpA-specific cardiac manifestations may be decreased by cardiovascular risk management or effective antirheumatic treatment. Overall it is important to realize that extra-articular manifestations frequently occur in patients with SpA and should be taken into account in the choice of treatment.
doi:10.1177/1759720X12458372
PMCID: PMC3512172  PMID: 23227118
Ankylosing spondylitis; anterior uveitis; arthritis; cardiac manifestations; enthesitis; IBD; psoriasis; spondyloarthritis
6.  Pathogenesis and clinical manifestations of juvenile rheumatoid arthritis 
Korean Journal of Pediatrics  2010;53(11):921-930.
Juvenile rheumatoid arthritis (JRA) is the most common rheumatic childhood disease; its onset is before 16 years of age and it persists for at least 6 weeks. JRA encompasses a heterogeneous group of diseases that is classified according to 3 major presentations: oligoarthritis, polyarthritis, and systemic onset diseases. These presentations may originate from the same or different causes that involve interaction with specific immunogenetic predispositions, and result in heterogeneous clinical manifestations. An arthritic joint exhibits cardinal signs of joint inflammation, such as swelling, pain, heat, and loss of function; any joint can be arthritic, but large joints are more frequently affected. Extra-articular manifestations include high fever, skin rash, serositis, and uveitis. The first 2 types of JRA are regarded as T helper 1 (Th1) cell-mediated inflammatory disorders, mainly based on the abundance of activated Th1 cells in the inflamed synovium and the pathogenetic role of proinflammatory cytokines that are mainly produced by Th1 cell-stimulated monocytes. In contrast, the pathogenesis of systemic onset disease differs from that of other types of JRA in several respects, including the lack of association with human leukocyte antigen type and the absence of autoantibodies or autoreactive T cells. Although the precise mechanism that leads to JRA remains unclear, proinflammatory cytokines are thought to be responsible for at least part of the clinical symptoms in all JRA types. The effectiveness of biologic therapy in blocking the action of these cytokines in JRA patients provides strong evidence that they play a fundamental role in JRA inflammation.
doi:10.3345/kjp.2010.53.11.921
PMCID: PMC3012271  PMID: 21218013
Juvenile arthritis; Child; Cytokines; Inflammation
7.  NOD2 and TLR2 function independently in a murine model of arthritis triggered by intra-articular peptidoglycan 
Arthritis and rheumatism  2010;62(4):1051-1059.
Objective
Blau syndrome is an autoinflammatory disease resulting from mutations in NOD2 (nucleotide-binding oligomerization domain 2), wherein granulomatous arthritis, uveitis and dermatitis develop. The mechanisms by which aberrant NOD2 causes joint inflammation are poorly understood. Indeed very few studies have addressed NOD2 function in the joint. Here, we investigate NOD2 function in an experimental model of arthritis and explore the potential interplay between TLR2 and NOD2 in joint inflammation.
Methods
Mice deficient for TLR2, MyD88, or NOD2 and their wildtype controls were administered an intra-articular injection of muramyl dipeptide (MDP), peptidoglycan (PGN) (a metabolite of which is MDP), or Pam3CSK4, a synthetic TLR2 agonist. Joint inflammation was assessed using near-infrared fluorescence imaging and histology.
Results
Locally administered PGN results in joint inflammation, which was markedly reduced in mice deficient for either TLR2 or the TLR signaling mediator, MyD88. In addition to TLR2 signaling events, NOD2 mediated joint inflammation since mice deficient for NOD2 showed significantly reduced PGN-induced arthritis. TLR2 or MyD88 deficiency did not influence arthritis induced by the specific NOD2 agonist, MDP. In addition, NOD2 deficiency did not alter TLR2-dependent joint inflammation elicited by the synthetic TLR2 agonist, Pam3CSK4.
Conclusion
Whereas NOD2 and TLR2 are both critical for the development of PGN-arthritis, they appear to elicit inflammation independently of each other. Our studies support an inflammatory role for NOD2 in arthritis.
doi:10.1002/art.27335
PMCID: PMC2945367  PMID: 20131263
8.  NOD1 Expression in the Eye and Functional Contribution to IL-1β–Dependent Ocular Inflammation in Mice 
PURPOSE
NOD1 plays an important role in host defense and recognizes the minimal component of bacterial cell walls, meso-diaminopimelic acid (iE-DAP). Polymorphisms in NOD1 are associated with autoinflammatory diseases characterized by uveitis such as Crohn’s disease and sarcoidosis. NOD1 is homologous to NOD2, which is responsible for an autosomal dominant form of uveitis. Nonetheless, the role of NOD1 in intraocular inflammation has not been explored. The induction of uveitis by iE-DAP in mice and the potential contribution of interleukin (IL)-1β were investigated.
METHODS
BALB/c mice or mice deficient in caspase-1 or IL-1R1 and their congenic controls were injected intravitreally with iE-DAP or saline. The time course, dose response, and contribution of IL-1β to ocular inflammation were quantified by intravital video microscopy, histology, and immunohistochemistry. NOD1 and IL-1β were measured in eye tissue by immunoblotting and ELISA.
RESULTS
NOD1 protein is expressed in the eye and promotes ocular inflammation in a dose- and time-dependent fashion. The authors previously defined the role of IL-1β in NOD2 uveitis and tested whether NOD1 and NOD2 used similar mechanisms. Treatment with iE-DAP significantly increased IL-1β, which was caspase-1 dependent. However, in contrast to NOD2, caspase-1 and IL-1R1 were essential mediators of iEDAP– induced uveitis, suggesting that NOD1 and NOD2 induce ocular inflammation by distinct mechanisms involving IL-1β.
CONCLUSIONS
These findings demonstrate that NOD1 is expressed within the eye and that its activation results in uveitis in an IL-1β–dependent mechanism. Characterizing the differences between NOD1 and NOD2 responses may provide insight into the pathogenesis of uveitis.
doi:10.1167/iovs.08-2852
PMCID: PMC3086269  PMID: 19074813
9.  Uveitis and juvenile idiopathic arthritis: A cohort study 
Objective:
Assess the incidence of intraocular inflammation (uveitis) and ocular complications in children with various types of JIA in a single cohort of patients.
Patients:
Included are 172 children (35 boys and 137 girls) diagnosed with JIA. All underwent thorough initial ophthalmologic examination and were followed for a minimum of 3 years.
Results:
Of 172 children with JIA, 152 (88.4%) presented with arthritis. Uveitis was detected in 14 of the152 children (9.2%) during the first ophthalmic examination. In 17 additional patients of this group (11.2%), uveitis developed during the follow up period of up to 15 years. Twenty children out of the total of 172 (11.6%) presented initially with uveitis. In children developing uveitis before or along with arthritic manifestations, the ocular disease was chronic with a high rate of secondary complications (band keratopathy, glaucoma, posterior synechiae and cataract). In all affected eyes the initial ocular inflammation was typically confined to the anterior segment. On longer follow up however, most children developed binocular disease and posterior segment involvement. Dense cataract and amblyopia were the major cause of severe visual disabilities.
Conclusion:
Pauciarticular JIA is associated with intraocular inflammation (uveitis) early during the arthritic disease course. The ocular disease course is unpredictable. Therefore education of parents regarding its signs and symptoms is of utmost importance. To preserve functional vision, secondary ocular complications and amblyopia should be avoided.
PMCID: PMC2704519  PMID: 19668530
arthritis; eye; JIA; uveitis; intraocular inflammation; visual acuity; cataract; glaucoma
10.  Uveitis- a rare disease often associated with systemic diseases and infections- a systematic review of 2619 patients 
Background
Uveitis is an autoimmune disease of the eye that refers to any of a number of intraocular inflammatory conditions. Because it is a rare disease, uveitis is often overlooked, and the possible associations between uveitis and extra-ocular disease manifestations are not well known. The aim of this study was to characterize uveitis in a large sample of patients and to evaluate the relationship between uveitis and systemic diseases.
Methods
The present study is a cross-sectional study of a cohort of patients with uveitis. Records from consecutive uveitis patients who were seen by the Uveitis Service in the Department of Ophthalmology at the Medical University of Vienna between 1995 and 2009 were selected from the clinical databases. The cases were classified according to the Standardization of Uveitis Nomenclature Study Group criteria for Uveitis.
Results
Data were available for 2619 patients, of whom 59.9% suffered from anterior, 14.8% from intermediate, 18.3% from posterior and 7.0% from panuveitis. 37.2% of all cases showed an association between uveitis and extra-organ diseases; diseases with primarily arthritic manifestations were seen in 10.1% of all cases, non-infectious systemic diseases (i.e., Behçet´s disease, sarcoidosis or multiple sclerosis) in 8.4% and infectious uveitis in 18.7%. 49.4% of subjects suffering from anterior uveitis tested positively for the HLA-B27 antigen. In posterior uveitis cases 29% were caused by ocular toxoplasmosis and 17.7% by multifocal choroiditis.
Conclusion
Ophthalmologists, rheumatologists, infectiologists, neurologists and general practitioners should be familiar with the differential diagnosis of uveitis. A better interdisciplinary approach could help in tailoring of the work-up, earlier diagnosis of co-existing diseases and management of uveitis patients.
doi:10.1186/1750-1172-7-57
PMCID: PMC3503654  PMID: 22932001
Uveitis; Etiology; Systemic associations; Arthritis; Infections
11.  A randomised controlled trial of the clinical effectiveness, safety and cost-effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis (SYCAMORE Trial) 
Trials  2014;15:14.
Background
Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Children with JIA are at risk of inflammation of the uvea in the eye (uveitis). Overall, 20% to 25% of paediatric uveitis is associated with JIA. Major risk factors for development of uveitis in JIA are oligoarticular pattern of arthritis, an age at onset of arthritis of less than seven years of age, and antinuclear antibody positivity. In the initial stages of mild to moderate inflammation the uveitis is asymptomatic. This has led to current practice of screening all children with JIA for uveitis. Approximately 12% to 38% of patients with JIA develop uveitis in seven years following onset of arthritis. In 30% to 50% of children with JIA-associated uveitis structural complications are present at diagnosis. Furthermore about 50% to 75% of those with severe uveitis will eventually develop visual impairment secondary to ocular complications such as cataract and glaucoma. Defining the severity of inflammation and structural complications in uveitis patients is now possible following Standardised Uveitis Nomenclature (SUN) guidelines, and modified to incorporate the consensus of end point and outcome criteria into the design of randomised trials. Despite current screening and therapeutic options (pre-biologics) 10% to 15% of children with JIA-associated uveitis may develop bilateral visual impairment and certified legally blind. To date, there remains no controlled trial evidence of benefits of biologic therapy.
Methods/design
This study will randomise 154 patients aged 2 to 18 years with active JIA-associated uveitis (despite methotrexate (MTX) treatment for at least 12 weeks). All participants will be treated for 18 months, with follow up of 3 years from randomisation (continuing on MTX throughout). All participants will receive a stable dose of MTX and in addition either adalimumab (20 mg/0.8 ml for patients <30 kg or 40 mg/0.8 ml for patients weighing 30 kg or more, subcutaneous (s/c) injection every 2 weeks based on body weight), or placebo (0.8 ml as appropriate according to body weight) s/c injection every 2 weeks.
Discussion
This is the first randomised controlled trial that will assess the clinical effectiveness, safety and cost effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis.
Trial registration
ISRCTN10065623
doi:10.1186/1745-6215-15-14
PMCID: PMC3892031  PMID: 24405833
Adalimumab; Juvenile idiopathic arthritis; Methotrexate; Ophthalmology; Paediatric; Rheumatology; Safety; Uveitis
12.  The NLRP3 inflammasome is active but not essential in endotoxin-induced uveitis 
Inflammation Research  2011;61(3):225-231.
Objective
The inflammasome complex involving caspase-1 and nucleotide-binding domain, leucine-rich repeat containing protein (NLRP)3, also known as NALP3 or cryopyrin is important for host responses to microbial pathogens and several autoinflammatory diseases. We investigated the extent to which NLRP3 and caspase-1 control ocular interleukin (IL)-1β production and severity of uveitis (intraocular inflammatory disease) in an established, acute inflammatory uveitis model, endotoxin-induced uveitis (EIU).
Methods
Expression of NLRP3, its adaptor molecule ASC, also known as PYCARD (PYD and CARD domain containing), and caspase-1 were examined by immunoblotting. IL-1β production was measured by enzyme-linked immunosorbent assay (ELISA). Using knockout mice, roles for caspase-1 and NLRP3 were examined in uveitis induced by intraocular injection of Escherichia coli lipopolysaccharide (LPS).
Results
NLRP3, ASC, and caspase-1 proteins are constitutively expressed in eye tissue. During EIU, IL-1β protein production increases; this requires the presence of both caspase-1 and NLRP3. However, severity of EIU is not altered by deficiency in either caspase-1 or NLRP3, as assessed by both intravital microscopy and histology.
Conclusions
These data identify the importance of the NLRP3 inflammasome for IL-1β production in the eye, yet indicate that its participation in EIU is nonessential.
doi:10.1007/s00011-011-0404-8
PMCID: PMC3335428  PMID: 22119862
NLRP3; Caspase-1; Inflammasome; Uveitis; Mice; Lipopolysaccharide
13.  Long-term efficacy of adalimumab in the treatment of uveitis associated with juvenile idiopathic arthritis 
Background
The purpose of this study was to investigate the long-term effects of adalimumab, a tumor necrosis factor alpha antagonist, in the treatment of uveitis associated with juvenile idiopathic arthritis.
Methods
Adalimumab was initiated in 94 patients with juvenile idiopathic arthritis to treat active arthritis and/or active associated uveitis. In 18 patients, therapy was discontinued after a short period because of inefficacy or side effects. The activity of uveitis (using Standardized Uveitis Nomenclature [SUN] criteria and clinical examination) and arthritis (number of swollen or active joints) was evaluated at the start and at end of the study.
Results
At the end of the study, uveitis was under good clinical control in two thirds of 54 patients (31% did not need any local treatment and 35% used only 1–2 corticosteroid drops a day), and one third had active uveitis (at least three corticosteroid drops a day). According to SUN criteria, adalimumab treatment for uveitis showed improved activity (a two-fold decrease in uveitis activity) in 28% of patients, with a moderate response in 16 patients, no change in a further 16 patients, and worsening activity (a two-fold increase in uveitis activity) in 13% of patients. The overall proportion of patients with active arthritis decreased. At the beginning of the study, 69% of patients with uveitis had more than two active joints, and at the end of the study only 27% had active joint disease. In 27 patients with juvenile idiopathic arthritis without uveitis on adalimumab, the number of active joints decreased from 93% to 59%. Systemic corticosteroid treatment could be stopped in 22% of patients with uveitis and in 11% of those without uveitis. Most of the patients had received methotrexate, other immunosuppressive therapy, or other biological drugs before initiating adalimumab.
Conclusion
Adalimumab is a valuable option in the treatment of uveitis associated with active juvenile idiopathic arthritis.
doi:10.2147/OPTH.S23646
PMCID: PMC3198418  PMID: 22034564
adalimumab; juvenile idiopathic arthritis; uveitis
14.  NOD2, the Gene Responsible for Familial Granulomatous Uveitis, in a Mouse Model of Uveitis 
Purpose
NOD2 plays an important role in the recognition of intracellular bacteria through its ability to sense the components of bacterial peptidoglycan (PGN), namely muramyl dipeptide (MDP) and muramyl tripeptide (MTP). Specific mutations in the human NOD2 gene cause Blau syndrome, an autosomal dominant form of uveitis, arthritis, and dermatitis. As a first step toward understanding the role of NOD2 in the pathogenesis of uveitis, the authors developed a mouse model of MDP-dependent uveitis.
Methods
BALB/c mice and mice deficient in L-selectin or NOD2 received intravitreal injection of MDP, MTP, or PGN. The intravascular response within the iris and cellular infiltration was quantified by intravital microscopy and histologic assessment.
Results
MDP induced an acute, ocular inflammatory response, wherein rolling and adhering leukocytes within the vasculature were significantly increased within 6 hours after MDP treatment. A minor increase in cellular infiltration occurred at 12 hours after MDP treatment. The adhesion molecule L-selectin participated in MDP-induced vascular inflammation because L-selectin knockout mice showed a significant decrease in the number of rolling cells. Importantly, NOD2 plays an essential role in ocular inflammation induced by MDP, as indicated by the fact that uveitis did not develop in Nod2 knockout mice in response to MDP. Nod2 knockout mice also showed abolished ocular inflammation in response to MTP but not to PGN treatment.
Conclusions
These findings demonstrate a novel mouse model of uveitis, wherein NOD2 plays an essential role in inflammation induced by the minimal components of PGN. Thus, innate immune responses mediated by NOD2 may participate in the development of uveitis in response to bacterial products.
doi:10.1167/iovs.07-1174
PMCID: PMC2430189  PMID: 18385071
15.  Psoriasis and uveitis: a literature review* 
Anais brasileiros de dermatologia  2012;87(6):877-883.
Psoriasis is a systemic, chronic, immunologically mediated disease, with significant genetic and environmental influences. It affects from 1 to 3% of the world population. Recently, the relation between psoriasis and different comorbidities, particularly metabolic syndrome, has become extremely relevant. Uveitis is characterized by a process of intraocular inflammation resulting from various causes. Considering psoriasis and uveitis as immune-mediated diseases, this study aims to evaluate the possible association of psoriasis and/or psoriatic arthritis with uveitis and its subtypes. Few studies have evaluated the association of uveitis and psoriasis without joint involvement. It seems that psoriasis without arthropathy is not a risk factor for the development of uveitis. Uveitis tends to develop more frequently in patients with arthropathy or pustular psoriasis than in patients with other forms of psoriasis. Ophthalmic examination should be performed periodically in patients with psoriasis and uveitis. If ophthalmopathy is diagnosed, the patient should receive adequate treatment with anti-inflammatory drugs or immunomodulators to prevent vision loss.
doi:10.1590/S0365-05962012000600009
PMCID: PMC3699904  PMID: 23197207
Arthritis, psoriatic; Psoriasis; Uveitis
16.  Visual loss in uveitis of childhood 
Aims: To investigate the manifestations and severity of uveitis in children and to identify the risk and specific causes of blindness in this population.
Methods: Retrospective study of data of 123 consecutive patients examined with active uveitis and the onset of ocular disease before the age of 16 years. Numerous variables were assessed including age and sex distribution, laboratory data, the presence of systemic diseases, onset and course of ocular inflammation, clinical features and complications, therapeutic strategies and their outcomes, final visual acuity, and characteristics associated with poor visual outcome.
Results: Systemic disease was observed in 36/123 patients (29%), with juvenile idiopathic arthritis being the most frequent (25/123, 20%). Toxoplasma retinochoroiditis was diagnosed in 12/23 patients with posterior uveitis (52%; 10% of all with uveitis). Severe intraocular inflammation required systemic drugs in 57 (46%) patients. Ocular complications were observed in 93 patients (76%), of which the most common was cataract (43/123, 35%). Intraocular surgery was required in 35 patients (28%; in total 75 procedures). Three patients (2%) became legally blind and an additional 20/121 (17%) had one legally blind eye caused by uveitis. The most frequent causes of blindness were chorioretinal scars in the macular area and glaucoma in contrast with cystoid macular oedema (CMO) in adults.
Conclusions: Uveitis in childhood is a potentially blinding disease, in the majority of patients characterised by a chronic course and a high complication rate.
PMCID: PMC1771761  PMID: 12812891
uveitis; childhood; blindness
17.  Identification of antihistone antibodies in subsets of juvenile chronic arthritis. 
Annals of the Rheumatic Diseases  1989;48(2):114-117.
Antihistone antibodies (AHAs) as measured by an enzyme linked immunosorbent assay (ELISA) were detected in the sera of 58 (48%) of 121 unselected patients with juvenile chronic arthritis (JCA). AHAs were found in 28 (93%) of 30 patients with JCA with uveitis but in only 30 (33%) of 91 patients with JCA without uveitis. AHA positivity was unrelated to the type of joint involvement, disease activity, and drug regimen. When the AHA positive group was divided into 28 patients with JCA with uveitis and 30 patients with JCA without uveitis a distinct response pattern of AHA was detected in each group. Anti-H3 dominated in the JCA/uveitis group, whereas a more heterogeneous AHA pattern was shown in the group without uveitis. The results indicate that subtyping for AHA reactivity may define patients who are highly susceptible for the development of anterior uveitis.
PMCID: PMC1003695  PMID: 2784658
18.  Inefficacy or Paradoxical Effect? Uveitis in Ankylosing Spondylitis Treated with Etanercept 
Case Reports in Medicine  2014;2014:471319.
Ankylosing spondylitis (AS) is presented with axial and peripheral articular involvement. Uveitis is a severe and rather specific manifestation of AS. Biologics targeting tumor necrosis factor (TNF) α are effective on both articular and ocular manifestations of disease. The occurrence of uveitis in patients that never had eye involvement or the relapse of uveitis is described during anti-TNFα treatment. The frequency of these events is slightly higher during therapy with etanercept. The available TNFα blockers show different pharmacokinetics and pharmacodynamics yielding different biological effects. There is an ongoing debate whether uveitis during anti-TNFα has to be considered as paradoxical effect or an inadequate response to therapy. Here, we present a case report and review what the evidences for the two hypotheses are.
doi:10.1155/2014/471319
PMCID: PMC4065678  PMID: 24991219
19.  Elevated serum IL-8 levels are associated with disease activity in idiopathic intermediate uveitis 
AIM—To find a laboratory indicator for systemic involvement in intermediate uveitis.
METHODS—Interleukin 8 (IL-8) and C reactive protein (CRP) serum levels were measured in patients with idiopathic intermediate uveitis (n=61), uveitis controls (n=143), and normal controls (n=29). The records of those with intermediate uveitis were reviewed with the emphasis on disease activity and severity as characterised by the presence of cystoid macular oedema, vitreous exudates or snowbank formation, papillitis, and periphlebitis.
RESULTS—Increased serum IL-8 (⩾20 pg/ml) was found in 27 out of 61 patients with intermediate uveitis (p< 0.01), 12 of 27 patients with sarcoid uveitis (p<0.05), in 19 of 30 patients with HLA-B27 associated acute anterior uveitis (p<0.05), and in five of 29 healthy controls. Raised IL-8 levels in intermediate uveitis were significantly associated with active disease (p<0.001) and the presence of vitreous exudates (p<0.001), papillitis, and periphlebitis (p<0.01). Elevated CRP levels were found in 12 of the 143 uveitis controls but in none of the intermediate uveitis patients or normal controls. During follow up an associated systemic disease was more frequently noticed in patients with an elevated serum IL-8 at entry into the study.
CONCLUSIONS—Elevated IL-8 serum levels were found in patients with active intermediate uveitis of unknown origin. An elevated IL-8 level seems to predispose the patient to a later development of associated systemic disease.

 Keywords: C reactive protein; interleukin 8; uveitis; multiple sclerosis; sarcoidosis
PMCID: PMC1722703  PMID: 9828768
20.  The importance of visual function in the quality of life of children with uveitis 
Background
Studies of quality of life (QOL) in children with juvenile idiopathic arthritis (JIA) have focused on changes in musculoskeletal function secondary to arthritis. The role of visual functionality as a result of JIA-associated uveitis and its complications has not been examined. We evaluated the individual impact of physical and visual disability on QOL in children with and without uveitis.
Methods
We administered patient-based questionnaires that measured visual function, physical function, and overall QOL to 27 children with JIA or idiopathic uveitis. Demographic data, assessed joint involvement, and reviewed medical records were recorded. Groups with and without uveitis were compared for differences in arthritis and uveitis disease characteristics using the Wilcoxon-Mann-Whitney, χ2, and Fisher exact tests. Associations between physical or visual function and overall QOL were measured using Pearson's correlation coefficient.
Results
Of 27 patients, 85.2% have had arthritis and 51.9% have had uveitis. The group without uveitis had increased morning stiffness (p = 0.036). The uveitis group reported more eye redness (p = 0.033) and photophobia (p = 0.013) than those without uveitis. We observed moderate associations between overall QOL and visual function in the uveitis group (r = −0.579), and overall QOL and physical function in the non-uveitis group (r = −0.562).
Conclusions
This study demonstrates that visual impairment is an important component of QOL in children with uveitis. It suggests that QOL studies should incorporate both visual and physical function measures in their analyses, especially since many children with JIA also suffer from uveitis and visual impairment.
doi:10.1016/j.jaapos.2009.12.160
PMCID: PMC2866793  PMID: 20236847
21.  Antinuclear antibody and HLA-B27 positive uveitis: combination of two diseases? 
AIMS/BACKGROUND—Anterior uveitis associated with juvenile chronic arthritis concerns two different clinical entities: firstly, antinuclear antibody (ANA) positive patients who have a chronic anterior uveitis with severe complications and often a poor visual prognosis; secondly, usually HLA-B27 positive children, predominantly boys, with unilateral recurrent anterior uveitis. Three patients are described who had a combination of clinical and laboratory features of both diseases.
METHODS—Retrospective clinical and laboratory analysis of three patients.
RESULTS—Ocular features in the three patients combined the clinical picture of ANA positive chronic anterior uveitis during early childhood with the clinical features of HLA-B27 unilateral acute anterior uveitis during adolescence. The patients fulfilled the diagnostic criteria of juvenile chronic arthritis, and they had no ankylosing spondylitis. All three patients had the HLA-B*2705 subtype.
CONCLUSIONS—Whether the association of ANA positive chronic anterior uveitis and HLA-B27 unilateral acute anterior uveitis is a coincidence or represents a distinct clinical entity is not yet clear.


PMCID: PMC1722318  PMID: 9422931
22.  Characterisation of uveitis in patients with psoriatic arthritis 
OBJECTIVE—The purpose of this study is to describe the clinical characteristics of uveitis related to psoriatic arthritis (PsA), and also to compare the uveitis in PsA to the uveitis in spondyloarthropathy (SA).
METHODS—Sixteen patients with uveitis and PsA were evaluated in a tertiary care uveitis clinic. These patients were compared retrospectively to a series of 89 patients with uveitis and SA.
RESULTS—Eight (50%) of the 16 patients with uveitis had strictly peripheral arthritis, while two (12.5%) had axial only, and six (37.5%) had axial and peripheral arthritis. Patients with uveitis and axial disease were more likely to be male (100% v 38%) and HLA-B27 positive (6 of 6 typed positive v 0 of 3 typed positive) when compared with those with uveitis and peripheral arthritis only. Compared with patients with SA, those with PsA were more likely to have insidious onset (19% v 3%), simultaneously bilateral (37.5% v 7%), chronic duration (31% v 6%), or posterior (44% v 17%) uveitis. Complications of uveitis were similar in the SA and PsA groups.
CONCLUSION—Uveitis in patients with PsA was more likely to be insidious in onset, continuous, posterior, and active bilaterally compared with uveitis in patients with SA. Patients with uveitis and axial involvement were more likely to be male and HLA-B27 positive compared with patients with uveitis and peripheral arthritis alone. Patients with seronegative arthritis and uveitis that begins insidiously, lasts longer than six months, is bilateral, or is posterior, should be carefully questioned about the presence of either psoriasis or inflammatory bowel disease.


doi:10.1136/ard.59.1.67
PMCID: PMC1752985  PMID: 10627431
23.  Efficacy of adalimumab in young children with juvenile idiopathic arthritis and chronic uveitis: a case series 
BMC Research Notes  2014;7:316.
Background
Juvenile idiopathic arthritis is a relatively common chronic disease of childhood, and is associated with persistent morbidity and extra-articular complications, one of the most common being uveitis. The introduction of biologic therapies, particularly those blocking the inflammatory mediator tumor necrosis factor-α, provided a new treatment option for juvenile idiopathic arthritis patients who were refractory to standard therapy such as non-steroidal anti-inflammatory drugs, corticosteroids and/or methotrexate.
Case presentations
The first case was a 2-year-old girl with juvenile idiopathic arthritis and uveitis who failed to respond to treatment with anti-inflammatories, low-dose corticosteroids and methotrexate, and had growth retardation. Adalimumab 24 mg/m2 every 2 weeks and prednisone 0.5 mg/kg/day were added to methotrexate therapy; steroid tapering and withdrawal started after 1 month. After 2 months the patient showed good control of articular and ocular manifestations, and she remained in remission for 1 year, receiving adalimumab and methotrexate with no side effects, and showing significant improvement in growth. Case 2 was a 9-year-old boy with an 8-year history of juvenile idiopathic arthritis and uveitis that initially responded to infliximab, but relapse occurred after 2 years off therapy. After switching to adalimumab, and adjusting doses of both adalimumab and methotrexate based on body surface area, the patient showed good response and corticosteroids were tapered and withdrawn after 6 months; the patient remained in remission taking adalimumab and methotrexate. The final case was a 5-year-old girl with juvenile idiopathic arthritis for whom adalimumab was added to methotrexate therapy after three flares of uveitis. The patient had two subsequent episodes of uveitis that responded well to local therapy, but was then free of both juvenile idiopathic arthritis and uveitis symptoms, allowing methotrexate and then adalimumab to be stopped; the patient remained in drug-free remission.
Conclusion
This report includes the first published case of the use of adalimumab in a child aged <3 years. Our clinical experience further supports the use of biologic therapy for the management of juvenile idiopathic arthritis and uveitis in children as young as two years of age.
doi:10.1186/1756-0500-7-316
PMCID: PMC4045933  PMID: 24886032
Adalimumab; Juvenile idiopathic arthritis; Children; Uveitis
24.  Ankylosing spondylitis in North India: a clinical and immunogenetic study. 
Annals of the Rheumatic Diseases  1984;43(3):381-385.
Fifty-one North Indian patients with ankylosing spondylitis (AS) are described with mean age of onset 21.2 years and male to female ratio of 16:1. AS began with peripheral arthritis in 47%, low back pain in 41%, acute anterior uveitis in 10%, and heel pain in 2% of the patients. 76% of 51 patients had one of the extra-axial features of AS: peripheral arthritis (61%), heel pain (24%), anterior uveitis (22%), urethritis (12%), kidney disease (10%), mucosal ulcerations (6%), aortic incompetence (4%), and apical pulmonary fibrosis (4%). A majority (71%) of the patients with peripheral arthritis had mono- or oligoarthritis affecting mainly the lower limb joints. Two patients had coexistent rheumatoid arthritis also. HLA-B27 antigen was detected in 48 (94%) of 51 patients compared with 7 (6%) of 118 controls (relative risk 254; Fisher's exact p = 3.49(-29]. On comparing patients with juvenile onset AS and patients with adult onset disease we found peripheral arthritis to be more frequent at the beginning and during the course of disease in the former.
PMCID: PMC1001350  PMID: 6611138
25.  Current approach in diagnosis and management of anterior uveitis 
Uveitis is composed of a diverse group of disease entities, which in total has been estimated to cause approximately 10% of blindness. Uveitis is broadly classified into anterior, intermediate, posterior and panuveitis based on the anatomical involvement of the eye. Anterior uveitis is, however, the commonest form of uveitis with varying incidences reported in worldwide literature. Anterior uveitis can be very benign to present with but often can lead to severe morbidity if not treated appropriately. The present article will assist ophthalmologists in accurately diagnosing anterior uveitis, improving the quality of care rendered to patients with anterior uveitis, minimizing the adverse effects of anterior uveitis, developing a decision-making strategy for management of patients at risk of permanent visual loss from anterior uveitis, informing and educating patients and other healthcare practitioners about the visual complications, risk factors, and treatment options associated with anterior uveitis.
doi:10.4103/0301-4738.58468
PMCID: PMC2841369  PMID: 20029142
Anterior uveitis; iridocyclitis; iritis; uveitis

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