[Intermediate and Posterior Uveitis - Disease entities]. / Intermediäre und posteriore Uveitis ­ Teil 2.

Intermediate and posterior uveitis can have multiple infectious and noninfectious causes, and posterior uveitis in particular is clinically multifaceted. Some entities require prompt initiation of therapy to ensure visual prognosis. This article presents typical characteristics of intermediate and posterior uveitides and explains special features of their treatment.

Ocular Involvement in Selected Rheumatic Diseases - Clinical Manifestation in Adulthood. / Augenbeteiligung bei ausgewählten rheumatischen Erkrankungen ­ Klinik im Erwachsenenalter.

Ocular manifestations of rheumatic diseases are common and contribute significantly to the morbidity and reduced quality of life of affected patients. Knowledge of typical clinical manifestations is important for the rheumatologist in order to support the reference of patients with corresponding symptoms for ophthalmological consultation at an early stage of disease, or to initiate regular screening examinations (e.g. in patients with Behçet's syndrome). Conversely, a (possibly urgent) rheumatological assessment is crucial for certain ophthalmological diseases, in order not to overlook a (possibly fatal) systemic associated disease. Patients with rheumatic or inflammatory ocular diseases should always be informed by the treating physician about possible symptoms of other organ manifestations, in order to avoid a delayed diagnosis. "Classic" associations for uveitis are (HLA-B27-associated) spondyloarthritis and acute anterior uveitis, as well as retinal vasculitis with or without panuveitis and Behçet's syndrome. In patients with rheumatoid arthritis or ANCA-associated vasculitis, however, scleritis (with or without peripheral ulcerative keratitis) typically occurs, but a variety of other findings are also possible. Close interdisciplinary collaboration, particularly regarding therapeutic decisions, is crucial to ensuring a good prognosis for the patient.

Peripheral Ulcerative Keratitis: Clinical Characteristics, Differential Diagnoses and Therapeutic Concepts. / Periphere ulzerative Keratitis: Klinik, Differenzialdiagnosen und Therapiekonzepte.

Peripheral ulcerative keratitis (PUK) is an inflammatory disease of the peripheral cornea, which may frequently be associated with several rare, but potentially life-threatening systemic diseases. The inflammatory pathogenesis of PUK results from humoral and cell-mediated inflammation. The diagnosis is usually based on the typical clinical findings and always requires detailed diagnostic testing to identify a potential systemic underlying disease. Treatment includes topical and systemic immunosuppressive and immunomodulatory therapeutic strategies and, in the event of impending or existing perforation, also various surgical interventions. PUK is a potentially blinding disease that initially affects the periphery, but, if left untreated, can lead to destruction of the entire cornea. Interdisciplinary diagnostic testing and therapy are crucial to preserve vision in the affected patients and reduce morbidity and mortality. The following article provides an overview of the pathophysiology, clinical findings, possible underlying systemic diseases, relevant differential diagnoses and therapeutic strategies.

[Intermediate and Posterior Uveitis - Classification, diagnostics, complications, and therapeutic algorithms]. / Intermediäre und posteriore Uveitis ­ Teil 1.

Intermediate and posterior uveitis describes a broad variety of different types of intraocular inflammation. Before starting treatment of intermediate or posterior uveitis, a differentiation between infectious or non-infectious uveitis must always be made. Pathognomonic symptoms do not exist, visual loss and vitreous floaters are the most common symptoms. The indication for therapy is influenced by the anatomical localization, the degree of inflammation, an association, complications and the activity of the inflammation. In addition to clinical ophthalmological standard examination, angiography and OCT are the most important investigations to classify and assess the course of inflammation. Macular edema is the most common complication of intermediate or posterior uveitis and should be treated at first onset, recurrence, or worsening. Oral, intravenous, or intravitreal corticosteroids are usually the primary therapy for intermediate or posterior uveitis. Systemic immunosuppression is indicated after steroid failure in non-infectious uveitis.

Assessment of angiogenesis-related parameters in juvenile idiopathic arthritis-associated uveitis.

PURPOSE: Juvenile idiopathic arthritis-associated uveitis (JIAU) may run a chronic and treatment-resistant course, and occasionally, alterations of the iris vasculature may be observed clinically. METHODS: Iris tissue (IT), aqueous humor (AH) and serum samples from patients with clinically inactive JIAU (n = 30), acute anterior uveitis (AAU; n = 18), and primary open angle glaucoma (POAG; n = 20) were obtained during trabeculectomy or cataract surgery. Samples were analyzed by RNA-Seq, qRT-PCR, LC-IMS, Western-Blot, and LEGENDplex™ analysis. Pattern of iris vasculature in JIAU patients was assessed qualitatively via fluorescein and indocyanine green angiography (FLA/ICGA). RESULTS: RNA-Seq of IT showed significantly differential expression (DE) of 136 genes between JIAU and POAG, of which 15 were associated with angiogenesis. qRT-PCR, performed to validate RNA-Seq results, showed upregulation of the angiogenesis-related genes Kdr, Angpt-1, Tie-1, Tie-2 and Mmrn2 in IT (JIAU vs POAG, p > 0.05). LC-IMS of IT revealed a total number of 56 DE proteins (JIAU vs POAG), of which Angiopoetin, Lumican and Decorin were associated with angiogenesis and showed increased (p > 0.05) expression on Western-Blot analysis. LEGENDplex™ analysis showed upregulation of ANGPT-2 in AH from JIAU compared to AAU and POAG, whereas VEGF was upregulated in AAU. Iris vascular leakage, hypoperfusion and neovascularization were observed by FLA/ICGA in JIA patients with treatment-refractory complicated course of uveitis. CONCLUSION: Angiogenesis-related factors could play a role in long-standing complicated JIAU, leading to clinically visible alterations in selected cases.

Viral Anterior Uveitis. / Virale anteriore Uveitis.

Differential diagnosis of viral anterior uveitis (AU) based on the typical clinical findings (anterior chamber inflammation, morphology of the keratic precipitates, severity of IOP increase in relapse) is often straightforward. When differential diagnosis is difficult clinically, analysis of aqueous humour by PCR and/or antibody testing (Goldmann-Witmer coefficient) may be helpful. While both modalities are highly specific, they lack absolute sensitivity. Patients with HSV, VZV and CMV associated uveitis require both antiviral as well as antiinflammatory medication and often additional antiglaucomatous therapy, depending on IOP. In contrast, specific antiviral treatment is not possible in rubella associated AU and steroids should be administered with extreme caution due to their adverse effects. With all subtypes of virus associated AU, recurrent episodes put the patients at risk of developing secondary glaucoma, which often requires surgical treatment.

Adherence to ophthalmological screening recommendations and course of uveitis in children with juvenile idiopathic arthritis: data from the Inception Cohort of Newly diagnosed patients with JIA (ICON-JIA) study.

OBJECTIVES: As JIA-associated uveitis (JIAU) is asymptomatic in the majority of patients, ophthalmologic screening examinations are recommended, depending on the risk constellation for uveitis development. This study analyses disease characteristics in JIAU depending on adherence with the screening intervals. METHODS: 953 patients were included in the ICON registry. In patients without uveitis, ophthalmologic screening was recommended in accordance with the standards currently applied in Germany. Dates and results of the screening examinations were noted for each patient. RESULTS: Until the 3-year-follow up, uveitis developed in 133 of 953 JIA patients. In 56 of them, uveitis was present before study inclusion, and those were excluded from the prospective analysis. For the remaining 897 JIA patients, screening results were available in 557, 46 of whom developed uveitis. In those patients, adherence with the suggested screening intervals until uveitis onset was assessed, and patients were classified accordingly: screenings as recommended (Sc+ group, n=356) vs. infrequent screening (Sc- group, n=201). Non-adherence with the screening schedule significantly correlated with younger age at study inclusion and JIA diagnosis, shorter JIA disease duration, JIA oligoarthritis subtype and positive antinuclear antibody status. The Sc+ group had a better visual acuity (VA) at initial uveitis diagnosis, however, at the 3-year-follow up, VA and uveitis complication rates did not differ significantly. CONCLUSIONS: Especially high-risk patients often do not adhere to the initial frequently recommended screening intervals, resulting in a reduced visual acuity at initial uveitis diagnosis. A recommendation for changing the current screening intervals cannot be deduced from our data.

[Intermediate Uveitis in Adults and Children - Update]. / Intermediäre Uveitis bei Erwachsenen und Kindern ­ Update.

Intermediate uveitis is a rare disease. Interdiscliplinary investigations to identify or exclude an associated systemic disease (in Central Europe, this would primarily mean sarcoidosis and multiple sclerosis) should be initiated even at the first manifestation of disease. Therapy should be started in those patients with marked inflammatory activity or secondary complications and primarily encompasses local and systemic corticosteroids, although some patients need second line steroid sparing systemic DMARD therapy (DMARD: disease-modifying antirheumatic drug).

Transcriptomic and proteomic analysis of iris tissue and aqueous humor in juvenile idiopathic arthritis-associated uveitis.

Gene and protein expression profiles of iris biopsies, aqueous humor (AqH), and sera in patients with juvenile idiopathic arthritis-associated uveitis (JIAU) in comparison to control patients with primary open-angle glaucoma (POAG) and HLA-B27-positive acute anterior uveitis (AAU) were investigated. Via RNA Sequencing (RNA-Seq) and mass spectrometry-based protein expression analyses 136 genes and 56 proteins could be identified as being significantly differentially expressed (DE) between the JIAU and POAG group. Gene expression of different immunoglobulin (Ig) components as well as of the B cell-associated factors ID3, ID1, and EBF1 was significantly upregulated in the JIAU group as compared to POAG patients. qRT-PCR analysis showed a significantly higher gene expression of the B cell-related genes CD19, CD20, CD27, CD138, and MZB1 in the JIAU group. At the protein level, a significantly higher expression of Ig components in JIAU than in POAG was confirmed. The B cell-associated protein MZB1 showed a higher expression in JIAU patients than in POAG which was confirmed by western blot analysis. Using bead-based immunoassay analysis we were able to detect a significantly higher concentration of the B cell-activating and survival factors BAFF, APRIL, and IL-6 in the AqH of JIAU and AAU patients than in POAG patients. The intraocularly upregulated B cell-specific genes and proteins in iris tissue suggest that B cells participate in the immunopathology of JIAU. The intracameral environment in JIAU may facilitate local effector and survival functions of B cells, leading to disease course typical for anterior uveitis.

Predictive factors and biomarkers for the 2-year outcome of uveitis in juvenile idiopathic arthritis: data from the Inception Cohort of Newly diagnosed patients with Juvenile Idiopathic Arthritis (ICON-JIA) study.

OBJECTIVE: To define predictors for the 2-year outcome in terms of achieving inactivity, subsequent uveitis reactivation and occurrence of uveitis-related complications of JIA-associated uveitis. METHODS: Demographic and clinical parameters and serum samples of JIA-associated uveitis patients enrolled in ICON at ⩽1 year of JIA diagnosis were collected at study enrolment, every 3 months during the first year and subsequently every 6 months. Predictors for the 2-year outcome were evaluated by linear mixed models. RESULTS: Of 954 JIA patients included, uveitis occurred in 106 up to the first 2-year follow-up, with 98 of them having complete ophthalmological documentation. In 81.8% and 80.0% of patients, uveitis inactivity was achieved at the 1- and 2-year follow-up after uveitis onset, respectively. JIA onset after the age of 5 years, no use of topical corticosteroids, and adalimumab treatment were significantly associated with an inactive uveitis for at least 6 months (n = 57). Correlates for subsequent uveitis reactivation (n = 16, 30.2%) were age at uveitis onset ⩽5 years and active disease (clinical Juvenile Arthritis Disease Activity Score >4.5). Uveitis-related complications were present in 29.8% of patients at first uveitis documentation and in 30.7% and 32.8% at 1- and 2-year follow-up, respectively. Older age at JIA onset, short duration between JIA and uveitis onset, high anterior chamber (AC) cell grades, poor visual acuity, and topical steroid use at first uveitis documentation correlated with uveitis-related complications. CONCLUSION: In addition to demographic risk factors, JIA disease and uveitis activity scores and adalimumab are significant predictors for the 2-year outcome of JIA-associated uveitis patients.

Peripheral blood monocytes reveal an activated phenotype in pediatric uveitis.

OBJECTIVE: To characterize peripheral blood monocytes in uveitis associated with juvenile idiopathic arthritis (JIAU). METHODS: Peripheral blood monocytes from children with JIA (either with (n = 18) or without uveitis (n = 11)), idiopathic anterior uveitis (IAU; n = 12) and healthy controls (n = 11) were analyzed by flow cytometry. RESULTS: Percentage of CD14 + CD86+ monocytes and CD86 expression on single cell level were significantly higher in all patient groups than in controls, whereas no major differences existed between patient groups. Frequency of CD39+ (p < 0.05 all groups) and CD73+ monocytes (p = 0.03 JIAU vs controls) was elevated in patients. Disease activity did not influence monocyte phenotypes, but in methotrexate-treated JIAU patients numbers of CCR2+ monocytes were reduced and numbers of CD86+ and CD39+ cells increased. CONCLUSION: Children with arthritis or uveitis display a distinct monocytic phenotype when compared to cells from healthy children. Phenotypic changes seem to be neither arthritis- nor uveitis-dependent, but may be modified by treatment.

Consensus-based recommendations for the management of uveitis associated with juvenile idiopathic arthritis: the SHARE initiative.

BACKGROUND: In 2012, a European initiative called Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases. Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children and uveitis is possibly its most devastating extra-articular manifestation. Evidence-based guidelines are sparse and management is mostly based on physicians' experience. Consequently, treatment practices differ widely, within and between nations. OBJECTIVES: To provide recommendations for the diagnosis and treatment of JIA-associated uveitis. METHODS: Recommendations were developed by an evidence-informed consensus process using the European League Against Rheumatism standard operating procedures. A committee was constituted, consisting of nine experienced paediatric rheumatologists and three experts in ophthalmology from Europe. Recommendations derived from a validated systematic literature review were evaluated by an Expert Committee and subsequently discussed at two consensus meetings using nominal group techniques. Recommendations were accepted if >80% agreement was reached (including all three ophthalmologists). RESULTS: In total, 22 recommendations were accepted (with >80% agreement among experts): 3 on diagnosis, 5 on disease activity measurements, 12 on treatment and 2 on future recommendations. CONCLUSIONS: The SHARE initiative aims to identify best practices for treatment of patients suffering from JIA-associated uveitis. Within this remit, recommendations for the diagnosis and treatment of JIA-associated uveitis have been formulated by an evidence-informed consensus process to suggest a standard of care for JIA-associated uveitis patients throughout Europe.

The effect of methotrexate and sulfasalazine on the course of HLA-B27-positive anterior uveitis: results from a retrospective cohort study.

PURPOSE: To investigate the effect of methotrexate (MTX) or sulfasalazine (SSZ) on the course of HLA-B27-positive, remitting acute anterior uveitis (AAU). METHODS: Forty-six patients with HLA-B27-positive AAU with or without associated systemic rheumatic disease either receiving MTX (n = 20), SSZ (n = 13), or no systemic immunomodulating treatment (Ctrl; n = 13) were studied retrospectively. Best-corrected visual acuity (BCVA), AAU relapse rate, and occurrence of uveitis-related ocular complications were analyzed at baseline (BL) and at 12-month follow-up (FU). RESULTS: Groups did not differ regarding age, gender, and presence of associated systemic diseases. BCVA at baseline was significantly worse in patients receiving MTX (logMAR 0.39 ± 0.4) than in those treated with SSZ (0.17 ± 0.2; P = 0.05) or in controls (Ctrl; 0.14 ± 0.2; P = 0.009). At the 12-month endpoint, MTX treatment was associated with significantly improved BCVA (0.18 ± 0.4 logMAR; P = 0.004). In contrast, BCVA did not significantly change in patients treated with SSZ (0.17 ± 0.3 logMAR) or in the controls (0.11 ± 0.2 logMAR). The annual uveitis relapse rate significantly decreased with MTX (BL 3.6 ± 2.4 relapses to FU 0.7 ± 0.8; P = 0.0001) and SSZ (BL 3.6 ± 1.9 to FU 1.8 ± 2.4, P < 0.01), but not in the controls (BL 1.9 ± 1.4 vs 1.9 ± 1.7 FU). The complication rate was slightly reduced with MTX (BL 1.75 ± 1.2 complications present versus FU 1.3 ± 1.2, P = 0.09) but not with SSZ (BL 0.9 ± 0.8 to FU 1.3 ± 1.4; P = 0.4) or in the controls (BL and FU 1.0 ± 0.95; P = 0.7). CONCLUSIONS: MTX and SSZ reduced the uveitis relapse rate in HLA-B27-positive AAU patients, with MTX showing a beneficial effect on AAU-related macular edema.

[Therapeutic Concepts for Treatment of Patients with Non-infectious Uveitis Biologic Disease Modifying Antirheumatic Drugs]. / Therapiekonzepte zur Behandlung von Patienten mit nicht infektiöser Uveitis: biologische Disease Modifying Antirheumatic Drugs.

Biologic disease modifying antirheumatic drugs (bDMARDs) can be highly efficient in the treatment of various non-infectious uveitis entities. Currently, the TNF-α-inhibitor Adalimumab is the only in-label therapeutic option, whereas, all other bDMARDs need to be given as an off-label therapy. bDMARDs are indicated in diseases refractory to conventional synthetic DMARD therapy and/or systemic steroids, or in patients in whom treatment with those is not possible due to side effects. Therapeutic mechanisms currently employed are cytokine-specific (interferons, inhibition of TNF-α or of interleukin [IL]-1-, IL-6- or IL-17-signalling), inhibit T cell costimulation (CTLA-4 fusion protein), or act via depletion of B cells (anti-CD20). All bDMARDs need to be administered parenterally, and therapy is initiated by the treating internal specialist only after interdisciplinary coordination of all treating subspecialties and after exclusion of contraindications. Regular clinical and laboratory monitoring is mandatory for all patients while under bDMARD therapy.

[Cataracts in Uveitis]. / Katarakt bei Uveitis.

Cataracts are a frequent complication of uveitis, and their management can be challenging. Operation planning requires knowledge of the cause (e.g., infectious versus noninfectious) and course of uveitis, including any intraocular comorbidities (e.g., macular edema). Preoperative patient selection is particularly important in uveitis patients to achieve good surgical results. Steroid-sparing disease-modifying antirheumatic drugs (DMARDs) can reduce the rate of postoperative complications and can improve visual acuity. Before the operation, a stable inactivity of intraocular inflammation must be achieved. The surgical approach should be minimally invasive. Intraocular lens implantation should only be performed under stable inflammatory control. By using intraocular corticosteroids (e.g., dexamethasone acetonide implant, triamcinolone acetonide) the complication rate can be reduced. Postoperatively, the additional anti-inflammatory medication should be intensified and continued for up to 3 months. With careful patient selection, planning and execution of cataract surgery and postoperative care, satisfactory anatomical and functional outcomes can be achieved in uveitis patients.

Behavioral Conditioning of Immune Responses with Cyclosporine A in a Murine Model of Experimental Autoimmune Uveitis.

OBJECTIVE: We examined the role of behavioral conditioning of immune responses with cyclosporine A (CsA) on the development of Th1/Th17-driven experimental autoimmune uveoretinitis (EAU). METHODS: Mice received a 0.2% w/v saccharin solution as conditioned stimulus combined with CsA (20 mg/kg) in 6 association trials at 72-h intervals. For evocation periods, conditioned mice were reexposed to saccharin, whereas the conditioned but not reexposed group received water only. Animals were immunized with human interphotoreceptor-retinoid-binding protein peptide 161-180 (hIRBPp161-180) peptide in complete Freund adjuvant (CFA) and a concomitant injection of pertussis toxin. RESULTS: In naïve mice subjected to the behavioral conditioning regimen, mitogen-induced interleukin (IL)-2 production was decreased in conditioned mice compared to conditioned but not reexposed animals. Incidence and severity of EAU were not significantly lower in behaviorally conditioned and immunized mice. ELISA analysis of splenocytes revealed a reduced interferon (IFN)-γ/IL-17 ratio in CsA-treated, conditioned but not reexposed, and conditioned animals. The adoptive transfer of antigen-specific splenocytes from animals behaviorally conditioned with CsA to naïve mice decreased the severity of EAU in recipient mice compared to the control group. In vitro activation of splenocytes isolated from immunized mice with agonists targeting TLR2 and NOD2 together with ß2-adrenergic activation (induced by epinephrine, norepinephrine, or salbutamol) resulted in decreased IFN-γ but increased IL-17 immune responses. The ß2-adrenergic antagonist propranolol could restore IFN-γ production, whereas only the norepinephrine-induced increase in IL-17 production was abrogated. CONCLUSIONS: We conclude that CsA conditioning in the EAU model mitigates Th1 but enhances Th17 immune responses, and does not ameliorate disease. The results imply that in EAU the mechanism of immune conditioning interacts with CFA components during active immunization, most likely via the TLR2/NOD2 pathway, and induces differentiation of Th17 cells that drive autoimmune diseases.

Reprogramming of monocytes by GM-CSF contributes to regulatory immune functions during intestinal inflammation.

Human and murine studies showed that GM-CSF exerts beneficial effects in intestinal inflammation. To explore whether GM-CSF mediates its effects via monocytes, we analyzed effects of GM-CSF on monocytes in vitro and assessed the immunomodulatory potential of GM-CSF-activated monocytes (GMaMs) in vivo. We used microarray technology and functional assays to characterize GMaMs in vitro and used a mouse model of colitis to study GMaM functions in vivo. GM-CSF activates monocytes to increase adherence, migration, chemotaxis, and oxidative burst in vitro, and primes monocyte response to secondary microbial stimuli. In addition, GMaMs accelerate epithelial healing in vitro. Most important, in a mouse model of experimental T cell-induced colitis, GMaMs show therapeutic activity and protect mice from colitis. This is accompanied by increased production of IL-4, IL-10, and IL-13, and decreased production of IFN-γ in lamina propria mononuclear cells in vivo. Confirming this finding, GMaMs attract T cells and shape their differentiation toward Th2 by upregulating IL-4, IL-10, and IL-13 in T cells in vitro. Beneficial effects of GM-CSF in Crohn's disease may possibly be mediated through reprogramming of monocytes to simultaneously improved bacterial clearance and induction of wound healing, as well as regulation of adaptive immunity to limit excessive inflammation.

Phenotypic changes of peripheral blood mononuclear cells upon corticosteroid treatment in idiopathic intermediate uveitis.

We analyzed phenotype and function of peripheral blood mononuclear cells in 9 patients with active idiopathic intermediate uveitis (IIU) before and after 6 and 12weeks of systemic corticosteroid (CS) treatment and compared to 28 healthy individuals. Monocytes from IIU patients showed increased MHCII expression compared with controls (p=0.09). Treatment reduced expression of MHCII, CD86, CD39 and CD124 (all p<0.05), whereas the percentage of CD121b-expressing monocytes was increased by week 6 (p=0.039). Patients showed alterations in T cell polarization (Th1/Th2 ratio: patients 5.2 versus controls 3.1, p=0.054; Th17/Treg ratio: 3.0 versus 1.7, p=0.027). S100A12 serum levels were higher in active IIU (p=0.057). Phagocytosis, oxidative burst and serum cytokine levels did not differ between patients and controls, and were not altered by treatment. In conclusion, monocytes from patients with active IIU show increased co-stimulatory capacities, which are modulated by systemic CS treatment, whereas innate immune cell functions are not altered.

Beneficial Effect of Upadacitinib in an Adult Patient with Juvenile Idiopathic Arthritis-associated Uveitis after Unsatisfactory Response to Tofacitinib: A Case Report.

OBJECTIVE: Several case reports have been published on the effect of janus kinase inhibitors (JAK-I) on juvenile idiopathic arthritis-associated uveitis (JIAU). Both tofacitinib and baricitinib have been described as therapeutically effective in JIAU. METHODS: We here present a case of a 24-years-old female with refractory course of JIAU receiving upadacitinib therapy. RESULTS: After failing multiple conventional and biologic disease-modifying antirheumatic drugs, the patient finally achieved clinical remission on upadacitinib monotherapy, despite a previously unsatisfactory clinical response of both arthritis and uveitis to tofacitinib monotherapy. CONCLUSION: This case suggests that switching JAK-I might be a successful strategy in the treatment of JIAU, despite previously incomplete response to other preparations.