The Challenge of Treating the Severest Forms of Chronic Noninfectious Posterior and Panuveitis.

BACKGROUND: Noninfectious posterior and panuveitis may exhibit a chronic relapsing clinical course and are challenging to treat. Most affected patients are continuously treated with systemic immunosuppressive therapy, which is potentially associated with significant adverse side effects. METHODS: A cohort of 18 patients presenting with severe noninfectious posterior or panuveitis were evaluated with respect to the clinical course of the disease, with particular focus on best-corrected visual acuity (BCVA), treatment duration, remission rates, reported negative side effects, and the necessity for switching medication. RESULTS: The mean follow-up was 27.8 months. Although BCVA improved significantly, complete or partial remission was observed in only 66.7% of patients. Of the patients, 72.2% underwent a change in medical treatment due to either adverse events or inefficacy of medication. CONCLUSION: Despite new immunosuppressive therapies, effective treatment of severe noninfectious posterior and panuveitis remains a major challenge. We discuss the urgent need for novel treatment strategies in order to prevent systemic adverse effects, and to improve visual outcome and quality of life.

On the Current Care Situation and Treatment of Ocular Mucous Membrane Pemphigoid in Germany. / Zur Versorgungssituation und konservativen Therapie des okulären vernarbenden Schleimhautpemphigoids in Deutschland.

BACKGROUND: Ocular involvement in mucous membrane pemphigoid (MMP) is relatively rare, with a prevalence of 25 cases per million population, equating to approx. 2,100 patients throughout Germany. Diagnosis can be difficult - especially in cases of isolated ocular involvement - and treatment can be complex and lengthy. Immunosuppressants or immunomodulatory drugs are often used. Due to the complexity of diagnosis and treatment, MMP patients are usually referred to specialized centers. The aim of this project was to evaluate the current care situation of patients with ocular MMP in Germany. METHODS: A paper-based survey was designed and sent to all university eye clinics and other specialized centers in Germany in April 2020. The survey asked about the existence of a specialized outpatient service, the total annual number of patients with MMP, the annual number of newly diagnosed patients, any interdisciplinary collaboration for diagnostic or therapeutic purposes, as well as the local and systemic therapy used. RESULTS: Of a total of 44 clinics, 28 (64%) responded, reporting a total average of 27 ± 42 (0 - 200) patients and 3.6 ± 2.2 (0 - 10) new cases per year. This corresponds to a total of 741 patients. Only nine (32%) of the responding clinics offer specialized MMP clinics. 93% of the centers collaborate with the local dermatology department. 79% perform serological and histological diagnostics in-house. About half of the centers (n = 16) apply a standardized treatment regime. Systemic glucocorticoids (66.7%) are most commonly used, followed by mycophenolate mofetil and dapsone (57.1%), rituximab (33.3%), azathioprine and cyclophosphamide (28.6%), as well as methotrexate (19.0%). The least frequently used treatment is intravenous immunoglobulin (14.3%). CONCLUSION: This survey of German ophthalmology departments obtained data from about one third of the estimated total cohort of all patients with MMP in Germany. These are presumed to be exclusively patients with at least one ocular involvement. The complex care of these patients is usually provided in collaboration with a dermatologist and with the use of systemic anti-inflammatory medication. Currently, an ophthalmological MMP register is being established to better record the epidemiology and care situation of this rare disease in Germany and to improve it in the long term.

[Clinical aspects, diagnostics and differential diagnostics of uveitis for rheumatologists]. / Klinik, Diagnostik und Differenzialdiagnostik der Uveitis für Rheumatologen.

This review article presents the different forms of uveitis and their clinical manifestations. The exact type and localization of the ocular inflammation is crucial for the probability of the underlying rheumatological disease and thus for a correct differential diagnosis. In this first part, in addition to the anatomy of the eye, the different forms of uveitis including the associated nomenclature, typical symptoms, diagnostics and possible complications are presented. In a following second part ("Association of the different forms of uveitis with inflammatory rheumatic diseases and their treatment"), the associations with rheumatological and other systemic diseases are explained and highlighted from an ophthalmological and rheumatological perspective.

[Association of the different forms of uveitis with inflammatory rheumatic diseases and their treatment]. / Assoziation der verschiedenen Uveitisformen mit entzündlich rheumatischen Erkrankungen und ihre Therapie.

The etiology of uveitis greatly varies worldwide, whereby in industrial nations noninfectious causes occur relatively more frequently. In Germany, 44% of all cases of uveitis are due to systemic diseases. In rheumatology, uveitis or other kinds of ocular inflammation, such as scleritis or retinal vasculitis, most commonly occur in spondylarthritis, vasculitis and sarcoidosis. Vice versa, ophthalmologists often ask rheumatologists about an underlying rheumatic disease in patients with uveitis. It is of utmost importance to differentiate between the different forms of uveitis. This review article presents the associations with inflammatory rheumatic diseases as well as treatment options from the point of view of both ophthalmologists and rheumatologists.

[Sarcoidosis as prime example of a granulomatous disease]. / Sarkoidose als Paradebeispiel einer granulomatösen Erkrankung.

Sarcoidosis is the most frequent immunologically related granulomatous disease and can serve as a model for understanding diseases within this category. The evidence on the diagnostics and treatment is so far limited. It is therefore all the more important that two new and significant guidelines on diagnosis and treatment of sarcoidosis were published during the last 2 years. Additionally, there were more new publications, which were considered for this review article. In this context, this review article provides a current update and overview of sarcoidosis. Pathophysiologically, there is an increasing understanding of the complex processes and interactions involved in the inflammatory processes and granuloma formation. The probability of a diagnosis of sarcoidosis is determined by compatible histology, the exclusion of differential diagnoses and if possible evidence of a multiorgan manifestation. The clinical course is variable and ranges from an asymptomatic manifestation to severe life-threatening organ failure. The most frequently affected organ are the lungs. Pulmonary fibrosis is the most severe form and is also decisive for mortality. An increasing focus is on the extrapulmonary organ manifestations, in particular, cardiac, hepatosplenic, gastrointestinal, renal, ocular and neurological involvement. Treatment, which consists primarily of immunosuppression, should be initiated in cases of organ-threatening or quality of life-impairing activity of the disease. Additional organ-specific management must also be evaluated. In cases of organ failure transplantation should be considered. Due to the limited evidence especially for the treatment of multiorgan sarcoidosis, when possible, patients with this disease should be included in clinical trials.

Infectious Posterior Uveitis - Toxoplasmosis, Treponema, Tuberculosis (TTT). / Infektiöse posteriore Uveitis ­ Toxoplasmose, Treponema, Tuberkulose (TTT).

Toxoplasma gondii, Treponema pallidum and Mycobacterium tuberculosis are the most important infectious causes of posterior uveitis. The epidemiology, clinical picture, diagnostic and treatment strategies of these diseases are presented.

Primary Vitreoretinal Lymphoma Therapy Monitoring: Significant Vitreous Haze Reduction After Intravitreal Rituximab.

BACKGROUND/AIMS: Intravitreal rituximab is an off-label treatment option for primary vitreoretinal lymphoma (PVRL). The objective of this study was to monitor the therapeutic response and safety profile of intravitreal rituximab in a cohort of PVRL patients. METHODS: In this retrospective, uncontrolled, open label, multicentre study, 20 eyes from 15 consecutive patients diagnosed with PRVL received at least one intravitreal injection of 1mg in 0.1ml rituximab. Biodata of the PVRL patients was recorded as well as visual acuity and vitreous haze score immediately before rituximab intravitreal injection and at follow-up examinations. Intravitreal rituximab safety data was also recorded. Additional rituximab injections were made during control visits on a pro re nata (PRN) regime using increased vitreous haze to indicate recurrence. RESULTS: There was significant vitreous haze reduction (p=0.0002) followed by significant improvement of visual acuity (mean best visual acuity before therapy 0.57 logMAR, after therapy 0.20 logMAR (p=0.0228) during the follow-up time up to 4 years. Only mild ocular side effects were reported. Median follow-up time was 565 days (range, 7-1253 days). CONCLUSION: Intravitreal rituximab therapy shows promising PVRL regression without any severe side effects. Although our clinical data support rituximab as intravitreal therapy in PVRL disease, further study is warranted.

[Uveitis in Behçet's Syndrome in Germany - Prognosis During Current Therapy]. / Uveitis bei Behçet-Syndrom in Deutschland ­ Prognose unter aktueller Therapie.

Behçet's syndrome (BS) is an inflammatory systemic disease associated with multiple organ manifestations. Major symptoms include oral and genital ulcerations, skin lesions and uveitis. Diagnosis of Behçet's syndrome is based on clinical findings. A typical for ocular Behçet's syndrome is recurrent non-granulomatous panuveitis with occlusive retinal vasculitis. Treatment used to be based only on the use of systemic corticosteroids and conventional immunosuppressives, but most often this treatment did not appear to be sufficient. In consequence, prognosis of ocular BS was very poor over a long period of time - especially if occlusive retinal vasculitis was present. In recent years, the introduction of biologicals has revolutionised the therapeutic regime and consecutively visual prognosis of ocular Behçet's syndrome has dramatically improved.

[Uveitis and multiple sclerosis : Clinical aspects, diagnostics, management and treatment]. / Uveitis und multiple Sklerose : Klinik, Diagnostik, Management und Therapie.

Approximately 0.5-1% of patients with multiple sclerosis (MS) have co-existing uveitis. Both intraocular inflammation and MS mainly affect women in younger adulthood. The MS in patients is most frequently associated with an often bilateral intermediate uveitis with typical concomitant retinal vasculitis. Both diseases share similar characteristics with chronic inflammatory diseases with a relapsing course and an immune-mediated pathogenesis; however, it is still unclear whether the co-occurrence of uveitis and MS in the same patient represents a coincidence of two separate disease entities or whether uveitis is a rare clinical manifestation of MS. In the differential diagnostics of intermediate uveitis, clinical symptoms and signs of MS should be considered. As both diseases are considered to be immune-mediated, immunotherapy is the main treatment option. In recent years the range of medications has expanded and includes several disease modifying drugs (biologics). When selecting the active substance it must be taken into account that tumor necrosis factor (TNF) alpha blockers are contraindicated in patients with MS.

[Association of the different forms of uveitis with inflammatory rheumatic diseases and their treatment]. / Assoziation der verschiedenen Uveitisformen mit entzündlich rheumatischen Erkrankungen und ihre Therapie.

The etiology of uveitis greatly varies worldwide, whereby in industrial nations noninfectious causes occur relatively more frequently. In Germany, 44% of all cases of uveitis are due to systemic diseases. In rheumatology, uveitis or other kinds of ocular inflammation, such as scleritis or retinal vasculitis, most commonly occur in spondylarthritis, vasculitis and sarcoidosis. Vice versa, ophthalmologists often ask rheumatologists about an underlying rheumatic disease in patients with uveitis. It is of utmost importance to differentiate between the different forms of uveitis. This review article presents the associations with inflammatory rheumatic diseases as well as treatment options from the point of view of both ophthalmologists and rheumatologists.

X-Linked Retinoschisis Masquerading Uveitis.

X-linked retinoschisis (XLRS) shows features also seen in patients with uveitis and is recognized as an uveitis masquerade syndrome. This retrospective study aimed to describe characteristics of XLRS patients with an initial uveitis diagnosis and to contrast these to patients with an initial XLRS diagnosis. Patients referred to a uveitis clinic, which turned out to have XLRS (n = 4), and patients referred to a clinic for inherited retinal diseases (n = 18) were included. All patients underwent comprehensive ophthalmic examinations, including retinal imaging with fundus photography, ultra-widefield fundus imaging, and optical coherence tomography (OCT). In patients with an initial diagnosis of uveitis, a macular cystoid schisis was always interpreted as an inflammatory macular edema; vitreous hemorrhages were commonly interpreted as intraocular inflammation. Patients with an initial diagnosis of XLRS rarely (2/18; p = 0.02) showed vitreous hemorrhages. No additional demographic, anamnestic, and anatomical differences were found. An increased awareness of XLRS as a uveitis masquerade syndrome may facilitate early diagnosis and may prevent unnecessary therapies.

Treatment in Latent Tuberculosis Uveitis-Is Immunosuppression Effective or Is Conventional 3- or 4-Drug Antituberculosis Therapy Mandatory?

Background/Aims: Controversy exists regarding 3- or 4 drug antituberculosis therapy (conventional ATT) in uveitis patients having latent tuberculosis (LTB), especially while initiating therapy with corticosteroids and/or other immunosuppressants. Methods: We performed a monocentral retrospective analysis of posterior uveitis patients with latent TB. Latent TB was diagnosed, in case of a positive QuantiFERON®-TB-Gold test and normal chest imaging, after ruling out other causes of infectious and noninfectious uveitis. Patients with active TB were excluded. From 2016 to 2020 we included 17 patients. Ophthalmological evaluation consisted of Best corrected visual acuity (BCVA), slit lamp examination, fundoscopy, OCT, and fluorescein- and indocyaningreen- angiography before and at months 3, 6, 12, 24, and the last follow-up after treatment. Results: Initially, all patients had active posterior uveitis with occlusive (n = 5 patients) and nonocclusive retinal vasculitis (n = 12 patients). Mean follow up was 28 ± 15 months. Therapy was started with systemic corticosteroids (mean prednisolone equivalent 71.3 mg/d) and already after 3 months it could be tapered to a mean maintenance dosage of 8.63 mg/d. Additional immunosuppressive treatment with cs- or bDMARDs was initiated in 14 patients (82%) due to recurrences of uveitis while tapering the corticosteroids <10 mg per/day or because of severe inflammation at the initial visit. While being on immunosuppression, best corrected visual acuity increased from 0.56 logMAR to 0.32 logMAR during follow-up and only three patients had one uveitis relapse, which was followed by switch of immunosuppressive treatment. As recommended, TB prophylaxis with 300 mg/d isoniazid was administered in 11 patients for at least 9 months while being on TNF-alpha-blocking agents. No patient developed active tuberculosis during immunosuppressive therapy. Conclusion: Mainly conventional ATT is strongly recommended­as monotherapy or in combination with immunosuppressives­for effective treatment in patients with uveitis due to latent TB. Although in our patient group no conventional ATT was initiated, immunosuppression alone occurred as an efficient treatment. Nevertheless, due to possible activation of TB, isoniazid prophylaxis is mandatory in latent TB patients while being on TNF-alpha blocking agents.

Behçet's disease: ocular effects and treatment.

Behçet's disease (BD) is a systemic immune-mediated vasculitis of unclear origin. Major symptoms include oral aphthous ulcers, genital ulcerations, skin lesions, and ocular lesions. Eye involvement, which affects 60-80% of BD patients, is characterized by posterior or panuveitis with occlusive retinal vasculitis. The pathogenesis of BD remains unclear, but research of the last decades has shown a complex role of genetic factors (HLA-B51) predisposing to inflammation with involvement of the innate-immune system (neutrophils, NK cells), perpetuated by the adaptive immune response, most importantly T cells, against infectious- and/or auto-antigens. Despite aggressive immunosuppressive treatment, the visual prognosis of ocular BD was generally poor to date. Recently, novel biologic drugs, including interferon-alpha and tumour necrosis factor (TNF)-alpha-antagonists have been introduced in the treatment of ocular BD with very promising results and seem for the first time to improve the prognosis of the disease. This article will provide a current review of BD including recent developments in epidemiology, immunology, genetics, and treatment.

Therapy Rationale for Mineralocorticoid-Receptor Antagonists, Acetazolamide and a Switch of Therapy in Nonresponders in Central Serous Chorioretinopathy.

PURPOSE: To evaluate the efficacy of mineralocorticoid-receptor antagonists in comparison to acetazolamide and observation in the treatment of central serous chorioretinopathy. METHODS: Retrospective, interventional cohort study on 93 patients with acute or chronic central serous chorioretinopathy (37 patients: acetazolamide group, 20 patients: mineralocorticoid-receptor antagonist group, 8 patients: observation group, and 27 patients with a therapy switch between both medications). Main outcome measures were the change in best-corrected visual acuity, subretinal fluid (SRF) volume, central retinal prominence, and highest retinal prominence (HRP) at 12 weeks. RESULTS: HRP and SRF volume improved with statistical significance (P ≤ 0.05) after mineralocorticoid-receptor antagonist (P = 0.0000003 for the prominence, P = 0.008 for the volume) and acetazolamide (P < 0.0000001 for the prominence, P = 0.0000007 for the volume) treatment. HRP and SRF volume also improved after observation, but without statistical significance (P = 0.08 for the prominence, P = 0.72 for the volume). Corresponding visual acuity improved significantly in acetazolamide (P = 0.002) and mineralocorticoid-receptor antagonist (P = 0.03) treated patients. Interestingly, HRP and SRF volume in acetazolamide nonresponsive patients improved after switch to mineralocorticoid-receptor antagonists, whereas no benefit was seen in patients switching vice versa. CONCLUSIONS: Both medical treatments are effective first-line treatment options for central serous chorioretinopathy. In patients who are nonresponsive to acetazolamide, therapy switch to mineralocorticoid-receptor antagonists could be beneficial.

Multimodal Imaging in Birdshot Retinochoroiditis.

PURPOSE: To describe retinal vascular changes in Birdshot Retinochoroiditis (BSRC) with multimodal imaging techniques and functional values. METHODS: In this single-center study, 64 eyes of 32 subjects with BSRC were classified according to disease activity and duration and underwent imaging with spectral domain optical coherence tomography, fluorescein angiography, indocyanine green angiography, fundus autofluorescence, and optical coherence tomography angiography (OCTA). RESULTS: Mean age of the patients was 60 years (range, 38-74). OCTA revealed capillary loops (58%), telangiectatic vessels (44%), increased intercapillary spaces (52%), altered vascular architecture (53%), and rarefication of C-scans (63%) in retinal layers. Increased rarefications of C-scans (p = 0.0056; p = 0.0046) and altered vascular architecture (p = 0.0120; p = 0.0243) in superficial and deep capillary layers were significantly correlated with disease activity. CONCLUSION: OCTA adds new insights in a multimodal imaging approach of retinal vascular layer visualization in BSRC and may contribute to existing methods for diagnosing severity and potentially progression of the disease.

CNS involvement occurs more frequently in patients with Behçet's disease under cyclosporin A (CSA) than under other medications--results of a retrospective analysis of 117 cases.

The aim of this study was to evaluate the incidence of neurological manifestations of Behçet's disease (BD) in patients on cyclosporin A (CSA) compared with those on other medications. The records of 117 patients with BD who visited our hospital between 1990 and 2003 were reviewed with respect to symptoms and medication. All episodes of constant therapy prior to central nervous system (CNS) involvement were counted, and then the associations were analysed by the exact Fisher-Freeman-Halton test and adjusted for multiple tests by the Bonferroni-Holm method. We observed ten new cases of CNS manifestations in our patients with BD being regularly seen and treated in our tertiary care centre. The overall prevalence of neuro-BD in our patient group was 8.5%. In a retrospective analysis, the incidence of new-onset neurological disease (neuro-BD) in all patients with BD who regularly visited our hospital was significantly higher in patients on CSA than in those on other medications (6 of 21 vs 0 of 175 episodes, P<0.0001). This contrasts the obvious efficacy of CSA on extracerebral manifestations of BD, such as severe ocular disease, mucocutaneous lesions or arthritis. CSA exerts differential efficacy on various manifestations of BD. It is very effective for severe ocular and other moderate to severe manifestations of BD, but its efficacy for the prevention of neuro-BD seems to be inferior to that of other medications used in BD, such as azathioprine or interferon-alpha. The reasons for this are unclear, but the potential toxic effects of CSA on the CNS may be a predisposing factor for CNS vasculitis in BD.

Subretinal fluid in eyes with active ocular toxoplasmosis observed using spectral domain optical coherence tomography.

PURPOSE: To describe the clinical finding of subretinal fluid (SRF) in the posterior pole by spectral domain optical coherence tomography (SD-OCT) in eyes with active ocular toxoplasmosis (OT). DESIGN: Retrospective case series. PARTICIPANTS: Thirty-nine eyes from 38 patients with active OT [corrected].. METHODS: Eyes with active OT which underwent SD-OCT were reviewed. SRFs in the posterior pole were further analyzed. MAIN OUTCOME MEASURES: Presence of SRF; its accompanying features, e.g. retinal necrosis, cystoid macular edema (CME), choroidal neovascularization (CNV); and longitudinal changes of SRF, including maximum height and total volume before and after treatment. RESULTS: SRF presented in 45.5% (or 15/33) of eyes with typical active OT and in 51.3% (or 20/39) of eyes with active OT. The mean maximum height and total volume of SRF were 161.0 (range: 23-478) µm and 0.47 (range: 0.005-4.12) mm3, respectively. For 12 eyes with SRF related to active retinal necrosis, SRF was observed with complete absorption after conventional anti-toxoplasmosis treatment. The mean duration for observation of SRF clearance was 33.8 (range: 7-84) days. The mean rate of SRF clearance was 0.0128 (range: 0.0002-0.0665) mm3/day. CONCLUSIONS: SRF (i.e., serous retinal detachment) is a common feature in patients with active OT when SD-OCT is performed. The majority of SRF was associated with retinal necrosis and reacted well to conventional therapy, regardless of total fluid volume. However, SRF accompanying with CME or CNV responded less favorably or remained refractory to conventional or combined intravitreal treatment, even when the SRF was small in size.

The use of interferon alpha in Behçet disease: review of the literature.

OBJECTIVES: To evaluate the efficacy and safety of interferon (IFN) alpha for the treatment of Behçet's disease (BD) and discuss its possible mechanisms of action. METHODS: Reports published until July 2002 in all languages were identified by the PubMed Database and the BD conference proceedings and abstract booklets. The indexing terms used were "Behçet" and "interferon." RESULTS: Thirty-two original reports and 4 selected abstracts were included in the analysis. Systemic IFN-alpha was administered to 338 patients. One hundred eighty-two patients with acute ocular disease were treated with IFN-alpha. Two hundred sixty-four patients received IFN-alpha2a, and 74 received IFN-alpha2b. Eighty-six percent of the patients with mucocutaneous symptoms, 96% with arthritis, and 94% with uveitis exhibited a partial or complete response. Higher IFN doses were more effective than low-dose regimens and led to up to 56% long-term remissions after discontinuation of IFN-alpha were reported. IFN-alpha2a apparently was superior to IFN-alpha2b, with more complete remissions, but this probably was the result of a bias caused by the larger number of patients treated with IFN-alpha2a. Side effects were dose-dependent and similar to those noted in patients with hepatitis C. CONCLUSIONS: Although the comparability of the studies is hampered because of different study designs, IFN-alpha is effective for the treatment of BD. It was beneficial even in resistant posterior uveitis, in which long-term remissions with preservation of visual acuity was achieved. In contrast, mostly partial remissions were reported for mucocutaneous symptoms.

Differential efficacy of human recombinant interferon-alpha2a on ocular and extraocular manifestations of Behçet disease: results of an open 4-center trial.

OBJECTIVE: Behçet disease (BD) is a multisystem vasculitis of unknown origin. Standard treatment mainly comprises systemic immunosuppressive agents. In a study primarily designed for refractory ocular disease, we additionally evaluated the efficacy of recombinant human interferon-alpha2a (rhIFN-alpha2a) on the extraocular manifestations of BD. METHODS: Fifty patients were included in the study. RhIFN-alpha2a was applied at a dose of 6 x 10(6) units subcutaneously daily. Dose reduction was performed according to a decision tree until discontinuation. Disease activity was evaluated by the Behçet's Disease Activity Scoring System and the Uveitis Scoring System. RESULTS: Response rate of the ocular manifestations was 92%. Visual acuity rose significantly from 0.56 to 0.84 at week 24 (P <.0001). Mean Behçet's Disease Activity Score fell in a dose-dependent fashion by 1.2 points in the first week (P <.0001) and from 5.8 to 3.3 at week 24 and further to 2.8 at week 52. After a mean observation period of 36.4 months, 17 patients have been off treatment and disease-free for 29.5 months (mean). In the other patients, maintenance IFN dosage is 3 million units 3 times weekly. Whereas extraocular manifestations such as genital ulcerations, arthritis, and skin lesions remitted with IFN, only 36% of oral aphthous ulcers responded. CONCLUSIONS: RhIFN-alpha2a is effective in ocular BD, resulting in significant improvement of vision and complete remission of ocular vasculitis in the majority of patients. It is also beneficial for the extraocular manifestations of the disease, although less so for oral aphthous ulcers.