The Pathogenesis of Extraintestinal Manifestations: Implications for IBD Research, Diagnosis, and Therapy.

This article reports on the sixth scientific workshop of the European Crohn's and Colitis Organisation [ECCO] on the pathogenesis of extraintestinal manifestations [EIMs] in inflammatory bowel disease [IBD]. This paper has been drafted by 15 ECCO members and 6 external experts [in rheumatology, dermatology, ophthalmology, and immunology] from 10 European countries and the USA. Within the workshop, contributors formed subgroups to address specific areas. Following a comprehensive literature search, the supporting text was finalized under the leadership of the heads of the working groups before being integrated by the group consensus leaders.

[Precision pulse capsulotomy : The new capsulorhexis?] / Präzisionspulskapsulotomie : Die neue Kapsulorhexis?

The manual capsulorhexis created by Neuhann is still the standard procedure for opening the anterior capsule for cataract surgery. A limitation is the inaccuracy in the size and placement of the opening due to manual execution. In addition to the femtosecond laser a possible improvement in the standardization of capsulorhexis is provided by the Zepto procedure (precision pulse capsulotomy, PPC). In this case a 5.25 mm rhexis is created in a standardized fashion with a flexible suction adapter in which a nitinol ring is located. Whether the strength of PPC is comparable or better than that of the manual technique and how it behaves in terms of capsule shrinkage has not yet been finally clarified.

[What rheumatologists can learn from ophthalmologists]. / Was der Rheumatologe vom Augenarzt lernen kann.

Intraocular inflammation with the imprecise and broad umbrella term "uveitis" is a diagnostic and therapeutic challenge in ophthalmology. Uveitis is one of the most common causes of blindness worldwide and due to the associated costs is comparable to diabetic retinopathy. Patients can be affected by uveitis at any age. Any part of the eye may be affected. The symptoms range from complete absence of symptoms, through all types of vision deterioration up to a red and even very painful eye. Uveitis can be strictly unilateral (also alternating from the left to the right eye) or bilateral with a relapsing or chronic course. The transitions are smooth and the differential diagnoses are very broad. In addition to infectious forms and ocular syndromes restricted to the eye, it also includes those with extraocular systemic diseases, such as ankylosing spondylitis or sarcoidosis. All commonly administered immunosuppressive treatment strategies in rheumatology can be used for non-infectious forms in addition to local and regional forms of treatment. The diagnostic and therapeutic impulses of this interdisciplinary interface between rheumatology and ophthalmology is discussed in more detail in this article.

[Switching Therapy from Ranibizumab and/or Bevacizumab to Aflibercept in Neovascular Age-Related Macular Degeneration (AMD): One-Year Results]. / Das klinische Ergebnis eines Therapiewechsels von Ranibizumab und/oder Bevacizumab zu Aflibercept bei neovaskulärer altersabhängiger Makuladegeneration (AMD).

BACKGROUND: The presented study is a retrospective evaluation of switching therapy from ranibizumab and/or bevacizumab to aflibercept in neovascular age-related macular degeneration in patients who had previously given an insufficient response to therapy with ranibizumab and/or bevacizumab. PATIENTS AND METHODS: 96 eyes with neovascular age-related macular degeneration (AMD) were included, which had been pretreated with ranibizumab and/or bevacizumab (T&E), but had responded insufficiently. An injection interval of less than six weeks or permanently persisting intra- and/or subretinal fluid or persistent pigment epithelial detachments (PED) were defined as an insufficient response. The patients were followed for 12 months after switching therapy to aflibercept. The change in central retinal thickness (CRT) was defined as the primary endpoint. Other endpoints were the axial height of PEDs and the injection interval. RESULTS: The primary endpoint, the average CRT, was significantly decreased twelve months after switching therapy to aflibercept (Wilcoxon Nemenyi-McDonald-Thompson post-hoc analysis - 31.36 µm; SD ± 70.64 µm; p < 0.001). Another morphological endpoint, the average axial height of PEDs, also decreased significantly (- 34.10 µm; SD ± 91.90 µm, p < 0.001) from 207.82 µm (SD ± 148.12 µm) at baseline to 173.72 µm (SD ± 132.30 µm) at month 12. Moreover, the average injection interval increased significantly (p < 0.001; Friedman test) from 1.30 months (SD ± 0.19 months) before switching therapy to 1.67 months (SD ± 0.19 months) at month 12 after switching therapy to aflibercept. However, the best corrected visual acuity (BCVA) as a functional endpoint did not significantly improve (+ 0.36 ETDRS letters = 0.0972 p; SD ± 16.94 ETDRS letters). CONCLUSION: In patients with neovascular AMD, who had initially exhibited an inadequate response to ranibizumab and/or bevacizumab, switching therapy to aflibercept improves clinical outcome measures. Besides morphological improvements, such as the decrease of the CRT and the axial height of PEDs, the average injection interval was prolonged. However, visual acuity did not improve.

[Pharmacokinetics of systemic, regional and topical drugs for therapy of intraocular inflammation]. / Pharmakokinetik systemischer, regionaler und lokaler Medikamente in der Therapie intraokularer Entzündungen.

A broad spectrum of anti-inflammatory drugs with different mechanisms is available for the treatment of intraocular inflammation. Corticosteroids are the mainstay of therapy. Mechanisms of action are quite well understood for most drugs in particular taken from animal research studies. However, pharmacokinetic evidence for treatment of ocular disease is generally limited for the human eye and especially for ocular inflammation. The bioavailability of a particular drug in an inflamed eye is expected to be faster due to a barrier breakdown. Therefore, intraocular level of effective substances should be lowered more rapidly than in a non-inflamed eye due to improved drainage. This article reviews current knowledge firstly about local, regional and systemic anti-inflammatory therapy of uveitis and finally on immuosuppressive systemic therapy.

Phase I pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies.

BACKGROUND: SF1126 is a peptidic pro-drug inhibitor of pan-PI3K/mTORC. A first-in-human study evaluated safety, dose limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of SF1126, in patients with advanced solid and B-cell malignancies. PATIENTS AND METHODS: SF1126 was administered IV days 1 and 4, weekly in 28day-cycles. Dose escalation utilised modified Fibonacci 3+3. Samples to monitor PK and PD were obtained. RESULTS: Forty four patients were treated at 9 dose levels (90-1110 mg/m(2)/day). Most toxicity was grade 1 and 2 with a single DLT at180 mg/m(2) (diarrhoea). Exposure measured by peak concentration (C(max)) and area under the time-concentration curve (AUC(0-)(t)) was dose proportional. Stable disease (SD) was the best response in 19 of 33 (58%) evaluable patients. MTD was not reached but the maximum administered dose (MAD) was 1110 mg/m(2). The protocol was amended to enrol patients with CD20+ B-cell malignancies at 1110 mg/m(2). A CLL patient who progressed on rituximab [R] achieved SD after 2 months on SF1126 alone but in combination with R achieved a 55% decrease in absolute lymphocyte count and a lymph node response. PD studies of CLL cells demonstrated SF1126 reduced p-AKT and increased apoptosis indicating inhibition of activated PI3K signalling. CONCLUSION: SF1126 is well tolerated with SD as the best response in patients with advanced malignancies.

[Treatment of acute postoperative endophthalmitis. New aspects in an emergency situation]. / Therapie der akuten postoperativen endophthalmitis : Aktuelle aspekte in der behandlung eines medizinischen notfalls.

Endophthalmitis is an emergency situation. The diagnosis is based on clinical suspicion. Changing age demographics in industrialized populations and increasing numbers of cataract surgeries as well as intravitreal injections in patients with age-related macular degeneration are resulting in increasing numbers of cases of postoperative endophthalmitis. Prevention and adequate treatment considering new data from the recently published study by the European Society of Cataract and Refractive Surgeons (ESCRS) are important factors for rehabilitation. This review summarizes ESCRS data on risk factors, surgical techniques, and therapeutic options. An early, complete vitrectomy with irrigation of the anterior chamber and capsular bag is recommended.

[EBM analysis: classic DMARDs (disease-modifying antirheumatic drugs) and immunosuppressants in arthritis and uveitis]. / EBM Analyse: Klassische DMARDs (Disease modifying antirheumatic drugs) und Immunsuppressiva bei Arthritis und Uveitis.

The best experience in the use of DMARDs/immunosuppressive drugs for treatment of juvenile idiopathic arthritis (JIA) and JIA-associated uveitis has been obtained with MTX. Controlled studies on the treatment of uveitis in JIA, however, are still lacking; this is also true for other DMARDs/immunosuppressive drugs. Thus, the grading of the evidence level for these substances only reaches evidence level III (expert opinion, clinical experience or descriptive studies). For the treatment of uveitis in JIA the utility of MTX in comparison to the new biological substance classes (e. g., tumor necrosis factor-alpha, blockers, interleukin-1 receptor antagonist) will have to be examined. Experience with Mycophenolate mofetil (MMF) in JIA uveitis is limited to single cases. According to data from a retrospective analysis cyclosporin A (CsA) appears to have a limited efficacy in JIA uveitis. The results with azathioprine are not consistent. Controlled studies which led to the approval of drugs for JIA are also mandatory for uveitis to offer the most effective and safe therapy for children.

[Diagnostic procedure for uveitis patients: reduction of costs by a targeted assessment of laboratory tests based on clinical findings]. / Abklärung bei Uveitis: Kostenreduktion durch befundorientiertes diagnostisches Vorgehen.

BACKGROUND: Interdisciplinarity is an essential prerequisite for extensive and high-quality diagnostic work-up, therapy, and care of patients with inflammatory rheumatic disease. The ophthalmological status significantly narrows down the possible causes for the primary disease and facilitates an effective diagnostic approach. METHODS: We developed an assessment procedure according to the individual clinical findings to use as an ideal diagnostic strategy for an interdisciplinary center. To permit comparability we first introduced this new diagnostic tool in November 2002 (intervention), replacing the existing cost-intensive standard diagnostic procedure for uveitis patients. RESULTS: The average costs for laboratory tests (calculated according to GOA numbers, scale of fees for physicians) were reduced from 670+/-11 euros per patient before the intervention to 238+/-18 euros per patient after the intervention. Before intervention 16 of 31 (52%) could be assigned to a specified disease compared to 27 of 53 (51%) after the intervention. With our strategy we were able to obtain a 64% reduction of costs in the diagnostics of uveitis patients without a deterioration of our diagnostic quality. CONCLUSION: It is possible to reduce costs and still improve the care of uveitis patients by using a targeted assessment according to the individual clinical findings.

Interferon as a treatment for uveitis associated with multiple sclerosis.

AIM: In addition to optic neuritis (ON), multiple sclerosis (MS) may also involve the eye with a typically bilateral intermediate uveitis. The aim of this pilot study was to evaluate the efficacy of type I interferons (IFN) for the treatment of MS associated uveitis. METHODS: In this non-randomised, retrospective observational case series 13 patients (eight female, five male) with proved MS and associated uveitis from five uveitis centres who were treated with interferon beta1a were included. Visual acuity (VA), cell count in the aqueous humour and vitreous, as well as the presence of cystoid macula oedema (CMO) were observed. RESULTS: All except one patient had a bilateral form of intermediate uveitis (total of 24 eyes). Seven patients had documented CMO before IFN treatment (n = 13 eyes). Median duration of treatment was 24.6 months (range 7.9-78.7). VA improved in 17 eyes (comparing VA before therapy and at last follow up); while 10 eyes (36%) improved >or=3 Snellen lines. Aqueous cell count improved by 1.2 (SD 1.1) grades in all eyes. Vitreous cell count improved by 1.7 (1.4) in all eyes. Only two patients still had minimal CMO on last follow up angiographically. CMO resolved after or during IFN treatment in nine eyes. CONCLUSIONS: IFN has been shown to have beneficial effects in patients with MS and/or ON. As shown in the models of experimental allergic encephalomyelitis (EAE) and uveitis, the neurological and ophthalmological manifestations seem to share similar pathogenic mechanisms. Treatment of MS associated uveitis with IFN appears to have beneficial effects on VA, intraocular inflammation activity, and the presence of CMO.

[Fuchs uveitis syndrome--heterochromia is no "conditio sine qua non"]. / Das Fuchs'sche Uveitis Syndrom -- die Heterochromie ist keine Conditio sine qua non.

Fuchs uveitis syndrome (FUS) is typically a unilateral, chronic, low-grade inflammation of the anterior segment which manifests in young adulthood. It is underdiagnosed because of its variable clinical spectrum. Although it can mimic various forms of anterior uveitis, it is important to make the correct diagnosis, based on clinical grounds, because both the management and prognosis differ from those of other uveitides. While its etiology remains unknown, it is possible that the disease has multiple causes that lead through different pathogenic mechanisms to the same clinical entity. Although many patients do not require treatment, it is not a benign condition, as often perceived. The high incidence of glaucoma makes it mandatory that all patients with FUS should be screened at regular intervals, even if they are not being actively treated and are relatively asymptomatic.

[Computer-based system for monitoring the course of intraocular inflammation]. / Computergestütztes System zur Verlaufskontrolle intraokularer Entzündungen.

BACKGROUND: Until now, there has been no consistent rating system for changes of intraocular inflammation. We present such a computer-based system. METHODS: This program is based on a FileMaker database. It is made of anterior and posterior uveitis scores on the basis of published evaluation guidelines of the International Ocular Inflammation Society (IOIS). An anterior uveitis score consisting of anterior chamber cells, flare, and perilimbal injection on the one hand and a posterior uveitis score consisting of vitreous haze, macula, and optic nerve head edema on the other hand are calculated. After adding visual acuity, intraocular pressure, and systemic dose of corticosteroids, all parameters can be visualized by a radar graph. RESULTS: This system of documentation is easy to handle and presents a simplified version of the disease course. The abstract visualization enables the patient to better understand the therapeutic management. CONCLUSIONS: The program presented here offers good opportunities for standardized monitoring of the disease course.

[Strategies for the immunosuppressive therapy of intraocular inflammation]. / Strategien zur immunsuppressiven Therapie intraokularer Entzündungen.

Over the past two decades, therapeutic options for the treatment of intraocular inflammation (uveitis) have developed into a highly differentiated approach with an increasing number of drug options. In contrast to some other common sight-threatening ocular diseases, the majority of patients with uveitis can expect to receive treatment which will positively alter the course of their eye disease. Besides corticosteroids (CS) as primary systemic treatment, the most popular CS-sparing drug appears to be MTX in the treatment of uveitis. This paper suggests a strategy for the therapeutic approach to treating patients with intraocular inflammation. A table summarizes detailed information about mechanisms of action, dosage, and side effects, etc.

[Diagnostic vitrectomy in uveitis: possibilities of molecular biology]. / Diagnostische Vitrektomie bei UveitisMöglichkeiten der Molekularbiologie.

Recent developments in molecular biology allow novel diagnostic approaches in intraocular inflammation. Genetic markers as well as species-specific sequences are used for the diagnostics of infection or masquerade syndromes. This article provides state-of-the art information about diagnostic vitrectomy.

[Therapeutic vitrectomy in uveitis: current status and recommendations]. / Therapeutische Vitrektomie bei UveitisAktueller Stand und Empfehlungen.

With the advent of modern vitreoretinal surgical techniques, the spectrum for surgical intervention in various forms of uveitis has been notably expanded. Removal of optically relevant vitreous opacities, improvement of secondary macular edema, delamination of epiretinal membranes, and release of traction in the presence of abnormal vitreoretinal adhesions represent indications for vitreoretinal procedures in uveitis patients. Furthermore, retinal and choroidal biopsies may be obtained if the precise etiology is unknown. This in turn offers the opportunity to better target pharmacological interventions. Combined cataract surgery or intravitreal implantation of drug devices may also be of therapeutic benefit. So far no prospective, controlled clinical trials have been performed to precisely evaluate the role of pars plana vitrectomy (ppV) as a single or combined surgical procedure in patients with intraocular inflammation. Inconsistent data exist regarding prognostic determinants and the role of perioperative immunosuppression. Here, the current knowledge on the subject is reviewed and critically discussed, and recommendations for patient management are given. Further studies are needed.

Simultaneous in vivo imaging of leukocyte migration: heterogeneity among iris, limbus, and choroid vessels.

PURPOSE: Endothelial cells of different vascular systems may express site-specific adhesion molecules to attract leukocyte subsets. This study describes a method to visualize and compare leukocyte-endothelial interactions in three vascular beds within the same eye in mice. METHODS: Digital in vivo fluorescence microscopy was used to record a trans-corneal iris view, a superficial limbus view, and a trans-scleral anterior choroid view of mouse tissue. Uveitis was induced by intravitreal injection of E. coli endotoxin into BALB/c mice. Leukocytes were labeled systemically with SYTO-16 or rhodamine 6G. Leukocyte rolling and sticking were quantified at baseline and 4, 6, and 24 hours after endotoxin injection. RESULTS: In a normal animal, the limbus had 18 times the number of rolling leukocytes and 6 times the number of sticking leukocytes relative to the iris. All three vascular beds were affected by intravitreal injection of endotoxin. Although they each showed increased numbers of rolling and sticking cells, the levels and kinetics of these increases differed. Rolling peaked at 6 hours in the iris (34-fold increase from baseline) and limbus (7-fold increase) but was maximal in the choroid earlier with a 16-fold increase. Sticking was maximal at 4 hours for iris (96-fold increase) and choroid (19-fold increase) but peaked in the limbus at 6 hours (47-fold increase from baseline). CONCLUSIONS: This study demonstrates that leukocyte-endothelial dynamics are not the same in different vascular beds in the normal mouse eye. Furthermore, site-specific differences in responses to intravitreally injected endotoxin, beyond what can be readily explained by differential distribution of endotoxin, were observed. The methodology can be used to test the hypothesis that endothelial cells within the eye have site-specific patterns of adhesion molecule expression.

Inhibition of leukocyte sticking and infiltration, but not rolling, by antibodies to ICAM-1 and LFA-1 in murine endotoxin-induced uveitis.

PURPOSE: Cell-adhesion molecules are critical elements in intravascular rolling and sticking of leukocytes during acute inflammation. In this process, selectins are thought to be involved in initial adhesion and rolling, and integrin-Ig superfamily interactions are believed primarily to mediate stronger adhesion and transendothelial migration. This study clarifies the role of two adhesion molecules, intercellular adhesion molecule (ICAM)-1 and leukocyte functional antigen (LFA)-1, in endotoxin-induced uveitis (EIU). METHODS: Intravital microscopy was used to record the movement and location of leukocytes in the irises of mice with uveitis induced by intravitreal injection of 250 ng Escherichia coli endotoxin. Each mouse concurrently received an intraperitoneal injection of monoclonal neutralizing antibodies for ICAM-1, LFA-1, or both or control irrelevant antibodies. RESULTS: Mice treated with endotoxin and control antibodies had an inflammatory response that was clearly present at the 6- and 24-hour time points and was mostly resolved by 48 hours. Mice that received anti-ICAM-1 or anti-LFA-1 had significantly fewer cells infiltrating their irises at 6 and 24 hours. Detailed analysis of the 6-hour time point recordings revealed that neither anti-ICAM-1 nor anti-LFA-1 significantly reduced the number of leukocytes rolling on venule endothelial surfaces, but the treatments reduced the number of firmly adherent cells. CONCLUSIONS: These data confirm previous reports that ICAM-1 and LFA-1 are important mediators of EIU. The dynamic in vivo images clearly support the hypothesis that integrin-mediated cell adhesion is more critical for the firm adhesion of sticking cells than for leukocyte rolling.

Intraocular in vivo imaging of activated T-lymphocytes expressing green-fluorescent protein after stimulation with endotoxin.

BACKGROUND: Intravital microscopy allows imaging of specific cell populations in vivo. The value of this technique is well established, but would be enhanced if one could distinguish functional states of cells in vivo. Interleukin-2 (IL-2) is expressed upon stimulation of T-cells and is a commonly used marker for T-cell activation. This study tests the use of enhanced green fluorescent protein (GFP) as a reporter gene for interleukin-2 (IL-2) expression in vivo. METHODS: Characterization of mice that have the GFP gene under the control of IL-2 regulatory sequences has previously been published. Uveitis was induced by injection of E. coli endotoxin into the vitreous of these IL-2/GFPki transgenic mice. Four hours later, 3 microg of recombinant mouse IL-2 was injected into the anterior chambers of one group of mice. In vivo imaging of infiltrating cells in the iris stroma was performed with fluorescence microscopy at 6, 24, 48, and 72 h after endotoxin injection. The absolute number of fluorescent cells per mm2 was evaluated. RESULTS: Eyes with endotoxin-induced uveitis had cells that expressed GFP and were identifiable by intravital microscopy. The fluorescent cells were exclusively seen in the subset of cells that had infiltrated the iris stroma or arrested along the vascular endothelium. The number of GFP-positive infiltrating cells in the iris increased from undetectable at baseline to 0.5 cells/mm2 at 6 h and 1.3 cells/mm2 at 72 h. The animals that received endotoxin as well as IL-2 tended to have more GFP-positive cells at the 48-h and 72-h time points, but these differences were not statistically significant CONCLUSIONS: GFP is commonly used as a reporter gene for in vitro expression assays. The results presented here document that transgenic mice with GFP under the control of IL-2 regulatory elements can be used with intravital microscopy for in vivo expression assays that allow detection of activated T-cells at multiple time points within the same animal. This provides a novel method for temporal and spatial studies on the state of cell activation in inflammatory responses.