[Extra-intestinal manifestations associated with Crohn's disease]. / Extra-intestinale uitingen van inflammatoire darmziekte.

Extra-intestinal manifestations (EIM) associated with Crohn's disease (CD) are frequently observed and can manifest as either the initial symptom or develop later in the disease course following gastrointestinal symptoms. The most common EIM affect the joints, skin, or eyes, with some correlating with active CD activity while others may occur during periods of inactivity. EIM can affect both pediatric and adult CD patients, potentially reducing their quality of life if not promptly identified and treated. Thus, emphasizing the prevalence and clinical presentation is essential to initiate appropriate diagnostic assessments and effectively treat both EIM and the underlying CD. In this case series, we present two pediatric and one adult case where EIM preceded CD diagnosis, resulting in delayed CD diagnosis. Additionally, we outline the most prevalent EIM, their epidemiology, and associated symptoms.

The enigma of sclera-specific autoimmunity in scleritis.

Scleritis is a severe and painful ophthalmic disorder, in which a pathogenic role for collagen-directed autoimmunity was repeatedly suggested. We evaluated the presence of sclera-specific antibodies in a large cohort of patients with non-infectious scleritis. Therefore, we prospectively collected serum samples from 121 patients with non-infectious scleritis in a multicenter cohort study in the Netherlands. In addition, healthy (n = 39) and uveitis controls (n = 48) were included. Serum samples were tested for anti-native human type II collagen antibodies using a validated enzyme-linked immunosorbent assay (ELISA). Further, sclera-specific antibodies were determined using indirect immunofluorescence (IIF) on primate retinal/scleral cryosections. Lastly, human leukocyte antigen (HLA) typing was performed in 111 patients with scleritis. Anti-type II collagen antibodies were found in 13% of scleritis patients, in 10% of healthy controls and in 11% of uveitis controls (p = 0.91). A specific reaction to scleral nerve tissue on IIF was observed in 33% of patients with scleritis, which was higher than in healthy controls (11%; p = 0.01), but similar to uveitis controls (25%; p = 0.36). Reactivity to the scleral nerve tissue was significantly associated with earlier onset of scleritis (48 versus 56 years; p < 0.001), bilateral involvement (65% versus 42%; p = 0.01), and less frequent development of scleral necrosis (5% versus 22%; p = 0.02). HLA-B27 was found to be twice as prevalent in patients with scleritis (15.3%) compared to a healthy population (7.2%). In conclusion, scleral nerve autoantibody reactivity was more common in scleritis and uveitis patients in contrast to healthy controls. Further research is needed to characterize these scleral-nerve directed antibodies and assess their clinical value.

Posterior vitreous membrane findings on OCT related to collagen type IV abnormalities.

INTRODUCTION: The pathological mechanisms of abnormal collagen type IV predisposing to macular hole formation in Alport syndrome are hypothesized to be related to defective Bruch's membrane leading to ruptured intraretinal cysts. However, abnormal collagen type IV may also predispose to macular hole formation due to vitreous cortex abnormalities. METHODS: An observational case series of Optical Coherence Tomography (OCT) findings in three patients. RESULTS: In two patients diagnosed with Alport syndrome and in one patient with a possibly pathogenic genetic variant in COL4A3 we observed a remarkable posterior vitreous cortex with a vitreoschisis-like appearance on OCT. Two of these patients developed a rhegmatogenous retinal detachment, of which one was caused by a giant retinal tear, and one patient developed a macular hole. During surgery, a firmly adherent vitreous cortex was observed centrally in the left eye and in the midperiphery in the right eye in one patient with a macular hole and giant retinal tear, respectively. CONCLUSION: These new vitreous cortex findings in patients with Alport syndrome are possibly related to pathogenic genetic variants affecting type IV collagen. Abnormal type IV collagen may cause pathological vitreoretinal traction, potentially leading to an increased risk of macular holes and rhegmatogenous retinal detachments.

Bilateral diffuse uveal melanocytic proliferation mistaken for nivolumab-induced VKH-like syndrome.

PURPOSE: To describe a case of bilateral diffuse melanocytic proliferation (BDUMP) that was mistaken for nivolumab-induced Vogt-Koyanagi-Harada-like syndrome. METHODS: We present the case of a 58-year-old Caucasian male with metastatic renal clear cell carcinoma for which he was palliatively treated with intravenous nivolumab immunotherapy. Patient developed subacute onset of blurry vision and grey spots in the visual fields of both eyes, macular subretinal fluid, thickening of the RPE and swollen optic nerve heads. Differential diagnosis included nivolumab-induced Vogt-Koyanagi-Harada-disease-like syndrome (nVKH) and patient was initially treated with steroids, which gave no improvement. Investigation showed the development of dark-grey patches in the peripheral retina of both eyes and cataract, which prompted re-evaluation of the diagnosis, deeming BDUMP most likely. The patient was successfully treated with plasmapheresis. DISCUSSION: The initial presentation of the case was incorrectly diagnosed as nVKH. Upon repeat studies of the patients' symptoms and imaging, we concluded we had missed signs of BDUMP. CONCLUSION: The diagnosis BDUMP was missed in the first evaluation. We present this case to discuss the similarities and differences between this disease and nVKH. More importantly, we want to highlight that re-evaluation of the diagnosis upon worsening of a disease was key in this unusual case.

Vitreous proteomics, a gateway to improved understanding and stratification of diverse uveitis aetiologies.

PURPOSE: The vitreous proteome might provide an attractive gateway to discriminate between various uveitis aetiologies and gain novel insights into the underlying pathophysiological processes. Here, we investigated 180 vitreous proteins to discover novel biomarkers and broaden disease insights by comparing (1). primary vitreoretinal lymphoma ((P)VRL) versus other aetiologies, (2). sarcoid uveitis versus tuberculosis (TB)-associated uveitis and (3). granulomatous (sarcoid and TB) uveitis versus other aetiologies. METHODS: Vitreous protein levels were determined by proximity extension assay in 47 patients with intraocular inflammation and a prestudy diagnosis (cohort 1; training) and 22 patients with a blinded diagnosis (cohort 2; validation). Differentially expressed proteins identified by t-tests on cohort 1 were used to calculate Youden's indices. Pathway and network analysis was performed by ingenuity pathway analysis. A random forest classifier was trained to predict the diagnosis of blinded patients. RESULTS: For (P)VRL stratification, the previously reported combined diagnostic value of IL-10 and IL-6 was confirmed. Additionally, CD70 was identified as potential novel marker for (P)VRL. However, the classifier trained on the entire cohort (cohort 1 and 2) relied primarily on the interleukin score for intraocular lymphoma diagnosis (ISOLD) or IL-10/IL-6 ratio and only showed a supportive role for CD70. Furthermore, sarcoid uveitis displayed increased levels of vitreous CCL17 as compared to TB-associated uveitis. CONCLUSION: We underline the previously reported value of the ISOLD and the IL-10/IL-6 ratio for (P)VRL identification and present CD70 as a potentially valuable target for (P)VRL stratification. Finally, we also show that increased CCL17 levels might help to distinguish sarcoid uveitis from TB-associated uveitis.

A CASE OF MIGRATING AND RESOLVING SUBRETINAL PERFLUOROCARBON LIQUID FOLLOWING RETINAL DETACHMENT SURGERY.

PURPOSE: To demonstrate unique behavior of subretinal perfluorocarbon liquid (PFCL) following macular reattachment surgery. METHODS: An observational case report. Changes in visual functioning and consecutive optical coherence tomograms are described. RESULTS: Following macular reattachment surgery with the aid of PFCL, a small residual PFCL bubble, measuring 175 µ m in diameter, is noted beneath the fovea on optical coherence tomogram. During nine months of follow-up, the bubble is shown to elongate and migrate toward the vitreous space. Once the bubble reaches the inner retinal surface, it gradually becomes smaller and disappears completely. We observed anatomical restoration of the retinal layers, and maintenance of fair visual acuity (20/32 feet) without scotoma. CONCLUSION: This report shows the potential of PFCL to migrate through the retina toward the vitreous. Rather than opt for a second surgery to remove small PFCL bubbles, observation may be clinically appropriate in selected cases.

BILATERAL SEROUS RETINAL DETACHMENT AND UVEITIS ASSOCIATED WITH PEMBROLIZUMAB TREATMENT IN METASTATIC MELANOMA.

PURPOSE: To describe the pathological features, treatment, and resolution of pembrolizumab-associated retinal detachment. METHODS: A case report with a brief review of the literature and details of patient presentation, physical examination, systemic workup, fluorescein angiography, and indocyanine angiography. RESULTS: A 25-year-old white woman was diagnosed with unresectable metastatic melanoma of the skin with a BRAF V600E mutation. The patient was treated with pembrolizumab injections every 3 weeks, upon which quick remission was seen of the metastases. After five injections, visual acuity of the patient deteriorated to 20/32 in the right eye. Ocular examination revealed bilateral panuveitis, papillitis, and serous retinal detachments. Treatment consisted of an oral prednisone taper schedule, topical prednisolone drops, and cessation of the pembrolizumab therapy, after which complete resolution of the subretinal fluid was seen. CONCLUSION: Pembrolizumab therapy may cause the development of panuveitis, papillitis, and serous retinal detachment, symptoms which are able to be controlled with lengthy steroid therapy.

Combined cellular and soluble mediator analysis for improved diagnosis of vitreoretinal lymphoma.

PURPOSE: Primary vitreoretinal lymphoma [(P)VRL]) is a rare malignancy of the eye localized in the retina, vitreous or choroid. Here, we aim to determine the value of the combination of innovative diagnostic methods for accurate differentiation between (P)VRL and non-(P)VRL in patients with suspect uveitis or vitritis. METHODS: Multicolour flow cytometric immunophenotyping of cells in the vitreous samples was performed using the EuroFlow small sample tube. Additionally, cytokines/chemokines and growth factors were measured in the vitreous specimens using a multiplex immunoassay. Data were evaluated in predefined clinical subgroups using omniviz unsupervised Pearson's correlation visualization and unsupervised heatmap analysis. RESULTS: A total of 53 patients were prospectively included in the period 2012-2015. In the (P)VRL subgroup (n = 10), nine cases showed aberrant surface membrane immunoglobulin (SmIg) light chain expression. In the non-(P)VRL group (n = 43) clearly skewed SmIg light chain expression was observed in two multiple sclerosis-related uveitis cases, but not in other uveitis types. Soluble mediator measurement revealed high interleukin (IL)-10/IL-6 ratios, and high IL-1RA levels in 9/10 (P)VRL cases, but not in any non-(P)VRL case. Further correlation and heatmap analysis revealed a minimal signature of cellular parameters (CD19+ B cells, aberrant SmIg light chain expression) and cytokine parameters (IL-10/IL-6 ratio >1, high IL-10, high IL-1 RA, high monocyte chemotactic protein-1, high macrophage inflammatory protein-1ß) to reliably distinguish (P)VRL from non-(P)VRL. CONCLUSION: Here, we show the power of a combined cellular and proteomics strategy for detecting (P)VRL in vitreous specimens, especially in cases with minor cellular (P)VRL infiltrates.

Uveitis causes according to immune status of patients.

PURPOSE: The advances in medicine have led to an increased number of people living with some form of immunodeficiency. Most ocular infections in immunocompromised patients may lead to irreversible blindness. We identify the causes of uveitis in immunocompetent and immunocompromised patients. METHODS: A retrospective cohort study of 1354 consecutive patients. All patients underwent a standard work-up for uveitis. RESULTS: An immunocompromised state was identified in 171/1354 patients (13%), of whom 40 had Human immunodeficiency virus (HIV) infection, 52 received immunosuppressive medications, 28 had concurrent malignant disorder and 20 had other causes for their immunosuppression. In addition, 93/1354 patients (7%) had diabetes mellitus (DM). The prevalence of intraocular infections was much higher in immunocompromised patients than in immunocompetent patients and DM (p < 0.001). Causes of uveitis differed between the diverse immunocompromised groups. The non-HIV immunocompromised patients showed primarily intraocular herpes simplex and varicella zoster virus infections, whilst HIV-positive patients exhibited frequently cytomegalovirus (CMV) retinitis and syphilis. Patients with generalized malignancies were characterized by a lower prevalence of infections and higher prevalence of sarcoidosis. Patients with DM typically showed sarcoidosis and bacterial intraocular infections. The percentage of undetermined uveitis diagnoses was markedly lower in immunosuppressed patients (p < 0.001). CONCLUSION: In immunocompromised patients with uveitis, infections were diagnosed in 46% of cases in contrast to 12% in the immunocompetent patients. The causes of uveitis differed among the various types of immunosuppression. Immunocompromised patients with uveitis require a rapid assessment for the most expected infections.

Post-operative Refractive Prediction Error After Phacovitrectomy: A Retrospective Study.

INTRODUCTION: Many authors have reported on a myopic post-operative refractive prediction error when combining phacoemulsification with pars plana vitrectomy (phacovitrectomy). In this study we evaluate the amount of this error in our facility and try to elucidate the various factors involved. METHODS: This was a retrospective study which included 140 patients who underwent phacovitrectomy (39 with macular holes, 88 with puckers, and 13 with floaters). Post-operative refractive error was defined as the difference between the actual spherical equivalent (SEQ) and expected SEQ based on the SRK/T and Holladay-II formulas. Both univariate (paired t test, independent t test, one-way analysis of variance, or Mann-Whitney test) and multivariate (regression analysis) statistical analyses were performed. RESULTS: Overall, a refractive error of - 0.13 dpt (p = 0.033) and - 0.26 dpt (p < 0.01) were found in the SRK/T and Holladay-II formulas, respectively. For the independent diagnoses, only macular holes showed a myopic error with the SRK/T (- 0.31 dpt; p < 0.01) and Holladay-II (- 0.44 dpt; p < 0.01) formulas. In univariate analysis, significant factors involved in myopic refractive error were macular hole as diagnosis (p < 0.01 for SRK/T and Holladay-II), gas tamponade (SRK/T p = 0.024; Holladay-II p = 0.025), pre-operative myopia (p < 0.01 for SRK/T), and optical technique for axial length measurement (SRK/T and Holladay-II p < 0.01). In the multivariate analysis, pre-operative axial length (p = 0.026), optical technique for axial length measurement (p < 0.01), and pre-operative SEQ (p < 0.01) were independent predictors for myopic refractive error in the SRK/T formula. For the Holladay-II formula, optical technique for axial length measurement (p < 0.01) and pre-operative SEQ (p = 0.04) were predictive. CONCLUSION: Various factors are involved in determining the myopic refractive error after phacovitrectomy. Not every factor seems to be as important in each individual patient, suggesting a more tailored approach is warranted to overcome this problem.

Rhegmatogenous retinal detachment in uveitis.

BACKGROUND: Retinal detachment is more common among uveitis patients than in the general population. Here, we aimed to assess the prevalence of rhegmatogenous retinal detachment (RRD) in a uveitis population. METHODS: We retrospectively studied 851 uveitis patients, recording characteristics such as uveitis duration, anatomical location, and cause; RRD occurrence; proliferative vitreoretinopathy (PVR) at presentation; surgical approach; reattachment rate; and initial and final visual acuity (VA). RESULTS: RRD occurred in 26 patients (3.1%; 29 affected eyes) and was significantly associated with posterior uveitis (p < 0.001), infectious uveitis (p < 0.001), and male gender (p = 0.012). Among cases of infectious uveitis, cytomegalovirus and varicella zoster virus were most commonly associated with RRD development. RRD in non-infectious uveitis was not found to be associated with any specific uveitis entity. The rate of single-operation reattachment was 48%, and the rate of final reattachment was 83%. Mean final VA was 20/125, with 41% of eyes ultimately having a VA of less than 20/200. CONCLUSION: Uveitis is a risk factor for RRD development, which carries a poor prognosis.

Successful surgical optic nerve decompression in a patient with hypertrophic pachymeningitis due to granulomatous polyangiitis.

A 57-year-old woman presented with subacute vision loss of first the left, and later the right eye. She was diagnosed with granulomatous polyangiitis with hypertrophic pachymeningitis and optic nerve compression. Her visual acuity could not be permanently restored with immune suppressants alone, so a surgical decompression of the right optic nerve, via a modified cranio-orbitozygomatic pretemporal approach, was performed. Her right eye regained 20/20 vision and has remained stable during 8 months of follow-up.

A case of central serous chorioretinopathy occurring after γ-hydroxybutyric acid (liquid ecstasy) ingestion.

PURPOSE: To describe a patient with acute central serous chorioretinopathy after use of γ-hydroxybutyric acid (GHB), also known as "liquid ecstasy." METHODS: Observational case report of a patient who developed central serous chorioretinopathy a day after use of GHB at a party. RESULTS: A young adult male patient presented at the department complaining of non-improving acute onset of vision loss in the left eye after use of GHB at a party 3 weeks before. Fundus examination, optical coherence tomography, and fluorescein angiography revealed a dome-shaped retinal elevation centered to the macula of the left eye, suggesting the diagnosis of central serous chorioretinopathy. Spontaneous subretinal fluid resolution with improvement of vision was observed a month later. CONCLUSION: γ-hydroxybutyric acid has been reported to induce an acute increase in cortisol secretion after its administration. In addition, a case of Cushing syndrome after chronic abuse of GHB has been described. The acutely increased cortisol levels, induced by GHB, might have been the cause of central serous chorioretinopathy in the patient.