Exacerbation Of Uveitis Research Articles

Clinical features of Behcet’s uveitis in patients with herpesvirus reactivation

Purpose. To study the possible impact of human herpes viruses (HHV) reactivation: herpes simplex virus type 1 (HSV 1), type 2 (HSV 2), cytomegalovirus (CMV) and Epstein — Barr virus (EBV) on the clinical course of uveitis in Behcet's disease (BD). Material and methods. Serum samples of 106 BD patients (ave. age 39) with uveitis were examined for the presence of antibodies — serological markers of chronic HHV infection and reactivation. Results. In 65 patients (25 with active uveitis (UA), 40 with uveitis remission (UR)), HHV reactivation was detected (mainly HSV 1, less often HSV 2, CMV and EBV — in individual cases), 41 patients had chronic HHV (17 with UA, 24 with UR). Certain clinical symptoms of uveitis were found to depend on HHV activity. Clinical signs of active uveitis (cells in the vitreous body), as well as severe irreversible changes (social blindness and low vision) were significantly more frequently detected in cases of HHV reactivation (p < 0.05) than in chronic HHV. The data obtained allow us to suggest, with some caution, that a subclinical HHV reactivation which stays after the onset of clinical uveitis remission, is an important factor of postuveal complications that are mainly manifested during remission. These complications include epiretinal fibrosis, pronounced optic nerve atrophy, and vasculitis (arterial and venous occlusion). Conclusion. The remission period in patients with subclinical herpesvirus activity is less favorable than in patients without serological markers of HHV reactivation. HHV reactivation that persists after uveitis activity is stopped can contribute to sudden exacerbations of uveitis.

Experience of switching biological therapy in a patient with juvenile idiopathic arthritis and uveitis. Case report

Uveitis associated with juvenile arthritis can be complicated by cataracts, retinal edema, and glaucoma, which carries a potential risk of disability in the child's organ of vision. Approximately 2540% of patients demonstrate insufficient effectiveness of the ongoing standard antirheumatic therapy, which requires the inclusion of genetically engineered biological therapy. According to the protocols, the drug of choice for juvenile arthritis associated with uveitis is adalimumab, which has shown high efficacy in many studies. However, some patients stop responding to therapy over time, which raises the question of switching to another genetically engineered biological drug (GЕBD). Our article presents a case of severe course with an early onset of juvenile idiopathic arthritis associated with uveitis. Due to the insufficient effectiveness of basic monotherapy with methorexate, as well as topical glucocorticoids, adilimumab was added to therapy a year after the onset of the disease. Over the next 5 years, the child was on this therapy with exacerbations of uveitis about 12 episodes per year. Subsequently, uveitis began to continuously recur, which raised the question of the development of probable resistance to adalimumab and the change of GEBD. The girl was switched to golimumab, which is a human monoclonal antibody that can bind to tumor necrosis factor-. This drug has been used for the treatment of juvenile idiopathic arthritis since 2017 for children weighing 40 kg and above, and after the completion of the multicenter GO-KIDS study, it is registered for children from 2 years of age. According to a number of studies, golimumab has shown its effectiveness in relation to the activity of uveitis in patients with arthritis, including those in childhood. In general, the issues of switching GEBD in cases of ineffective therapy with first-line drugs are a very urgent problem in pediatric rheumatology. In our case, switching to the GIBP golimumab resulted in a positive effect on the activity of rheumatoid uveitis and induction of remission of the articular syndrome.

Photoreceptor Cells Constitutively Express IL-35 and Promote Ocular Immune Privilege.

Interleukin-27 is constitutively secreted by microglia in the retina or brain, and upregulation of IL-27 during neuroinflammation suppresses encephalomyelitis and autoimmune uveitis. However, while IL-35 is structurally and functionally similar to IL-27, the intrinsic roles of IL-35 in CNS tissues are unknown. Thus, we generated IL-35/YFP-knock-in reporter mice (p35-KI) and demonstrated that photoreceptor neurons constitutively secrete IL-35, which might protect the retina from persistent low-grade inflammation that can impair photoreceptor functions. Furthermore, the p35-KI mouse, which is hemizygous at the il12a locus, develops more severe uveitis because of reduced IL-35 expression. Interestingly, onset and exacerbation of uveitis in p35-KI mice caused by extravasation of proinflammatory Th1/Th17 lymphocytes into the retina were preceded by a dramatic decrease of IL-35, attributable to massive death of photoreceptor cells. Thus, while inflammation-induced death of photoreceptors and loss of protective effects of IL-35 exacerbated uveitis, our data also suggest that constitutive production of IL-35 in the retina might have housekeeping functions that promote sterilization immunity in the neuroretina and maintain ocular immune privilege.

Оптимизация хирургического лечения вторичной закрытоугольной глаукомы у пациентов с органическим блоком угла передней камеры

Purpose. Optimization of surgical treatment of secondary closed-angle glaucoma in patients with organic block of the anterior chamber angle. Material and methods. The analysis of the results of 6 AGO using autologous scleral drains treated with MMC is presented in children with an organic block of the anterior chamber angle without the phenomena of neovascularization is privided. Five children had uveal glaucoma; one child had an essential mesodermal iris dystrophy with secondary glaucoma. In all cases before the formation of autologous scleral drains, intraoperative applications of MMC were performed, followed by a plentiful washing of the operating field with normal saline solution. The duration of follow-up was from 1.5 to 7 years. Results. The operations proceeded without complications. There was a long choroidal edema on one eye in the early postoperative, stopped with the help of conservative treatment for 10 days. In the long term, on one eye in the period of exacerbation of uveitis, dislocation of autodrainages arose, which was facilitated by the appearance of exudative effusion in the anterior chamber. Later on this eye the failure of the AGO developed. On the other eyes, the intraocular pressure remained compensated, and the functions were stable. Conclusion. Treatment of drainages from the autosclera with MMC before implanting them into the anterior chamber of the eye, in patients with organic block of the anterior chamber angle, is effective against the hypotensive effect of the operation and is safe for intraocular structures while observing the processing technique. Key words: secondary closed-angle glaucoma, anterior chamber, autologous

Comparative effectiveness of various immunosuppressive therapy regimens for uveitis in patients with Behçet’s disease

The aim – to evaluate the effectiveness of various immunosuppressive therapy schemes for current uveitis used in real clinical practice in patients with Behçet’s disease (BD).Material and methods. The study included 531 patients with a reliable (ICBD criteria 2014) diagnosis of BD, observed in the V.A. Nasonova Research Institute of Rheumatology from 2006 to 2020. The majority were men (331 (62.3%)). The average age (M±SD) was 32.9±10.0 years, the median duration of BD (Me (25%; 75%)) – 96 (48; 174) months. 60.4% patients had uveitis, 70.7% – exacerbation of uveitis (EU). Uveitis activity was assessed by the BOS24 index (Behçet’s disease Ocular attack Score 24) in 202 patients with EU. The total activity of BD was evaluated according to BDCAF index (Behçet’s Disease Current Activity Form). Glucocorticoids (GC) was systematically received by 68.7% patients with EU, including 51.5% in the form of pulse therapy. 88.9% patients with EU received cytotoxics: 33.5% – cyclosporine (CS), 20.7% – azathioprine (AZA), 11.4% – AZA+COL, 8.8% – AZA+CS, 7.5% – colchicine (COL), 3.9% – cyclophosphamide (CPh). 11.9% patients with EU were prescribe Biologics, mainly i-TNF-α (11,4%: 8,8% – adalimumab, 2.2% – infliximab, 0.4% – golimumab) and rituximab (0.4%). The effectiveness of therapy was evaluated on average after 18.0 (8.0; 36.0) months.Results. According to the dynamics of BDCAF, by the end of follow-up, BD activity significantly decreased in all groups, with the exception of patients who received COL. A more significant decrease in BDCAF was observed in the combination therapy groups: AZA+CS (ΔBDCAF=–4.08±3.60), AZA+COL (ΔBDCAF=–3.57±2.50), as well as in the CS group (ΔBDCAF=–3.57±3.39), but no statistically significant differences in ΔBDCAF between the groups were obtained, which does not allow us to speak about a significant advantage of a particular drug. There were no significant differences in ΔBDCAF between patients who received (ΔBDCAF=–3.41±3.89) and those who did not receive (ΔBDCAF=–3.59±3.23) Biologics. According to the dynamics of BOS24, the most effective for relieving symptoms of intraocular inflammation were CS (ΔBOS24=–7.0 (–12.0; –3.0)), AZA (ΔBOS24=–7.0 (–15.0; –2.0)), a combination of CS+AZA (ΔBOS24=–5.0 (–8.0; –2.0)) and CPh (ΔBOS24=–4.0 (–14.0; –2.0). The differences between BOS24 before and after treatment in these groups were statistically significant. When assigning AZA+COL (ΔBOS24=–1.0 (–4.0; 0)) or COL (ΔBOS24=–0.5 (–2.0; 0)) uveitis activity decreased during therapy, but not significantly. According to ΔBOS24, uveitis therapy by CS was statistically significantly more effective compared to AZA+COL and COL; and AZA treatment, compared to COL. Biologics, mainly adalimumab, significantly and rapidly reduce the severity of intraocular inflammation (ΔBOS24=–7.0 (–18.0; 0)) compared with GC and cytotoxics (ΔBOS24=–4,0 (–9,0; –1,0)), however statistically significant differences between the groups were not obtained due to the small number of Biologics groups.Conclusion. CS, AZA and their combination, as well as i-TNF-α (mainly adalimumab) are more effective for relieving uveitis symptoms in patients with BD. BOS24 is a reliable tool for quantifying the activity of uveitis in BD patients and its dynamics against the background of anti-inflammatory and immunosuppressive therapy.

HLA-B27-associated uveitis: an independent disease or a variant of spondyloarthritis?

The paper highlights the relationship between HLA-B27-associated uveitis and spondyloarthritis (SpA). It presents the genetic aspects of inflammation of the eyes and musculoskeletal system, the role of the HLA-B27 histocompatibility antigen, and the contribution of other genes to the development of uveitis and spondylitis. The authors characterize the general pathogenetic mechanisms of the development of these diseases: the importance of factors of innate immunity, proinflammatory cytokines in the initiation of inflammation of the eyes and joints. The detection rate of SpA is analyzed in various forms of uveitis; the predictors of SpA development are identified in the patients. An algorithm is presented, which makes it possible to timely diagnose SpA in the presence of acute anterior uveitis. HLA-B27, inflammation in the ocular anterior chamber, unilateral alternating eye lesions, an acute recurrent course, and uveitis onset at the age of less than 30 years are singled out as the most significant signs associated with SpA in patients with uveitis. The features of the course and the frequency of complications in uveitis with and without SpA are compared. It is shown that exacerbations of uveitis and associated complications occur statistically significantly more frequently in SpA. There is evidence for the need for a close interaction between ophthalmologists and rheumatologists in the management of patients with uveitis.

Golimumab in the treatment of extra-skeletal manifestations of ankylosing spondylitis

Extra-skeletal manifestations (EMs) of ankylosing spondylitis (AS) can occur and proceed in parallel with inflammatory changes in the joints and spine and often dominate in the clinical picture of AS, determining its high activity and significantly worsening the quality of life in patients. In a number of cases, EMs are characterized by an insufficient response to standard anti-inflammatory therapy for back pain, arthritis, and enthesitis; and there is a need to prescribe another class of drugs.The review highlights the results of studies evaluating the efficacy of golimumab (GLM) in treating EMs in patients with AS: uveitis (GO-EASY Study) and ulcerative colitis (UC) (PURSUIT-SC, PURSUIT-M studies). Analysis of these studies have shown the high efficacy and safety of GLM in reducing the clinical manifestations of AS and in preventing the exacerbations of uveitis and UC. However, despite the successes achieved in treating AS and its EMs, there are many unresolved issues, including those related to the elaboration of optimal treatment regimens, which required longer observational studies with a large sample size.

New onset or exacerbation of uveitis with infliximab: paradoxical effects?

ObjectiveTo report four cases of new onset or exacerbation of uveitis following administration of infliximab.MethodsThis retrospective observational case series includes four patients who developed new onset or exacerbation of uveitis...

Targeted over-expression of S100B in the retina of transgenic mice induced exacerbated experimental autoimmune uveitis

Abstract S100B, originally found in glial cells (astrocyte and microglial cells), acts as an intracellular Ca++-sensor and an extracellular regulator protein. Its neuronal trophic or toxic effect on cells might be dependent on its cellular concentrations. Human uveitis is an intraocular inflammatory disease of infectious or autoimmune etiology and neuroinflammatory responses orchestrated by retinal microglia cells are implicated in exacerbation of uveitis. The S100B protein is predominantly secreted by glial cells in central nerve system (CNS). In this study we examined whether S100B protein plays a role in regulating inflammatory responses in the neuroretina. To this end we generated retinal S100B transgenic mice and investigated whether experimental autoimmune uveitis (EAU) would be exacerbated in these transgenic mice. We monitored EAU progression and severity by fundoscopy and ERG (Electroretinogram)and found that over-expression of S100B+ promoted retinal inflammatory responses and vision loss during EAU. Results of FACS and ELISA analysis did not indicate significant difference in the numbers of uveitogenic Th1 and Th17 cells in the draining lymph-nodes. However, significant amounts of pathogenic Th1 and Th17 cells were detected in the retina of S100B transgenic mice. Conversely, the numbers of IL-10-producing CD4+Foxp3+Treg cells in the retina was significantly decreased in the S100B transgenic mice. These results suggest that S100B can serve as a biomarker for ocular inflammatory diseases.

EVALUATION OF UVEITIS ACTIVITY USING BOS24 IN PATIENTS WITH BEHСET'S DISEASE

Objective:to estimate changes of uveitis activity using BOS24 (Behсet's disease Ocular attack Score 24) during antiinflammatory and immunosuppressive therapy in patients with Behcet's disease (BD).Subjects and methods.103 (75.6%) of the 138 patients with BD fulfilled the 1990 International Study Group for Behсet's Disease (ISGBD) criteria had eye lesions; 55 (53.4%) of the 103 patients had an exacerbation of uveitis. 55 patients with an exacerbation of uveitis were found to have active inflammation in 94 eyes. The activity of uveitis was monitored during anti-inflammatory and immunosuppressive therapy, by using BOS24 that consists of 6 parameters with maximal possible value 24.Results and discussion.The mean BOS24 for 94 eyes with active uveitis at baseline was 9.33±0.91. The most pronounced inflammatory changes were found in the posterior chamber of the eye, mainly in the area of the peripheral retina, rarely in the area of the fovea and in the optic disc. All the patients with an exacerbation of uveitis received systemic therapy with glucocorticoids, cyclosporine and/or azathioprine. After 8.92±3.47 months of treatment, the mean BOS2 decreased significantly (p < 0.001) to 2.20±1.02. The most substantial positive changes were noted in the anterior chamber of the eye (p = 0.03), vitreous humor (p < 0.01), and peripheral retina (p < 0.001).Conclusion. BOS24 is a reliable tool to quantify uveitis activity in patients with BD and its dynamics during antiinflammatory and immunosuppressive therapy.

Safety and Efficacy of Gevokizumab in Patients with Behçet’s Disease Uveitis: Results of an Exploratory Phase 2 Study

ABSTRACTPurpose: To evaluate the safety and efficacy of gevokizumab for the treatment of Behçet’s disease uveitis in a prospective, open-label, randomized phase 2 trial.Methods: Behçet’s disease patients with new acute ocular exacerbation or at risk of exacerbation received 30 or 60 mg gevokizumab every 4 weeks intravenously or subcutaneously, on top of a stable regimen of immunosuppressives and corticosteroids (≤20 mg/day equivalent prednisolone). Patients withdrew in cases of ocular exacerbation.Results: A total of 21 patients were included (17 acute and 4 at-risk; mean duration of uveitis 45.6 ± 37.4 months). There were no serious adverse events related to gevokizumab. Recorded adverse events were mostly associated with exacerbation of uveitis or its complications. Response was evaluated for 14 acute patients and all showed rapid control of acute ocular exacerbation, mostly within 1 week, without any increase in corticosteroid dosage.Conclusions: Gevokizumab was well tolerated and rapidly controlled acute ocular exacerbations of Behçet’s disease uveitis without the need for high-dose corticosteroid.

Outcome of viscodilation and tensioning of Schlemm’s canal for uveitic glaucoma

ObjectiveTo evaluate the safety and efficacy of circumferential viscodilation and tensioning of Schlemm’s canal (canaloplasty) in the treatment of uveitic glaucoma (UG). DesignPilot, retrospective, noncomparative case series. ParticipantsNineteen uveitic eyes of 15 patients with UG. MethodsThe main outcome measure was surgical success. Secondary outcome measures included intraocular pressure, usage of ocular hypotensive medication, visual acuity, and sight-threatening complications. Patients were included when UG could not be controlled despite maximum tolerated medical therapy. Exclusion criteria were peripheral anterior synechiae and previous glaucoma surgery. ResultsMean follow-up time from canaloplasty was 2.6 ± 1.1 years. Mean intraocular pressure decreased from 30.4 ± 8.4 mm Hg preoperatively to 13.8 ± 5.0 mm Hg at last follow-up (p < 0.001). The mean number of ocular hypotensive medications decreased from 3.7 ± 0.8 preoperatively to 0.4 ± 1.0 at last follow-up (p < 0.001). At last follow-up, the complete success, qualified success, and failure rates were 73.7%, 10.5%, and 15.8%, respectively. No canaloplasty-related permanent sight-reducing complications occurred. Preoperative best corrected visual acuity decreased more than 1 Snellen line in 1 eye due to exacerbation of uveitis 18 months postoperatively. ConclusionsCanaloplasty appears to be a relatively safe and effective initial surgical intervention in UG.

IMPACT OF THE THERAPY WITH TUMOR NECROSIS FACTOR α INHIBITORS ON THE FREQUENCY OF UVEITIS EXACERBATIONS IN PATIENTS WITH ANKYLOSING SPONDYLITIS

Система комплексной поддержки и сопровождения научного журнала Elpub позволяет запустить двуязычный сайт журнала со встроенной системой электронной редакции в соответствии с лучшими издательскими практиками, а так же предусматривает техническую и методическую поддержку со стороны специалистов НЭИКОН.

THU0304 Efficacy of biologic therapies for pediatric rheumatic diseases associated uveitis

BackgroundPediatric uveitis often take a serious course refractory to standard immunosuppression. Biologics provide new options for patients with resistant rheumatic diseases (RD). However, their efficacy in associated uveitis is less...

AB0554 Abatacept (ORENCIA): Experience of practical application

BackgroundJuvenile idiopathic arthritis is a quite widespread pathology in the group of connective tissue diseases and leads to severe disability in case of inefficient treatment. With the extension of medical...

Efficacy of genetically engineered biological agents in the treatment of uveitis associated with rheumatic diseases in children

Система комплексной поддержки и сопровождения научного журнала Elpub позволяет запустить двуязычный сайт журнала со встроенной системой электронной редакции в соответствии с лучшими издательскими практиками, а так же предусматривает техническую и методическую поддержку со стороны специалистов НЭИКОН.

INTRAVITREAL RANIBIZUMAB FOR THE TREATMENT OF INFLAMMATORY CHOROIDAL NEOVASCULARIZATION

To evaluate the effect of individualized repeated intravitreal injections of ranibizumab (Lucentis) on visual acuity and central foveal thickness in patients with choroidal neovascular membrane (CNV) associated with various ocular inflammatory clinical entities. Our study was a retrospective, noncomparative, interventional, and observational case series. Sixteen eyes of 15 consecutive patients diagnosed with inflammatory CNV treated with repeated intravitreal injections of ranibizumab were evaluated. The underlying diagnoses were toxoplasmosis (n = 4), serpiginous choroidopathy (n = 2), punctate inner choroidopathy (n = 5), multifocal choroiditis (MFC, n = 3), and scleroderma (n = 2). All patients underwent monthly optical coherence tomography (OCT) scans and fluorescein angiography/indocyanine green angiography every 1 month after every injection and then every 3 months. Optical coherence tomography scans and fluorescein angiography were performed by the same experienced physician. Repeated intravitreal injections were performed when persistent/recurrent fluid on OCT and/or signs of active CNV on angiography were present. Changes in Early Treatment Diabetic Retinopathy Study visual acuity and central foveal thickness were statistically analyzed. The mean follow-up time was 70.4 ± 24 weeks (17.6 months; range, 44-116 weeks [11-29 months]). The mean number of injections performed was 2.3, and the mean best-corrected visual acuity improved from 55 Early Treatment Diabetic Retinopathy Study letters (logarithm of the minimum angle of resolution, 0.9 ± 0.4 [mean ± SD]) at baseline to 70.3 Early Treatment Diabetic Retinopathy Study letters (logarithm of the minimum angle of resolution, 0.6 ± 0.4) at the end of the follow-up, a statistically significant change compared with baseline (P < 0.0001). The mean letter gain was 15.3 letters, and best-corrected visual acuity improved in 14 of 16 patients (88%) and remained stable in 2 patients (12.5%) without any patient demonstrating deterioration. The mean central foveal thickness (although not excessively increased at baseline) improved from 285 ± 20 μm at baseline to 233 ± 21 μm (statistically significant compared with baseline, P < 0.0001) at the end of the follow-up. At the end of the follow-up, all patients demonstrated CNV regression, and retinal pigment epithelial atrophy surrounding the regressed CNV was developed in 11 of the 16 eyes (68.8%). During the same period, no CNV recurrence was observed and no injection-related complications such as cataract, retinal detachment, endophthalmitis, or exacerbation of uveitis were noted. Overall, our findings suggest that intravitreal injections of ranibizumab have shown promising results in visual acuity improvement and a decrease in macular thickness in patients with inflammatory CNV. Of course, further studies are needed to confirm the exact benefit and standardize the optimal treatment regimen.

Etanercept (Enbrel)-Associated Inflammatory Eye Disease: Case Report and Review of the Literature

Purpose: To report a case of severe anterior uveitis flare following the administration of etanercept (Enbrel) for ankylosing spondylitis and to review the literature pertaining to inflammatory eye disease associated with the use of etanercept. Methods: Clinical data were collected from a 52-year-old female with chronic symptomatic ankylosing spondylitis. The relationship between etanercept administration and the patient's systemic and ocular inflammation was assessed. A review of the literature was conducted to identify additional reports. Results: A patient with a history of ankylosing spondylitis exhibited acute exacerbations of uveitis that were temporally related to etanercept injections. Re-challenge was associated temporally with a worsening of symptoms, and drug withdrawal, in concert with aggressive systemic steroid treatment, resulted in rapid resolution. Seventeen cases of inflammatory eye disease (uveitis, scleritis, orbital myositis) believed to be associated with etanercept therapy were found in the recent literature. Conclusions: Ocular inflammation is paradoxically a potential adverse event following the use of etanercept in both previously uninvolved and inflamed eyes. Careful surveillance of patients on etanercept is warranted to assure that flares in ocular inflammation are not secondary to etanercept therapy.

Human T-lymphotropic virus type I-associated uveitis in patients with Graves' disease treated with methylmercaptoimidazole.

Human T-lymphotropic virus type I (HTLV-I) is responsible for a certain form of uveitis [HTLV-I-associated uveitis (HAU)]. A previous history of Graves' disease has been reported in 9-17% of the patients with HAU. In this study, the prevalence of patients with either HTLV-I antibody or uveitis was evaluated in 819 consecutive patients with thyroid disorders between 1991 and 1992. Serum HTLV-I antibody was found in 25 of 392 patients with Graves' disease, 19 of 257 with chronic thyroiditis, and 3 of 170 with nodular goiter. Five of 25 HTLV-I-positive patients with Graves' disease developed HAU. All of these 5 patients had been treated with methylmercaptoimidazole (MMI). Within a few months before the onset of uveitis, 3 patients were hyperthyroid, and 2 were hypothyroid. In 2 of 5 patients, an exacerbation of uveitis occurred soon after the readministration of MMI for the relapse of hyperthyroidism. None of the 367 HTLV-I negative patients with Graves' disease nor 22 HTLV-I-positive patients with chronic thyroiditis or nodular goiter developed uveitis. It was therefore suggested that Graves' disease, thyroid dysfunction and/or MMI administration might be related to the development of HAU.

Cyclosporin therapy in Vogt Koyanagi Harada disease

Vogt Koyanagi Harada Disease (VKHD) is a rare cause of uveitis and has not been previously reported in the Australian literature. The natural history of this severe inflammatory eye disease may be modified by the early use of high-dose immunosuppressive therapy, especially oral corticosteroids. We report three cases of VKHD who either failed to respond to high-dose corticosteroid (oral and intravenous) therapy alone or developed significant side effects, one of whom subsequently showed a beneficial response and another a transient beneficial response to cyclosporin therapy. Disease relapse or exacerbation of uveitis was the major problem encountered on attempted cyclosporin withdrawal. Further research is needed to define the optimum timing and indications for cyclosporin therapy in patients with VKHD.