Longterm Safety and Efficacy of Adalimumab and Infliximab for Uveitis Associated with Juvenile Idiopathic Arthritis.

OBJECTIVE: Anti-TNF-α agents have significantly changed the management of juvenile idiopathic arthritis (JIA). We evaluated the safety and efficacy of adalimumab (ADA) and infliximab (IFX) for the treatment of JIA-associated uveitis in patients treated for ≥ 2 years. METHODS: Patients with JIA-associated uveitis treated with IFX and ADA were managed by a standardized protocol and data were entered in the ORCHIDEA registry. At baseline, all patients were refractory to standard immunosuppressive treatment or were corticosteroid-dependent. Data recorded every 3 months were uveitis course, number/type of ocular flares and complications, drug-related adverse events (AE), and treatment switch or withdrawal. Data of patients treated for ≥ 2 years were analyzed by descriptive statistics. RESULTS: Up to December 2014, 154 patients with ≥ 24 months followup were included in the study. Fifty-nine patients were treated with IFX and 95 with ADA. Clinical remission, defined as the absence of flares for > 6 months on treatment, was achieved in 69 patients (44.8%), with a better remission rate for ADA (60.0%) as compared to IFX (20.3%; p < 0.001). A significant reduction of flares was observed in all patients without difference between the 2 treatment modalities. The number of new ocular complications decreased in both groups but was lower for ADA (p = 0.015). No serious AE were recorded; 16.4% of patients experienced 35 minor AE and the incidence rate was lower with ADA than with IFX. CONCLUSION: At the 2-year followup, ADA showed a better efficacy and safety profile than IFX for the treatment of refractory JIA-associated uveitis.

Ocular Involvement in Children with Inflammatory Bowel Disease.

BACKGROUND: Data on ocular manifestations of inflammatory bowel disease (IBD) in children are limited. Some authors have reported a high prevalence of asymptomatic uveitis, yet the significance of these observations is unknown and there are no recommendations on which ophthalmologic follow-up should be offered. METHODS: Children with IBD seen at a single referral center for pediatric gastroenterology were offered ophthalmologic evaluation as part of routine care for their disease. Ophthalmologic evaluation included review of ocular history as well as slit-lamp and fundoscopic examination. Medical records were also reviewed for previous ophthalmologic diagnoses or complaints. RESULTS: Data from 94 children were included (52 boys; median age 13.4 yr). Forty-six patients had a diagnosis of Crohn's disease, 46 ulcerative colitis, and 2 IBD unclassified. Intestinal disease was in clinical remission in 70% of the patients; fecal calprotectin was elevated in 64%. One patient with Crohn's disease had a previous diagnosis of clinically manifest uveitis (overall uveitis prevalence: 1.06%; incidence rate: 0.3 per 100 patient-years). This patient was also the only one who was found to have asymptomatic uveitis at slit-lamp examination. A second patient had posterior subcapsular cataract associated with corticosteroid treatment. No signs of intraocular complications from previous unrecognized uveitis were observed in any patient. CONCLUSIONS: Children with IBD may have asymptomatic uveitis, yet its prevalence seems lower than previously reported, and it was not found in children without a previous diagnosis of clinically manifest uveitis. No ocular complications from prior unrecognized uveitis were observed.

Superior efficacy of Adalimumab in treating childhood refractory chronic uveitis when used as first biologic modifier drug: Adalimumab as starting anti-TNF-α therapy in childhood chronic uveitis.

BACKGROUND: Nonetheless biologic modifier therapies are available treatment strategies for sight-threatening uveitis in children, the lack of evidence from head-to-head randomized controlled studies limits our understanding of timing of therapy when to commence therapy, which agent to choose and how long to continue treatment, and, in case of failure, if switching to another anti-TNF-α strategy might be eventually an option. Our aim was to compare the efficacy of Adalimumab when used as first anti-TNFα therapy versus Adalimumab used after the failure of a previous anti-TNFα (Infliximab) in an open-label, comparative, multi-center, cohort study of childhood chronic uveitis. METHODS: 26 patients (14 F, 12 M; median age: 8.6 years) with refractory, non-infectious active uveitis were enrolled. Due to the refractory course of uveitis to previous DMARD treatment, Group 1 received Adalimumab (24 mg/sq mt, every 2 weeks), as first anti-TNFα choice; Group 2 received Adalimumab, as second anti-TNFα drug, due to the loss of efficacy of Infliximab, administered after a period of at least 1 year. Both groups received Adalimumab for at least 1 year of treatment. Primary outcome was, once remission was achieved, the time to a first relapse. RESULTS: 14 children (10 with JIA, 3 with idiopathic uveitis, 1 with Behçet's disease) were recruited in Group 1; 12 children (7 with JIA, 3 with idiopathic uveitis, 1 with early-onset sarcoidosis, 1 with Behçet's disease) in Group 2. Group 2 showed a lower probability to steroid discontinuation during the first 12 months of treatment (Mantel-Cox χ(2)4.12, p<0.04). In long-term follow-up, Group 1 had higher probability of uveitis remission during the time of treatment on Adalimumab (median ±SE: 18 ±1.1 vs 4 ±0.6 months, CI 95%: 15.6-27.5 vs 2.7-5.2, Mantel-Cox χ(2)10.12, p<0.002). CONCLUSIONS: Even if limited to a relatively small group, our study suggests a better efficacy of Adalimumab when used as first anti-TNFα treatment in childhood chronic uveitis.

Safety and efficacy of infliximab and adalimumab for refractory uveitis in juvenile idiopathic arthritis: 1-year followup data from the Italian Registry.

OBJECTIVE: To evaluate safety and efficacy of adalimumab (ADA) and infliximab (IFX) for the treatment of juvenile idiopathic arthritis-related anterior uveitis (JIA-AU). METHODS: Starting January 2007, patients with JIA-AU treated with IFX and ADA were managed by a standard protocol and data were entered into the National Italian Registry (NIR). At baseline, all patients were refractory to standard immunosuppressive treatment and/or were corticosteroid-dependent. Data recorded every 3 months included uveitis course, number/type of ocular complications, drug-related adverse events (AE), treatment change or withdrawal, and laboratory measures. Data of patients treated for at least 1 year were retrieved from the NIR and analyzed using descriptive statistics. Treatment efficacy was based on change in uveitis course and in number of ocular complications. RESULTS: Up to December 2009, data for 108 patients with JIA-AU treated with anti-tumor necrosis factor-α agents were recorded in the NIR and data from 91, with at least 12 months' followup, were included in the study. Forty-eight patients were treated with IFX, 43 with ADA. Forty-seven patients (55.3%) achieved remission of AU, 28 (32.9%) had recurrent AU, and 10 (11.8%) maintained a chronic course. A higher remission rate was observed with ADA (67.4% vs 42.8% with IFX; p = 0.025). Ocular complications decreased from 0.47 to 0.32 per subject. Five patients experienced resolution of structural complications. No patient reported serious AE; 8 (8.8%) experienced 11 minor AE (9 with IFX, 2 with ADA). CONCLUSION: IFX and ADA appear to be effective and safe for treatment of refractory JIA-related uveitis, with a better performance of ADA in the medium-term period.

A singular case of congenital self-healing histiocytosis with skin, liver and atypical eye involvement.

PURPOSE: To describe a rare case of congenital self-healing Langerhans cell histiocytosis (CSHLCH) presenting with atypical eye involvement. DESIGN: Case report. METHODS: A female newborn presented with purpuric lesions over the trunk, limbs, and face. Liver ultrasonography revealed hypoechogenic lesions with blurred borders. Biomicroscopy showed right posterior synechiae with fibrinoid deposits on the lens. At 7 months she presented with right acute glaucoma. RESULTS: Biomicroscopy showed the presence of inflammatory pseudo-membrane covering the anterior surface of the lens, iris, and iridocorneal angle. Ab externo trabeculotomy was performed; access to the anterior chamber with capsulorrhexis forceps permitted a peeling of the pseudo-membrane with normalization of the intraocular pressure. Histologic examination of the membrane revealed an inflammatory tissue with CD1a and S-100 positive histiocytic cells. CONCLUSIONS: This is the first case of CSHLCH describing acute glaucoma secondary to a pseudo-inflammatory membrane with typical histiocytic cells, occluding the iridocorneal angle.

Congenital aplasia of the optic chiasm and esophageal atresia: a case report.

INTRODUCTION: The complete absence of the chiasm (chiasmal aplasia) is a rare clinical condition. Hypoplasia of the optic nerve and congenital nystagmus are almost invariably associated characteristics. Microphthalmos or anophthalmos are common features in chiasmal aplasia, while central nervous system abnormalities are less frequent. Esophageal atresia can be isolated or syndromic. In syndromic cases, it is frequently associated with cardiac, limb, renal or vertebral malformations and anal atresia. More rarely, esophageal atresia can be part of anophthalmia-esophageal-genital syndrome, which comprises anophthalmia or microphthalmia, genital abnormalities, vertebral defects and cerebral malformations. Here, a previously unreported case of chiasmal aplasia presenting without microphthalmos and associated with esophageal atresia is described. CASE PRESENTATION: Aplasia of the optic chiasm was identified in a Caucasian Italian 8-month-old boy with esophageal atresia. An ultrasound examination carried out at 21 weeks' gestation revealed polyhydramnios. Intrauterine growth retardation, esophageal atresia and a small atrial-septal defect were subsequently detected at 28 weeks' gestation. Repair of the esophageal atresia was carried out shortly after birth. A jejunostomy was carried out at four months to facilitate enteral feeding. The child was subsequently noted to be visually inattentive and to be neurodevelopmentally delayed. Magnetic resonance imaging revealed chiasmal aplasia. No other midline brain defects were found. His karyotype was normal. CONCLUSION: If achiasmia is a spectrum, our patient seems to depict the most severe form, since he appears to have an extremely severe visual impairment. This is in contrast to most of the cases described in the literature, where patients maintain good--or at least useful-- visual function. To the best of our knowledge, the association of optic nerve hypoplasia, complete chiasmal aplasia, esophageal atresia and atrial-septal defect, choanal atresia, hypertelorism and psychomotor retardation has never been described before.

Horizontal gaze palsy and progressive scoliosis without ROBO3 mutations.

BACKGROUND: To describe clinical and genetic observations in a patient with horizontal gaze palsy and progressive scoliosis (HGPPS) without identified mutations in the ROBO3 gene. MATERIALS AND METHODS: Neurologic and orthopedic evaluation of the proband; sequencing all exons, exon-intron boundaries, and promoter region of ROBO3 in the proband and his mother. Array CGH was also carried out in the proband and his mother to evaluate possible chromosomal deletion(s) and/or duplication(s). RESULTS: The proband had complete horizontal gaze restriction with full vertical gaze and small amplitude horizontal pendular nystagmus. He also had severe scoliosis and brainstem hypoplasia pathognomonic of HGPPS. However, complete sequencing of ROBO3 twice in both forward and reverse directions did not reveal any mutations. Array CGH investigation revealed no chromosomal abnormalities. CONCLUSIONS: This patient had clinical and neuroimaging characteristics considered pathognomonic of HGPPS and yet did not have ROBO3 mutations. A clinical misdiagnosis is unlikely in the absence of facial weakness (typical of Moebius syndrome), deafness (typical of the HOXA1 spectrum), or mental retardation (typical of other central decussation abnormalities). It is perhaps more likely that a phenotype identical to HGPPS can be caused by abnormalities in ROBO3 splice variant expression, by mutations of a gene other than ROBO3, or by some environmental or epigenetic factor(s) inhibiting the action of ROBO3 or its protein product in the developing brainstem.

Paediatric Behçet's disease presenting with recurrent papillitis and episcleritis: a case report.

INTRODUCTION: Behçet's disease is a chronic multisystem vasculitis characterized by mucocutaneous, articular, neurological, gastrointestinal and ophthalmological lesions. Ocular involvement is mainly represented by recurrent uveitis, especially posterior uveitis; however, iridocyclitis, retinal and choroidal vasculitis, optic neuritis and retinal vascular occlusion can also occur. CASE PRESENTATION: A 12-year-old Caucasian boy with a history of recurrent buccal aphthosis and nonspecific gastrointestinal symptoms was admitted to our hospital with blurred vision associated with acute episcleritis and papillitis. The patient's pathergy test was positive, suggesting a diagnosis of Behçet's disease. Corticosteroid and cyclosporine therapy was started, but further episodes were noted in both eyes. The patient was then switched to intravenous infliximab, with complete resolution of the inflammation after the second infusion. CONCLUSION: Episcleritis and papillitis should be added to the list of uncommon manifestations of pediatric Behçet's disease. Infliximab is an effective, new therapeutic approach for Behçet's disease that is refractory to the conventional corticosteroid and immunosuppressive therapy.

Corneal curvature and thickness development in premature infants.

PURPOSE: Analysis of postnatal changes in central corneal thickness (CCT) and corneal curvature (CC) in premature infants, their relation, and their possible influence on eye growth and intraocular pressure (IOP) evaluation. METHODS: CCT and CC were assessed in both eyes of 56 premature infants, born at 24 to 32 weeks of gestational age (GA), and then two or three times at post-conceptional ages (PCAs) of 28 to 42 weeks. RESULTS: CC changed from 65.83 diopters at 28 weeks of PCA to 49.38 diopters at 42 weeks of PCA. CCT decreased from 794 to 559 µm at the same ages. The reductions of these two corneal parameters seem to be related to each other and begin immediately after birth. CONCLUSION: In light of the few data available in the literature, these data provide more certainty about the CCT values of premature infants. The importance of CCT and CC fast variations after premature birth concerns both the knowledge of anterior segment development and the correct evaluation of IOP in immature eyes; the influence of these two parameters on the methods of IOP evaluation could be more remarkable at the lowest PCAs.

Eye movement impairment recovery in a Gaucher patient treated with miglustat.

In Gaucher Disease (GD) the enzyme (imiglucerase) replacement therapy (ERT) is not able to stop the progression of the neurological involvement, while the substrate reduction therapy (SRT), performed by N-Butyldeoxynojirimycin (miglustat), is an alternative that should be evaluated. Two sisters, presenting the same genotype (R353G/R353G), were diagnosed as suffering from GD; one of them later developed neurological alterations identified by quantitative saccadic eye movements analysis. The aim of the study was to quantitatively measure the miglustat effects in this GD neurological patient. Eye movement analysis during subsequent controls was performed by estimating the characteristic parameters of saccadic main sequence. The study demonstrates that the SRT alone can be effective in GD3. Moreover, it confirms that quantitative eye movement analysis is able to precociously identify also slight neurological alterations, permitting more accurate GD classification.

Central corneal thickness in children with growth hormone deficiency.

PURPOSE: To evaluate central corneal thickness (CCT), intraocular pressure (IOP) and eye refraction in patients with congenital growth hormone (GH) deficiency. METHODS: Retrospective case series. Forty-five patients with growth defect treated with recombinant GH and 45 healthy children underwent ophthalmological examination, including CCT measurements, applanation tonometry and cycloplaegic refraction. RESULTS: The average CCT in the GH deficiency group was 570.6µm [standard deviation (SD) 37.4]. In the control group, it was 546.0 (SD 24.9). The average IOP in the GH deficiency group was 18.2mmHg (SD 3.4). In the control group, it was 14.6 (SD 2.0). The mean refractive error (spherical equivalent) in the GH deficiency group was 0.59D (SD 1.9). In the control group, it was 0.11 (SD 2.1). CONCLUSION: GH and insulin-like growth factor 1 are involved in ocular growth by influencing the synthesis of the extracellular matrix of the sclera. Children with congenital GH deficiency or insensitivity have a mean hyperopic defect related to a shorter axial length. A number of studies have demonstrated that CCT in newborns is significantly greater than in adults; a decrease in CCT is closely correlated with an increase in corneal diameter. This finding suggests that the growth of the eye, with possible remodelling and stretching of collagen fibres, may play an important role in the reduction of corneal thickness in the first years of life. Therefore, we conclude that a greater CCT can represent a sign of a delayed growth of the eye in patients with GH deficiency. Finally, our study confirms the influence of corneal thickness on IOP measures, and the prevalence of hyperopia among children with growth defect.

Double adverse drug reaction: Recombinant human growth hormone and idiopathic intracranial hypertension - acetazolamide and metabolic acidosis: a case report.

A 9-year-old girl, treated for growth hormone deficiency, developed bitemporal progressive headache, diplopia, acute comitant esotropia and visual loss 3 months after starting recombinant growth hormone. An increased intracranial pressure was revealed by examination of ocular fundus and lumbar puncture, and the absence of other causes, ruled out through a brain scan, led to the diagnosis of idiopathic intracranial hypertension.Recombinant growth hormone was discontinued and acetazolamide started up to 30 mg/kg/die without any clinical improvement but developing metabolic acidosis. The switch to intravenous dexamethasone (0.4 mg/kg/die) led to a dramatic clinical improvement after only 1 day, then confirmed by examination of ocular fundus and visual evoked potentials. Currently, there are no evidence-based guidelines for the management of intracranial hypertension, and even though acetazolamide is recognized as the first-line drug, its efficacy and safety have not been proven: some patients might not respond and others will present unacceptable side-effects. Therefore we suggest the use of corticosteroids in intracranial hypertension when acetazolamide is inefficient or intolerable.

Ophthalmic features in a dysmorphic boy with chromosome 4q deletion and duplication.

The 4q deletion syndrome shows varying phenotype, ranging from severe and complex malformations, unconformable with life, to more specific findings, as genitourinary, gastrointestinal and cardiac malformations, cleft palate,microcephaly, hypertelorism and abnormal ears and limbs. Strabismus, nystagmus, ophthalmoplegia, and optic nerve anomalies have been rarely described in literature. We report an original case of simultaneous deletion and duplication of chromosome 4q, confirmed by SNPs-array analysis of DNA, and characterized by a previously unreported association between optic nerve hypoplasia and progressive external ophthalmoplegia.

Parinaud's oculoglandular syndrome due to herpes simplex virus type 1.

PURPOSE: To describe the clinical findings in a patient with Parinaud's oculoglandular syndrome as an uncommon manifestation of primary herpes simplex virus type 1 (HSV-1) infection. METHODS: The clinical course, the laboratory findings, the therapy, and the outcome regarding a 14-year-old girl are described. RESULTS: The culture and PCR detection of HSV-1 on conjunctiva and skin scrapings, along with seroconversion to HSV, confirmed the etiology. The oral and local acyclovir therapy led to a prompt improvement in the patient's symptoms. CONCLUSION: The solitary ocular-glandular syndrome due to HSV-1 primary infection has never been reported before. Parinaud's oculoglandular syndrome is found in 5% of patients with cat-scratch disease and only on rare occasion associated with other conditions. Herpetic infection should be considered in the differential diagnosis of young patients with conjunctivitis, periorbital swelling, and painful preauricular and submandibular lymphadenopathy, combined with systemic symptoms of malaise and fever.

Polymicrobial keratomycosis in a three-year-old child.

PURPOSE: To describe a previously unreported case of polymicrobial mycotic keratitis caused by an association between Candida lusitaniae, C. parapsilosis, and Geotrichum candidum. METHODS: A three-year-old child with an antecedent trauma with vegetable matter and a prolonged use of corticosteroid eyedrops developed fungal keratitis. RESULTS: The isolates of the corneal scraping using Sabaraud dextrose agar grew C. lusitaniae, C. parapsilosis, and G. candidum. After topical 0.2% and systemic fluconazole treatment, the corneal lesion resolved with no recurrence. CONCLUSIONS: Corneal trauma with vegetables and the indiscriminate use of corticosteroids are important risk factors for mycotic keratitis. A combination of topical 0.2% and systemic fluconazole therapy was effective in the treatment of this mycotic association. This is the first report of fungal keratitis caused by C. lusitaniae and G. candidum.

Congenital growth hormone deficiency and eye refraction: a longitudinal study.

The aim of this study was to study the influence of growth hormone deficiency (GHD) on emmetropization and to evaluate the effect of growth hormone replacement therapy on eye refraction. Twenty-eight children affected by congenital GHD and undergoing substitutive therapy (group 1), and 28 healthy subjects (group 2), were prospectively studied. All patients had a thorough eye examination, including cycloplegic refraction and axial length measurement (only GHD children). After 2 years, we found in both groups a reduction of the dioptric power of the eye. A t test for paired data showed statistically significant differences in both groups (p<0.001), but the change of refraction was higher in group 2 (p<0.01). Axial length showed a statistically significant increase, according to the myopic shift (p<0.001). The change of the refraction found in GHD children could be related to the somatic growth and partially induced by growth hormone therapy. The difference between the two groups could be explained with the late beginning of the therapy in GHD children. It is possible to form the hypothesis that a correct and well-timed substitutive therapy could permit a normal emmetropization process.