Oral tacrolimus for ocular involvement in pediatric neutrophilic dermatoses.
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ABSTRACT:
SUBMITTER: Swaffar C
PROVIDER: S-EPMC8857544 | biostudies-literature | 2022 Mar
REPOSITORIES: biostudies-literature
Publications
Oral tacrolimus for ocular involvement in pediatric neutrophilic dermatoses.
Swaffar Caitlan C McShane Diana D Googe Paul P Kovalick Leonard L Morrell Dean S DS Wu Eveline Y EY
JAAD case reports 20220106
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Project description:BackgroundNo studies have been reported on the efficacy and safety of long-term (≥12 months) use of topical tacrolimus for refractory ocular surface inflammation in pediatric patients.MethodsMedical records of pediatric patients who were prescribed topical 0.02% tacrolimus ointment for refractory ocular surface inflammation between January of 2010 and March of 2018 were reviewed retrospectively. Changes in ocular surface signs during slit-lamp examination, clinical symptoms and concurrent steroid use were graded with a scoring system. The presence of side effects was also assessed. The changes in disease severity and patient symptoms were compared between baseline and after the treatment.ResultsAmong 72 patients (55% males, mean age 10.8 ± 3.9 years, range 3 to 17 years), 25 patients (48% males, mean age 11.4 ± 3.9 years) fully recovered, resulting in discontinuance of the ointment treatment before 12 months. Six patients experienced intolerable burning sensation, which required treatment cessation. Cessation days of those who quit were 1,5,14,20,26, and 35 days. Seven patients were lost during follow-up. Thirty-four patients (56% males, mean age 11.2 ± 4.2 years, range 3 to 17 years) were treated with tacrolimus ointment for over 12 months (average 23.1 ± 19.1 months, range 12 to 98 months). During the follow-up period, all patients showed improved clinical signs and symptoms, and no adverse reaction was noted.ConclusionsLong-term maintenance of topical tacrolimus 0.02% ointment is safe and effective in improving refractory ocular surface inflammation in pediatric patients.
| S-EPMC8178927 | biostudies-literature
Project description:Mice homozygous for the Y208N amino acid substitution in the carboxy terminus of SHP-1 (referred to as Ptpn6spin mice) spontaneously develop a severe inflammatory disease resembling neutrophilic dermatosis in humans. Disease in Ptpn6spin mice is characterized by persistent footpad swelling and suppurative inflammation. Recently, in addition to IL-1α and IL-1R signaling, we demonstrated a pivotal role for RIPK1, TAK1, and ASK1 in promoting inflammatory disease in Ptpn6spin mice. In the current study we have identified a previously unknown role for CARD9 signaling as a critical regulator for Ptpn6spin-mediated footpad inflammation. Genetic deletion of CARD9 significantly rescued the Ptpn6spin-mediated footpad inflammation. Mechanistically, enhanced IL-1α-mediated signaling in Ptpn6spin mice neutrophils was dampened in Ptpn6spinCard9-/- mice. Collectively, this study identifies SHP-1 and CARD9 cross-talk as a novel regulator of IL-1α-driven inflammation and opens future avenues for finding novel drug targets to treat neutrophilic dermatosis in humans.
| S-EPMC6483079 | biostudies-literature
Project description:We have found a B2 repeat insertion in the gene encoding protein tyrosine phosphatase nonreceptor type 6 (PTPN6) in a mouse that developed a skin disorder with clinical and histopathological features resembling those seen in human neutrophilic dermatoses. Neutrophilic dermatoses are a group of complex heterogeneous autoinflammatory diseases that all demonstrate excessive neutrophil infiltration of the skin. Therefore, we tested the cDNA and genomic DNA sequences of PTPN6 from patients with Sweet's syndrome (SW) and pyoderma gangrenosum and found numerous novel splice variants in different combinations. Isoforms resulting from deletions of exons 2, 5, 11, and 15 and retention of intron 1 or 5 were the most common in a patients with a familial case of SW, who had a neonatal onset of an inflammatory disorder with skin lesions and a biopsy specimen consistent with SW. These isoforms were associated with a heterozygous E441G mutation and a heterozygous 1.7-kbp deletion in the promoter region of the PTPN6 gene. Although full-length PTPN6 was detected in all other patients with either pyoderma gangrenosum or SW, it was always associated with splice variants: a partial deletion of exon 4 with the complete deletion of exon 5, alterations that were not detected in healthy controls. The defect in transcriptional regulation of the hematopoietic PTPN6 appears to be involved in the pathogenesis of certain subsets of the heterogeneous group of neutrophilic dermatoses.
| S-EPMC3078441 | biostudies-literature
Project description:Sweet syndrome (SS) is a prototypical neutrophilic dermatosis, a class of inflammatory diseases marked by elevated levels of tumor necrosis factor (TNF)-α and IL-17A, pathologic neutrophil recruitment, and microvascular remodeling. Histologic analyses of four matrix proteins-collagen I and IV, laminin, and fibronectin-in skin biopsies of patients with SS reveal that the basement membrane of dermal postcapillary venules undergoes changes in structure and composition. Increased neutrophil recruitment in vivo was associated with increases in collagen IV, decreases in laminin, and varied changes in fibronectin. In vitro studies using TNF-α and IL-17A were conducted to dissect basement membrane remodeling. Prolonged dual activation of cultured human pericytes with TNF-α and IL-17A augmented collagen IV production, similar to in vivo remodeling. Co-activation of pericytes with TNF-α and IL-17A also elevated fibronectin levels with little direct effect on laminin. However, the expression of fibronectin- and laminin-specific matrix metalloproteinases (MMPs), particularly MMP-3, was significantly up-regulated. Interactions between pericytes and neutrophils in culture yielded even higher levels of active MMPs, facilitating fibronectin and laminin degradation, and likely contributing to the varied levels of detectable fibronectin and the decreases in laminin observed in vivo. These data indicate that pericyte-neutrophil interactions play a role in mediating microvascular changes in SS and suggest that targeting MMP-3 may be effective in protecting vascular wall integrity.
| S-EPMC5530916 | biostudies-literature
Project description:PurposeTo describe the ophthalmic symptoms and histopathological findings in a case of primary neurolymphomatosis (NL).ObservationsA man in his 60s with a prior diagnosis of chronic inflammatory demyelinating polyneuropathy developed facial numbness, diplopia, drooling, and difficulty swallowing. Over a 3-month period, he developed total ptosis and ophthalmoplegia of the right eye with a dilated, non-reactive pupil considered secondary to cranial nerve III and VI palsies. His left pupil subsequently became non-reactive to light and accommodation, and extraocular motility of the left eye was partially limited in all directions of gaze without ptosis. Autopsy findings included primary NL, diffuse large B-cell lymphoma of activated B-cell subtype, involving right and left cranial nerves V, VI, IX, and X; spinal nerve roots; both femoral nerves; and extrascleral, intrascleral, and intraocular short and long posterior ciliary nerves with extension into the adjacent choroid of both eyes. No evidence of lymphoma was identified elsewhere in the body.Conclusions and importanceOur patient is only the second histological demonstration of ciliary nerve involvement by NL, and the first, to our knowledge, of primary NL spreading secondarily from the ciliary nerves into the choroid. Our patient demonstrates that NL, though rare, should be included in the differential diagnosis of ocular cranial nerve palsies and ophthalmoplegia.
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Project description:The periocular area may be affected by infectious or noninfectious diseases such as inflammatory dermatoses, systemic disease, drug reactions, benign and malignant lesions, traumatic lesions, and esthetic complications. We present a review of the most common periocular dermatoses.
| S-EPMC5715233 | biostudies-literature
Project description:The eye is a highly complex, yet readily accessible organ within the human body. As such, the eye is an appealing candidate target for a vast array of drug therapies. Despite advances in ocular drug therapy research, the focus on pediatric ocular drug delivery continues to be highly underrepresented due to the limited number of degenerative ocular diseases with childhood onset. In this review, we explore more deeply the reasons underlying the disparity between ocular therapies available for children and for adults by highlighting diseases that most commonly afflict children (with focus on the anterior eye) and existing prognoses, recent developments in ocular drug delivery systems and nanomedicines for children, and barriers to use for pediatric patients.
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Project description: Not available
| S-EPMC11652059 | biostudies-literature
Project description:Hansen's disease (HD) belongs to the group of neglected diseases and can cause physical deformities and disabilities, in addition to leading to social discrimination. Ocular involvement in HD is estimated at 70-75% worldwide. About 10-50% suffer from severe ocular symptoms and loss of vision occurs in approximately 5% of cases. Ocular changes may persist or worsen even after patients are considered cured and it is necessary to better understand these conditions in order to determine the need for additional public policies. The objective of this study was to identify the prevalence of ocular involvement in patients with HD at two specialist referral centers for treatment of the disease. A cross-sectional study was conducted with ophthalmological evaluations of patients with HD from June 2017 to June 2018. Diagnostic ocular findings, corrected visual acuity, and refractive error were described. Findings were correlated with patients' clinical and epidemiological variables. A total of 86 patients were evaluated, with a mean age of 50.1 years, predominantly males (59.3%), and with multibacillary HD (92%). The prevalence of ophthalmologic changes was 100% and the most common were dysfunction of the Meibomian glands (89.5%) and dry eye syndrome (81.4%). Cataracts were observed in 22 patients (25.6%), but best corrected visual acuity was normal or near normal in 84 patients (97.7%) and there were no cases of bilateral blindness. Patients with some degree of physical disability had more ophthalmological alterations, involving both the ocular adnexa (p = 0.03) and the ocular globe (p = 0.04). Ocular involvement is common in patients with Hansen's disease, reinforcing the importance of ophthalmologic examination in the evaluation and follow-up of these patients.
| S-EPMC7505469 | biostudies-literature
Project description:Background and aimsThis multicenter trial compared immediate-release tacrolimus (IR-T) vs prolonged-release tacrolimus (PR-T) in de novo kidney, liver, and heart transplant recipients aged <16 years. Each formulation had similar pharmacokinetic (PK) profiles. Follow-up efficacy and safety results are reported herein.Materials and methodsPatients, randomized 1:1, received once-daily, PR-T or twice-daily, IR-T within 4 days of surgery. After a 4-week PK assessment, patients continued randomized treatment for 48 additional weeks. At Year 1, efficacy assessments included the number of clinical acute rejections, biopsy-confirmed acute rejection (BCAR) episodes (including severity), patient and graft survival, and efficacy failure (composite of death, graft loss, BCAR, or unknown outcome). Adverse events were assessed throughout.ResultsThe study included 44 children. At Year 1, mean ± standard deviation tacrolimus trough levels were 6.6 ± 2.2 and 5.4 ± 1.6 ng/mL, and there were 2 and 7 acute rejection episodes in the PR-T and IR-T groups, respectively. No cases of graft loss or death were reported during the study. The overall efficacy failure rate was 18.2% (PR-T n = 1; IR-T n = 7).ConclusionsIn pediatric de novo solid organ recipients, the low incidence of BCAR and low efficacy failure rate suggest that PR-T-based immunosuppression is effective and well tolerated to 1-year post-transplantation.
| S-EPMC6900073 | biostudies-literature