Defining a therapeutic range for adalimumab serum concentrations in the management of pediatric noninfectious uveitis, a step towards personalized treatment.
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ABSTRACT: Background
Adalimumab is currently considered the most efficacious anti-TNFα agent for childhood noninfectious uveitis (NIU). The objective of this study was to define a therapeutic range for adalimumab trough levels in the treatment of childhood NIU.Methods
A retrospective, observational, pilot study of 36 children with NIU aged < 18 years, treated with adalimumab. Serum adalimumab through levels and adalimumab anti-drug antibodies (ADA) were analysed at least 24 weeks after start adalimumab.Results
Adalimumab trough levels were significantly higher in complete responders 11.8 μg/mL (range 6.9-33.0) compared to partial or non-responders 9,2 μg/mL (range 0-13.6) (p = 0,004). Receiver-operator characteristics analyses with an area under the curve of 0,749 (95% CI, 0,561-0,937) defined 9.6 µg/mL as the lower margin for the therapeutic range. This cut-off corresponds with a sensitivity of 88% and a specificity of 56% (positive predictive value, 85%; negative predictive value, 62.5%). A concentration effect curve defined 13 µg/mL as the upper margin. Approximately one-third (30.5%) of patients had an adalimumab trough concentration exceeding 13 µg/mL. Free ADA were observed in 2 patients (5.5%).Conclusions
A therapeutic range of adalimumab trough levels of 9.6 to 13 µg/mL, which corresponds with an optimal clinical effect, was identified. Therapeutic drug monitoring may guide the optimisation of treatment efficacy in children with NIU in the treat-to-target era.
SUBMITTER: Dehoorne JL
PROVIDER: S-EPMC10734081 | biostudies-literature | 2023 Dec
REPOSITORIES: biostudies-literature
Publications
Defining a therapeutic range for adalimumab serum concentrations in the management of pediatric noninfectious uveitis, a step towards personalized treatment.
Dehoorne Jo L JL Groth Helena H Carlé Emma E De Schrijver Ilse I Sys Celine C Delbeke Patricia P Kreps Elke O EO Renson Thomas T Bonroy Carolien C
Pediatric rheumatology online journal 20231220 1
<h4>Background</h4>Adalimumab is currently considered the most efficacious anti-TNFα agent for childhood noninfectious uveitis (NIU). The objective of this study was to define a therapeutic range for adalimumab trough levels in the treatment of childhood NIU.<h4>Methods</h4>A retrospective, observational, pilot study of 36 children with NIU aged < 18 years, treated with adalimumab. Serum adalimumab through levels and adalimumab anti-drug antibodies (ADA) were analysed at least 24 weeks after sta ...[more]
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Project description:PurposeTo characterize the risk and risk factors for intraocular pressure (IOP) elevation in pediatric noninfectious uveitis.DesignMulticenter retrospective cohort study.ParticipantsNine hundred sixteen children (1593 eyes) younger than 18 years at presentation with noninfectious uveitis followed up between January 1978 and December 2007 at 5 academic uveitis centers in the United States.MethodsMedical records review by trained, certified experts.Main outcome measuresPrevalence and incidence of IOP of 21 mmHg or more and 30 mmHg or more and incidence of a rise in IOP by 10 mmHg or more. To avoid underascertainment, outcomes were counted as present when IOP-lowering therapies were in use.ResultsInitially, 251 (15.8%) and 46 eyes (2.9%) had IOP ≥21 mmHg and ≥30 mmHg, respectively. Factors significantly associated with presenting IOP elevation included age of 6 to 12 years (versus other pediatric ages), prior cataract surgery, pars plana vitrectomy, duration of uveitis ≥6 months, contralateral IOP elevation, presenting visual acuity worse than 20/40, and topical corticosteroid use (in a dose-response relationship). The median follow-up was 1.25 years (interquartile range, 0.4-3.66). The estimated incidence of any observed IOP elevation to ≥21 mmHg, to ≥30 mmHg, and increase in IOP by ≥10 mmHg was 33.4%, 14.8%, and 24.4%, respectively, within 2 years. Factors associated with IOP elevation included pars plana vitrectomy, contralateral IOP elevation (adjusted hazard ratio [aHR], up to 9.54; P < 0.001), and the use of topical (aHR, up to 8.77 that followed a dose-response relationship; P < 0.001), periocular (aHR, up to 7.96; P < 0.001), and intraocular (aHR, up to 19.7; P < 0.001) corticosteroids.ConclusionsIntraocular pressure elevation affects a large minority of children with noninfectious uveitis. Statistically significant risk factors include IOP elevation or use of IOP-lowering treatment in the contralateral eye and local corticosteroid use that demonstrated a dose-and route of administration-dependent relationship. In contrast, use of immunosuppressive drug therapy did not increase such risk. Pediatric eyes with noninfectious uveitis should be followed up closely for IOP elevation, especially when strong risk factors such as the use of local corticosteroids and contralateral IOP elevation are present.
| S-EPMC4581960 | biostudies-literature
Project description:BackgroundUveitis is less common in children than in adults; however, pediatric uveitis has a relatively severe disease course that affects the quality of life. Although it is important to understand the epidemiological characteristics of pediatric uveitis, few studies have been conducted in large populations without referral bias. This study investigated the nationwide incidence and prevalence of pediatric uveitis in South Korea according to period, age, anatomic type, and systemic associations.MethodsThis nationwide population-based cohort study used data from the Korean National Health Insurance Service from 2002 to 2018. This study included patients younger than 19 years of age with noninfectious uveitis with at least three claims of diagnostic codes of uveitis on separate days with at least once claim of prescription codes of steroid and immunosuppressive agents. All the cases were classified as anterior or non-anterior uveitis, and the overall incidence and prevalence were estimated by age, sex, and period. Patients with noninfectious uveitis were categorized by the presence of associated systemic conditions.ResultsA total of 10,862,616 patients over 128,688,078 person-years were evaluated from 2005 to 2016. Overall, 5,368 cases of anterior uveitis and 604 cases of non-anterior uveitis were identified. The incidence and prevalence of pediatric noninfectious uveitis were 4.64 per 100,000 person-years (95% confidence interval [CI], 4.52-4.76) and 8.25 per 100,000 persons (95% CI, 8.09-8.41). Both the incidence and prevalence of pediatric uveitis increased with age. Anterior uveitis accounted for 84.7% of pediatric noninfectious uveitis prevalent cases (6.99 per 100,000 persons). Cases of juvenile idiopathic arthritis (JIA)-associated uveitis accounted for 8.7% (926 cases) of pediatric noninfectious uveitis cases with a prevalence of 0.72 per 100,000 (95% CI, 0.67-0.77). The proportion of systemic associations was higher and JIA-related uveitis accounted for 11.2% (803 cases) of recurrent or chronic noninfectious uveitis cases with a prevalence of 0.62 per 100,000.ConclusionThis is the first population-based study investigating the largest population of pediatric patients with uveitis in Korea. The nationwide incidence and prevalence of pediatric noninfectious uveitis in 2005-2016 were 4.64 per 100,000 person-years and 8.25 per 100,000, respectively. The proportion of JIA in pediatric noninfectious uveitis was 8.7%. These population-based study findings provide a better understanding of the public health burden and aid in the planning of health-care strategies for pediatric patients with uveitis.
| S-EPMC9763706 | biostudies-literature
Project description:ImportanceAdalimumab was recently approved for the treatment of noninfectious intermediate uveitis, posterior uveitis, and panuveitis.ObjectiveTo assess the effect of adalimumab on the visual functioning and quality of life in patients with corticosteroid-dependent noninfectious intermediate uveitis, posterior uveitis, and panuveitis.DesignA post hoc analysis of clinical trials of adults with active (VISUAL-1) and inactive (VISUAL-2) noninfectious intermediate uveitis, posterior uveitis, and panuveitis was conducted in the United States, Canada, Europe, Israel, Australia, Latin America, and Japan. A total of 217 patients (110 adalimumab, 107 placebo) in VISUAL-1 and 226 patients (115 adalimumab, 111 placebo) in VISUAL-2 were studied using intent-to-treat analyses. The clinical trials were conducted between August 10, 2010, and May 14, 2015.InterventionsIn VISUAL-1 and VISUAL-2, patients were randomized to receive adalimumab, 80-mg, subcutaneous loading dose followed by 40 mg every other week or placebo for 80 weeks. All patients underwent prednisone tapering, with patients in VISUAL-1 receiving an initial prednisone burst.Main outcomes and measuresThe 25-item National Eye Institute Vision Function Questionnaire (NEI VFQ-25) composite score questionnaire assessed the impact of visual impairment from the patient's perspective; scores on the questionnaire range from 0 to 100, with higher scores indicating better vision-related quality of life. The change in NEI VFQ-25 from best state achieved prior to week 6 (VISUAL-1) and from baseline state (VISUAL-2) to the final or early termination visit was determined in each group and statistically compared using analysis of variance. The temporal effects of adalimumab and placebo on NEI VFQ-25 were investigated using a longitudinal model.ResultsOf the 217 patients in VISUAL-1, 124 (57.1%) were women; the mean (SD) age was 42.7 (14.9) years. Of the 226 patients in VISUAL-2, 138 (61.1%) were women; the mean (SD) age was 42.5 (13.4). In VISUAL-1, the change from final score to best score in NEI VFQ-25 was -1.30 for adalimumab and -5.50 for placebo-a difference of 4.20 (95% CI, 1.04 to 7.36; P = .01) associated with adalimumab compared with placebo. In VISUAL-2, the change from baseline NEI VFQ-25 was 3.36 for adalimumab and 1.24 for placebo-a difference of 2.12 (95% CI, -0.81 to 5.04; P = .16). In both trials, the longitudinal models showed a significant difference in NEI VFQ-25 between adalimumab and placebo of 3.07 (95% CI, 2.09 to 4.06; P < .001) and 4.66 (95% CI, 0.05 to 9.26; P = .048) in the VISUAL-1 (74.15 vs 71.08) and VISUAL-2 (82.39 vs 77.73) trials, respectively.Conclusions and relevanceThis post hoc analysis suggests that adalimumab is associated with statistically significant and clinically meaningful improvements in patient-reported visual functioning for patients with noninfectious intermediate uveitis, posterior uveitis, and panuveitis.Trial registrationclinicaltrials.gov Identifiers: NCT01138657 (VISUAL-1) and NCT01124838 (VISUAL-2).
| S-EPMC5847080 | biostudies-literature
Project description:BackgroundLong-term, potentially lifelong therapy is needed to treat noninfectious uveitis (NIU) in children. Previous research has focused primarily on treatment approaches, but few studies have investigated the effect of children's chronic illness on other family members. The aim of this study is to explore the experiences of burden and needs in caregivers of children with NIU, and to provide a reference for formulating targeted intervention strategies.MethodsA total of 11 caregivers of children with NIU were recruited from a tertiary-level eye hospital in Wenzhou Province, China. For data collection, semi-structured interviews were conducted. Data analysis was conducted using Colaizzi's seven-step analysis method. Themes were encoded and created with NVivo 14.0 for Mac software.ResultsBased on the Social Ecosystem Theory, three major themes and ten subthemes emerged from the analysis: (1) Micro system - Caregiver distress and growth coexist (subthemes: Affected physical health, difficulties in the child's health management, emotional well-being, psychological Adjustment and Growth); (2) Mezzo system - Changes in family lifestyle (subthemes: Family financial challenges, family management dilemmas, weakened family socialization); (3) Macro system - Weak support system (subthemes: Insufficient information support, limited medical support conditions, lack of social understanding and support).ConclusionsThe social-ecological systems of caregivers for children with NIU present numerous difficulties impacting their caregiving experiences. It is imperative for healthcare providers to address the psychosocial issues faced by caregivers and to develop family-centered intervention strategies and support systems, enabling them to cope effectively and overcome challenges.
| S-EPMC11658343 | biostudies-literature
Project description:ObjectiveWe sought to describe the risk and risk factors for hypotony in a noninfectious uveitis cohort.DesignRetrospective cohort study.ParticipantsPatients with noninfectious uveitis seen between 1979 and 2007 at 4 academic ocular inflammation specialty clinics.MethodsData were collected from medical records by trained, certified, expert reviewers.Main outcome measuresHypotony (<5 mmHg) and low intraocular pressure (<8 mmHg), each sustained for ? 2 visits spanning ? 30 days.ResultsDuring follow-up, 126 of 6785 patients (1.86%) developed hypotony at the rate of 0.61% (95% confidence interval [CI], 0.50-0.75%) per eye-year. Cataract surgery was associated with a 7.5-fold risk (adjusted hazard ratio [aHR], 7.51; 95% CI, 3.97-14.23) of incident hypotony. Phacoemulsification, the type of cataract surgery associated with the least hypotony risk still was associated with nearly 5-fold higher hypotony incidence (aHR, 4.87; 95% CI, 2.25-10.55). Increased risk was observed in children (aHR, 2.92; 95% CI, 1.20-7.10) with respect to young adults, and duration of uveitis of >5 years (aHR, 3.08; 95% CI, 1.30-7.31) with respect to uveitis of <6 month duration. Band keratopathy, ? 3+ vitreous cells, exudative retinal detachment, posterior synechia, and a history of pars plana vitrectomy also were associated with greater hypotony incidence. With respect to anterior uveitis, intermediate uveitis (aHR, 0.17; 95% CI, 0.05-0.56) and posterior uveitis (aHR, 0.11; 95% CI, 0.03-0.45) were associated with lower hypotony risk, whereas panuveitis (aHR, 1.25; 95% CI, 0.67-2.35) was similar. Approximately five-sixths (84.1%) of eyes presenting with hypotony had a visual acuity of ? 20/200 (aOR for visual acuity ? 20/200, 13.85; 95% CI, 7.23-26.53). Risk factors for prevalent hypotony were similar.ConclusionsThe risk of hypotony is low among eyes with noninfectious uveitis, but is more frequently observed in cases with anterior segment inflammation. Signs of present or past inflammation were associated with greater risk, suggesting excellent inflammatory control may reduce the risk of hypotony. Prior ocular surgery also was associated with higher risk; cataract surgery in particular was associated with much higher risk of hypotony. Lower risk of hypotony with phacoemulsification than with alternative cataract surgery approaches suggests the phacoemulsification approach is preferable.
| S-EPMC3475753 | biostudies-literature
Project description:It is well known that drug responses differ among patients with regard to dose requirements, efficacy, and adverse drug reactions (ADRs). The differences in drug responses are partially explained by genetic variation. This paper highlights some examples of areas in which the different responses (dose, efficacy, and ADRs) are studied in children, including cancer (cisplatin), thrombosis (vitamin K antagonists), and asthma (long-acting ?2 agonists). For childhood cancer, the replication of data is challenging due to a high heterogeneity in study populations, which is mostly due to all the different treatment protocols. For example, the replication cohorts of the association of variants in TPMT and COMT with cisplatin-induced ototoxicity gave conflicting results, possibly as a result of this heterogeneity. For the vitamin K antagonists, the evidence of the association between variants in VKORC1 and CYP2C9 and the dose is clear. Genetic dosing models have been developed, but the implementation is held back by the impossibility of conducting a randomized controlled trial with such a small and diverse population. For the long-acting ?2 agonists, there is enough evidence for the association between variant ADRB2 Arg16 and treatment response to start clinical trials to assess clinical value and cost effectiveness of genotyping. However, further research is still needed to define the different asthma phenotypes to study associations in comparable cohorts. These examples show the challenges which are encountered in pediatric pharmacogenomic studies. They also display the importance of collaborations to obtain good quality evidence for the implementation of genetic testing in clinical practice to optimize and personalize treatment.
| S-EPMC4920853 | biostudies-other
Project description:ImportanceUveitis involves dysregulation of the ocular immune system. Stress has been shown to affect immune function, but it is unclear whether there is an association between stress and uveitis.ObjectiveTo determine whether having uveitis is associated with psychological stress.Design, setting, and participantsA cross-sectional, case-control study including a self-administered survey, medical records review, and diurnal salivary cortisol test was conducted at a university-based uveitis clinic and comprehensive eye clinic. Participants included 146 consecutive adults with noninfectious uveitis and age-matched controls with no eye disease. The study was conducted from December 1, 2017, to March 14, 2018.Main outcomes and measuresParticipants completed the self-administered, Cohen 10-item Perceived Stress Scale (PSS-10), a demographics questionnaire. Responses to each question were categorized on a 5-point Likert scale, with total scores ranging from 0 (no stress) to 40 (high stress). In addition, participants submitted 3 salivary cortisol samples. Those with uveitis were classified as having recently active or controlled disease through medical records review. The prespecified primary analysis was a linear regression of PSS-10 score and uveitis correcting for age, sex, educational level, employment, and median income. Secondary analyses included comparing PSS-10 scores in patients with recently active and controlled uveitis, determining predictors of stress, and comparing diurnal salivary cortisol between uveitis and control groups.ResultsOf 146 eligible patients, 17 declined participation and 9 consented but were excluded because they did not complete both questionnaires, resulting in 120 patients (80 uveitis; 40 controls) in the final analysis. Eighty participants (66.7%) were women, and 70 (58.3%) were white. Median age was 40 years (interquartile range, 29-59 years). Having uveitis was associated with a 4.3-point increase in PSS-10 score (95% CI, 1.8 to 6.9; P = .002). There was no significant difference in PSS-10 scores between patients with recently active and controlled uveitis (1.0 point greater for patients with active uveitis; 95% CI, -2.0 to 3.9; P = .52). Factors associated with increased PSS-10 score in patients with uveitis included female sex (coefficient, 4.0; 95% CI, 1.6 to 6.5; P = .002), current immunomodulatory therapy (coefficient, 2.5; 95% CI, -0.3 to 5.2; P = .08), history of depression (coefficient, 3.8; 95% CI, 0.8 to 6.8; P = .02), and having posterior or panuveitis (coefficient, 2.6; 95% CI, 0.8 to 4.4; P = .006). Of the 70 participants (58.3%) who had testable samples for cortisol analysis, diurnal salivary cortisol levels did not significantly differ between uveitis and nonuveitis groups.Conclusions and relevanceThese findings suggest that patients with uveitis have higher levels of psychological stress compared with controls, yet no significant difference was identified in the stress of patients with active vs controlled uveitis. Consequently, comprehensive treatment for noninfectious uveitis may be able to address the psychological results of this disease.
| S-EPMC6439831 | biostudies-literature
Project description:IntroductionNoninfectious inflammation of the posterior eye segment represents an important cause of visual impairment. It often affects relatively young people and causes a significant personal and social impact. Although steroids and nonbiologic- Disease-Modifying Antirheumatic Drugs (nbDMARDs) are effective both in acute and long- lasting diseases, however they are increasingly being replaced by biologic (DMARDs). bDMARD. This article therefore aims to identify recent advances in the therapy of noninfectious posterior segment uveitis.MethodsA Medline-search was conducted using the terms: nbDMARD, bDMARD, posterior uveitis, intermediate uveitis, treatment, corticosteroid. In addition, clinical studies were included as registered at ClinicalTrials.gov.ResultsCurrently two major lines of treatments can be identified: (1) the intraocular application of anti-inflammatory agents and (2) the introduction of new agents, e.g., (bDMARDs) and small-molecule-inhibitors. Whereas intravitreal treatments have the advantage to avoid systemic side effects, new systemic agents are progressively earning credit on the basis of their therapeutic effects.ConclusionEven when current treatment strategies are still hampered by the limited number of randomized controlled trials, promising progress and continuous efforts are seen.
| S-EPMC8172489 | biostudies-literature
Project description:PurposeAdalimumab (ADA) is a systemic biological treatment option approved for the treatment of noninfectious uveitis (NIU); however, up to 40% of patients do not respond to the drug, either in a primary or secondary manner. Here, we evaluated the proteomic profile of patients with NIU who fail to ADA to identify proteins implicated in intraocular inflammation, as well as potential biomarkers for treatment response and novel therapeutic targets.MethodsCross-sectional observational study of patients with NIU under ADA treatment for six or more months. Tears were collected with microcapillary tubes and protein analyzed by data-independent acquisition/sequential window acquisition of all theoretical mass spectra. Differentially expressed proteins (DEPs) were defined based on the fold change between their expression in nonresponders (NR) and responders (R). Protein network and gene ontology analysis were performed. The χ2 test for trend and receiver operating characteristic (ROC) curves were used to evaluate potential biomarkers of treatment response.ResultsTwenty-nine DEPs, 14 upregulated and 15 downregulated, were detected in NR. These proteins were mainly related to enhanced neutrophil effector functions and redox imbalance. ROC analysis identified defensin-1,3 (DEF-1,3), biotinidase, and ATP-binding cassette transporter A1 as potential biomarkers for treatment response.ConclusionsThis is the first study on a clinical cohort of patients with noninfectious uveitis that identifies tear proteins related to neutrophil hyperactivation as drivers of the persistent intraocular inflammation observed in NR to ADA and provides evidence that targeting interleukin 6, Janus kinases, or the complement cascade could be potential alternative therapeutic strategies in these patients. Our results indicate the potential of high-throughput proteomics to provide insights into the underlying pathological mechanisms of persistent intraocular inflammation observed in patients who do not adequately respond to anti-TNF treatment and the value of tear proteomics as a tool for personalized medicine.
| S-EPMC11572757 | biostudies-literature
Project description:OBJECTIVE:To evaluate CD4(+)Foxp3(+) (forkhead box P3) T-regulatory cell populations in patients with uveitis and to determine if T-regulatory cell populations are associated with disease features. METHODS:Patients with uveitis were evaluated for CD4(+)Foxp3(+) T-regulatory cells by flow cytometry. Systemic and ocular diagnoses, disease activity, and the presence of cystoid macular edema were reviewed. Percentages of CD4(+)Foxp3(+) lymphocytes were compared for patients with inactive vs active disease, systemic vs ocular diagnoses, and the presence or absence of cystoid macular edema. Real-time polymerase chain reaction testing was performed on 2 patients with extremely low CD4(+)Foxp3(+) cell populations to assess Foxp3 mRNA. RESULTS:A total of 20 patients with intermediate uveitis, posterior uveitis, and panuveitis were evaluated. The mean age was 40.6 years and the mean visual acuity was 20/57. Percentages of CD4(+)Foxp3(+) cells were lower in patients with active compared with inactive uveitis (P< .05). No differences in T-regulatory cells were observed between the other subgroups. Two patients with recalcitrant uveitis who demonstrated less than 1% CD4(+)Foxp3(+) lymphocytes showed extremely low or absent Foxp3 mRNA. CONCLUSION:T-regulatory cells are reduced in patients with active compared with inactive disease. Severe depletion of CD4(+)Foxp3(+) T cells and Foxp3 mRNA in 2 patients with severe uveitis suggests that loss of the T-regulatory cells of uveitis may be a salient feature in certain patients.
| S-EPMC2928652 | biostudies-literature