First Year Of Treatment Research Articles

#2242 mTORi: edging closer to targeted therapy in tuberous sclerosis complex

Abstract Background and Aims Tuberous sclerosis complex (TSC) is an autosomal dominant condition with an estimated incidence of 1 in 6000 births. TSC is caused mostly by mutations in either TSC1 or TSC2 genes, with 70–80% of cases resulting from sporadic mutations; however in 10-15% of cases no mutations are identified. A dysregulation of these genes that encode the hamartin and tuberin proteins, respectively, results in an aberrant signaling of the mammalian target of the rapamycin (mTOR) pathway and subsequent tumor growth. Indeed, the clinical features of TSC are characterized by the proliferation of different types of hamartomas in various organs, including brain, heart, skin, lungs, eyes, bone, kidneys and less frequently pancreas. TSC is mainly diagnosed clinically according to diagnostic criteria with genetic testing performed in cases of diagnostic uncertainty or/and to support the clinic diagnosis. Renal angiomyolipomas (AMLs), observed in more than 80% of patients with TSC, are benign, mostly bilateral tumors, composed of immature smooth muscle cells, abnormal blood vessels and fat cells in variable portions. Their size and the prevalence of their vascular component are directly associated with risk of acute bleeding that in 25% of cases may require embolization or nephrectomy. As a consequence, renal complications are the leading cause of death in adult TSC patients and AML-related surgery is performed in a high percentage of these patients. In the last decade, mTOR inhibitor (mTOR-i) therapy has demonstrated to be a potential alternative to embolization and nephrectomy for managing TSC-AML. The aim of this study was to evaluate over time, potential changes in the relative tissue composition of renal AMLs and their overall size following the initiation of mTOR-i therapy based on MRI measurements. Method From August 2011 to May 2023, 86 potentially eligible adult TSC patients with AML, across a great part of Italy were referred for assessment and monitoring at our center. 14 of these patients were eligible for mTOR-i therapy. An ethics committee approved its use as a compassionate therapy as mTOR-is are not approved as a conventional therapy for renal AMLs in Italy. These patients underwent baseline renal magnetic resonance imaging (MRI) assessment and a regular follow-up with MRI scan every 6-9 months after initiation of therapy. Dose titration was guided by trough levels, side effects and lesion radiological responsiveness on MRI. Results No AML bleeding events were documented during the study. None of the 14 patients on treatment discontinued therapy. Overall, 5 of them (35.7%) required dose adjustments during the course of treatment due to adverse events (40%), sub-optimal trough levels (40%) or minimal radiological response (20%). Radiologic assessment with MRI confirmed a halted growth trend in all treatment-naive cases (100%) and in 64% of them, a regression in AML volume and a reduction of their vascular component within the first year of treatment. Conclusion Our experience confirmed results that emerged from different clinical studies evaluating mTOR inhibition in TSC patients conducted in the last decade. For renal angiomyolipoma, mTOR-i treatment, carefully monitored, fundamentally changed the approach from preventive embolization or even partial nephrectomy to pharmacological treatment; drastically limiting the number of urgent interventional procedures that TSC patients often might undergo. In conclusion, mTOR-i therapy represents a valid and important therapeutic strategy to arrest the growth or regress of renal AMLs.

#1346 Inpatient and outpatient service review of a Greek reference centre for glomerular diseases

Abstract Background and Aims The glomerulonephritis (GN) is a rare and complicated disease with high demand of hospital resources while the chronic kidney disease and end-stage renal disease present increased prevalence in these patients. Method We retrospectively assessed the inpatient and outpatient service of a Greek reference centre for glomerular diseases during the pre-Covid-19 period 2018-2020. Results 267 patients (38% female, median age 65 ± 23 years) included. All patients underwent a kidney biopsy by the nephrologist without complications. ANCA associated GN (18%), Focal Segmental Glomerulosclerosis/Minimal Change Disease (17.5%), IgA nephropathy (17%), Membranous Nephropathy (12.6%), Lupus Nephritis (5%), Membranoproliferative GN (3%), Fibrillary GN (3%), Monoclonal Gammopathy of Renal Significance (3.3%) and IgG4-related disease (2%.) are encompassed. We reported median 75 new patients per year. Regarding the inpatient service, we observed an increasing trend to the hospitalizations during this period (274, 452, 461 hospitalizations in 2018, 2019, 2020 respectively). The AAGN was the most common disease of hospitalizations through this period (53% in 2018, 33% in 2019, 39% in 2020), whereas the second most common was the FSGS/MCD (28% in 2018, 13% in 2019, 23.8% in 2020). The outpatient's service review also revealed an increasing number of visits per person per year (279, 456 and 464 total visits in 2018, 2019 and 2020 respectively). The disease with the highest number of visits per person was reported the AAV (median 3.25 visits per patient per year). All the patients were managed in adherence to the latest guidelines for GN in collaboration with a multidisciplinary team, consisting of nephrologist, rheumatologist, cardiologist, and pathologist. Finally, we reported complete response at 76% of the patients and in terms of renal improvement, 46% presented eGFR≥60 ml/min/1.73 m2, 45% eGFR<60 ml/min/1.73 m2 and only 9% progressed to ESRD after the first year of treatment. Conclusion Patients with GN present an increased need for hospitalization and regular outpatient visits. Addressing these diseases necessitates the expertise of a multidisciplinary team to provide comprehensive care that maximizes the potential for sustained positive long-term outcomes.

Burden of Disease Study of Patients with Diabetic Macular Oedema in Spain.

Diabetic macular oedema (DMO) is a complication of diabetic retinopathy that can result in vision loss. The disease can impact different spheres of a patient's life, including physical and psychological health, work, and activities of daily living, entailing an important use of healthcare and non-healthcare resources. This study aimed to estimate the socio-economic burden of DMO in Spain. The burden of DMO was estimated from a societal perspective, per patient, year of treatment since diagnosis, and type of treatment. Four categories were considered: direct healthcare costs (DHC), direct non-healthcare costs (DNHC), labour productivity losses (LPL), and intangible costs (IC) associated with loss of quality of life. Average annual costs were calculated by multiplying the resources used per patient by their corresponding unit price (or financial proxy). For a more accurate estimation, differences in resource use between treatments (intravitreal anti-vascular endothelial growth factor injections of ranibizumab or aflibercept, and intravitreal dexamethasone implants) and year since diagnosis (first, second, and third year or beyond) were considered and presented separately. The reference year for costs was 2021. The average annual costs of DMO in the first year of treatment after diagnosis was estimated at €18,774, €17,512, and €16,188 per patient treated with ranibizumab, aflibercept, and dexamethasone, respectively. This burden would be reduced to €15,783, €15,701, and €12,233 in the second year, and to €15,119, €15,043, and €12,790 in the third year, respectively. Diagnosis of DMO entails an additional one-off cost of €485. DHC accounted for the greatest proportion of total annual costs per patient, independent of the year, with LPL also making an important contribution to total costs. The socio-economic impact of DMO on patients, the healthcare system, and society at large is substantial. The constant increase in its prevalence accentuates the need for planning and implementation of healthcare strategies to prevent vision loss and reduce the socio-economic burden of the disease.

Association Between Statin Use and the Incidence of Clinically Diagnosed Osteoarthritis: A Nationwide Retrospective Cohort Study in Taiwan.

To investigate the effect of higher cumulative defined daily dose per year (cDDD/y) compared with lower cDDD/y of statin use in the incidence of any joint osteoarthritis (OA). In this population-based retrospective cohort study, patients who were aged ≥40 years were newly initiated on statin therapy between 2002 and 2011, and had a statin prescription for ≥90 days in the first year of treatment were identified from the 2000 Longitudinal Generation Tracking Database. All patients were separated into groups with higher cDDD/y (>120 cDDD/y) and lower cDDD/y (≤120 cDDD/y; as an active comparator) values. Propensity score matching was performed to balance potential confounders. All recruited patients were followed up for 8 years. Marginal Cox proportional hazard models were used to estimate time-to-event outcomes of OA. Compared with lower cDDD/y use, higher cDDD/y use did not reduce the risk of any joint OA (adjusted hazard ratio, 1.07; 95% confidence interval, 0.99-1.14). Dose-related analysis did not reveal any dose-dependent association. A series of sensitivity analyses showed similar results. Joint-specific analyses revealed that statin did not reduce the incidence of knee, hand, hip, and weight-bearing (knee or hip) OA. Higher cDDD/y statin use did not reduce the risk of OA in this Taiwanese nationwide cohort study. The complexity of OA pathogenesis might contribute to the ineffectiveness of statin. Repurposing statin with its anti-inflammation properties might be ineffective for OA development, and balancing the catabolism and anabolism of cartilage might be a major strategy for OA prevention.

Preexisting Diabetes and Breast Cancer Treatment Among Low-Income Women

Diabetes is associated with poorer prognosis of patients with breast cancer. The association between diabetes and adjuvant therapies for breast cancer remains uncertain. To comprehensively examine the associations of preexisting diabetes with radiotherapy, chemotherapy, and endocrine therapy in low-income women with breast cancer. This population-based cohort study included women younger than 65 years diagnosed with nonmetastatic breast cancer from 2007 through 2015, followed up through 2016, continuously enrolled in Medicaid, and identified from the linked Missouri Cancer Registry and Medicaid claims data set. Data were analyzed from January 2022 to October 2023. Preexisting diabetes. Logistic regression was used to estimate odds ratios (ORs) of utilization (yes/no), timely initiation (≤90 days postsurgery), and completion of radiotherapy and chemotherapy, as well as adherence (medication possession ratio ≥80%) and persistence (<90-consecutive day gap) of endocrine therapy in the first year of treatment for women with diabetes compared with women without diabetes. Analyses were adjusted for sociodemographic and tumor factors. Among 3704 women undergoing definitive surgery, the mean (SD) age was 51.4 (8.6) years, 1038 (28.1%) were non-Hispanic Black, 2598 (70.1%) were non-Hispanic White, 765 (20.7%) had a diabetes history, 2369 (64.0%) received radiotherapy, 2237 (60.4%) had chemotherapy, and 2505 (67.6%) took endocrine therapy. Compared with women without diabetes, women with diabetes were less likely to utilize radiotherapy (OR, 0.67; 95% CI, 0.53-0.86), receive chemotherapy (OR, 0.67; 95% CI, 0.48-0.93), complete chemotherapy (OR, 0.71; 95% CI, 0.50-0.99), and be adherent to endocrine therapy (OR, 0.71; 95% CI, 0.56-0.91). There were no significant associations of diabetes with utilization (OR, 0.95; 95% CI, 0.71-1.28) and persistence (OR, 1.09; 95% CI, 0.88-1.36) of endocrine therapy, timely initiation of radiotherapy (OR, 1.09; 95% CI, 0.86-1.38) and chemotherapy (OR, 1.09; 95% CI, 0.77-1.55), or completion of radiotherapy (OR, 1.25; 95% CI, 0.91-1.71). In this cohort study, preexisting diabetes was associated with subpar adjuvant therapies for breast cancer among low-income women. Improving diabetes management during cancer treatment is particularly important for low-income women with breast cancer who may have been disproportionately affected by diabetes and are likely to experience disparities in cancer treatment and outcomes.

Abstract PO3-19-05: Phase III study to evaluate the efficacy and safety of GLSI-100 (GP2 + GM-CSF) in breast cancer patients with residual disease or high-risk PCR after both neo-adjuvant and postoperative adjuvant anti-HER2 therapy, Flamingo-01

Abstract Background: GP2 is a biologic nine amino acid peptide of the HER2/neu protein delivered in combination with Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) that stimulates an immune response targeting HER2/neu expressing cancers, the combination known as GLSI-100. In a prospective, randomized, single-blinded, placebo-controlled, multicenter Phase IIb study, no recurrences were observed in the HER2+ population after 5 years of follow-up, if the patient was treated with GLSI-100, survived, and was followed for more than 6 months (p = 0.0338). Immunotherapy elicited a potent response measured by skin tests and immunological assays. Of the 146 patients that have been treated with GLSI-100 over 4 clinical trials, GLSI-100 was well-tolerated and no serious adverse events observed were considered related to the immunotherapy. Methods: This Phase III trial is a prospective, randomized, double-blinded, multi-center study. After 1 year of trastuzumab-based therapy, 6 intradermal injections of GLSI-100 or placebo will be administered over the first 6 months and 5 subsequent boosters will be administered over the next 2.5 years for a total of 11 injections over 3 years. The participant duration of the trial will be 3 years treatment plus 1 additional year follow-up for a total of 4 years following the first year of treatment with trastuzumab-based therapy. Patients will be stratified based on residual disease status at surgery, hormone receptor status and region. Study Size – Interim Analysis: Approximately 498 patients will be enrolled. To detect a hazard ratio of 0.3 in invasive breast cancer free survival (IBCFS), 28 events will be required. An interim analysis for superiority and futility will be conducted when at least 14 events have occurred. This sample size provides 80% power if the annual rate of events in placebo patients is 2.4% or greater. Up to 100 non-HLA-A*02 subjects will be enrolled in an open-label arm. Eligibility Criteria: The patient population is defined by these key eligibility criteria: Objectives: Study Status: The study has been initiated at a number of sites in the US. The study is also expected to be opened in Spain, Germany, and France. Contact Information: Greenwich LifeSciences, Inc. Stafford, TX Email: Flamingo-01@greenwichlifesciences.com Website: greenwichlifesciences.com Funding: This trial is supported by Greenwich LifeSciences. Citation Format: Snehal Patel, Jaye Thompson, Mira Patel, F. Joseph Daugherty, Mothaffar Rimawi. Phase III study to evaluate the efficacy and safety of GLSI-100 (GP2 + GM-CSF) in breast cancer patients with residual disease or high-risk PCR after both neo-adjuvant and postoperative adjuvant anti-HER2 therapy, Flamingo-01 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-19-05.

Prevalence, incidence, and treatment patterns of fistulizing Crohn disease: A US population-based cohort study.

Population-based studies for patients with fistulizing Crohn disease (CD), a severe complication of CD, are limited. To report estimates of the prevalence and incidence rates of fistulizing CD in the United States and examine associated treatment patterns among incident cases. This retrospective, observational cohort study used a US administrative claims database from January 1, 2016, to December 31, 2019, with at least 365 days' continuous insurance enrollment. The prevalent patient population comprised patients with incident or existing cases of fistulizing CD. Crude, age, and sex-adjusted prevalence and incidence rates of fistulizing CD were estimated. Baseline characteristics, comorbidities, and CD-related medications and medical procedures were examined for patients with fistulizing CD. The overall crude prevalence (prevalent cases: n = 5,082) and incidence rates (incident cases: n = 2,399) between 2017 and 2019 were 25.2 (95% CI = 24.5-25.9) per 100,000 persons and 6.9 (95% CI = 6.6-7.1) per 100,000 person-years, respectively. Age- and sex-adjusted prevalence and incidence rates were 24.9 (95% CI = 24.2-25.6) per 100,000 persons and 7.0 (95% CI = 6.7-7.3) per 100,000 person-years, respectively. Approximately half of all patients with incident fistulizing CD were prescribed biologic therapies within 1 year of an incident fistula diagnosis, with anti-tumor necrosis factor therapies the most widely prescribed biologic class; antibiotic and corticosteroid use was also common. Among the incident cases, approximately one-third of patients required surgery during the follow-up period, most of which occurred within 3 months of the index date. This study reports age- and sex-adjusted prevalence and incidence rates for fistulizing CD of 24.9 per 100,000 persons and 7.0 per 100,000 person-years, respectively. As a concerning complication of CD, first-year treatment of fistulas in the United States commonly includes anti-tumor necrosis factor therapy, and there is a considerable surgical burden.

First-year Treatment Intensity and Prognosis in Early Parkinson’s Disease: A Retrospective, Longitudinal Study in Israel

First-year Treatment Intensity and Prognosis in Early Parkinson’s Disease: A Retrospective, Longitudinal Study in Israel

Potential for Optimization of Growth Hormone Treatment in Children with Growth Hormone Deficiency, Small for Gestational Age, and Turner Syndrome in Germany: Data from the PATRO® Children Study

Introduction: Growth hormone (GH) treatment in children with growth hormone deficiency (GHD), short children born small for gestational age (SGA), and Turner syndrome (TS) is well established. However, a variety of parameters are still under discussion to achieve optimal growth results and efficiency of GH use in real-world treatment. Methods: German GH-treatment naïve patients of the PATRO Children database were grouped according to their start of treatment into groups of 3 years from 2007 to 2018. Time trends in age, gender, GH dose, height standard deviation score (SDS), first-year growth response, and Index of Responsiveness (IoR) were investigated in children with GHD, short children born SGA, and TS starting GH treatment in the German patient population of the PATRO Children database from 2007 to 2018 to determine specific parameters for GH treatment optimization. Results: All patient groups started GH treatment at a relatively high chronological age (2007–2009: GHD 8.33 ± 3.19, SGA 7.32 ± 2.52, TS 8.65 ± 4.39) with a slight but not significant trend towards younger therapy start up to 2016–2018 (GHD 8.04 ± 3.36, SGA 6.67 ± 2.65, TS 7.85 ± 3.38). In the GHD and SGA groups, female patients were underrepresented compared to male patients (GHD 32.3%, SGA 43.6%) with no significant change over the 4 time periods. Patients with GHD started GH treatment at a low dose (0.026 mg/kg/day). In SGA and TS patients, GH therapy was started below the registered dose recommendation (30.0 μg/kg/day and 33.7 μg/kg/day, respectively). In the first year of treatment, the mean GH dose was increased moderately (GHD: 30.7, SGA: 35.7, TS: 40.8 μg/kg/day). There was no significant change of GH dosing over time from 2007 to 2018. The IoR was comparable between time-groups for all 3 diagnoses. Discussion: This study shows potential for improvement of GH treatment results in GHD, SGA, and TS patients in terms of early dose adjustment and younger age at the start of treatment. This is in accordance with important parameters used in prediction models.

Photocoagulation or sham laser in addition to conventional anti-VEGF therapy in macular edema associated with TelCaps due to diabetic macular edema or retinal vein occlusion (TalaDME): a study protocol for a multicentric, French, two-group, non-commercial, active-control, observer-masked, non-inferiority, randomized controlled clinical trial

BackgroundMacular edema (ME) results from hyperpermeability of retinal vessels, leading to chronic extravasation of plasma components into the retina and hence potentially severe visual acuity loss. Current standard of care consists in using intravitreal injections (IVI), which results in a significant medical and economic burden. During diabetic retinopathy (DR) or retinal vein occlusion (RVO), it has recently been shown that focal vascular anomalies (capillary macro-aneurysms, also termed TelCaps) for telangiectatic capillaries may play a central role in the onset, early recurrence, and/or persistence of ME. Since targeted photocoagulation of TelCaps may improve vision, identification, and photocoagulation of TelCaps, it may represent a way to improve management of ME.ObjectiveThe Targeted Laser in (Diabetic) Macular Edema (TalaDME) study aims to evaluate whether ICG-guided targeted laser (IGTL), in association with standard of care by IVI, allows reducing the number of injections during the first year of treatment compared with IVI only, while remaining non-inferior for visual acuity.MethodsTalaDME is a French, multicentric, two-arms, randomized, sham laser-controlled, double-masked trial evaluating the effect of photocoagulation of TelCaps combined to IVI in patients with ME associated with TelCaps. Patients with vision loss related to center involved ME secondary to RVO or DR and presenting TelCaps are eligible. Two hundred and seventy eyes of 270 patients are randomized in a 1:1 ratio to standard care, i.e., IVI of anti-VEGF solely (control group) or combined with IGTL therapy (experimental group). Stratification is done on the cause of ME (i.e., RVO versus diabetes). Anti-VEGF IVI are administered to both groups monthly for 3 months (loading dose) and then with a pro re nata regimen with a monthly follow-up for 12 months. The primary endpoint will be the number of IVI and the change in visual acuity from baseline to 12 months. Secondary endpoints will be the changes in central macular thickness, impact on quality of life, cost of treatment, and incremental cost-utility ratio in each groups.Key safetyRare but severe AE linked to the use of IVI and laser, and previously described, are expected. In the sham group, rescue laser photocoagulation may be administered by the unmasked investigator if deemed necessary at month 3.DiscussionThe best management of ME associated with TelCaps is debated, and there have been no randomized study designed to answer this question. Given the fact that TelCaps may affect 30 to 60% of patients with chronic ME due to DR or RVO, a large number of patients could benefit from a specific management of TelCaps. TalaDME aims to establish the clinical and medico-economic benefits of additional targeted laser. The results of TalaDME may raise new recommendations for managing ME and impact healthcare costs.Trial registrationEudraCT: 2018-A00800-55/ NCT03751501. Registration date: Nov. 23, 2018.

Prevalence of Adverse Drug Reactions in HIV/AIDS Patients on Highly Active Anti-Retroviral Therapy in Bushenyi Medical Centre, Ishaka Adventist Hospital, and Kampala International University Teaching Hospital in Bushenyi District, Western Uganda

The World Health Organization (WHO) delineates an Adverse Drug Reaction (ADR) as an unintended and harmful response to a drug when it is used for disease prevention, diagnosis, treatment, or physiological function modification in humans. This definition specifically excludes therapeutic failures, overdose, drug abuse, noncompliance, and medication errors. The objective of this study is to determine the prevalence of ADRs among HIV/AIDS patients undergoing Highly Active Antiretroviral Therapy (HAART) at Bushenyi Medical Centre, Ishaka-Adventist Hospital, and KIU Teaching Hospital in the Bushenyi district, western Uganda. Patient interviews were conducted using structured questionnaires. A cohort of 333 patients participated in the study. The investigation revealed a prevalence of ADRs at 13.5% (95% CI: 10.2-17.6). Among the 333 patients interviewed, 44 reported experiencing ADRs, with a significant 97.8% of these cases occurring in female patients. Importantly, individuals with co-morbidities had a 55.6-fold higher likelihood of developing ADRs compared to those without any co-morbid conditions (95% CI: 2.4-1286.7). Furthermore, the study indicated an increased risk of ADR development among patients starting HAART within the first year of treatment. In summary, our findings highlight the notable prevalence of ADRs among females, emphasizing the need for gender-specific initiatives to raise awareness and prevent ADRs. Regular monitoring is particularly important for patients with co-morbidities due to the established association between co-medication and susceptibility to ADRs. Additionally, adherence to HAART therapy is essential, as the incidence of ADRs tends to decrease over time. Keywords: Adverse drug reaction (ADR), HIV/AIDS, Co-morbidities, Anti-Retroviral Therapy, Uganda

The Depth of the Molecular Response in Patients with Chronic Myeloid Leukemia Correlates with Changes in Humoral Immunity.

Background and Objectives: The effective treatment of chronic myeloid leukemia leads to the restoration of proper immune system function. We aimed to investigate fluctuations in circulating cytokines, angiogenic factors and complement components in patients with CML during the first year of treatment with TKI and correlate them with the degree of achieved molecular response. Material and Methods: We recruited 31 patients with newly diagnosed CML. Peripheral blood and bone marrow samples were obtained, and concentrations of serum proteins were measured using an immunology multiplex assay. Results: The study cohort was divided into two groups of optimal or non-optimal in accordance with the European Leukemia Net (ELN) guidelines. We found significantly higher concentrations of C1q, C4 and C5a in serum after 3 months of TKI treatment in patients who achieved optimal responses in the 6 months after diagnosis. The most alterations were observed during 12 months of therapy. Patients in the optimal response group were characterized by higher serum concentrations of TGF-β, EGF, VEGF, Angiopoietin 1, IFN-γ and IL-8. Conclusions: The later plasma concentrations of complement components were significantly increased in patients with optimal responses. The changes after 12 months of treatment were particularly significant. Similar changes in bone marrow samples were observed.

Mechanisms and management of loss of response to anti-TNF therapy for patients with Crohn's disease: 3-year data from the prospective, multicentre PANTS cohort study

We sought to report the effectiveness of infliximab and adalimumab over the first 3 years of treatment and to define the factors that predict anti-TNF treatment failure and the strategies that prevent or mitigate loss of response. Personalised Anti-TNF therapy in Crohn's disease (PANTS) is a UK-wide, multicentre, prospective observational cohort study reporting the rates of effectiveness of infliximab and adalimumab in anti-TNF-naive patients with active luminal Crohn's disease aged 6 years and older. At the end of the first year, sites were invited to enrol participants still receiving study drug into the 2-year PANTS-extension study. We estimated rates of remission across the whole cohort at the end of years 1, 2, and 3 of the study using a modified survival technique with permutation testing. Multivariable regression and survival analyses were used to identify factors associated with loss of response in patients who had initially responded to anti-TNF therapy and with immunogenicity. Loss of response was defined in patients who initially responded to anti-TNF therapy at the end of induction and who subsequently developed symptomatic activity that warranted an escalation of steroid, immunomodulatory, or anti-TNF therapy, resectional surgery, or exit from study due to treatment failure. This study was registered with ClinicalTrials.gov, NCT03088449, and is now complete. Between March 19, 2014, and Sept 21, 2017, 389 (41%) of 955 patients treated with infliximab and 209 (32%) of 655 treated with adalimumab in the PANTS study entered the PANTS-extension study (median age 32·5 years [IQR 22·1-46·8], 307 [51%] of 598 were female, and 291 [49%] were male). The estimated proportion of patients in remission at the end of years 1, 2, and 3 were, for infliximab 40·2% (95% CI 36·7-43·7), 34·4% (29·9-39·0), and 34·7% (29·8-39·5), and for adalimumab 35·9% (95% CI 31·2-40·5), 32·9% (26·8-39·2), and 28·9% (21·9-36·3), respectively. Optimal drug concentrations at week 14 to predict remission at any later timepoints were 6·1-10·0 mg/L for infliximab and 10·1-12·0 mg/L for adalimumab. After excluding patients who had primary non-response, the estimated proportions of patients who had loss of response by years 1, 2, and 3 were, for infliximab 34·4% (95% CI 30·4-38·2), 54·5% (49·4-59·0), and 60·0% (54·1-65·2), and for adalimumab 32·1% (26·7-37·1), 47·2% (40·2-53·4), and 68·4% (50·9-79·7), respectively. In multivariable analysis, loss of response at year 2 and 3 for patients treated with infliximab and adalimumab was predicted by low anti-TNF drug concentrations at week 14 (infliximab: hazard ratio [HR] for each ten-fold increase in drug concentration 0·45 [95% CI 0·30-0·67], adalimumab: 0·39 [0·22-0·70]). For patients treated with infliximab, loss of response was also associated with female sex (vs male sex; HR 1·47 [95% CI 1·11-1·95]), obesity (vs not obese 1·62 [1·08-2·42]), baseline white cell count (1·06 [1·02-1·11) per 1 × 109 increase in cells per L), and thiopurine dose quartile. Among patients treated with adalimumab, carriage of the HLA-DQA1*05 risk variant was associated with loss of response (HR 1·95 [95% CI 1·17-3·25]). By the end of year 3, the estimated proportion of patients who developed anti-drug antibodies associated with undetectable drug concentrations was 44·0% (95% CI 38·1-49·4) among patients treated with infliximab and 20·3% (13·8-26·2) among those treated with adalimumab. The development of anti-drug antibodies associated with undetectable drug concentrations was significantly associated with treatment without concomitant immunomodulator use for both groups (HR for immunomodulator use: infliximab 0·40 [95% CI 0·31-0·52], adalimumab 0·42 [95% CI 0·24-0·75]), and with carriage of HLA-DQA1*05 risk variant for infliximab (HR for carriage of risk variant: infliximab 1·46 [1·13-1·88]) but not for adalimumab (HR 1·60 [0·92-2·77]). Concomitant use of an immunomodulator before or on the day of starting infliximab was associated with increased time without the development of anti-drug antibodies associated with undetectable drug concentrations compared with use of infliximab alone (HR 2·87 [95% CI 2·20-3·74]) or introduction of an immunomodulator after anti-TNF initiation (1·70 [1·11-2·59]). In years 2 and 3, 16 (4%) of 389 patients treated with infliximab and 11 (5%) of 209 treated with adalimumab had adverse events leading to treatment withdrawal. Nine (2%) patients treated with infliximab and two (1%) of those treated with adalimumab had serious infections in years 2 and 3. Only around a third of patients with active luminal Crohn's disease treated with an anti-TNF drug were in remission at the end of 3 years of treatment. Low drug concentrations at the end of the induction period predict loss of response by year 3 of treatment, suggesting higher drug concentrations during the first year of treatment, particularly during induction, might lead to better long-term outcomes. Anti-drug antibodies associated with undetectable drug concentrations of infliximab, but not adalimumab, can be predicted by carriage of HLA-DQA1*05 and mitigated by concomitant immunomodulator use for both drugs. Guts UK, Crohn's and Colitis UK, Cure Crohn's Colitis, AbbVie, Merck Sharp and Dohme, Napp Pharmaceuticals, Pfizer, and Celltrion Healthcare.

Analysis of prognostic and predictive factors in neovascular age-related macular degeneration Kuopio cohort.

The aim of the study was to explore factors affecting the progression of neovascular age-related macular degeneration (nAMD) and identify predictive factors that can estimate the duration of intravitreal treatments. This retrospective real-world study included 421 nAMD patients treated at the Kuopio University Hospital during years 2007-2021. The collected data included background demographics, treatment history, visual acuity and retinal biomarker analysis. Impact of baseline factors on age at diagnosis, treatment duration, received treatment intensity and visual acuity gains were analysed. Heavy smoking and high body mass index (BMI) were associated with an earlier onset, while the use of anticoagulation and anti-aggregation medication were associated with a later onset of nAMD. A low number of injections during the first year of treatment and the presence of intraretinal fluid (IRF) at baseline were associated with shorter treatment duration. Interestingly, when IRF only patients were compared to subretinal fluid (SRF) only patients, IRF patients showed higher occurrences of subretinal drusenoid deposits (43.5% vs. 15%, p = 0.04). In addition, when all patients with IRF were compared to SRF only patients, more hyperreflective foci (HRF) and complete RPE and outer retinal atrophy (cRORA; 20.7% vs. 5%, p = 0.02) were observed in patients with IRF. Our results reveal that heavy smoking and high BMI are accelerating factors for earlier emergence of nAMD, while the presence of IRF results in a fast-progressing disease. More intriguingly, the link between IRF and appearance of subretinal drusenoid deposits, HRF, and increased retinal atrophy was observed.

Effects of Froggy Mouth Appliance in Pediatric Patients with Atypical Swallowing: A Prospective Study.

Atypical swallowing has a high incidence in growing subjects. Orthopedic treatment with orthodontic appliances and speech therapy are the main approaches to this problem. The aim of this prospective study was to evaluate the changes in the dental arches induced by one year of treatment with the Froggy Mouth myofunctional appliance designed to correct atypical swallowing. In total, 16 patients with atypical swallowing were instructed to use the Froggy Mouth appliance. A digital intraoral impression was taken at baseline (T0). The Froggy Mouth appliance had to be used for 15 min/day throughout the treatment period. At the end of the first year of treatment (T1), another impression was taken with the same intraoral scanner. Digital casts of the T0 and T1 impressions were obtained using software and the two casts were superimposed to record the following measurements: upper intercanine distance, upper arch diameter, upper arch width, overbite and overjet. The data were statistically analyzed (significance threshold: p < 0.05). Student's t-test was used to compare pre- and post-treatment measurements. Linear regressions were performed to assess the influence of arch width on anterior and posterior diameters. A significant increase was found for the upper arch diameters (p < 0.05), whereas no statistically significant difference was found for the incisor relationship (overjet/overbite) (p > 0.05). To date, the efficacy of this appliance has not been extensively studied. According to the present prospective study, the Froggy Mouth protocol could be a valuable method as a myofunctional therapy for atypical swallowing, but further studies are needed to confirm these preliminary results.

Predictors and long-term patterns of medication adherence to glaucoma treatment in Denmark—an observational registry study of 30 100 Danish patients with glaucoma

BackgroundSelf-treatment with glaucoma medication (eye drops) has been associated with adherence challenges. Poor adherence results in worse outcomes in terms of visual field loss.ObjectiveTo investigate patterns in medication adherence among...

Comparing The Effectiveness Of Mentalization-Based Therapy And Dialectical Behavior Therapy In An Adult Population With Cluster B Personality Disorders To Reduce Hospital Service Use

IntroductionMentalization-based therapy (MBT) and dialectical behavior therapy (DBT) are two treatments known to be effective for borderline personality disorder (BPD). However, head-to-head comparisons between those two treatments are scarce and their effectiveness in naturalistic clinical services, where BPD is often comorbid with other cluster B personality disorders (PD), needs to be further explored.ObjectivesThe study’s goal was to answer the following question: Is there a difference in emergency department visits, hospitalizations and dropout rates after one year of treatment in MBT compared to DBT for a clinical adult population with cluster B PD?MethodsWe compared the effectiveness of MBT and DBT in 288 patients between 2015 and 2019 with at least one cluster B PD by measuring their emergency services use and hospitalizations one year before and one year after beginning therapy. Drop-out rates for those two treatment modalities are also compared. Image 1 illustrates the patient distribution for the study.ResultsIn terms of reducing emergency room use, patients in each treatment group experienced a significant decrease with medium effect sizes (p &lt; .001 for both, d=.768 for MBT and d=.640 for DBT).In terms of reducing hospitalizations, the MBT group had a significant decrease (p &lt; .05) with a medium effect size (d=.568) whereas the DBT group had a non-significant decrease (p = .595) with a negligible effect size (d=.140).When we compare both therapies, no significant differences were found between them in terms of reductions in emergency room use (p = .358) and hospitalizations (p =.195), as well as dropout rates (p = .743). Image 2 further illustrates the dropout trends in the first year of treatment for both groups in intervals of 3 months.Hospitalizations were rare in our population, which may hinder the validity of results containing this variable. In absolute numbers, total emergency room visits decreased from 119 to 37, whereas hospitalizations were reduced from 24 to 12. Drop-out rates before entering treatment were high (20.6%), as it was during treatment for both therapies (around 30% in the first year of treatment).Image:Image 2:ConclusionsThis study emphasizes that both DBT and MBT are linked to a reduction in service use over time. Dropout rates in both treatments are also similar to other studies. Therefore, future research should investigate the factors that can help clinicians guide individuals with PDs towards the type of therapy that is most suitable for them.Disclosure of InterestNone Declared

Anti-VEGF Treatment for Secondary Neovascularization in Pseudoxanthoma Elasticum - Age of Onset, Treatment Frequency, and Visual Outcome

PurposeTo assess the onset, treatment frequency, and visual outcome of anti-vascular endothelial growth factor (anti-VEGF) treatment due to secondary choroidal neovascularization (CNV) in patients with pseudoxanthoma elasticum (PXE). DesignRetrospective cohort study MethodsOne-hundred six eyes of 53 patients with PXE were analyzed. The assessment of CNV activity relied on hemorrhage visible on funduscopy and intra- / subretinal fluid on optical coherence tomography (OCT), individually defining a shortening or extension of treatment interval. Best-corrected visual acuity (BCVA) at baseline, age at anti-VEGF therapy initiation, and BCVA-drop events at exudation onset (worsening of BCVA of 2 or more lines) were documented. Further, we assessed the number of injections during the first year and the total number of injections, the time to treatment initiation of the fellow eye, and BCVA over time. ResultsDuring a median observation period of 77 months (IQR 49; 126) patients received a median number of 28.0 anti VEGF-injections (IQR 9.8; 43.5). Eight patients received no injection (median age at baseline 38.1 years), 11 patients underwent anti-VEGF treatment in one eye (median age 47.2 years) and 34 patients in both eyes (median age 51.8 years). The median age at the first anti-VEGF treatment was 52.80 years (IQR 47.2 – 57.6). Applying Cox regression models, the median 'survival' time of fellow eye until treatment initiation was 16.8 months. In the group of bilateral treated patients, the median time difference was 9.6 months (IQR 2.1 – 32.4, range 0 – 122) The median number of injections was 5.5 per eye in the first year of treatment (IQR 3 – 7) and was associated with the total number of injections in the observation period (2.33, CI 1.22 – 3.44, p<0.001). A better BCVA at the last follow-up visit was associated with a better baseline BCVA (p<0.001, R2=0.318) and with the absence of a BCVA drop at the onset of exudation (p=0.035, R2=0.339). ConclusionsThe results of this study indicate that anti-VEGF treatment is required for most PXE patients at a relatively young age. Once treatment in one eye is initiated, the time to fellow eye treatment is relatively short. A BCVA drop before treatment initiation is a risk factor for worse visual outcomes, suggesting that treatment is prudent before exudation affects the central retina. Given the young age of onset and intensive treatment needs, patients with PXE might particularly benefit from longer-acting anti-VEGF therapeutics.

Gluten-Free Diet Induces Rapid Changes in Phenotype and Survival Properties of Gluten-Specific T Cells in Celiac Disease

Background and AimsThe treatment of celiac disease (CeD) with gluten-free diet (GFD) normalizes gut inflammation and disease-specific antibodies. CeD patients have HLA-restricted, gluten-specific T cells persisting in the blood and gut even after decades of GFD, which are re-activated and disease driving upon gluten exposure. Our aim was to examine the transition of activated gluten-specific T cells into a pool of persisting memory T cells concurrent with normalization of clinically relevant biomarkers during the first year of treatment. MethodsWe followed 17 CeD patients during their initial GFD year, leading to disease remission. We assessed activation and frequency of gluten-specific CD4+ blood and gut T cells with HLA-DQ2.5:gluten tetramers and flow cytometry, disease-specific serology, histology and symptom scores. We assessed gluten-specific blood T cells within the first three weeks of GFD in six patients and serology in additional nine patients. ResultsGluten-specific CD4+ T cells peaked in blood at day 14 while upregulating Bcl-2 and downregulating Ki-67, then decreased in frequency within 10 weeks of GFD. CD38, ICOS, HLA-DR and Ki-67 decreased in gluten-specific cells within three days. PD-1, CD39 and OX40 expression persisted even after 12 months. IgA-TG2 decreased significantly within four weeks. ConclusionGFD induces rapid changes in phenotype and number of gluten-specific CD4+ blood T cells, including a peak of non-proliferating, non-apoptotic cells at day 14. Subsequent alterations in T-cell phenotype associate with the quiescent but chronic nature of treated CeD. The rapid changes affecting gluten-specific T cells and disease-specific antibodies offer opportunities for clinical trials aiming at developing non-dietary treatments for newly diagnosed CeD patients.

A healthy dietary pattern is associated with microbiota diversity in recently diagnosed bipolar patients: The Bipolar Netherlands Cohort (BINCO) study

BackgroundDiet largely impacts the gut microbiota, and may affect mental and somatic health via the gut-brain axis. As such, the relationship between diet and the microbiota in Bipolar Disorder (BD) could be of importance, but has not been studied before. The aim was therefore to assess whether dietary quality is associated with the gut microbiota diversity in patients with recently diagnosed BD, and whether changes occur in dietary quality and microbiota diversity during their first year of treatment. MethodsSeventy recently (<1 year) diagnosed patients with BD were included in the “Bipolar Netherlands Cohort” (BINCO), and a total of 45 participants were assessed after one year. A 203-item Food Frequency Questionnaire (FFQ) data yielded the Dutch Healthy index (DHD-15), and the microbiota composition and diversity of fecal samples were characterized by 16S rRNA gene amplicon sequencing at baseline and 1-year follow-up. Associations and changes over time were analyzed using multivariate regression analyses and t-tests for paired samples. ResultsIncluded patients had a mean age of 34.9 years (SD ± 11.2), and 58.6 % was female. Alpha diversity (Shannon diversity index), richness (Chao1 index) and evenness (Pielou's Evenness Index) were positively associated with the DHD-15 total score, after adjustment for sex, age and educational level (beta = 0.55; P < 0.001, beta = 0.39; P = 0.024, beta = 0.54; P = 0.001 respectively). The positive correlations were largely driven by the combined positive effect of fish, beans, fruits and nuts, and inverse correlations with alcohol and processed meats. No significant changes were found in DHD-15 total score, nor in microbiota diversity, richness and evenness indexes during one year follow-up and regular treatment. ConclusionA healthy and varied diet is associated with the diversity of the microbiota in BD patients. Its potential consequences for maintaining mood stability and overall health should be studied further.