Search

BACKGROUND: For extended-release drug formulations, effective half-life (t 1/2eff ) is a relevant pharmacokinetic parameter to inform dosing strategies and time to reach steady state. Tacrolimus, an immunosuppressant commonly used for the prophylaxis of organ rejection in transplant patients, is available as both immediate- and extended-release formulations. To the best of our knowledge, the t 1/2eff of tacrolimus from these different formulations has not yet been assessed. The objective of this study was to characterize the t 1/2eff and terminal half-life (t 1/2z ) of an extended-release once-daily tacrolimus formulation (LCPT) and twice-daily immediate-release tacrolimus (IR-Tac). METHODS: A noncompartmental analysis of pharmacokinetic data obtained from a phase 2 study in de novo kidney transplant recipients receiving either LCPT or IR-Tac was conducted. Intensive blood sampling was performed on days 1, 7, and 14, and tacrolimus whole blood concentrations were measured using a validated liquid chromatography with tandem mass spectrometry method. T 1/2eff was estimated using within-participant accumulation ratios. T 1/2z was estimated by linear regression of the terminal phase of the concentration versus time profile. RESULTS: The median accumulation ratios of LCPT and IR-Tac on day 14 were 3.18 and 2.06, respectively.The median (interquartile range; IQR) t 1/2eff for LCPT at day 14 of dosing was 48.4 (37.4-77.9) hours, whereas the t 1/2z was 20.3 (17.6-22.9) hours. For IR-Tac, the median (IQR) t 1/2eff and t 1/2z on day 14 were 12.5 (8.8-23.0) hours and 12.2 (9.2-15.7) hours, respectively. CONCLUSIONS: Consistent with its prolonged release of tacrolimus, LCPT demonstrated a higher accumulation ratio and a longer t 1/2eff compared with IR-Tac. These findings underscore the pharmacokinetic differences between different drug formulations of the same moiety and may help inform dose adjustments for LCPT in kidney transplantation.

IMPORTANCE: Immunocompromised status is a risk factor for severe SARS-CoV-2 infection. Little is known about how systemic corticosteroid dose and concurrent use of immunosuppressants are associated with COVID-19 outcomes. OBJECTIVE: To assess the association between corticosteroid dose/duration and concurrent immunosuppressant use on COVID-19 hospitalisation and death in the era of COVID-19 vaccinations. DESIGN: This is a retrospective cohort study using a deidentified insurance claims database from 1 July 2020 to 30 June 30, 2022, with the risk period starting on 1 July 2021. Impact of corticosteroid exposures and concurrent use of other immunosuppressants was assessed with attributable risk analysis and Cox regression that included COVID-19 vaccination status and time-updated dichotomous immunosuppressive medication exposures. PARTICIPANTS: There were 10 109 596 eligible patients enrolled during the risk period, each with at least 365 days of continuous enrolment prior to 1 July 2021. EXPOSURES: Systemic corticosteroids, disease-modifying antirheumatic drugs (DMARDs), tumour necrosis factor-alpha inhibitors (TNFis) and other immunosuppressive drug categories. MAIN OUTCOMES: Incidence rate ratios and hazard ratios for COVID-19 hospitalisation and death. RESULTS: Corticosteroids were prescribed to 1 379 049 (13.6%) of 10 109 596 individuals. After adjustment, corticosteroids were associated with an increased risk of COVID-19 hospitalisation (HR: 5.40; 95% CI 5.27 to 5.53; p

BACKGROUND: Patients with inflammatory bowel disease (IBD) exhibit considerable interindividual variability in medication response, highlighting the need for precision medicine approaches to optimize and tailor treatment. Pharmacogenetics (PGx) offers the ability to individualize dosing by examining genetic factors underlying the metabolism of medications such as thiopurines. Pharmacogenetic testing can identify individuals who may be at risk for thiopurine dose-dependent adverse reactions including myelosuppression. We aimed to evaluate PGx variation in genes supported by clinical guidelines that inform dosing of thiopurines and characterize differences in the distribution of actionable PGx variation among diverse ancestral groups. METHODS: Pharmacogenetic variation in TPMT and NUDT15 was captured by genome-wide genotyping of 1083 pediatric IBD patients from a diverse Canadian cohort. Genetic ancestry was inferred using principal component analysis. The proportion of PGx variation and associated metabolizer status phenotypes was compared across 5 genetic ancestral groups within the cohort (Admixed American, African, East Asian, European, and South Asian) and to prior global estimates from corresponding populations. RESULTS: Collectively, 11% of the cohort was categorized as intermediate or poor metabolizers of thiopurines, which would warrant a significant dose reduction or selection of alternate therapy. Clinically actionable variation in TPMT was more prevalent in participants of European and Admixed American/Latino ancestry (8.7% and 7.5%, respectively), whereas variation in NUDT15 was more prevalent in participants of East Asian and Admixed American/Latino ancestry (16% and 15% respectively). CONCLUSIONS: These findings demonstrate the considerable interpopulation variability in PGx variation underlying thiopurine metabolism, which should be factored into testing diverse patient populations.

INTRODUCTION: High-dose glucocorticoid (GC)-based dual immunosuppressive treatment regimens are still frequently used in active lupus nephritis (LN) despite their known association with dose-dependent toxicities and incomplete efficacy. We hypothesised that the addition of voclosporin to low-dose GCs and mycophenolate mofetil (MMF) would reduce exposure to the toxicities of high-dose GC-based dual immunosuppressive therapy regimens, resulting in an improved safety profile without compromising efficacy. METHODS: Propensity score matching generated two groups of matched participants from the voclosporin arms (in combination with MMF (2 g/day) and low-dose GCs) of the Phase 2 AURA-LV and Phase 3 AURORA 1 studies and the MMF (3 g/day) and intravenous cyclophosphamide (IVC) arms (both in combination with high-dose GCs) of the Aspreva Lupus Management Study (ALMS) induction study. Safety and efficacy outcomes were assessed over 6 months. RESULTS: There were 179 matched participants identified between the AURA-LV/AURORA 1 studies and ALMS. The overall incidence of adverse events (AEs) was higher in IVC- and MMF-treated participants of ALMS; more voclosporin-treated participants reported AEs by preferred term of glomerular filtration rate decreased, hypertension and anaemia. The incidence of serious AEs was similar across treatments. There were four (2.2%) deaths in IVC- and MMF-treated participants of ALMS compared with seven (3.9%) deaths in voclosporin-treated participants. Significantly more voclosporin-treated participants achieved a ≥25% reduction in urine protein creatinine ratio (UPCR) from baseline at 3 months and ≥50% reduction in UPCR from baseline at 6 months. CONCLUSIONS: Compared with the high-dose GC-based regimens used in ALMS, voclosporin-based triple immunosuppressive therapy resulted in fewer AEs overall and greater and earlier reductions in proteinuria over the first 6 months of treatment. These data reinforce the feasibility of using low doses of GCs and MMF to treat LN when combined with voclosporin as a third agent.

BACKGROUND/OBJECTIVES: The phase 3 REGAIN study and its open-label extension demonstrated the efficacy of the complement C5 inhibitor eculizumab in patients with treatment-refractory, acetylcholine receptor antibody-positive generalized myasthenia gravis (gMG). The aim of the ELEVATE study was to assess the effectiveness of eculizumab in clinical practice in adults with MG in the United States. METHODS: A retrospective chart review was conducted in adults with MG who initiated eculizumab treatment between October 23, 2017 and December 31, 2019. Outcomes assessed before and during eculizumab treatment using a pre- versus post-treatment study design included Myasthenia Gravis-Activities of Daily Living (MG-ADL) total scores; minimal symptom expression (MSE); physician impression of clinical change; minimal manifestation status (MMS); and concomitant medication use. RESULTS: In total, 119 patients were included in the study. A significant reduction was observed in mean MG-ADL total score, from 8.0 before eculizumab initiation to 5.4 at 3 months and to 4.7 at 24 months after eculizumab initiation (both p

Dose optimization of sirolimus may further improve outcomes in allogeneic hematopoietic cell transplant (HCT) patients receiving post-transplantation cyclophosphamide (PTCy) to prevent graft-versus-host disease (GVHD). Sirolimus exposure-response association studies in HCT patients (i.e., the association of trough concentration with clinical outcomes) have been conflicting. Sirolimus has important effects on T-cells, including conventional (Tcons) and regulatory T-cells (Tregs), both of which have been implicated in the mechanisms by which PTCy prevents GVHD, but there is an absence of validated biomarkers of sirolimus effects on these cell subsets. Considering the paucity of existing biomarkers and the complexities of the immune system, we conducted a literature review to inform a quantitative systems pharmacology (QSP) model of GVHD. The published literature presented multiple challenges. The sirolimus pharmacokinetic models insufficiently describe sirolimus distribution to relevant physiological compartments. Despite multiple publications describing sirolimus effects on Tcons and Tregs in preclinical and human ex vivo models, consistent parameters relating sirolimus concentrations to circulating Tcons and Tregs could not be found. Each aspect presents a challenge in building a QSP model of sirolimus and its temporal effects on T-cell subsets and GVHD prevention. To optimize GVHD prevention regimens, phase I studies and systematic studies of immunosuppressant concentration-effect association are needed for QSP modeling.

Radiation therapy (RT) has been a primary treatment modality in cancer for decades. Increasing evidence suggests that RT can induce an immunosuppressive shift via upregulation of cells such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). MDSCs inhibit antitumor immunity through potent immunosuppressive mechanisms and have the potential to be crucial tools for cancer prognosis and treatment. MDSCs interact with many different pathways, desensitizing tumor tissue and interacting with tumor cells to promote therapeutic resistance. Vascular damage induced by RT triggers an inflammatory signaling cascade and potentiates hypoxia in the tumor microenvironment (TME). RT can also drastically modify cytokine and chemokine signaling in the TME to promote the accumulation of MDSCs. RT activation of the cGAS-STING cytosolic DNA sensing pathway recruits MDSCs through a CCR2-mediated mechanism, inhibiting the production of type 1 interferons and hampering antitumor activity and immune surveillance in the TME. The upregulation of hypoxia-inducible factor-1 and vascular endothelial growth factor mobilizes MDSCs to the TME. After recruitment, MDSCs promote immunosuppression by releasing reactive oxygen species and upregulating nitric oxide production through inducible nitric oxide synthase expression to inhibit cytotoxic activity. Overexpression of arginase-1 on subsets of MDSCs degrades L-arginine and downregulates CD3ζ, inhibiting T-cell receptor reactivity. This review explains how radiation promotes tumor resistance through activation of immunosuppressive MDSCs in the TME and discusses current research targeting MDSCs, which could serve as a promising clinical treatment strategy in the future.

PurposeWe evaluate the efficacy and safety profiles of currently available conservative management options for penile and urethral lichen sclerosus.Materials and methodsA systematic review of existing literature on lichen sclerosus was conducted utilizing the PubMed, Embase, and Web of Science databases. References were assessed for relevance to nonsurgical management of male genital lichen sclerosus by title and abstract by 3 independent reviewers, then reviewed in full and in duplicate by 5 independent reviewers.ResultsSeventeen studies describing conservative management of histologically confirmed penile and urethral lichen sclerosus in male patients were included in the final review. We present available evidence supporting the use of 4 major treatment modalities represented in the existing literature: topical corticosteroids, tacrolimus, platelet-rich plasma, and CO2 laser. We also briefly discuss the limited studies on the use of oral acitretin and polydeoxyribonucleotide injections. Outcomes assessed include symptoms, clinical appearance, quality of life, sexual satisfaction, adverse effects, and long-term efficacy of treatment.ConclusionsTopical corticosteroids remain the mainstay of conservative management of penile and urethral lichen sclerosus, with current literature supporting the use of other therapies such as tacrolimus and platelet-rich plasma as alternatives or adjuvant treatments when escalation of treatment is necessary. Future research should further explore the efficacy and safety of newer therapies through additional controlled clinical trials in the targeted population.

PurposeMethodsResultsConclusionsTo identify the incidence of cataract and the outcomes of cataract surgery in eyes with ocular cicatricial pemphigoid (OCP)Phakic eyes were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study and followed for the incidence of visually significant cataract defined as: newly reduced visual acuity 20/50 or worse attributed to cataract; and/or incident cataract surgery. Secondarily, all eyes with OCP that underwent cataract surgery and had a year of follow up thereafter, were included in an analysis of visual outcome.Three hundred fifty-five phakic eyes (200 patients) with OCP were at risk. Eighty eyes developed visually significant cataract over 1064 eye years (incidence rate = 7.5%/eye-year, 95% confidence interval [CI] = 5.6 to 10.1). Higher age was associated with increased incidence of cataract (adjusted hazard ratio [aHR] = 4.47; 95% CI, 1.95–10.23 for age 60–75 inclusive and aHR = 8.37; 95% CI, 3.60–19.42 for age > 75, each compared with age <60 years). Seventy-nine eyes of 61 patients were monitored for > = 1 year following cataract surgery. Cataract surgery was associated with an improvement of vision around 4 lines, which was sustained through at least 48 months. Poorer pre-operative visual acuity was associated with poorer long-term visual outcome.The incidence of cataract was high in this older population. No factors predictive of cataract such as duration of OCP or use of corticosteroids were identified. Visual acuity improved after surgery by a median of 4 lines’ gain at one year; poorer long-term outcome among those with initially poorer visual acuity may be secondary to corneal scarring. [ABSTRACT FROM AUTHOR]

Background: Cystic Fibrosis (CF) significantly affects the respiratory system, often requiring lung transplantation in advanced stages. This life-saving procedure presents substantial challenges and uncertainties. While there is existing research on support and information needs post-lung transplant from various perspectives, this study aims to specifically address the unique experiences and challenges faced by individuals with CF during both the pre-transplant and post-transplant periods. Methods: Twenty-three lung-transplanted individuals with CF participated in this exploratory qualitative study. Data was collected through individual semi-structured interviews and analyzed using inductive content analysis. Results: Participants faced physical and mental challenges, including fatigue, depression, and anxiety. The waiting period involved isolation, dependence on family, and guilt. Post-transplant, they dealt with relief but also severe pain and adjusted to a new identity. Participants highlighted the importance of taking immunosuppressive medications as prescribed, even though the regimen was complicated and these medications had side effects. Participants stressed the need for earlier and more open dialogue with healthcare professionals and better emotional preparation for the transplant process, including preparedness for pain and previously inadequately addressed concerns such as depression and anxiety. Conclusions: This study underscores the significant physical and emotional challenges individuals with CF face during lung transplantation, highlighting the need for comprehensive, person-centered care. Psychological support, effective post-transplant pain management, and early palliative care may be beneficial approaches to improve the patient experience. Nurses can play a pivotal role in this process by ensuring clear communication, managing pain, educating patients on immunosuppressive regimens, and advocating for holistic care. [ABSTRACT FROM AUTHOR]

Purpose: To report an unusual case of retained caterpillar hair in the vitreous cavity presenting as recurrent Intermediate Uveitis with cystoid macular edema. Method: Case Report. Results: A 40-year-old male presented to our uveitis clinic with recurrent episodes of redness and diminution of vision in his left eye for 3 years. He was diagnosed and treated elsewhere as a case of recurrent intermediate uveitis and was referred to our center for a second opinion to initiate immunosuppressive therapy. A detailed history revealed that a caterpillar had fallen into his left eye 3 years back, followed by severe irritation, pain, and redness. He received topical antibiotics and corticosteroids, and retained caterpillar hair was removed from the ocular surface. During the last 3 years, the patient had multiple episodes of inflammation despite being treated with oral and topical corticosteroids. At the current visit, a meticulous clinical examination at our centre revealed multiple, migrated, retained caterpillar hair in the vitreous cavity. The patient was diagnosed with Ophthalmia Nodosa (Type V) and managed with surgical intervention (vitreous surgery). The case highlights an unusual presentation of ON and the role of pars plana vitrectomy in its successful management. Conclusion: We highlight a rare and unusual presentation of ophthalmia nodosa and its successful management. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the trends in immunomodulator use and pregnancy outcomes among pregnant women with systemic lupus erythematosus (SLE), a condition requiring medication to maintain disease activity. Methods: This descriptive study used data from the National Health Information Database in Korea from 2002 to 2018. We included 5,044 pregnancies initiated between 2005 and 2017 in 3,120 SLE patients. Annual trends in SLE therapy, drug utilisation patterns during the preconception and pregnancy periods, and pregnancy outcomes were analysed. Results: Pregnancy compatible immunosuppressant (PC-IS) and hydroxychloroquine use during the first trimester were 10.7% and 41.4%, respectively. Most SLE medications exhibited a decline in usage from the preconception period to the first trimester. A prescription rate of 0.9% for pregnancy incompatible immunosuppressants (PIC-IS) was observed during the first trimester, and the incidence of live births, stillbirths, and abortions remained consistent from 2005 to 2017. Conclusions: Insufficient usage of hydroxychloroquine and PC-IS, along with a reduction in PIC-IS usage primarily during early pregnancy rather than before conception, highlights the unmet need for preconceptional family planning with appropriate medication management strategies in SLE pregnancies. [ABSTRACT FROM AUTHOR]

Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder which can be life-threatening. AHA is due to autoantibodies against coagulation factor VIII. Disease onset may be idiopathic (approximately half of the cases) or triggered by autoimmune disorders, cancers, drugs, infections, or pregnancy. Besides treating the underlying disorder, specific AHA treatments include management of bleeding and inhibitor eradication. Various first-line and second-line hemostatic and immunosuppressive agents are currently available for the management of AHA. Recently, the hemostatic drug emicizumab and the immunosuppressive drug rituximab have been the object of intense research from investigators as innovative promising therapies for AHA. This narrative review will be focused on the current status of the clinical use of these two off-label therapeutic agents in AHA. [ABSTRACT FROM AUTHOR]

IgA nephropathy and IgA vasculitis with nephritis, albeit rare, represent two relatively frequent glomerular conditions in childhood. Compared to adults, pediatric IgA nephropathy has a more acute presentation, most frequently with synpharyngitic macrohematuria and histologically with more intense inflammation and less intense chronic damage. Management of these conditions is controversial and supported by little high-quality evidence. The paucity of evidence is due to the disease heterogeneity, its inter-ethnic variability, and the difficulty of extrapolating data from adult studies due to the peculiarities of the condition in children. IgA vasculitis with nephritis is a kidney manifestation of a systemic disorder, typical of the pediatric age, in which both the diagnosis of kidney involvement and its management are poorly defined, and an interdisciplinary approach is crucial. Both conditions can have a profound and long-lasting impact on kidney function and the global health of affected children. The International Pediatric Nephrology Association has therefore convened a diverse international group of experts from different disciplines to provide guidance on the recommended management of these conditions in children and to establish common definitions and define priorities for future high-quality, evidence-based collaborative studies for the benefit of children. [ABSTRACT FROM AUTHOR]

Background: Intravenous steroid pulses (SP) are successfully used for the treatment of patients with idiopathic nephrotic syndrome (INS) resistant to oral prednisone. Methods: We performed a retrospective analysis of all patients in the three pediatric nephrology centers of the Paris region from 2002 to 2022 who were resistant to a 30-day course of oral prednisone and who received SP for their first INS flare and analyzed their disease course over 4 years. Results: Forty-seven patients (17 girls), median age 3.4 years, were analyzed. Of them, 68% reached remission within 7 days of SP. No significant short-term side effects were noted. Half of the patients started immunosuppressive treatment immediately after their first remission and 62% of them relapsed at least once, whereas all the patients who did not receive immunosuppressive treatment since their first remission relapsed. Among the SP-sensitive patients, 75% needed calcineurin inhibitor (CNI) or B-cell depletion during their disease course to achieve stable remission. Forty-two percent of the whole cohort received B-cell-depleting agents. Among the 15 SP-resistant patients, all received CNI. Twelve/fifteen patients reached remission. After 4 years, 68% among the SP-sensitive patients and 87% of SP-resistant patients still had an active disease. Conclusions: SP are helpful to obtain rapid remission in pediatric INS patients resistant to oral steroids. However, as most SP-sensitive patients need immunosuppressive drugs, mainly CNI and B-cell-depleting agents it could be interesting to discuss the possibility to start CNI directly after the 30-day course of prednisone instead of SP. [ABSTRACT FROM AUTHOR]

Background: There is a paucity of literature on the seroprevalence of SARS-CoV-2 antibodies among pediatric patients with underlying kidney disorders; few serosurveys among healthy children have shown seropositivity of 20–65% after different waves of infections. Methods: The study had a cross-sectional design and was conducted between January 2023 and July 2023; 163 children and adolescents (1–18 years) with nephrotic syndrome and chronic kidney disease (CKD) were screened for Anti-Spike SARS-COV-2 IgG antibodies as detected by a quantitative chemiluminescence immunoassay. Children with nephrotic syndrome, both steroid sensitive (SSNS) and steroid resistant (SRNS) were enrolled during disease remission. Correlation of SARS-CoV-2 seropositivity status was done with age, gender, disease type, treatment duration, immunosuppressants, previous SARS-CoV-2 infection, and immunization status. Results: Of 163 children (63.8% boys) with median age of 9 years; 101 (62%) had underlying nephrotic syndrome (61 SSNS and 40 SRNS), and 62 (38%) children had CKD. Seroprotective titers for SARS-COV2 antibodies were present in 100 (61.3%) children. The median titers for all patients were 37.1 BAU/mL; for nephrotic syndrome they were 27.1 BAU/mL and for CKD they were 76.7 BAU/mL (p = 0.0033). A total of 43 (26.4%) children had high positive antibody levels (> 200 BAU/ml). Among those with nephrotic syndrome 60.7% with SSNS and 43.5% SRNS had seropositive titers. Only 4 (2.5%) children had a history of previous COVID infection and 6 (3.7%) were vaccinated. Conclusions: In a largely unvaccinated population of children with nephrotic syndrome and CKD, 61.3% were seropositive for SARS-CoV-2 IgG antibody indicating a past asymptomatic infection; titers were significantly higher in CKD compared to nephrotic syndrome. [ABSTRACT FROM AUTHOR]

Background: This study by the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) was designed to determine the incidence, risk factors, current management strategies, and outcomes of antibody-mediated rejection (ABMR) in pediatric kidney transplant recipients (pKTR). Methods: We performed an international, multicenter, longitudinal cohort study of data reported to the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry. Three hundred thirty-seven pKTR from 21 European centers were analyzed. Clinical outcomes, including kidney dysfunction, rejection, HLA donor-specific antibodies, BK polyomavirus-associated (BKPyV) nephropathy, and allograft loss, were assessed through 5 years post-transplant. Results: The cumulative incidence of de novo donor-specific class I HLA antibodies (HLA-DSA) post-transplant was 4.5% in year 1, 8.3% in year 3, and 13% in year 5; the corresponding data for de novo class II HLA-DSA were 10%, 22.5%, and 30.6%, respectively. For 5 years post-transplant, the cumulative incidence of acute ABMR was 10% and that of chronic active ABMR was 5.9%. HLA-DR mismatch and de novo HLA-DSA, especially double positivity for class I and class II HLA-DSA, were significant risk factors for ABMR, whereas cytomegalovirus (CMV) IgG negative recipient and CMV IgG negative donor were associated with a lower risk. BKPyV nephropathy was associated with the highest risk of graft dysfunction, followed by ABMR, T-cell mediated rejection, and older donor age. Conclusions: This study provides an estimate of the incidence of de novo HLA-DSA and ABMR in pKTR and highlights the importance of BKPyV nephropathy as a strong risk factor for allograft dysfunction. [ABSTRACT FROM AUTHOR]

Objective: Limited sampling strategies are widely employed in clinical practice to minimize the number of blood samples required for the accurate area under the curve calculations, as obtaining these samples can be costly and challenging. Traditionally, the maximum a posteriori Bayesian estimation has been the standard method for the area under the curve estimation based on limited samples. However, machine learning is emerging as a promising alternative for this purpose. Here, we review studies that utilize machine learning approaches to develop limited sampling strategies and compare the strengths and weaknesses of these machine learning methods. Methods: We searched the literature for studies that used machine learning to estimate the area under the curve using a limited sampling strategy approach. Results: We identified ten studies that developed machine learning models to estimate the area under the curve for six different drugs. Several of these models demonstrated good accuracy and precision in area under the curve estimation in reference to the traditional Bayesian approach, highlighting the potential of machine learning models in precision dosing. Conclusions: Despite these promising early results, the development of machine learning for limited sampling strategies is still in its early stages. Further research might be needed to validate machine learning models with larger, high-quality clinical datasets to ensure their reliability and applicability in clinical settings. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICI), i.e., anti-PD1/PDL1 and anti-CTLA-4, have reshaped the prognosis of many cancers. Increased use of ICI has led to the onset of new adverse events. Neurological immune-related adverse events are rare, heterogenous, and potentially life-threatening. Chronic intestinal pseudo-obstruction (CIPO) is an immune-related autonomic plexus neuropathy that may be caused by infiltration of the myenteric plexus by CD8 + T cells. It is a rare and potentially fatal side effect that can be difficult to diagnose early because of initial nonspecific clinical presentation including vomiting, nausea, diarrhea, and constipation. Some rare cases have been described in the literature reporting a frequent resistance to corticosteroids making it necessary to use other immunosuppressive therapy. Vedolizumab is an antibody (Ab) blocking integrin α4-β7 used to treat inflammatory bowel disease. We report the first three cases of ICI-induced CIPO-treated with vedolizumab after corticosteroid failure, with very limited benefits (only one patient with transitory improvement). Based on our results in three cases, vedolizumab does not currently appear to be a therapeutic option. Earlier administration with a standardized dose and frequency schedule may provide better outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Over the past decade, advancements in ocular drug delivery systems, particularly anti-vascular endothelial growth factor (VEGF) injections, have improved the management of various ocular conditions. However, their short half-life necessitates frequent injections, burdening both patients and the healthcare system. This review examines recent developments in ocular injectables designed to extend dosing intervals, enhance adherence, and improve outcomes. Areas covered: This review examines clinical trials and studies assessing two recently FDA approved medications, faricimab, and high-dose aflibercept, for the treatment of wet age-related macular degeneration (wet AMD), diabetic macular edema (DME), and macular edema due to retinal vein occlusion (RVO-ME). Additionally, we review existing data that exist for pegcetacoplan and avacincaptad pegol for dry AMD. Expert opinion: Most studies evaluating new ocular injectables focus on faricimab for wet AMD. While further studies are necessary, both faricimab and high-dose aflibercept seem to improve anatomical outcomes, with varying significant improvements in BCVA. Faricimab is approved for RVO-ME and is non-inferior to aflibercept; trials are ongoing for high-dose aflibercept. Pegcetacoplan and avacincaptad pegol slow the progression of geographic atrophy size; however, concerns remain regarding increased risk of macular neovascularization and lack of data supporting clinically relevant improvement in secondary visual outcomes. [ABSTRACT FROM AUTHOR]

Activated PI3K delta syndrome (APDS) is a primary immunodeficiency that is caused by mutations in the PI3K signalling pathway resulting in either gain-of-function or loss-of-function phenotypes of APDS 1 and 2. Malignancy is one of the most serious complications associated with APDS patients, with the most commonly occurring of these being lymphoma, and is the most common cause of death in APDS patients. Management of APDS is complex and variable due to the heterogeneous nature of the disease and ranges from antimicrobial and immunosuppressant agents to haematopoetic stem cell transplantation. More recently, an increasing level of interest has been shown in the use of more targeted agents such as PI3Kδ-specific inhibitors. Here, we provide expert perspective on the suspected causality of a case of lymphoma observed in a 20-year-old female patient who was included in a clinical trial of leniolisib, a PI3K inhibitor. [ABSTRACT FROM AUTHOR]

Background: The regenerative potential of mesenchymal stromal/stem cells (MSCs) has been extensively studied in clinical trials in the past decade. However, despite the promising regenerative properties documented in preclinical studies, for instance in osteoarthritis (OA), the therapeutic translation of these results in patients has not been fully conclusive. One factor contributing to this therapeutic barrier could be the presence of senescent cells in OA joints. Methods: This study evaluated a novel approach to OA treatment by combining adipose tissue-derived MSCs (AD-MSCs) with rapamycin, a clinically approved immunosuppressive drug with anti-senescence properties. First, rapamycin effects on senescence and fibrosis markers were investigated in freshly isolated OA chondrocytes by immunostaining. Next, the in vitro differentiation capacities of AD-MSCs, their regulatory immune functions on activated immune cells and their regenerative effects on OA chondrocyte signature were assessed in the presence of rapamycin. Results: In OA chondrocytes, rapamycin reduced the senescence marker p15INK4B and the fibrosis marker COL1A1 without affecting the expression of the master chondrogenic markers SOX9 and COL2. Rapamycin also enhanced AD-MSC differentiation into chondrocytes and reduced their differentiation into adipocytes. In addition, rapamycin improved AD-MSC immunoregulatory functions by promoting the expression of immunosuppressive factors, such as IDO1, PTGS2 and also CD274 (encoding PD-L1). Finally, RNA sequencing analysis showed that in the presence of rapamycin, AD-MSCs displayed improved chondroprotective regenerative effects on co-cultured OA chondrocytes. Conclusions: Our findings suggest that the rapamycin and AD-MSC combination enhances the therapeutic efficacy of these cells in senescence-driven degenerative diseases such as OA, notably by improving their anti-fibrotic and anti-inflammatory properties. [ABSTRACT FROM AUTHOR]

Background: Pure red cell aplasia (PRCA) is a rare cause of anemia characterized by decreased red blood cell production, often associated with thymomas. While thymectomy is commonly performed to treat thymoma-associated PRCA, the development of PRCA post-thymectomy is less understood. Case Presentation: We present a case of a 25-year-old woman who developed PRCA and autoimmune diabetes mellitus (DM) following radical thymectomy for malignant thymoma. Initial treatment with prednisolone showed minimal improvement, leading to the inclusion of rituximab. This combination resulted in a significant increase in reticulocyte counts and transfusion independence. Discussion: This case highlights the potential for PRCA to develop after thymectomy and the challenges of treating PRCA in the context of additional conditions like autoimmune DM. While immunosuppressive therapies such as cyclosporin A and corticosteroids are standard, their side effects necessitated exploring alternative treatments. Rituximab proved effective and was well-tolerated, suggesting its potential as a primary option in similar cases. Conclusion: This case illustrates the occurrence of PRCA after thymectomy and highlights rituximab’s effectiveness as a treatment option, offering a viable alternative to standard therapies in managing this complex condition. [ABSTRACT FROM AUTHOR]

Background: Inflammatory bowel disease (IBD) occurs in up to 70%–80% of patients with primary sclerosing cholangitis (PSC). Oral vancomycin therapy (OVT) has been reported to be effective in the treatment of IBD associated with PSC (IBD-PSC). Objectives: To examine the effectiveness and safety of OVT in the treatment of IBD-PSC by performing a systematic review and pooled analysis of the literature. Design: We performed a systematic review and pooled analysis of studies reporting IBD clinical response to OVT in IBD-PSC. Data sources and methods: A systematic search was conducted in Cochrane Library, Embase, Google Scholar, Medline, PubMed, Scopus, and Web of Science from database inception to June 3, 2024. We included adult and pediatric studies that reported on clinical response (defined as any improvement in IBD-related clinical symptoms) of IBD-PSC patients treated with OVT (including pre- and post-liver transplantation cohorts). Pooled analyses of OVT response and safety were performed. Results: A total of 21 (open-label, non-controlled) studies including 290 patients with IBD-PSC treated with OVT were included. The median duration of OVT to treat IBD-PSC was 32.5 weeks (interquartile range (IQR): 19–83 weeks). The total daily dose of OVT ranged from 250 to 1500 mg. Concomitant treatment included the following: mesalamine in 14.5% (n = 42), advanced therapies in 10.7% (n = 31), and immunosuppressive agents in 14.1% (n = 41). Clinical response was noted in 47.6% (138/290) and clinical remission in 43.5% (100/230). The biochemical remission rate post-OVT was 68.8% (55/80) and endoscopic remission was 39.4% (80/203). Three studies (n = 11) reported no episodes of acute cholangitis while on OVT. Five studies (n = 69) reported an incidence rate of 8.7% of vancomycin-resistant enterococci post-OVT to treat IBD-PSC. Conclusion: OVT was associated with clinical response/remission in almost half of patients with IBD-PSC with a favorable side effect profile. Further prospective randomized trials are needed to confirm the dosing, efficacy, treatment duration, and long-term safety of OVT for the treatment of IBD-PSC. Trial registration: The study protocol was registered with PROSPERO a priori (no. CRD42023438341). [ABSTRACT FROM AUTHOR]

ABSTRACT Background Aim Methods Results Conclusions Up to 30% of patients with Crohn's disease (CD) will experience a mild disease course. However, there is no consensus definition for mild CD.To examine the Simple Endoscopic Score for Crohn's disease (SES‐CD) thresholds best associated with low likelihood of long‐term disease progression.We conducted a multicentre retrospective cohort study at three tertiary care centres in United States and Europe. We analysed data from 177 surgery‐naïve patients with CD who had endoscopic assessment while not on immunosuppressive therapy. The primary outcome was disease progression (systemic steroids, biologic or immunomodulator therapy initiation; new stricturing or penetrating complications; or CD‐related hospitalisation or surgery). Univariable and multivariable Cox proportional hazards modelling identified predictors of the primary outcome at 2 and 5 years following endoscopy.Disease progression occurred in 23% and 35% of patients at years two and five, respectively. Endoscopic severity at enrolment independently predicted disease progression. Compared to those with an SES‐CD of 0, an SES‐CD ≥ 7 had a greater risk of progression at 2 years (HR 2.50, 95% CI 1.09–5.72) and 5 years (HR 2.89, 95% CI 1.41–5.91). SES‐CD > 7 remained independently predictive of disease progression among the 129 immunosuppression‐naïve patients (HR 5.65, 95% CI 1.49–21.52) and after excluding patients with prior penetrating disease (HR 2.32, 95% CI 1.00–5.45).SES‐CD ≥ 7 predicts disease progression in mild CD. A score ≤ 6 may help identify patients less likely to progress and be part of the definition of mild CD. [ABSTRACT FROM AUTHOR]

Superficial duodenal epithelial tumors were previously considered rare. Laparoscopic and endoscopic cooperative surgery for duodenal tumors (D-LECS) has been developed to achieve successful endoscopic treatment. Patients who have undergone living-donor liver transplantation (LDLT) may have severe abdominal adhesions, and immunosuppressive agents (IAs) may affect the degree of postoperative abdominal adhesions and wound healing, but their effects remain unclear. Herein, we present the first case of D-LECS for duodenal adenoma after LDLT. A 66-year-old man underwent D-LECS for a non-ampullary duodenal high-grade adenoma after LDLT with an IA. The patient's condition was uneventful 36 months after the surgery. In gastrointestinal surgery, IAs may affect the resected duodenal repair process. For duodenal neoplasms in high-risk patients, D-LECS may be better than endoscopic submucosal dissection alone. D-LECS after LDLT is a feasible and less invasive procedure. [ABSTRACT FROM AUTHOR]

Background: To analyze the clinical course and outcomes of autoimmune vs. non-autoimmune surgically induced scleral necrosis (SISN). Methods: Multicentric, retrospective, comparative cohort study. Eighty-two eyes of 70 patients with SISN were classified according to pathogenic mechanism into autoimmune vs. non-autoimmune. Main outcome measures included necrosis onset, type of surgery, associated systemic disease, visual acuity, and treatment were analysed in patients followed for ≥ 6 months. Results: Forty-six (65.7%) patients were women, and the median age was 66 (range: 24–90) years. Most patients (82.9%) had unilateral disease. The median time between surgery and SISN onset was 58 (1–480) months. Thirty-one (37.8%) eyes were classified as autoimmune, and 51 (62.2%) as non-autoimmune SISN. Autoimmune SISN was associated with a shorter time between the surgical procedure and SISN onset than non-autoimmune cases (median of 26 vs. 60 months, p = 0.024). Also, autoimmune SISN was associated with cataract extraction (93.5% vs. 25.5%, p < 0.001), severe scleral inflammation (58.1% vs. 17.6%, p < 0.001), and higher incidence of ocular complications (67.7% vs. 33.3%, p = 0.002) than non-autoimmune cases. Remission was achieved with medical management alone in 44 (86.3%) eyes from the non-autoimmune and in 27 (87.1%) from the autoimmune group (p = 0.916). Surgical management was required in 11 (13.4%) eyes, including two requiring enucleations due to scleral perforation and phthisis bulbi. Conclusions: Eyes with autoimmune SISN had a higher rate of cataract surgery, severe scleral inflammation, and ocular complications. Early SISN diagnosis and appropriate management, based on clinical features and pathogenic mechanisms, are critical to avoid sight-threatening complications. [ABSTRACT FROM AUTHOR]

Purpose: Behcet's Disease is a chronic multisystem vasculitis associated with a blinding uveitis. Few comparative studies exist between conventional disease-modifying antirheumatic drugs (DMARDs) and biologic DMARDs in Behcet's uveitis (BU). We therefore used drug retention time (DRT), an accepted surrogate measure of pharmacological efficacy and tolerability, to compare these treatments in patients with BU. Methods: Retrospective chart review of patients who met the revised International Criteria for Behcet's Disease (ICBD) treated at the Royal Victorian Eye and Ear Hospital, Australia, between 1985–2021. DRT was analysed with Kaplan-Meier plots and defined as total time on drug in the first medication-period for each DMARD in each patient. Results: Forty-eight patients (37 males) with median age of 28.6 years were followed-up for a median of 8.0 years. At initial presentation, half had bilateral disease and median logMAR visual acuity was 0.176 (Snellen 6/9) in 62 uveitic eyes (16 anterior uveitis, 11 intermediate, 2 posterior, and 33 panuveitis). Thirty-three patients met ICBD initially. Prescribed corticosteroid-sparing agents were Cyclosporin (N = 24), Mycophenolate (N = 22), Azathioprine (N = 22), Methotrexate (N = 16), and Adalimumab (N = 15). Median DRT was 14.0, 27.4, 8.3, 24.0, and 52.0 months, respectively. DMARDs were discontinued 116 times and adverse effects (N = 37) were the main reason for cessation. Over time, patients were switched from Cyclosporin to Adalimumab earlier in the disease course due to poorer tolerance of adverse events. Conclusion: Adalimumab's drug retention time was found to be similar to and possibly better than cDMARDs in patients with BU, who often suffer from vision-threatening disease at first presentation. [ABSTRACT FROM AUTHOR]