Immunosuppressive Therapy Research Articles

Adult-Onset Female Focal Segmental Glomerulosclerosis with Nephrotic Syndrome Caused by a TBC1D8B Variant: a Case Report

Abstract We report the case of a 49-year-old Chinese woman with nephrotic syndrome, characterized by normal kidney function but poor response to hormonal and immunosuppressive therapy, indicative of steroid-resistant nephrotic syndrome (SRNS). Through renal biopsy, the patient was diagnosed as FSGS (perihilar type), and subsequent whole exome sequencing (WES) identified a pathogenic frameshift variant concerning the TBC domain of the TBC1D8B gene. This patient represents the first late-onset Chinese female who was found to carry a novel, pathogenic variant in the gene TBC1D8B.

Systemic sclerosis-associated interstitial lung disease: How to manage in 2024?

Systemic sclerosis (SSc) or scleroderma is an autoimmune disease characterized by immune dysregulation which leads to progressive fibrosis of the skin and internal organs. Interstitial lung disease (ILD) is present in approximately 65% of patients with SSc and it accounts for approximately 40% of all SSc deaths. Risk factors associated with the development of systemic sclerosis related interstitial lung disease (SSc-ILD) include male sex, African heritage, high modified Rodnan skin score (mRSS), presence of anti-Scl-70/Topoisomerase I antibodies, and nucleolar pattern on antinuclear antibody (ANA). The primary tool to diagnose ILD in patients with SSc is high-resolution computed tomography (HRCT). Full pulmonary function tests (PFTs) with diffusing capacity of the lungs for carbon monoxide (DLco) and ambulatory desaturation testing should be obtained following the diagnosis of SSc-ILD for disease monitoring. The purpose of this review is to provide an updated guide for the management of SSc-ILD. Our proposed first line treatment for SSc-ILD is immunosuppressive therapy such as mycophenolate mofetil, tocilizumab, and rituximab which are discussed in depth, and we present the evidence-based data that has justified the use of these pharmacotherapies. Other immunosuppressive treatments are also reviewed, and we discuss the role of antifibrotic therapy. Finally, we dive into other avenues of treatments such as chimeric antigen receptor (CAR)-T cell therapy and hematopoietic stem cell transplant.

Incidence of serious respiratory tract infections and associated characteristics in a population exposed to immunosuppressive therapies: a register-based population study

BackgroundImmunosuppressive therapies are associated with a risk of infections. Nevertheless, their incidence in this population remains unclear. This study aims to determine the incidence of serious respiratory tract infections (SRI) in a population exposed to immunosuppressive therapies.MethodsData from a representative sample of the French healthcare claims from 01/01/2014 to 12/31/2019 were analyzed. Exposure to immunosuppressive therapy was defined by the dispensation of drugs through community pharmacies or in hospitals. SRI diagnosis was based on ICD-10 codes from hospitalization records. A cohort analysis was performed to estimate standardized SRI incidence rates. A nested case-control analysis within this cohort was used to study the characteristics associated with SRI.ResultsWe identified 24,122 individuals exposed to immunosuppressive therapies, among which 1,559 developed SRI, resulting in a standardized incidence rate of 1,398 per 100,000 person-years. In this population, the risk of SRI was associated with a history of cancer (OR 2.68, 95% Confidence Intervals (CI) 2.24–3.21; p < 0.001), chronic respiratory disease (2.62, 95%CI 2.17–3.16; p < 0.001), end-stage renal failure (2.38, 95%CI 1.37–4.13; p = 0.003), neurodegenerative diseases (1.52, 95%CI 1.07–2.17; p = 0.026), diabetes (1.44, 95%CI 1.14–1.82; p < 0.001), psychiatric diseases (1.27, 95%CI 1.06–1.52; p < 0.001), and cardiovascular diseases (1.26, 95%CI 1.04–1.52; p = 0.002). Compared to corticosteroids alone, the risk of SRI was lower in individuals treated with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD) only (0.44, 95%CI 0.25–0.78; p < 0.001).ConclusionIn the population exposed to immunosuppressive therapies, a history of chronic disease is associated with an increased risk of SRI. This risk is lower in those receiving csDMARD alone than corticosteroids alone.

Long-term outcome of tacrolimus-based immunosuppressive treatment for patients with paediatric-onset lupus nephritis.

We have previously reported the mid-term efficacy and safety of tacrolimus (Tac)-based immunosuppressive therapy in such patients, and herein, we aimed to determine their long-term outcomes (over 10 years). We retrospectively evaluate the data of 13 consecutive patients with biopsy-proven long-standing LN who underwent a long-term Tac-based treatment regimen. Tac was administered once daily at a dose of 3 mg as reinduction or maintenance treatment. Treatment outcomes were defined using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), urinary protein/creatinine ratio (Up/cr), serum creatinine, estimated glomerular filtration rate (eGFR) and serological lupus markers (complement C3, complement hemolytic activity [CH 50], and anti-dsDNA antibody titre), and the concomitantly administered prednisolone (PDN) dose. Data on clinical parameters and serological lupus activity were collected annually from each patient throughout the study period. The patients' baseline characteristics at the treatment initiation were as follows: mean age, 18 years; Up/cr, 0.63 ± 0.69; serum C3 level, 57.2 ± 22.4 mg/dL (normal range, 79-152 mg/dL); CH50, 27.9 ± 15.7 U/mL (normal range, 23.0-46.0 U/mL); serum anti-dsDNA antibody titre, 111.7 ± 123.4 IU/mL (normal range, <12.0 IU/mL); serum creatinine, 0.60 ± 0.19 mg/dL; eGFR, 115.6 ± 21.3 mL/min and SLEDAI, 13 ± 8.1. Despite the gradual tapering of the concomitantly administered PDN dose from 18.7 ± 13.5 mg/day at baseline to 3.5 ± 2.8 mg/day at 10 years (p = .002), a marked improvement in the outcomes, compared with the baseline values, was observed within a year. Additionally, these favourable changes persisted throughout study period in most patients. Compared with the baseline values, the following measures confirmed sustained outcome improvements after a 10-year treatment: SLEDAI, 1.7 ± 2.0; serum C3 level, 83.8 ± 16.1 mg/dL; CH50, 45.6 ± 10.9 U/mL (all p < .01) and Up/cr, 0.16 ± 0.18 and serum anti-dsDNA antibody titre, 25.8 ± 28.8 IU/mL (both p < .05). Serum creatinine level and eGFR remained within the normal range in all study participants except for one patient who experienced several flare-ups. No serious adverse effects were observed. Our results suggest that long-term Tac-based immunosuppressive treatment as maintenance therapy is beneficial and has low cytotoxicity. Therefore, it represents an attractive option for the treatment of selected patients with paediatric-onset LN in a real-world setting.

Antimalarials in Lupus Nephritis: How Strong is the Evidence?

Systemic lupus erythematosus is a chronic multisystem autoimmune disease that affects the kidneys in approximately 50% of patients, with prevalence rising to as high as 70% in certain populations, such as African Americans and Asians. Antimalarials -and particularly hydroxychloroquine- are currently considered a mainstay of therapy, together with immunosuppressants. Over the last decades, several studies have extensively investigated the mechanisms of action of antimalarial agents, and their potential beneficial properties in patients with SLE in general. However, the evidence for the therapeutic benefit of hydroxychloroquine in patients with lupus nephritis (LN) derives mainly from observational studies, conducted in an era prior to the refinement of induction and maintenance protocols for immunosuppressive therapy. Despite the paucity of high-quality evidence on its efficacy in LN, the nephrology community widely supports the universal use of hydroxychloroquine in LN patients, and recommendations for its use are firmly entrenched in various clinical practice guidelines. Nonetheless, the use of antimalarials may also carry inherent risks, underscoring the importance of personalized approaches in these patients. Herein, we comprehensively review the available literature on antimalarials in LN aiming to update the current evidence, limitations, and future perspectives for the use of antimalarials in adults.

Early Immunosuppressive Therapy and Ocular Complications in Pediatric and Young Adult Patients with Non-Infectious Uveitis at a Tertiary Referral Center in Japan

ABSTRACT Purpose To evaluate differences in the incidence of ocular complications among pediatric and young adult patients with non-infectious uveitis receiving immunosuppressive therapy (IMT), according to the time from uveitis onset to IMT initiation in Japan. Methods Patients aged < 20 years exhibiting uveitis treated with IMT (e.g. methotrexate, cyclosporine, infliximab, or adalimumab) were categorized into three groups according to the time from uveitis onset to IMT initiation: ≤6 months, early IMT group; 7 months to 2 years, intermediate IMT group; and ≥ 2 years, late IMT group. The percentage of ocular complications was compared among these groups. Laser flare values were recorded to evaluate disruption of the blood-aqueous barrier (BAB). Results Forty-three patients (84 eyes) who received IMT during the follow-up period were included. Among them, 28 patients (65.1%) experienced ≥ 1 ocular complication, with percentage of 56.0% in the early IMT group, 77.8% in the intermediate group, and 77.8% in the late group. Common complications were cataract (27.4%), posterior synechiae (17.9%), and macular edema (10.7%). The early IMT group did not require surgical intervention. The late IMT group experienced a high percentage of ocular complications despite IMT initiation. The mean laser flare value during follow-up was consistently higher in the late group (113.2 pc/ms) than in the early group (14.4 pc/ms) and intermediate group (28.7 pc/ms). Conclusion In pediatric and young adult patients with chronic non-infectious uveitis, early IMT initiation may prevent permanent breakdown of the BAB, reduce the incidence of ocular complications, and decrease the need for surgical intervention.

The role of trimethoprim/sulfamethoxazole in preventing opportunistic infections in systemic lupus erythematosus patients receiving low-level immunosuppressive treatment: an open-label, randomized, controlled trial

Objective: Systemic lupus erythematosus (SLE) patients receiving immunosuppressive therapy are at risk for opportunistic infections (OIs), particularly Pneumocystis pneumonia (PCP). This study aimed to evaluate the effectiveness of trimethoprim/sulfamethoxazole (TMP/SMX) as primary prophylaxis against OIs and its adverse effects in SLE patients receiving low-level immunosuppressive treatment in a real-world setting. Methods: This open-label randomized controlled trial enrolled SLE patients receiving low-level immunosuppressive treatment at Ramathibodi Hospital between May 2021 and December 2022. Patient demographics and relevant clinical data were collected. Participants were randomized 1:1 to receive TMP/SMX or no prophylaxis, with dose adjustments according to renal function. The incidences of TMP/SMX-sensitive OIs and adverse events were monitored for 12 months post-enrollment. Results: The trial was terminated early due to a high rate of adverse drug reactions (ADRs) associated with TMP/SMX. In total, 138 SLE patients receiving low-level immunosuppressive treatment were enrolled. Most patients (98.4%) were in disease remission. No TMP/SMX-sensitive OIs were observed in either group during the 12-month follow-up period. Among individuals receiving TMP/SMX, 10/70 (14.3%) developed ADRs. Of these 10 patients, eight experienced grade 1 ADRs, and two had grade 3 ADRs; all declined to resume prophylaxis. There were no deaths in the study. Conclusions: During the 12-month follow-up period, no TMP/SMX-sensitive OIs occurred in SLE patients receiving low-level immunosuppressive therapy, suggesting that primary prophylaxis with TMP/SMX may not significantly benefit this population. The high rate of ADRs observed underscores the need for clinicians to carefully consider the risks and benefits of TMP/SMX prophylaxis in these patients.

Scabies in 604 Patients: A Glimpse into the Disease Burden and Its Associated Mortality in Hong Kong.

Scabies is a worldwide parasitic dermatosis with a significant health burden on the young and the elderly. Statistics about the prevalence of scabies in Hong Kong are not available. This is a retrospective study of patients from a regional hospital cluster in Hong Kong with microscopy-documented Sarcoptes scabiei infestations from January 2018 to December 2022. The condition was categorised into classical scabies and crusted scabies upon clinical presentation. Demographic data, comorbid diseases, mobility and residential status, seasonal variability, secondary bacterial infection, treatment and outcomes were described. These were compared between classic and crusted scabies. In total, 604 patients were identified, representing 51.65 per 100,000 discharged patients during the study period. The median age was 84 years and 54.5% were male. The majority (506 or 83.8%) came from residential care homes for the elderly. The mean time from admission to diagnosis was 8.8 days for community-acquired infestation. There were 564 and 40 cases of classic and crusted scabies, respectively. The two groups of patients were comparable in terms of residence in elderly homes, co-existing chronic illnesses, mobility, and time from admission to diagnosis. Forty-five (7.5%) patients had positive blood cultures temporally associated with scabies. Patients with crusted scabies were at higher risk for bacteraemia (7/40 versus 38/564, p = 0.022). Permethrin and benzyl benzoate were the most popular treatment regimens, with treatment failure observed in 59/397 (14.4%) and 18/173 (10.4%), respectively. There were 172 (28.5%) mortalities within 30 days of scabies diagnosis. Thus, the burden of scabies infestation is significant in Hong Kong. Hospitalised patients diagnosed with scabies are mainly senior citizens living in residential care homes for the elderly, suggesting reservoirs of S. scabiei in the community. Of concern, bacteraemic illnesses are common and significant mortality is temporarily associated with infestation. With a rising elderly population, there is a pressing need to understand and control scabies in Hong Kong. Our study did not find that common medical illness, besides immunosuppressive therapy, predisposed patients to crusted scabies. The crusted form of scabies was associated with a higher risk of bacteraemia. The current study provides a better perspective of the disease load of scabies in Hong Kong.

Ultrasonography of the salivary glands in Sjögren's disease: own data analysis

Objective: to investigate feasibility of using ultrasonography (US) to evaluate structural changes of salivary glands (SG) in patients with Sjögren's disease (SD).Material and methods. The study included 159 patients who were examined in V.A. Nasonova Research Institute of Rheumatology from 2016 to 2022 who met V.A. Nasonova Research Institute of Rheumatology 2001, and/or ACR 2012, and/or ACR/EULAR 2016 criteria for SD, and who had not previously received immunosuppressive therapy. All patients underwent a comprehensive classical examination (ophthalmological, dental, immunological) to diagnose SD. Disease activity was determined using ESSDAI index. US of the parotid gland (PG) and submandibular SGs was performed using a GE LOGIQ 9 device, and the images obtained were scored according to the OMERACT SGUS scoring system (SGUS SS).Results and discussion. All SGUS SS scores statistically significantly correlated (p&lt;0.05) with mouth sicca symptoms, enlargement of PG, ESSDAI activity index, presence of lymphohistiocytic infiltrate and focus score in labial SG biopsy, and parenchymatous parotitis according to sialography. No significant correlation was found with the results of sialometry. There was a significant correlation between the changes detected by US and sialography (r=0.422; p=0.001). Considering the data obtained, the consistency of the results of the different examination methods was analyzed. Bland-Altman diagrams were created to reflect the dependence of the differences between the results of US and sialography. At various stages of the comparison, not all data points were within the standardized range. In addition, 5% of the parameters were not within the interval of two standard deviations. The Bland-Altman analysis revealed a systematic discrepancy indicating a low degree of agreement between the two methods for determining structural changes in SG. According to the ROC analysis, sensitivity of ultrasound was 94% and specificity 51%. The area under the curve (AUC) was 0.787 (95% confidence interval 0.700–0.875).Conclusion. SG US and sialography are not interchangeable, but complement each other in the assessment of SG structure. SG US is a safer and non-invasive method of SG examination that does not require contrast agent administration and is likely to play an important role in the dynamic monitoring of patients during the therapy. However, sialography is a more accurate method of diagnostics and assessment of the extent of SG lesions.

Anti-Müllerian Hormone Serum Levels as Biomarker of Ovarian Reserve in Adult Women with Juvenile Idiopathic Arthritis Treated with csDMARDs and/or bDMARDs: A Pilot Study

Background/Objectives: Juvenile idiopathic arthritis (JIA) is a chronic childhood disease that often persists into the reproductive years. JIA may impact long-term fertility due to the prolonged exposure to immunosuppressive therapies. Methods: A total of 35 adult JIA female patients of childbearing age and 20 age-matched healthy controls were studied to test their anti-Müllerian hormone (AMH) serum levels as a biomarker of ovarian reserve. Demographic characteristics, disease duration, previous and current treatments, disease activity (DAS44), and a health assessment questionnaire (HAQ) were recorded. Results: JIA patients had a mean age of 22.3 ± 2.9 years, a disease duration of 12.3 ± 6.1 years, and a DAS44 of 1.24 ± 0.61. No differences were found in AMH serum levels between JIA and controls (5.78 ± 2.37 ng/mL vs. 6.60 ± 2.68 ng/mL, respectively; p = 0.17). Among the patients, 22 (62.9%) were receiving a stable dose of methotrexate (MTX) and 19 (54.3%) a dose of TNFα inhibitors. No difference in AMH serum levels was observed between JIA patients who were or were not exposed to MTX (p = 0.29) or to TNFα inhibitors (p = 0.50). Conclusions: Ovarian reserve as assessed by AMH serum levels appears to be comparable between those with JIA and age-matched controls and does not appear to be influenced by disease characteristics or prior/concomitant exposure to immunosuppressive drugs.

Prospective study on immune function in renal transplant patients during perioperative period: A prospective cohort study.

Delayed graft function (DGF) is a type of acute renal failure that is closely linked to the immune system. The objective of this study is to investigate immune trends during the perioperative period of renal transplantation and compare the variations between patients with DGF and immediate graft function (IGF). A total of 48 kidney transplant patients were enrolled. Parameters including stimulated adenosine triphosphatase concentrations (sATP), nonstimulated ATP concentrations, white blood cells, and lymphocyte count were assessed. Patients were categorized into the DGF or IGF group. Clinical information and changes in immune markers were compared. Receiver operating characteristic analysis was performed to determine the sensitivity and specificity in predicting DGF. Additionally, separate immune function analyses were conducted for the 3 infection cases. Following induction immunosuppressive therapy, white blood cells, and neutrophil count showed a significant initial increase followed by a gradual decline. Lymphocyte count, nonstimulated ATP concentrations, and sATP exhibited an initial significant decrease followed by a slow recovery. Immune markers between the DGF and IGF groups were significantly different at day 4 after renal transplantation. Only sATP levels at day 4 after renal transplantation (area under the curve = 0.731, sensitivity = 0.864, specificity = 0.684) demonstrated predictive value for DGF occurrence. Among the 3 infection cases, 2 cases exhibited persistently decreased sATP levels and died within the first month and 6 months, while the remaining case showed a recovery of sATP levels at D9 and survived. These findings indicate that sATP level can potentially serve as a biomarker reflecting the impact of immunosuppressants. Poor recovery of sATP may be associated with DGF, infection, or even mortality.

The Impact of FDA-Approved Novel Agents for Steroid-Refractory Chronic Graft vs. Host Disease on Treatment Patterns and Outcomes—A Single-Center Longitudinal Cohort Analysis

Objectives—chronic graft vs. host disease (cGVHD) is associated with substantial morbidity and mortality. We aimed to analyze advances in treatment strategy and outcomes during the last decade due to the incorporation of novel immunosuppressive therapy (IST) drugs in the armamentarium. Methods—we retrospectively analyzed all patients &gt; 18 years with cGVHD after their first hematopoietic cell transplantation (HCT) between 2012 and 2020 (n = 91), divided into three treatment periods: 2012–2014, 2015–2017, and 2018–2020 (groups 1, 2, and 3, respectively). Results—mean cumulative steroid dose and dose/total cGVHD-treatment days was lower in groups 2–3 compared to 1 (p = 0.008 and p = 0.042, respectively). The median IST-free survival was 79 (95%CI54–94) months, with more patients in group 3 (47% (95%CI 25–54%) discontinuing IST at 3 years, p = 0.1). Groups 2–3 compared to 1 had better glycemic control (p &lt; 0.01), higher bone density (p = 0.06), and fewer cardiovascular events. The number of admissions/patient dropped from 0.7/year in group 1 to 0.24/year and 0.36/year in groups 2–3, respectively (p = 0.36). Employment reintegration was higher in groups 2–3 compared with 1 (p = 0.05) and so was earlier return to work (p = 0.01). There were no differences in survival outcomes. Conclusions—the incorporation of novel agents appears to be associated with reduced overall steroid burden, improved cGVHD control, and fewer long-term side effects.

A limbal stem cell deficiency murine model with residual limbal stem cells.

Bilateral limbal stem cell deficiency (LSCD) is a significant cause of corneal blindness and is more difficult to treat, as compared with unilateral LSCD because no source of autologous limbal stem cells (LSCs) remains in these patients. Thus, bilateral patients could be candidates for treatment with allogeneic LSC transplants that require long-term systemic immunosuppression therapy. Thus, if possible, for the correct candidates, using autologous LSCs could be a preferred treatment. Recent in vivo laser confocal microscopic examination of the ocular surface in situ , combined with impression cytology, has indicated that some patients diagnosed with a complete bilateral LSCD possess residual LSCs. However, it remains unknown whether these residual LSCs still have stem cell potential due to the lack of animal models that mimic this pathology. The goal of the current study is to make a complete LSCD model that possesses evidence of residual LSCs. We induced complete LSCD in mice using two methods: (1) removed the corneal epithelium and the epithelial basement membrane using a rotating burr, and (2) removed the corneal epithelium using 20% ethanol but retained an intact epithelial basement membrane. A complete LSCD was defined by a lack of CK12-positive corneal epithelial cells and the presence of infiltrating CK19-positive conjunctival epithelial cells. Corneas were examined for wound closure, corneal opacity, LSC exhaustion, and inflammation. We observed that complete LSCD mice without an intact epithelial basement membrane resulted in few residual LSCs. By contrast, complete LSCD mice that retained the epithelial basement membrane were accompanied by a reduced inflammatory response plus a significant number of residual LSCs. This model will allow future studies to determine the function of residual LSCs in complete LSCD.

Anticoagulant Treatment May Decrease the Relapse Rate of Pulmonary Arterial Involvement in Behçet's Disease.

Pulmonary arterial involvement (PAI) is one of the most common causes of mortality in Behçet's disease (BD). In this study, we aimed to evaluate the clinical features, course, and recurrence risk factors of BD-associated PAI. BD patients who were followed up in Marmara University BD outpatient clinic between 1990 and 2023 were included. All data were acquired from the medical records of the patients. PAIs were classified according to the type of the vascular involvement as thrombosis or aneurysm. Factors affecting the risk of relapses were determined using multivariate Cox regression analysis. Among 1350 BD patients, 110 (8.1%) had PAI. The mean age (SD) of patients with PAI was 42.4 (11.6) years, and the male/female ratio was 2.2 (76/34). Thirty-two (29.1%) of 110 patients were asymptomatic. Asymptomatic patients with PAI were significantly younger (p = 0.031) than the symptomatic group. Also, a greater prevalence of females (p = 0.001) and higher recurrence rates (p = 0.019) were observed in the symptomatic group. Pulmonary arterial thrombosis was seen in 104 (94.5%) and aneurysms in 9 patients (6.6%). At least one PAI relapse was observed in 31 patients (28.2%). In multivariate analysis, the Cox regression model was significant (p = 0.013), and not starting anticoagulants independently increased the PAI relapse risk (hazards ratio, 4.36; 95% confidence interval, 1.14-24.1; p = 0.042). Pulmonary arterial thrombosis is the main presentation type of PAI in BD, whereas aneurysmatic formation is rare. Despite immunosuppressive treatment, relapses occur during follow-up in one third of patients with PAI. When anticoagulant therapy is added to immunosuppressive therapy, the relapse rate in BD patients with PAI is significantly reduced.

Development and characterization of HCMV recombinant subunit vaccines based on T-cell epitopes

Human cytomegalovirus (HCMV), a ubiquitous β-herpes virus, mostly causes asymptomatic infections in adults with healthy immune systems. Due to immunosuppressive therapy, solid organ transplantation (SOT) recipients are at increased risk of HCMV infection. In recent years, the interdisciplinary, filed of immunoinformatics, based on computer science, and modern immunology, has emerged. In this study, we designed three types of recombinant subunit vaccines, which are expressed by the E. coli BL21 strain according to immunoinformatics prediction. Subsequently, we evaluated the innate and cellular immune responses of recombinant subunit vaccines in vivo and/or in vitro. Flow cytometry analysis, revealed that recombinant subunit vaccines enhanced both innate and cellular immune responses in vivo and/or in vitro. We also found that the novel herb adjuvant hesperetin (HES) increased memory T cell inflation. Overall, we developed three types of recombinant subunit vaccines based on HCMV antigen fragments containing multiple T-cell epitopes and assessed the innate and cellular immune responses in vivo and/or in vitro.

Long-Term Outcomes of Rituximab-Treated Adult Patients with Podocytopathies

Background: Long-term outcomes of rituximab-treated adult patients with podocytopathies (either minimal change disease or focal segmental glomerulosclerosis) are largely unknown. Methods: A retrospective study at 30 nephrology departments from 15 countries worldwide included rituximab-treated adults with primary podocytopathies and a minimum clinical follow-up of 36 months. The primary outcome was relapse-free survival at 36 months. Results: 183 adult patients (n=64 with focal segmental glomerulosclerosis and n=119 with minimal change disease) with difficult-to-treat nephrotic syndrome (68% steroid-dependent/frequently relapsing, 22% steroid-resistant, 85% previously treated with two or more lines of immunosuppressive therapy) were treated with rituximab as part of a remission induction regimen. Complete or partial remission at 6 months after rituximab treatment was achieved in 82%. Eighty-three of 151 (55%) initial responders achieved long-term relapse-free survival over three years. Maintenance therapy with rituximab was associated with a better relapse-free survival (HR 2.05, 95% CI: 1.07-3.91), irrespective of the dosing regimen. At 36 months, 61% of initial responders receiving maintenance therapy with rituximab achieved long-term relapse-free survival and withdrawal of all concomitant immunosuppressive medication compared to 36% of patients without maintenance treatment (OR 2.69, 95% CI: 1.27-5.73). Relapses per year were reduced from an annual relapse rate of 1.0 (95% CI: 1.0-1.7) before to 0.17 (95% CI: 0.00-0.24) relapses/year after rituximab initiation. Over the 36 months of follow-up, a stable course of estimated glomerular filtration rate (eGFR) was observed in those who initially responded with either complete or partial remission, whereas non-responders experienced a reduction in eGFR reaching -11 (95% CI: -18 to -8) mL/min/1.73m2 . Conclusions: Rituximab facilitated achievement of initial and long-term response in a majority of adult patients with difficult-to-treat podocytopathies. Maintenance treatment with rituximab further associated with long-term relapse-free survival over three years. Non-response to initial rituximab treatment was associated with poor kidney prognosis.

Overcoming Graft Rejection in Induced Pluripotent Stem Cell-Derived Inhibitory Interneurons for Drug-Resistant Epilepsy.

Cell-based therapies for drug-resistant epilepsy using induced pluripotent stem cell-derived inhibitory interneurons are now in early-phase clinical trials, building on findings from trials in Parkinson's disease (PD) and Huntington's disease (HD). Graft rejection and the need for immunosuppressive therapy post-transplantation pose potential barriers to more epilepsy patients becoming potential candidates for inhibitory interneurons transplantation surgery. The present literature review weighs the evidence for and against human leukocyte antigen (HLA)-mediated graft rejection in PD and HD and examines the potential advantages and drawbacks to five broad approaches to cell-based therapies, including autologous cell culture and transplantation, in vivo reprogramming of glial cells using viral vectors, allogeneic transplantation using off-the-shelf cell lines, transplantation using inhibitory interneurons cultured from HLA-matched cell lines, and the use of hypoimmunogenic-induced pluripotent stem cell-derived inhibitory interneurons. The impact of surgical technique and associated needle trauma on graft rejection is also discussed. Non-systematic literature review. While cell-based therapies have enjoyed early successes in treating a host of central nervous system disorders, the immunologic reaction against surgical procedures and implanted materials has remained a major obstacle. Adapting cell-based therapies using iPSC-derived inhibitory interneurons for epilepsy surgery will similarly require surmounting the challenge of immunogenicity.

Cross-cultural validation of the Spanish version of the Kidney AlloTransplant Immunosuppressive Therapy Adherence Questionnaire (KATITA-25)

The KATITA-25 (Kidney AlloTransplant Immunosuppressive Therapy Adherence) Questionnaire is a multidimensional self-administered scale developed in Brazilian Portuguese that measures the predisposition for non-adherence to immunosuppressive medication in candidate patients for kidney transplantation, in the pre-transplant setting. The aim of this study was the cross-cultural validation of the Spanish version of the KATITA-25 scale. The translation/back-translation method was used, followed by cognitive interviews and a pre-test. The Spanish version of KATITA-25 was administered to 163 candidate patients for kidney transplantation from 2 kidney transplant centres and 2 dialysis centres in Catalonia, Spain. The scale was re-administered to the first 79 patients included into the study, after a 2 to 4 weeks interval. Internal consistency was assessed using Cronbach’s alpha, test–retest reliability with the intraclass correlation coefficient (ICC); construct validity with goodness of fit indices after confirmatory factor analysis using structural equation modelling. The Cronbach’s alpha of the Spanish version was 0.83, the ICC was 0.86. Confirmatory factor analysis showed adequate fit of the structural model. Overall, the analytical results closely resembled those obtained in the validation of the original scale. In conclusion, this cross-cultural validation study showed adequate reliability and construct validity of the Spanish version of the KATITA-25 questionnaire.

Impact of Neutropenia on Clinical Outcomes after Lung Transplantation.

Neutropenia is a frequent complication among solid organ transplant (SOT) recipients receiving immunosuppressive therapy and antimicrobial prophylaxis. However, there are limited studies analysing the frequency and impact of neutropenia in lung transplant recipients (LTRs). Our aim was to analyse the frequency of neutropenia, the need for granulocyte colony-stimulating factor (GCSF) treatment within the first 18 months post-transplant and its association with acute rejection, chronic lung allograft dysfunction (CLAD), overall survival and the development of infections. This observational and retrospective study recruited 305 patients who underwent lung transplantation between 2009 and 2019, with outpatient quarterly follow-up during the first 18 months post-surgery. During this period, 51.8% of patients experienced at least one episode of neutropenia. Neutropenia was classified as mild in 50.57% of cases, moderate in 36.88% and severe in 12.54%. GCSF treatment was indicated in 23.28% of patients, with a mean dose of 3.53 units. No statistically significant association was observed between neutropenia or its severity and the development of acute rejection, CLAD or overall survival. However, the patients who received GCSF treatment had a higher mortality rate compared to those who did not. Sixteen patients (5.25%) developed infections during neutropenia, with bacterial infections being the most common. Neutropenia is common in the first 18 months after lung transplantation and most episodes are mild. We did not find an association between neutropenia and acute rejection, CLAD, or mortality. However, the use of GCSF were associated with worse post-transplant survival.

Durable Immune Response and Long-term Efficacy of COVID-19 Vaccination in Children With Inflammatory Bowel Disease.

Children with inflammatory bowel disease (IBD) may have diminished serologic response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination and increased risk for subsequent severe coronavirus disease 2019 (COVID-19) infection. We sought to describe outcomes among those who developed SARS-CoV-2 infection following vaccination, characterize SARS-CoV-2 antibodies 1 year post-vaccination, and identify factors associated with durable serologic response. We recruited children with IBD who received ≥2 doses of SARS-CoV-2 vaccine and prospectively collected data on (1) demographics, IBD characteristics, and therapy and (2) SARS-CoV-2 vaccination, testing, and infection symptoms. Serum was obtained for measurement of anti-receptor-binding domain IgG antibodies following a 2-part immunization at 12 and 52 weeks. We enrolled 298 participants (mean age 11.9 ± 3.82, 50% female, 67% Crohn's disease). Symptomatic COVID-19 infection after vaccination occurred in half of the participants, although only 2 (1%) required hospitalization. Anti-tumor necrosis factor alpha (TNF-α) was associated with higher likelihood of symptomatic COVID-19 infection, with an adjusted hazard ratio of 2.7 (95% CI, 1.5-5.0; P = .001). Nearly all participants (99%) had detectable antibody at Week 52. Children aged 1-5 years had lower 52-week antibody level compared to older children (P = .04), as did those on anti-TNF-α therapy (P = .007) and those who received only 2 vaccine doses prior to Week 52 (P < .001). SARS-CoV-2 vaccination provides lasting serologic response and protection against severe COVID-19 for most children with IBD, despite the use of lower vaccine doses in younger children and wide-ranging classes of immunosuppressive therapies.