Use Of Immunosuppressive Drugs Research Articles

Infections in Patients with Systemic Lupus Erythematosus: The Contribution of Primary Immune Defects Versus Treatment-Induced Immunosuppression.

Patients with systemic lupus erythematosus experience high rates of infections. The use of immunosuppressive drugs to treat the disease, along with the fact that both the innate and adaptive branches of the immune system are compromised, account for the development of infections. In this communication, we briefly discuss the aberrant function of the immune system in patients with systemic lupus erythematosus and review the occurrence of infections that have been reported in clinical trials conducted to develop new therapeutics. Understanding the immune dysfunction in patients with systemic lupus erythematosus and the appearance of infections while trying to control the disease using immunosuppressive or immunomodulatory drugs should help limit infections and mitigate the associated morbidity and mortality.

Back to the future: targeting the extracellular matrix to treat systemic sclerosis.

Fibrosis is the excessive deposition of a stable extracellular matrix (ECM); fibrotic tissue is composed principally of highly crosslinked type I collagen and highly contractile myofibroblasts. Systemic sclerosis (SSc) is a multisystem autoimmune connective tissue disease characterized by skin and organ fibrosis. The fibrotic process has been recognized in SSc for >40 years, but drugs with demonstrable efficacy against SSc fibrosis in ameliorating the lung involvement have only recently been identified. Unfortunately, these treatments are ineffective at improving the skin score in patients with SSc. Previous clinical trials in SSc have largely focused on the cross-purposing of anti-inflammatory drugs and the use of immunosuppressive drugs from the transplantation field, which address inflammatory and/or autoimmune processes. Limited examination has taken place of specific anti-fibrotic agents developed through their ability to directly target the ECM in SSc by, for example, alleviating the persistent matrix stiffness and mechanotransduction that might be required for both the initiation and maintenance of fibrosis, including in SSc. However, because of the importance of the ECM in the SSc phenotype, attempts have now been made to identify drugs that specifically target the ECM, including some drugs that are currently under consideration for the treatment of cancer.

The role of efferocytosis and transplant rejection: Strategies in promoting transplantation tolerance using apoptotic cell therapy and/or synthetic particles.

Recently, efforts have been made to recognize the precise reason(s) for transplant failure and the process of rejection utilizing the molecular signature. Most transplant recipients do not appreciate the unknown length of survival of allogeneic grafts with the existing standard of care. Two noteworthy immunological pathways occur during allogeneic transplant rejection. A nonspecific innate immune response predominates in the early stages of the immune reaction, and allogeneic antigens initiate a donor-specific adaptive reaction. Though the adaptive response is the major cause of allograft rejection, earlier pro-inflammatory responses that are part of the innate immune response are also regarded as significant in graft loss. The onset of the innate and adaptive immune response causes chronic and acute transplant rejection. Currently employed immunosuppressive medications have shown little or no influence on chronic rejection and, as a result, on overall long-term transplant survival. Furthermore, long-term pharmaceutical immunosuppression is associated with side effects, toxicity, and an increased risk of developing diseases, both infectious and metabolic. As a result, there is a need for the development of innovative donor-specific immunosuppressive medications to regulate the allorecognition pathways that induce graft loss and to reduce the side effects of immunosuppression. Efferocytosis is an immunomodulatory mechanism with fast and efficient clearance of apoptotic cells (ACs). As such, AC therapy strategies have been suggested to limit transplant-related sequelae. Efferocytosis-based medicines/treatments can also decrease the use of immunosuppressive drugs and have no detrimental side effects. Thus, this review aims to investigate the impact of efferocytosis on transplant rejection/tolerance and identify approaches using AC clearance to increase transplant viability.

Disseminated tuberculosis: Clinical presentation, diagnosis, and outcomes in a tertiary-care hospital in Saudi Arabia.

Tuberculosis (TB) is the primary infectious cause of mortality worldwide. Although TB incidence and prevalence are declining, the use of immunosuppressive drugs and the growing prevalence of immunocompromising conditions such as comorbidities, malignancies, and the use of immunosuppressive agents are risk factors for disseminated TB (DTB). This study aims to identify the relevant clinical, laboratory, radiological, and histopathological features of DTB, as well as to assess the typical anatomical distributions and treatment outcomes of patients diagnosed with the disease at King Abdulaziz Medical City (KAMC). A retrospective chart review was conducted, including all patients diagnosed with miliary or DTB at KAMC with retrievable medical files. The study included 55 patients, of whom 35 (63.6%) were male and the median age was 64 years old. 35 (63.6%) of the infected patients were timely diagnosed and eventually cured from the illness. The most common comorbid conditions were diabetes, chronic kidney disease, and immunocompromising conditions, which were present in 37 (67.2%), 12 (21.8%), and 11 (20%) of the patients, respectively. The most common presenting symptoms were fever and cough, present in 31 (56.3%) and 26 (47.2%) of the patients, respectively, followed by weight loss in 25 (45.4%), night sweats in 15 (27.2%), and shortness of breath in 14 (25.4%). Approximately two-thirds of the patients had pulmonary miliary TB (MTB) (38; 69.1%), followed by TB lymphadenitis (21; 38.2%), central nervous system involvement (13; 23.6%), skeletal involvement (11; 20%), gastrointestinal involvement (5; 9.1%), pleural involvement (3; 5.5%), and urogenital TB (2; 3.6%). The mortality rate was 14 (25.5%) patients. MTB is challenging to diagnose due to nonspecific clinical, laboratory, and imaging findings. Clinicians dealing with patients who are at risk of developing DTB should be aware of the typical presentations and abnormal clinical findings. They should also have a low threshold to initiate specific investigations for the disease, as early diagnosis and effective treatment is critical in reducing morbidity and mortality rates.

Evaluation of leukocyte depletion of packed red blood cell units and impact on clinically observed transfusion reactions.

The aim of this retrospective study was to determine whether there is an association between leukoreduction of packed red blood cell (pRBC) units and reduction of clinically observed transfusion reactions (TR), particularly febrile non-haemolytic transfusion reactions (FNHTR), and better outcomes in dogs. Secondary aims were to evaluate the effects of other factors suspected to influence transfusion reaction frequency or survival, including crossmatching, use of immunosuppressive drugs, and age and number of the blood products being administered. Medical data on dogs transfused with leukocyte-reduced (LR) and non-leukocyte-reduced (N-LR) pRBC units at the Animal Hospital Zürich, University of Zürich, Switzerland between January 1, 2007, and December 17, 2018 were searched. Before 2014, only N-LR blood were transfused. After 2014, both LR and N-LR blood were available. A total of 339 canine patients were transfused with 413 pRBC units; 30.5% (126/413) were LR units and 69.5% (287/413) were N-LR. Data collected from medical records was analyzed using univariate and multivariate logistic regression. In the present study, TR occurred in 19.8% of pRBC units (25/126) with LR and in 17.7% (51/287) of pRBC with N-LR; p > 0.05. FNHTR occurred in 6.3% of pRBC units (8/126) with LR and in 4.5% (13/287) of those with N-LR; p > 0.05. There was no correlation between the occurrence of TR and discharge from hospital (p > 0.05). Crossmatching, immunosuppressive therapy, and age of the blood product were not associated with the frequency of TR; p > 0.05 for all. The duration of survival days was not related to the number of transfusions dogs received. In the present study, the leukocyte-depletion of transfused pRBC units was not associated with fewer TR nor to fewer FNHTR compared to N-LR units. Discharge of dogs from hospital was not dependent on the occurrence of TR.

Biologics and Hypereosinophilic Syndromes: Knowledge Gaps and Controversies.

Hypereosinophilic syndromes (HES) are a heterogeneous group of disorders defined by blood and/or tissue hypereosinophilia and clinical manifestations attributable to the eosinophilia. Although various clinical subtypes of HES have been described, the general approach to therapy in all subtypes has focused on the reduction of blood and tissue eosinophilia to improve symptoms and halt disease progression. Until recently, this typically involved the use of corticosteroids and/or other immunosuppressive or cytotoxic drugs with significant toxicity. Whereas imatinib, the first targeted therapy approved for treatment of HES, has dramatically changed the prognosis of patients with primary (myeloid) forms of HES, it is ineffective in patients with other HES subtypes. For these nonmyeloid patients with HES, the development of eosinophil-targeting biologics (most notably, mepolizumab, the first biologic approved for the treatment of HES) has been transformative. Nevertheless, important issues remain with respect to the efficacy and safety of these biologics in the treatment of the varied subtypes of HES. Moreover, with the increasing number of commercially available biologics with direct or indirect effects on eosinophils, questions related to the choice of initial biologic, potential reasons for biologic failure, and treatment options in the setting of incomplete response are becoming increasingly common.

VEXAS syndrome: Current clinical, diagnostic and treatment approaches.

VEXAS syndrome, is a hemato-inflammatory chronic disease characterized with predominantly rheumatic and hematologic systemic involvement. It was first described in 2020 by a group of researchers in the United States. VEXAS syndrome is a rare condition that primarily affects adult males and is caused by a mutation in the UBA1 gene located on the X chromosome. Its pathogenesis is related to the somatic mutation affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. Mutant gene lead to decreased ubiquitination and activated innate immune pathways and systemic inflammation occur. The specific mechanism by which the UBA1 mutation leads to the clinical features of VEXAS syndrome is not yet fully understood. VEXAS is a newly define adult-onset inflammatory syndrome manifested with treatment-refractory fevers, arthritis, chondritis, vasculitis, cytopenias, typical vacuoles in hematopetic precursor cells, neutrophilic cutaneous and pulmonary inflammation. Diagnosing VEXAS syndrome can be challenging due to its rarity and the overlap of symptoms with other inflammatory conditions. Genetic testing to identify the UBA1 gene mutation is essential for definitive diagnosis. Currently, there is no known cure for VEXAS syndrome, and treatment mainly focuses on managing the symptoms. This may involve the use of anti-inflammatory medications, immunosuppressive drugs, and supportive therapies tailored to the individual patient's needs. Due to the recent discovery of VEXAS syndrome, ongoing research is being conducted to better understand its pathogenesis, clinical features, and potential treatment options. In this review article, the clinical, diagnostic and treatment approaches of VEXAS syndrome were evaluated in the light of the latest literature data.

Coronavirus Disease-2019 Infection among Asians with Autoimmune Rheumatic Diseases—Single Centre Experience in Malaysia

Objectives The coronavirus disease-2019 (COVID-19) pandemic had swiped through the globe since March 2020, claiming many lives. Patients with autoimmune rheumatic diseases (ARD) are potentially at high-risk for severe infection and poor outcome, due to concomitant co-morbidities, disease activity, and immunosuppressive (IS) therapy. We conducted a retrospective observational study to examine the severity and outcome of COVID-19 infection among the Asian population. Materials and Methods The cases were identified through our local healthcare network and patients’ own narration, from March 2020 until April 2022. The data were analyzed with both parametric and non-parametric tests using StatPlus, which included Kruskal-Wallis ANOVA and logistic regression. Results A total 71 cases of COVID-19 infection were recorded, with 9 recurrent infections. All patients were South East Asians and the majority (95.8%) were female. Their median age was 39-years-old. The most common diagnosis was systemic lupus erythematosus (SLE) (56.5%), followed by rheumatoid arthritis (RA) (27.4%). Most patients (54.9%) attained remission and low disease activity for ARD prior to infection. As per treatment, 56.3% of patients were prescribed at least one IS. Fifty-nine point two percent (59.2%) had used steroids, with a mean dose of 6.8±10.5 mg once daily. The COVID-19 infection was asymptomatic and mild in most cases (81.7%). Twelve point seven percent (12.7%) of patients were in severe and critical stages. The case fatality rate was 4.2%. Prior to infection, only 57.7% of patients had a complete vaccination (≥2 doses). Seventy-seven point five percent (77.5%) had at least 1 risk factor portending severe infection. Univariate logistic regression (LR) analyses showed severe COVID-19 infection could be predicted by number of vaccines received, ARD activity and COVID-19 variant type. The use of IS could be associated with better infection outcomes (full recovery without sequelae) and reduced fatality. The type of IS used might affect the infection outcomes too. In patients with complete vaccination, active ARD could predict severe infection. Better infection outcomes could be associated with use of IS. In contrary, risk of fatality could be higher in patients with active ARD and use of high-dose steroids. Further multivariate LR analyses however, did not reveal any predictive factors associated with severe infection, poor infection outcomes and case fatality. Conclusion Our study showed that ARD patients are potentially at risk of severe COVID-19 infection and poor outcomes especially in active ARD state. IS use may be associated with better infection outcomes, perhaps through immunomodulatory effects. In patients with complete vaccination, active ARD and high-dose steroids could be the significant confounding factors. The limitations of this study are the small sample size, and potential bias and error.

Longitudinal study of antibody response following SARS-CoV-2 vaccination with Pfizer-BioNTech BNT162b2

Abstract Objectives To assess the immunity of healthcare and non-healthcare workers in the Alcoy health area (Spain) after completing three doses of the Pfizer-BioNTech vaccine and how it relates with individual factors. Methods We conducted a prospective, observational, longitudinal, analytical study to observe immunogenicity in healthcare and non-healthcare workers at Virgen de los Lirios Hospital following administration of three doses of the Pfizer-BioNTech vaccine. Anti-SARS-CoV-2 spike protein IgG antibody concentrations were determined, while COVID-19 infections were identified by qualitative detection of IgG against the nucleocapsid protein. Samples from volunteers were analyzed 15 days, 3 months, and 6 months after receiving the second vaccine dose, and 12 months after receiving the third (booster) dose. A questionnaire was used to collect demographic data, risk factors, and use of immunosuppressive drugs. Statistical analyses were performed with SPSS software, and mean antibody levels over time were compared using ANOVA. Results Participation was 99.5 % (199/200). The IgG concentration was higher in men and in obese individuals. No significant changes were noted in factors such as smoking. Conclusions All participants developed humoral immunity, except for three subjects who were receiving immunosuppressive treatment. Participants with previous COVID-19 infection had higher antibody levels.

Acute intestinal obstruction in systemic lupus Erythematosus: Case report and review of the literature

Introduction: Gastrointestinal manifestations in systemic lupus erythematosus are common and may involve any segment of the digestive tract. Lupus enteritis is one of the manifestations responsible for abdominal pain. Its treatment is based essentially on corticosteroids. The use of immunosuppressive drugs is reserved for recurrent forms or in case of failure of corticosteroids. Materials and methods: We report a case of “acute intestinal obstruction in systemic lupus erythematosus” in the Department of Emergency visceral surgery. Results: Mrs. SQ, S, 24 years old, was diagnosed one week ago with systemic lupus erythematosus at the beginning of treatment, with a history of pancreatitis stage E, history of current illness goes back to 05 days before her admission by the installation of a sub-occlusive syndrome made of cessation of matter and gas associated with food vomiting, with cessation of matter and gas in the last 48 hours. Para-clinical The Abdomen without preparation showed hydroaeric levels. With an abdominal CT scan which showed: CT scan appearance in favor of bowel obstruction with evidence of a transitional level above the umbilical: inflammatory stenosis? The spontaneously hyper-dense appearance of the colonic lumen and some ileal intestines is most probably related to a digestive hemorrhage that could be part of lupus enteritis given the patient’s past history with the spontaneously hyper-dense appearance of the colonic lumen and ileal intestines most probably related to a digestive hemorrhage. And distension of the jejunal and some ileal coves, measuring: 36mm in maximum diameter, the seat of hydrophobic level with a transitional level above umbilical. Significant gastric distension. No parietal pneumatosis with no parietal enhancement defect. In view of the clinical symptomatology and the CT scan results, the patient underwent an exploratory laparotomy with the following findings: Absence of peritoneal effusion with the presence of a 3 cm distension of the bowel without any sign of flange, stenosis, or detectable obstacle, with the performance of multiple biopsies at the level of the greater omentum, the mesentery, and the anterior parietal peritoneum Conclusion: Intestinal pseudo-obstruction is a rarely reported manifestation during systemic lupus erythematosus. It is a rare but potentially serious manifestation that can reveal the disease or occur during the course of the disease. The use of immunosuppressive drugs is reserved for recurrent forms or in case of failure of corticosteroids. However, recurrences are frequent. Azathioprine is an alternative therapy to control the disease. However, recurrences are frequent. Azathioprine is an alternative therapy to control the disease.

A COVID-19 Overview from the Perspective of the Brazilian Kidney Transplantation Program

The Coronavirus disease 2019 (COVID-19) has significantly affected kidney transplantation activities around the world, thus resulting in a substantial decrease in both deceased and living transplants. This study presents a COVID-19 overview from the perspective of the Brazilian kidney transplant program by comparing its differences or similarities with the situations observed in other countries. During the first year of the pandemic, there was a 40% reduction in the number of kidney transplants worldwide. A similar scenario was observed in Brazil, which has the world’s largest public transplantation program. Beyond its effect on transplant activity, COVID-19 has influenced the outcomes of prevalent kidney transplant recipients (KTRs) because the prolonged use of immunosuppressive drugs and comorbidities increase the susceptibility of such patients to severe disease and death. In the pre-vaccination era, almost two-thirds of KTRs required hospitalization, more than 20% required dialysis, and one-third was admitted to the intensive care unit. In the pre-vaccination period in Brazil, 15% and 21% of KTRs died within 28 and 90 days of COVID-19 diagnosis, respectively. Although high vaccination coverage rates have altered the COVID-19 landscape in many populations, persistently low immunogenicity rates following sequential vaccination shots and the absence of targeted treatments for severe cases continue to classify KTRs as highly vulnerable, thus warranting significant concern.

Incidence of and Risk Factors for Active Tuberculosis Disease in Individuals With Glomerular Disease: A Canadian Cohort Study

Kidney failure is an established risk factor for active tuberculosis (TB) but the risk of TB has not been reported in specific kidney diseases. We sought to determine the incidence of and risk factors for active TB in patients with glomerular disease. Observational cohort study. A provincial kidney pathology registry (2000-2012) was used to identify 3,079 adult patients with IgA nephropathy, focal segmental glomerulosclerosis (FSGS), antineutrophil cytoplasmic antibody (ANCA)-related glomerulonephritis, lupus nephritis, membranous nephropathy, minimal change disease, or "other" glomerular diseases in British Columbia, Canada. Predictors included demographics, immigration status, comorbidities, immunosuppression use, estimated glomerular filtration rate (eGFR), and proteinuria. A diagnosis of active TB was ascertained using administrative data linkages and defined based on (1) the dispensation of 1 or more unique combinations of medications used to treat active TB, or (2) physician or hospital visits for active TB. The definition of TB was validated in an external cohort linked to the Provincial TB registry at the BC Centre for Disease Control (BCCDC). Standardized incidence ratios were calculated using the age-matched general population. Risk factors for active TB were identified using Cox proportional hazards regression analysis. The sensitivity and specificity of the outcome definition of active TB were 87.6% and 99.5%, respectively. During a median follow-up of 6.2 years, 41 patients developed active TB with an incidence of 197 of 100,000 person-years, approximately 23 times as high as the general population and>6 times higher than the threshold of 30 per 100,000 used to define high TB incidence. A high incidence was observed in all glomerular diseases (range, 110-403 per 100,000), in both Canadian- and foreign-born patients (range, 124-424 per 100,000), and in patients exposed or not to immunosuppression (282 vs 147 per 100,000). Factors associated with higher TB risk included immigration from a high-incidence country (HR, 3.90 [95% CI, 1.75-8.68]), diminished eGFR (HR, 2.81 [95% CI, 1.18-6.69]), higher levels of proteinuria (HR, 1.15 [95% CI, 1.04-1.27]), lupus nephritis (HR, 2.79 [95% CI, 1.37-5.68]), and immunosuppression use (HR, 2.13 [95% CI, 1.13-4.03]). A relatively low number of events contributed to uncertainty in risk estimates. Patients with glomerular disease have a high incidence of active TB irrespective of disease type, demographics, or use of immunosuppression. Prospective studies are needed to evaluate the utility of screening for latent TB infection in this population. Patients with kidney failure are at high risk of developing tuberculosis (TB), a major infection that can be prevented by identifying and treating patients who have had prior exposure to TB. The risk of TB in specific kidney diseases is unknown. In this Canadian study of 3,079 patients with glomerular disease, a group of autoimmune kidney conditions, the rate of TB was 23 times higher than in the general population. The rate was high irrespective of the use of immunosuppressive drugs or whether patients had immigrated to Canada from another country. These findings suggest that screening patients with glomerular disease for prior TB exposure may be beneficial; however, this needs to be evaluated in a prospective study.

Toxicity, disease management and outcome of treatment with immune checkpoint inhibitors by sex in patients with cancer and preexisting autoimmune disease.

Female sex is associated with a higher risk for autoimmune diseases (ADs) and immune-related adverse events (irAEs) from immune checkpoint inhibitors (ICIs). While the safety of ICIs in AD cohorts has been reported, sex-segregated data on patient characteristics and outcomes are lacking. In the present study, the disease and treatment characteristics of 51 patients with cancer and preexisting AD (PAD) treated with ICIs at Bern University Hospital Cancer Center (Bern, Switzerland) between January 2017 and June 2021 were analyzed by sex. Rheumatic (n=12/27, 44.4%) and endocrine (n=11/24, 45.8%) PADs were most common among male and female patients, respectively. At the time of ICI initiation, 29.6% (n=8/27) of male and 20.8% (n=5/24) of female patients received immunosuppression for their PAD. Female patients were more likely to experience an irAE (58.3 vs. 48.1%), and less likely to encounter an exacerbation of their PAD (38.5 vs. 14.3%) compared with male patients. Multiple-site irAEs (46.2 vs. 21.4%), implication of an organ specialist for irAEs (100.0 vs. 57.1%) and use of additional immunosuppressive drugs (38.4 vs. 7.7%) were more common in male patients. IrAEs were resolved and ICIs were discontinued in 69.2% (n=9/13) and 71.4% (n=10/14) of the total male and female patients, respectively. Median progression-free survival was higher in male than female patients with irAEs (19.9 vs. 10.7 months) and without irAEs (4.4 vs. 1.8 months). The median overall survival time was higher in male than female patients with irAEs (not estimable vs. 22.5 months) and without irAEs (10.1 vs. 7.4 months). Taken together, these results suggested that sex-related differences existed regarding the clinical presentation of irAEs and treatment outcome.

Imaging Findings in Aspergillosis: From Head to Toe.

Aspergillosis is a mycotic infection induced by airborne fungi that are ubiquitous. Inhalation of Aspergillus conidia results in transmission through the respiratory tract. The clinical presentation is dependent on organism and host specifics, with immunodeficiency, allergies, and preexisting pulmonary disease constituting the most important risk factors. In recent decades, the incidence of fungal infections has increased dramatically, due in part to the increased number of transplants and the pervasive use of chemotherapy and immunosuppressive drugs. The spectrum of clinical manifestations can range from an asymptomatic or mild infection to a swiftly progressive, life-threatening illness. Additionally, invasive infections can migrate to extrapulmonary sites, causing infections in distant organs. Recognition and familiarity with the various radiological findings in the appropriate clinical context are essential for patient management and the prompt initiation of life-saving treatment. We discuss the radiological characteristics of chronic and invasive pulmonary aspergillosis, as well as some of the typically unexpected extrapulmonary manifestations of disseminated disease.

PA34 A case of disseminated herpes zoster in an immunocompetent child

Abstract Herpes zoster (HZ) caused by the reactivation of varicella-zoster virus (VZV) affects mainly the adult population. The incidence is low in children (0.45 cases per 1000 individuals annually), especially in the immunocompetent. It is said to be disseminated when there are > 20 lesions outside the primary and adjacent affected dermatome. We present this case to highlight a rare complication of cutaneous dissemination in a previously healthy child with HZ, following in utero exposure to varicella at 28 weeks’ gestation. A 15-year-old boy presented with painful blisters in the T2 dermatome of 1 week’s duration, which later spread to trunk, extremities and face. This was associated with fever and neuralgia. There was no previous history of varicella and no recent contact history. He had no significant past medical history and was not on any medications. Antenatal history revealed that his mother had varicella at 28 weeks’ gestation and was treated with aciclovir. He was febrile on admission (39°C). There were coalesced vesiculopustules and crusted lesions with marked perilesional erythema in the T2 dermatome. In addition, disseminated vesicular lesions were seen on the trunk, extremities and face. Remaining systemic examination was unremarkable. C-reactive protein was elevated. Complete blood count and renal function tests were normal. Liver function tests, namely alanine transaminase and γ-­glutamyl transferase were elevated. Blood culture showed no growth. Varicella-zoster IgG was positive. Viral swab (polymerase chain reaction) from the skin lesions was positive for varicella-zoster DNA. Infectious serology for HIV, hepatitis B and hepatitis C was negative. Antinuclear antibody and antineutrophil cytoplasmic antibodies were negative. A clinical diagnosis of HZ with cutaneous dissemination was made, and he was treated with intravenous aciclovir. Intravenous antibiotics were added for suspected secondary bacterial infection. Disseminated zoster is less common in children and mainly occurs in patients with underlying immunodeficiency like HIV, immunosuppressive drug use or malignancy. In immunocompetent children, this can happen when primary infection (varicella) has occurred in utero or the first year of life due to the low response in specific varicella-zoster virus immunity. Complications like cutaneous dissemination due to viraemia are rare in healthy children, but can affect 2–10% of immunocompromised patients. It occurs 3–4 days after the onset of dermatomal lesions. It is important to look for other complications, especially in the immunocompromised, as viraemia can affect the brain, kidneys, lung and liver. Sequelae like postherpetic neuralgia is rare, but it is important to follow-up these children to look for its development.

Current Status Regarding Immunosuppressive Treatment in Patients after Renal Transplantation.

Renal transplantation is now the best treatment for end-stage renal failure. To avoid rejection and prolong graft function, organ recipients need immunosuppressive therapy. The immunosuppressive drugs used depends on many factors, including time since transplantation (induction or maintenance), aetiology of the disease, and/or condition of the graft. Immunosuppressive treatment needs to be personalised, and hospitals and clinics have differing protocols and preparations depending on experience. Renal transplant recipient maintenance treatment is mostly based on triple-drug therapy containing calcineurin inhibitors, corticosteroids, and antiproliferative drugs. In addition to the desired effect, the use of immunosuppressive drugs carries risks of certain side effects. Therefore, new immunosuppressive drugs and immunosuppressive protocols are being sought that exert fewer side effects, which could maximise efficacy and reduce toxicity and, in this way, reduce both morbidity and mortality, as well as increase opportunities to modify individual immunosuppression for renal recipients of all ages. The aim of the current review is to describe the classes of immunosuppressive drugs and their mode of action, which are divided by induction and maintenance treatment. An additional aspect of the current review is a description of immune system activity modulation by the drugs used in renal transplant recipients. Complications associated with the use of immunosuppressive drugs and other immunosuppressive treatment options used in kidney transplant recipients have also been described.

Analysis of Adeno-Associated Virus Serotype 8 (AAV8)-antibody complexes using epitope mapping by molecular imprinting leads to the identification of Fab peptides that potentially evade AAV8 neutralisation

Gene therapy is a promising approach for treating genetic disorders by delivering therapeutic genes to replace or correct malfunctioning genes. However, the introduced gene therapy vector can trigger an immune response, leading to reduced efficacy and potential harm to the patient. To improve the efficiency and safety of gene therapy, preventing the immune response to the vector is crucial. This can be achieved through the use of immunosuppressive drugs, vector engineering to evade the immune system, or delivery methods that bypass the immune system altogether. By reducing the immune response, gene therapy can deliver therapeutic genes more effectively and potentially cure genetic diseases. In this study, a novel molecular imprinting technique, combined with mass-spectrometry and bioinformatics, was used to identify four antigen-binding fragments (Fab) sequences of Adeno-Associated Virus (AAV) - neutralising antibodies capable of binding to AAV. The identified Fab peptides were shown to prevent AAV8's binding to antibodies, demonstrating their potential to improve gene therapy efficiency by preventing the immune response.

Tetrandrine inhibits the proliferation of mesangial cells induced by enzymatically deglycosylated human IgA1 via IgA receptor/MAPK/NF-κB signaling pathway.

Objective: Despite the use of renin-angiotensin system blockade and immunosuppressive drugs, including corticosteroids, the current treatment regimens for Immunoglobulins A nephropathy (IgAN) are severely limited. The proliferation of mesangial cell and deposition of deglycosylated human IgA1 immune complex are the most common pathologic features of IgAN. We examined the tetrandrine potential of suppressing the proliferation of mesangial cells and explored its underlying mechanisms with a focus on IgA receptor/MAPK/NF-κB signaling pathway. Methods: Standard human IgA (native IgA) were enzymatically desialylated (deS IgA) or further degalactosylated (deS/deGal IgA) using neuraminidase and β-galactosidase. Rat glomerular mesangial cells (HBZY-1) and human renal mesangial cells (HRMC) stimulated by IgA were used to observe the suppressive effect of tetrandrine. The MTT assay was used to detect the cell viability. The protein expression of IgA receptor/MAPK/NF-κB signaling pathway was examined by Western blot. Cell cycle analysis was measured by flow cytometer. Results: Native IgA and deS IgA showed limited stimulation effect on both HBZY-1 cells and HRMCs, whereas deS/deGal IgA significantly stimulated the proliferation of both HBZY-1 cells and HRMCs (p < 0.05). Compared with non-stimulation of deS/deGal IgA, 1-3μM of tetrandrine had stronger inhibitory effect on the proliferation of HBZY-1 cells and HRMCs with the stimulation of deS/deGal IgA (p < 0.05), suggesting that tetrandrine possibly inhibited the proliferation of mesangial cells induced by deglycosylated human IgA1 specifically. Molecular mechanism study revealed that tetrandrine decreased the expression of IgA1 receptor, CD71 and β4GALT1, and inhibited the activation of MAPK/NF-κB significantly (p < 0.05). Moreover, these inhibitory effect of tetrandrine caused cell cycle arrest and stopped the cell growth in the S phase companied with the upregulating of cyclin A2 and downregulating of cyclin D1. Conclusion: Taken together, tetrandrine inhibited the proliferation of mesangial cells induced by enzymatically deglycosylated human IgA1 via IgA receptor/MAPK/NF-κB signaling pathway. Based on these potential molecular mechanisms, tetrandrine would be an appealing therapeutic option for IgAN.

#3045 EFFICACY AND SAFETY OF MONTHLY-STEROID PULSE THERAPY AND TONSILLECTOMY IN PATIENTS WITH IGA NEPHROPATHY

Abstract Background and Aims In Japan, tonsillectomy and corticosteroid therapy is widely performed in patients with IgA nephropathy, to improve kidney outcomes and reduce proteinuria and hematuria. Over the last decade, patients with IgA nephropathy with ≥1g/day of proteinuria are treated with corticosteroid globally. However, after the results of the STOP-IGA and TESTING trials regarding efficacy and safety, the KDIGO 2021 clinical practice guideline suggest the use of immunosuppressive drugs only in patients who remain at high-risk for progressive chronic kidney disease despite maximal supportive care, after considering the risks and benefits. The TESTING trial showed that even in the reduced-dose group, severe adverse events occurred. In order to reduce steroid-induced toxicity, we administrated steroid pulse therapy monthly for 3 consecutive months and tonsillectomy without post-treatment. Thereafter, the effects and adverse events were evaluated. Method Forty-two patients diagnosed with IgA nephropathy on biopsy at our hospital, with ≥0.3g/day of proteinuria, and who had undergone tonsillectomy and steroid pulse therapy were included in the study. Of these patients, 16 were treated with three months of consecutive steroid pulse therapy without follow-up steroid administration (MSP); the remaining patients were administrated the conventional steroid pulse therapy (SP), including modified Pozzi's (Lancet 1999) and Hotta's (AJKD 2001) regimens. We evaluated and compared the time to proteinuria remission and both hematuria and proteinuria remission between the two groups using Kaplan-Meier curve and log-rank test. Remission of proteinuria was defined as three consecutive urinary protein results of &amp;lt;0.3g/day over 6 months, and that of hematuria was defined as three consecutive results of &amp;lt;5 RBCs/high-power field in the urinary sediment. In addition to efficacy, we compared the incidence rates of adverse events between the two groups. Results There were no significant differences in the age, sex, time to diagnosis, histopathological findings according to the Oxford classification, or RAS inhibitor use between the MSP and SP groups. The eGFR(ml/min/1.73m2) was 81.3 and 78.5, and the urinary protein excretion (g/day) was 1.01 and 1.18, in the MSP and SP groups, respectively. The proteinuria remission rates in the MSP and SP groups were 81% and 69% after one year and 94% and 81% after two years, respectively, with no significant difference. The remission rates of both hematuria and proteinuria were 47% and 46% after one year and 77% and58% after two years, respectively, with no significant differences. The incident rates of adverse events, including diabetes and infections, was 13% and 54% in the MSP and SP groups, respectively, and was significantly lower in the MSP group (p = 0.005). Conclusion Tonsillectomy with monthly steroid pulse therapy was effective and safer than the conventional steroid pulse therapy in patients with IgA nephropathy.

#4843 EFFECT OF MORNING VACCINATION COMPARED WITH AFTERNOON/EVENING VACCINATION ON HUMORAL RESPONSE TO COVID-19 VACCINE IN HEMODIALYSIS PATIENTS

Abstract Background and Aims Patients with ESKD who are undergoing hemodialysis have impaired immunogenicity to SARS-CoV-2 vaccination. Age, dialysis vintage, use of immunosuppressive drugs, serum albumin, lymphocyte count, vaccine type, and COVID-19 experience have been identified to be associated with humoral and cellular responses. A recent review highlights that vaccination responses also exhibit circadian rhythmicity. However, the benefits of vaccination in the morning compared with later times in the day among hemodialysis patients remain unclear. Therefore, we aimed to determine if morning vaccination with a COVID-19 vaccine was able to induce a higher antibody response than afternoon/evening vaccination among hemodialysis patients. Method We conducted a prospective observational study in the hemodialysis unit of Taipei Tzu Chi Hospital, Taiwan. Prevalent hemodialysis patients aged 20 years or over with no history of SARS-CoV-2 infection were eligible for enrollment. Patients were excluded if they had been vaccinated, refused vaccination, had inadequate dialysis, or declined to participate. Patients with current use of immunosuppressants were also excluded. All participants received a priming dose of ChAdOx1 nCoV-19, an adenovirus-vectored vaccine, on June 16 or 17, 2021 during the hemodialysis session. IgG antibodies to the receptor binding domain (RBD) of the S1 subunit of the spike protein of SARS-CoV-2 were measured using the AdviseDx SARS-CoV-2 IgG II assay (Abbot Laboratories, Abbott Park, IL, USA) at Day 28 and Day 56 after vaccination. The cutoff value for positivity was set at ≥50 arbitrary units per mL (AU/mL) based on manufacturer's recommendations. Multivariate logistic regression analyses were used to evaluate the relationship between time of day of vaccination and antibody response. Covariates identified by prior studies as significant predictors of vaccine response or with a P value &amp;lt;0.1 between responders and nonresponders were fitted. Results A total of 201 participants were included, with a male to female distribution of 52% to 48%, a mean age of 67 years, and a median dialysis vintage of 7.7 years. Among the participants, 70 were dialyzed in the morning (between 7:00 AM and 12:00 PM), 69 in the afternoon (between 12:00 and 5:00 PM), and 62 in the evening (between 5:00 and 10:00 PM). Overall, 137 (68.2%) participants developed antibodies against the SARS-CoV-2 spike protein after a single dose of ChAdOx1 nCoV-19. The median antibody level was 184.6 AU/mL. In the multivariate model, morning vaccination, age, coronary artery disease, and lymphocyte count independently predicted a humoral response at Day 28. Participants who received morning vaccination were more likely to develop seroconversion compared with those who received afternoon/evening doses (odds ratio 3.81, 95% confidence interval 1.59–9.15; P = 0.003). Anti-spike antibody titers were measured in 198 participants at Day 56. The median antibody level was 153.7 AU/mL. A significantly higher proportion of morning-vaccinated hemodialysis patients remained seropositive (odds ratio 2.54, 95% confidence interval 1.15–5.61; P = 0.021). Conclusion Our preliminary results showed that circadian rhythms might be harnessed to optimize vaccination strategies for hemodialysis patients. Future studies with larger sample size are required to validate our findings.