Immunosuppressive Doses Research Articles

A Single Centre Case-Series of Covid-19 Infection in Kidney Transplant Recipients

INTRODUCTION: Severe acute respiratory syndrome coronavirus (SARS-CoV) has mutated over time, affecting its virulence, pathogenicity and disease severity. In December 2019, a new coronavirus (SARS-CoV-2) has emerged causing a disease known as coronavirus disease (COVID-19). The COVID-19 has a broad spectrum of severity ranging from an asymptomatic to a severe acute respiratory syndrome requiring mechanical ventilation. COVID-19 is often more severe in people aged 60 years or more, or those with health conditions like lung or heart disease, diabetes, or conditions that affect the immune system including kidney transplant recipients. In this case series, we presented our experience with 17 kidney transplant recipients who had COVID-19 infection. In India, COVID-19 peaked twice: once between August and November 2020, and again between March and June 2021. Thus, there was paucity of COVID-19 data in kidney transplant recipients in India during these times. MATERIAL AND METHODS: Our case series constituted a retrospective observational study involving 17 kidney transplant recipients who experienced COVID-19 infection from November 2020 to September 2021 at a solitary tertiary care center in Pune. Within our institution, the nephrology team assessed kidney transplant recipients with COVID-19 for appropriate immunosuppression dosing, renal drug clearance when deemed necessary, and overall well-being. Treatment for COVID-19 adhered to institutional protocols. RESULTS: In our case series, majority of the patients (n=13) had COVID-19 in March 2021 to July 2021 and the commonest presenting symptoms were fever and cough. Out of 17 kidney transplant recipients included in this case series, 13 patients survived while 4 patients succumbed to infection. CONCLUSION: An individualized, case-based approach to managing transplant recipients with COVID-19 is crucial for achieving favorable clinical outcomes.

Protective Effect of Subcutaneous Drains on Wound Infections in Kidney Transplantation

Wound infections following kidney transplantation are common, with a reported incidence of 5%-19%. In the first few days after surgery, these patients receive extremely high doses of immunosuppression and high volumes of intravenous fluids, and they represent a specific subgroup of surgical patients that may benefit from using prophylactic subcutaneous drains. We analyzed a nonrandomized series of 112 consecutive kidney transplants between January 2017 and December 2019: those who received a subcutaneous drain in addition to the standard retroperitoneal drain (SQ drain group) vs those with a retroperitoneal drain alone (standard group). The SQ drain group had a significantly higher median BMI (31.2 vs 25.8, P < .0001) and a trend towards more patients having diabetes and receiving thymoglobulin on induction. Nonetheless, 1/36 (3%) of patients in the SQ drain group had a documented wound infection requiring packing compared to the standard group 13/73 (17%) (P = .032). When multivariate regression analysis accounted for the potential confounders BMI, thymoglobulin use, and diabetes, the protective effect of the SQ drain was more significant (P = .001). An SQ drain may be a simple and inexpensive method to reduce the rate of wound complications in kidney transplant recipients; prospective studies are warranted.

Cell Communication‐Mediated Selective Drug Delivery for Epitope‐Specific Deletion of Alloreactive T Cells in Organ Transplant

AbstractAllogeneic grafts are vulnerable to the attack launched by host alloreactive T cells, which accounts primarily for allograft failure in the clinic. Conventional pharmacological intervention mainly involves broad‐acting, nonspecific immunosuppressants that provide limited protection over the graft and may cause deleterious side effects due to insufficient allospecificity. Here, core–shell structured nanoparticles co‐loaded with allogeneic antigen (Ag) and immunosuppressive agent Tacrolimus (Ag@FK506‐NPs) are constructed. Dendritic cells (DCs) pulsed with Ag@FK506‐NPs present alloantigenic epitopes on the cell surface as a bait to capture specific T cells, especially CD8+ T cells, for intercellular FK506 transfer and alloreactive T‐cell deletion. Meanwhile, DCs are maintained in an immature tolerogenic state that induces the functional inactivation of recruited T cells. Compared with free FK506, the adoptive transfer of low immunosuppressant dose (25 000‐fold lower) of Ag@FK506‐NPs pulsed DCs is enough to yield a superior antirejection effect in a major histocompatibility complex‐mismatched murine skin transplant model. Of note, due to the cell–cell communication conferred selective T‐cell suppression, the recipient mouse is able to respond to the subsequent stimulation of an irrelevant Ag, indicating that off‐target toxicity is bypassed. Overall, this work may address some of the limitations of current allograft therapeutics.

The involvement of NETs in ANCA-associated vasculitis.

Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a serious autoimmune disease that is characterized by vascular necrosis. The pathogenesis of AAV includes ANCA-mediated neutrophil activation, subsequent release of inflammatory cytokines and reactive oxygen species (ROS), and formation of neutrophil extracellular traps (NETs). Excessive NETs could participate not only in ANCA-mediated vascular injury but also in the production of ANCAs per se as autoantigens. Thus, a vicious cycle of NET formation and ANCA production is critical for AAV pathogenesis. Elucidating the molecular signaling pathways in aberrant neutrophil activation and NETs clearance systems will allow specific therapeutics to regulate these pathways. Currently, standard therapy with high doses of glucocorticoids and immunosuppressants has improved outcomes in patients with AAV. However, AAV frequently develops in elderly people, and adverse effects such as severe infections in the standard regimens might contribute to the mortality. Mechanistically, cytokines or complement factors activate and prime neutrophils for ANCA-binding; thus, C5a receptor blocker has garnered attention as potential replacement for glucocorticoids in clinical settings. Recent studies have demonstrated that receptor-interacting protein kinases (RIPK3) and cyclophilin D (CypD), which regulate cell necrosis, may be involved in ANCA-induced NETs formation. Meanwhile, targeting NETs clearance, including the addition of deoxyribonuclease I (DNase I) and macrophage engulfment, may improve vasculitis. In this review, we focus on the pathogenesis of NETs and discuss potential targeted therapies for AAV based on recent experimental evidence.

Long-term survival from progressive multifocal leukoencephalopathy in living-donor liver transplant recipient with preformed donor-specific antibody

Intensive immunosuppression has enabled liver transplantation even in recipients with preformed donor-specific antibodies (DSA), an independent risk factor for graft rejection. However, these recipients may also be at high risk of progressive multifocal encephalopathy (PML) due to the comorbid immunosuppressed status. A 58-year-old woman presented with self-limited focal-to-bilateral tonic-clonic seizures 9 months after liver transplantation. She was desensitized using rituximab and plasma exchange before transplantation and was subsequently treated with steroids, tacrolimus, and everolimus after transplantation for her preformed DSA. Neurological examination revealed mild acalculia and agraphia. Cranial MRI showed asymmetric, cortex-sparing white matter lesions that increased over a week in the left frontal, left parietal, and right parieto-occipital lobes. Polymerase chain reaction (PCR) of the cerebrospinal fluid for the JC supported the diagnosis of PML. Immune reconstitution by reducing the immunosuppressant dose stopped lesion expansion, and PCR of the cerebrospinal fluid for the JC virus became negative. Graft rejection occurred 2 months after immune reconstitution, requiring readjustment of immunosuppressants. Forty-eight months after PML onset, the patient lived at home without disabling deficits. Intensive immunosuppression may predispose recipients to PML after liver transplantation with preformed DSA. Early immune reconstitution and careful monitoring of graft rejection may help improve outcomes.

Use of steroids in the management of low-risk myelodysplastic syndromes with autoimmune features.

The boundaries between myelodysplastic syndromes (MDS) and immune-mediated cytopenias are often difficult to establish and both conditions may benefit from immunosuppressive therapy. The optimal timing and doses of immunosuppressants are largely unknown. We systematically evaluated a retrospective cohort of 79 patients with low-risk MDS tested for anti-erythrocyte or anti-platelet autoantibodies to assess their frequency and the efficacy of immunosuppression, particularly with steroids. We found autoantibody positivity in 43% of cases and overt autoimmune diseases in 18%, including autoimmune hemolytic anemia, immune thromboctyopenia, and Evans syndrome. Steroid treatment improved cytopenia in about half of patients, with 26% achieving a complete recovery lasting for a median of 12 months. Better responses were observed in anemic patients with anti-erythrocyte autoantibodies than in those with anti-platelet autoantibodies, and the combination with recombinant erythropoietin (7/10) had a possible synergistic effect. Steroid doses were heterogeneous depending on the clinical intent (i.e., anti-inflammatory, immunosuppressive, anabolizing). Patients treated with a dose of 1 mg/kg day of prednisone for overt autoimmune cytopenia showed high rates of complete responses (60%). This observation suggests a trial with a short course (2-3 weeks) of standard steroid doses to ascertain efficacy and properly silence the autoimmune pathogenic mechanism. Steroid-related adverse events (16% of cases) should be monitored carefully in this elderly, frail population. In conclusion, features of autoimmunity are present in more than two-thirds of low-risk MDS patients and a trial with prednisone 0.5-1 mg/kg day for 2-3 weeks, with proper monitoring of adverse events, may be useful to improve cytopenias in selected cases.

Impact of COVID-19 on renal transplant recipients

Introduction: It was essential to explore immunosuppressant management strategies and potential clinical variables associated with COVID-19 related mortality in order to provide insight for clinicians attempting to manage kidney transplant recipients during the ongoing severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) pandemic. Objectives: The aim of the study was to assess the impact of COVID-19 on post-transplant renal function and outcome of immunosuppressant management on COVID-19. Patients and Methods: This is a cross sectional observational study conducted from March 2020 to January 2022 in a tertiary care hospital in South India. Baseline characteristics, comorbidities, history of graft dysfunction, symptoms and immunosuppressant modification was noted. Outcomes of COVID-19 such as acute kidney injury (AKI), need for dialysis and post COVID-19 complications were noted. The statistics were expressed as percentage for categorical variables and mean ± SD for continuous variables. Results: Out of 400 renal transplant patients on regular follow up, 28 patients developed COVID-19. The incidence of AKI was 64.2%. Immunosuppressant dose modification was done in majority of patients [mycophenolate mofetil (28.5%), steroids (53.5%) and tacrolimus (39.2%)]. Outcomes included recovery from AKI in 61.1%, recovery from oxygen dependence in 100% patients with an overall mortality rate of 7.1% patients. About 17.8% patients developed post-COVID-19 complications. Conclusion: Immunosuppressant dose modification during COVID-19 could play a role in development of AKI; infection being an independent risk factor. Patients should be monitored for development of post-COVID-19 complications.

Adalimumab rapidly controls both anterior and posterior inflammation in patients with ocular Behçet syndrome and non-infectious uveitis refractory to conventional therapy: a prospective, 6-month follow-up investigation.

To evaluate the efficacy and safety of adalimumab (ADA, Humira®) for treatment of non-infectious uveitis (NIU)refractory to conventional medications. Anti-tumor necrosis factor-α naive patients with NIU unresponsive to conventional immunosuppressive treatment were treated with ADA. Most cases with NIU were related to ocular Behçet syndrome. Adult cases used 80mg ADA subcutaneously on day 0, 40mg in the first week, and then 40mg every 2-week, while this was 20mg in children. Evaluations were performed pre-treatment and at weeks 2, 8, and 24. The study endpoints were best-corrected visual acuity (BCVA, LogMAR) improvement, anterior chamber (AC) cell grade, vitreous cell and haze grades, decrease in macular thickness and edema, prednisolone dose, immunosuppressive dose, and adverse reactions. Thirty-eight eyes (19 right, 19 left) of 24 patients (14 female, 10 male) with (ocular Behçet syndrome)OBS (n = 27 eyes/18 patients) and NIU (n = 11 eyes/6 patients) were included. Mean age was 29.0 ± 14.1years (range, 5-49) and follow-up time was 24weeks. After ADA, BCVA increased (p < 0.001), and improvements in AC cell grade (p < 0.001), vitreous cell grade (p < 0.001), and vitreal haze grade (p < 0.001) were achieved at the final visit. Mean macular thickness decreased from 243.5 to 235.5µm (p < 0.001). Such a rapid control of both anterior and posterior uveitis was observed in all eyes as early as the second week without relapses during follow-up. No ocular or systemic complications emerged during treatment. ADA is effective and well-tolerated in pediatric and adolescent patients with NIU including OBS refractory to traditional medications and demonstrated corticosteroid- and immunosuppressive-sparing effects with no major side effects.

Use of Immunosuppression and the Risk of Subsequent Overall or Cancer Mortality

To determine the incidence of all-cause and cancer mortality (CM) in association with immunosuppression. Retrospective cohort study at ocular inflammatory disease (OID) subspecialty centers. We harvested exposure and covariate data retrospectively from clinic inception (earliest in 1979) through 2010 inclusive. Then we ascertained overall and cancer-specific mortalities by National Death Index linkage. We constructed separate Cox models to evaluate overall and CM for each class of immunosuppressant and for each individual immunosuppressant compared with person-time unexposed to any immunosuppression. Patients with noninfectious OID, excluding those with human immunodeficiency infection or preexisting cancer. Tumor necrosis factor (TNF) inhibitors (mostly infliximab, adalimumab, and etanercept); antimetabolites (methotrexate, mycophenolate mofetil, azathioprine); calcineurin inhibitors (cyclosporine); and alkylating agents (cyclophosphamide) were given when clinically indicated in this noninterventional cohort study. Overall mortality and CM. Over 187 151 person-years (median follow-up 10.0 years), during which 15 938 patients were at risk for mortality, we observed 1970 deaths, 435 due to cancer. Both patients unexposed to immunosuppressants (standardized mortality ratio [SMR]= 0.95, 95% confidence interval [CI], 0.90-1.01) and those exposed to immunosuppressants but free of systemic inflammatory diseases (SIDs) (SMR= 1.04, 95% CI, 0.95-1.14) had similar mortality risk to the US population. Comparing patients exposed to TNF inhibitors, antimetabolites, calcineurin inhibitors, and alkylating agents with patients not exposed to any of these, we found that overall mortality (adjusted hazard ratio [aHR]= 0.88, 0.89, 0.90, 1.11) and CM (aHR= 1.25, 0.89, 0.86, 1.23) were not significantly increased. These results were stable in sensitivity analyses whether excluding or including patients with SID, across 0-, 3-, or 5-year lags and across quartiles of immunosuppressant dose and duration. Our results, in a cohort where the indication for treatment was proven unassociated with mortality risk, found that commonly used immunosuppressants-especially the antimetabolites methotrexate, mycophenolate mofetil, and azathioprine; the TNF inhibitors adalimumab and infliximab, and cyclosporine-were not associated with increased overall and CM over a median cohort follow-up of 10.0 years. These results suggest the safety of these agents with respect to overall and CM for patients treated with immunosuppression for a wide range of inflammatory diseases. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Association of torque teno virus viremia with liver fibrosis in the first year after liver transplantation.

Torque teno virus (TTV) replication is controlled by immune status, mirroring a degree of immunosuppression after solid organ transplantation. TTV viraemia (TTVv) was associated with acute cellular rejection and infection within the first year after liver transplantation (LT). Long-term data on TTV after LT and correlation with graft injury from protocol biopsies are limited. One hundred plasma samples paired with graft biopsies from a prospective single-center biorepository were analyzed. The median time post-LT was 23 months (range, 2-298). TTVv was detectable in 97%. TTVv decreased over time after LT and showed a significant decline from year 1 to later time points. Hence, TTVv correlated negatively with histologic liver fibrosis (liver allograft fibrosis and Ishak scores) and positively with the overall immunosuppression degree quantified by an immunosuppression score in the first year after LT. There was no association with dosages or trough levels of single immunosuppressants. The pharmacodynamic marker TTVv did not correlate with pharmacokinetic assessments of immunosuppression degree [calcineurin inhibitor (CNI) trough levels or immunosuppressant dosages]-our clinical gold standards to guide immunosuppressive therapy. TTVv was independently associated with histologically proven liver fibrosis after LT in the first year after LT in multivariate analysis. The independent association of histological graft fibrosis with lower TTVv in year 1 underscores that a pharmacodynamic marker would be preferable to individualize immunosuppression after LT. However, a high variability of TTVv at the low immunosuppression doses given after the first year precludes TTV as a clinically useful marker after LT in the long-term liver transplant recipients.

CYTOKINE PROFILE IN RENAL TRANSPLANT PATIENTS IN A LONG-TERM PERIOD AFTER SURGERY

In the long-term period after kidney transplantation, a certain level of tissue inflammation and therefore the production of proinflammatory cytokines, including TNF-α, IL-1β, IL-18 and IL-2 can be found. The aim of our study was to determine the concentrations of TNF-α, IL-1β, IL-18, IL-2 and its soluble receptor (IL-2R) in renal transplant patients, regarding the length of the postoperative period. The study involved 65 patients, transplanted at least 12 months prior to our investigation, divided into three groups, regarding the time passed since the transplantation (12-24, 24-48, and &gt;48 months consecutively). Concentrations of the cytokines in the plasma of the subjects were measured using ELISA method. Group I showed significantly higher concentrations of IL-1b compared to the III (p&lt;0.05), IL-18 compared to the II and III (p&lt;0.05) and TNF-a compared to the II (p&lt;0.05). Cytokine concentrations correlated with the time passed since the transplantation (p&lt;0.05), except for TNF-a. Interleukin-2 correlated negatively with IL-18 and immunosuppressant dosage (p&lt;0.05). Interleukin-1b, IL-18 and TNF-α measurements should be considered for monitoring and detecting potentially subclinical allograft damage in the second year after surgery. However, the dynamics of the change of cytokine concentration may also have been altered by the components of the immunosuppressive protocols used, such as tacrolimus, which is a link that is yet to be examined.

#4667 IMMUNOSUPPRESSION FOR FAILED ALLOGRAFT: HOW PROLONGED AND MUCH IS ADEQUATE?

Abstract Background and Aims The development of human leukocyte antigen (HLA) antibodies towards a failed allograft is a critical factor for the feasibility and outcomes of future transplantation. Therefore, we investigated the factors contributing to sensitization in patients with failed allografts. Method A single-center retrospective study of patients with failed allografts between 2010 and 2020 was performed. Samples for HLA antibodies were tested at the time of graft failure and after immunosuppression withdrawal. Sensitization was defined as more than 80% of calculated Korean panel reactive antibody (PRA) I or PRA II. In addition, variables for affecting sensitization were collected. Results Twenty-three patients were included in the study. The mean flow-up duration after failed allograft was 43 ±33.3 months. The sensitized patients tended to have a longer follow-up period and were exposed to less total calcineurin inhibitor (CNI) than non-sensitized patients. (non-sensitized vs sensitized patients : 27.1±12.9 vs 51.7±37.8 months, p = 0.196; 4.2±4.9 vs. 5.1±2.9 months, p = 0.231 respectively). In multivariate logistic analysis, there was no significant difference regarding the total exposure to CNI and follow-up duration (sensitization group: multivariate odds ratio [OR] 1.188, 95% confidence interval [CI] 0.55–2.52, p = 0.655, OR 1.03, 95% CI 0.97–1.10, p = 0.282, respectively). In some patients, even prolonged immunosuppression after returning dialysis therapy did not prevent sensitization toward failed allograft. Conclusion In this study, there was no significant difference regarding the contributing factors for sensitization in the multivariate logistic analysis. However, in sensitized patients, trends were showing longer follow-up duration and less CNI exposure. Sensitization towards a failed graft might be affected by the dose and duration of immunosuppressant. Finally, the small sample size is one of the limitations of this study, and additional prospective research analysis for patients with failed allografts is needed in the future.

#3385 A STUDY OF CLINICAL SPECTRUM AND THE OUTCOME IN LIVE KIDNEY TRANSPLANT RECIPIENTS IN A TERTIARY CARE CENTRE OF INDIA

Abstract Background and Aims Kidney transplantation has become the treatment of choice for end-stage renal disease as it leads to longer survival and superior quality of life. There is a remarkable disparity in the access and outcome of kidney transplant across the world. Limited health care resources, difficulty in access or sometimes non availability of appropriate medications, difficulties with transportation, limited availability of Nephrologists are common challenges in developing countries and also within a country like India due to diverse socioeconomic and cultural backgrounds. We present the pattern of infection, various causative organisms, causes of allograft dysfunction and the clinical outcome of the admitted live kidney transplant recipients in Nephrology department of a tertiary care center from North-East India. Method This was a single center retrospective observational study carried out in Nephrology Department of Gauhati Medical College, Guwahati, India. The data were collected from the medical records. All the admissions of live renal allograft recipients during the period May 2017- May 2022, were included in the study. Results Out of a total of 156 admissions of renal transplant recipients, male to female ratio was 3.7: 1. Among the live KTRs basic disease, most common was chronic glomerulonephritis (44.8%) followed by CTID (23.9%). Infection related complications were present in 72 (46.1%) cases. Among infection UTI (n = 29, 16.6%) was most common followed by pneumonia (n = 24, 15.4%). Various causes of graft dysfunction (biopsy proven) were ATI (Acute tubular injury), CNI toxicity, chronic ABMR, acute ABMR, recurrence of basic disease, acute TCMR and chronic TCMR. NODAT was found in 14 (9%) of the cases. Out of theses 4 cases, 1 had bacterial pneumonia and 3 had UTI. Of 72 admissions with infection, total 8 patients succumbed to their illness with mortality rate of 11.1%. The most common cause of mortality was sepsis due to UTI. Conclusion The number of admissions of renal transplant cases has increased significantly in last 5 years, indicating the increased availability and affordability of renal transplantation in our country. Of 156 admitted live KTRs, infection was seen in 46.1% (n = 72) cases. UTI remained the most common infection (n = 29, 16.6%) followed by pneumonia (n = 24, 15.4%). Graft dysfunction was seen in 33.9% (n = 53) cases. Chronic ABMR was the most common cause (n = 30, 19.2%) for graft dysfunction. Neglect of necessary hygiene, ignorance of regular follow up and dysregulated immunosuppressive doses have contributed to high infection rate. Lack of regular follow up in post-transplant period due to logistic issues or lack of education and awareness, lack of access to immunosuppressive drugs, etc. are major contributing factors for graft dysfunction in our set up. The condition worsens with the difficult terrain, repeated floods, and lack of transportation from remote areas in Nort Eastern part of India.

Health Related Quality of Life in Juvenile-Onset Systemic Lupus Erythematosus: A Questionnaire-Based Study

ObjectivesThis study aimed to evaluate health related quality of life (HRQOL) in Egyptian children with systemic lupus erythematosus (SLE) using 3 different tools.MethodsIn this questionnaire-based study, 100 children with SLE were included. HRQOL was assessed using the Pediatric Quality of Life Inventory Generic Core Scales (PedsQL™ 4.0 GCS), PedsQL™ 3.0 Rheumatology Module (PedsQL3-RM) and the Simple Measure of the Impact of Lupus Erythematosus in Youngsters (SMILEY). SLE disease activity index (SLEDAI) was used to evaluate activity and SLE International Collaborating Clinics/ American College of Rheumatology Damage Index (SDI) was used to evaluate chronic damage.ResultsAll mean scores of PedsQLTM4.0 GCS domains in SLE patients were lower than published normative data and previously published results of Egyptian healthy controls (p < 0.001). All mean scores of PedsQL-3RM domains were significantly lower than published normative data except for the treatment and pain and hurt domains (p = 0.1, 0.2 respectively). SMILEY scores were low and the lowest domain scores was “Burden of SLE”. Longer duration of illness, higher cumulative steroid doses, higher SLEDAI and SDI scores and presence of obesity were associated with lower scores for all 3 tools (p < 0.001).Conclusion for PracticeThe Arabic copies of PedsQL™ 4.0 GCS, PedsQL3-RM and SMILEY are easily used for Arabic speaking subjects and easily interpreted by physician and can be implemented for frequent monitoring of SLE HRQOL. Controlling the disease activity and using lowest doses of steroids and other immunosuppressive drugs are the corner stone strategies for improving HRQOL in SLE children.

Evaluation and management of abnormal liver enzymes in the liver transplant recipient: When, why, and what now?

Evaluation and management of abnormal liver enzymes in the liver transplant recipient: When, why, and what now?

Role of T cells in the pathogenesis of systemic lupus erythematous: Focus on immunometabolism dysfunctions.

Evidence demonstrates that T cells are implicated in developing SLE, and each of them dominantly uses distinct metabolic pathways. Indeed, intracellular enzymes and availability of specific nutrients orchestrate fate of T cells and lead to differentiation of regulatory T cells (Treg), memory T cells, helper T cells, and effector T cells. The function of T cells in inflammatory and autoimmune responses is determined by metabolic processes and activity of their enzymes. Several studies were conducted to determine metabolic abnormalities in SLE patients and clarify how these modifications could control the functions of the involved T cells. Metabolic pathways such as glycolysis, mitochondrial pathways, oxidative stress, mTOR pathway, fatty acid and amino acid metabolisms are dysregulated in SLE T cells. Moreover, immunosuppressive drugs used in treating autoimmune diseases, including SLE, could affect immunometabolism. Developing drugs to regulate autoreactive T cell metabolism could be a promising therapeutic approach for SLE treatment. Accordingly, increased knowledge about metabolic processes paves the way to understanding SLE pathogenesis better and introduces novel therapeutic options for SLE treatment. Although monotherapy with metabolic pathways modulators might not be sufficient to prevent autoimmune disease, they may be an ideal adjuvant to reduce administration doses of immunosuppressive drugs, thus reducing drug-associated adverse effects. This review summarized emerging data about T cells that are involved in SLE pathogenesis, focusing on immunometabolism dysregulation and how these modifications could affect the disease development.

A review of heart transplant immunosuppressants and nonmelanoma skin cancer.

Heart transplant recipients experience high rates of skin cancer, likely due to greater length or dosage of immunosuppression. We review the impact of immunosuppressive medications on development of nonmelanoma skin cancer (NMSC) in heart transplant recipients. The authors searched keywords "heart transplant" and "nonmelanoma skin cancer" on PubMed in October 2022 for eligible articles available in English. Articles were selected for inclusion based on relevance to heart transplantation and NMSC. If any cited articles within included articles were related to our search they were also included. Of the 29 identified articles, 18 met the inclusion criteria with a total of 11,699 patients. Two studies found that tacrolimus and azathioprine increased the risk of NMSC. Five studies demonstrated that tacrolimus, everolimus, sirolimus, azathioprine and mycophenolate mofetil decreased the risk of NMSC. Three studies described that cyclosporine, tacrolimus, everolimus, sirolimus, azathioprine, mycophenolate mofetil and prednisone had no significant association with the development in NMSC. Two studies did not specify the correlation between immunosuppressant use and NMSC development. Ten studies did not discuss the association of immunosuppressants use with the development of NMSC. Our review highlights the commonly used immunosuppressive drugs that can impact the development of NMSC in heart transplant recipients. A management strategy in immunosuppression-associated skin cancers may ultimately involve adjusting the immunosuppressive regimen. This review serves as a summary of the most commonly used immunosuppressive drugs in heart transplant patients and their tumorigenic mechanisms to guide recommendations for dermatologic follow-up in heart transplant recipients.

Long-term mepolizumab treatment reduces relapse rates in super-responders with eosinophilic granulomatosis with polyangiitis

BackgroundThe mainstay of treatment for eosinophilic granulomatosis with polyangiitis (EGPA) is systemic corticosteroid therapy; some patients also receive intravenous immunoglobulins, other immunosuppressive agents, and biologics. Mepolizumab, an anti-interleukin-5 monoclonal antibody, induces remission and decreases the daily corticosteroid dose; however, the clinical efficacy of mepolizumab in EGPA and the prognosis with long-term treatment with this drug are unknown.MethodsSeventy-one EGPA patients were treated at Hiratsuka City Hospital, Japan, between April 2018 and March 2022. We administered mepolizumab for a mean of 2.8 ± 1.7 years to 43 patients in whom remission could not be induced by conventional treatment. After excluding 18 patients who had received mepolizumab for less than 3 years, we classified 15 patients into a “super-responder group” (the daily dose of corticosteroids or other immunosuppressant could be decreased, or the interval between IVIG treatments could be prolonged) and 10 patients into a “responder group” (neither of these changes was achievable). Eosinophil numbers, serum IgG levels, daily doses of corticosteroids and other immunosuppressants, Birmingham Vasculitis Activity Score (BVAS), and relapse frequency before and after mepolizumab initiation were determined.ResultsBlood eosinophil count at diagnosis and the lowest serum IgG level before mepolizumab treatment were significantly higher in super-responders than in responders (p < 0.05). In super-responders, the prednisolone dose at last visit on mepolizumab treatment was lower than that before treatment (p < 0.01) and lower than that at last visit in the responders (p < 0.01). In both groups, peripheral blood eosinophil numbers and BVAS were lower after starting mepolizumab than before (p < 0.01). BVAS before mepolizumab (p < 0.05) and at last visit (p < 0.01) were lower in super-responders than in responders. Relapse rates every year after the start of mepolizumab were lower in super-responders than in responder groups (p < 0.01). In super-responders, relapse rates were lower during the 3 years following mepolizumab initiation (p < 0.01) and at last visit (p < 0.01) were significantly lower than after 1 year of treatment.ConclusionMepolizumab treatment of super-responders sustainably reduced the relapse rate.

Ultraviolet exposure regulates skin metabolome based on the microbiome

Skin metabolites (< 1500 Da) play a critical role in barrier function, hydration, immune response, microbial invasion, and allergen penetration. We aimed to understand the global metabolic profile changes of the skin in relation to the microbiome and UV exposure and exposed germ-free (devoid of microbiome), disinfected mice (partially devoid of skin microbiome) and control mice with intact microbiome to immunosuppressive doses of UVB radiation. Targeted and untargeted lipidome and metabolome profiling was performed with skin tissue by high-resolution mass spectrometry. UV differentially regulated various metabolites such as alanine, choline, glycine, glutamine, and histidine in germ-free mice compared to control mice. Membrane lipid species such as phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin were also affected by UV in a microbiome-dependent manner. These results shed light on the dynamics and interactions between the skin metabolome, microbiome, and UV exposure and open new avenues for the development of metabolite- or lipid-based applications to maintain skin health.

Treatment of Central Nervous System Post-Transplant Lymphoproliferative Disorder in Immunocompromised Patients with Pancreas Transplant– Between the Rock and a Hard Place (P2-13.002)

<h3>Objective:</h3> To describe the clinical presentation and management of two patients who developed pancreatic transplant rejection during treatment of post-transplant CNS lymphoma (PT-CNSL). <h3>Background:</h3> PT-CNSL is a rare neoplasm developing after immunosuppressive therapy following solid-organ transplantation. Treatment involves reducing immunosuppression, which risks graft rejection. In pancreas transplant recipients, this is associated with increased mortality rates with limited therapeutic alternatives. <h3>Design/Methods:</h3> NA <h3>Results:</h3> <h3>Case Description:</h3> <h3>Case 1:</h3> a 43-year-old female status post pancreas-kidney transplant was diagnosed with PT-CNSL in 2022, initially managed by withholding tacrolimus and initiating rituximab therapy at 375 mg/m2 IV (starting weekly for 3 months, then monthly). The lymphoma regressed with treatment until the patient experienced pancreatic graft rejection (lipase peak 1,124 U/L). This was treated by adding on low-dose tacrolimus which resulted in an improvement in graft rejection and allowed ongoing therapy with rituximab, yielding a complete response of the PT-CNSL. <h3>Case 2:</h3> A 55-year-old female status post pancreas-kidney transplant in 2010, was diagnosed with PT-CNSL in 2021. Treatment involved discontinuation of mycophenolate and tacrolimus and initiation of rituximab at 375 mg/m2 IV (starting weekly for six months, then monthly). Although the lymphoma regressed, the patient experienced acute epigastric pain with a lipase peak of 2,715 U/L with CT of the abdomen illustrating acute pancreatitis. Due to concern for transplant rejection, low-dose tacrolimus was initiated along with rituximab, resulting in resolution of elevated lipase. Continued serial neuroimaging studies demonstrated a complete response. <h3>Conclusions:</h3> PT-CNSL increases morbidity and mortality in pancreas transplant patients with limited treatment options. Treatment should balance maintaining CNS response with careful re-initiation of immunosuppression in the setting of graft rejection; however, there is limited knowledge regarding ideal doses of immunosuppression. We demonstrate that low-dose tacrolimus to prevent graft rejection was safe and effective in treating two patients with PT-CNSL, highlighting the need for further investigation into optimal management strategies. <b>Disclosure:</b> Mrs. Haque has nothing to disclose. Prof. ORLANDO has nothing to disclose. Glenn Lesser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cancer Expert Now. Glenn Lesser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for SDP Oncology. Glenn Lesser has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Agios. Glenn Lesser has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Incysus . Glenn Lesser has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ONO Pharma. Glenn Lesser has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer. The institution of Glenn Lesser has received research support from Denovo Biopharma. The institution of Glenn Lesser has received research support from Oblato . The institution of Glenn Lesser has received research support from Novocure. The institution of Glenn Lesser has received research support from GBM Agile - GCAR. Dr. Strowd has received personal compensation for serving as an employee of Kaplan. Dr. Strowd has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Monteris Medical, Inc. Dr. Strowd has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novocure. Dr. Strowd has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Academy of Neurology. The institution of Dr. Strowd has received research support from Southeastern Brain Tumor Foundation. The institution of Dr. Strowd has received research support from Jazz Pharmaceuticals. The institution of Dr. Strowd has received research support from National Institutes of Health. The institution of Dr. Strowd has received research support from Alpha Omega Alpha. The institution of Dr. Strowd has received research support from American Board of Psychiatry and Neurology. Dr. Strowd has received publishing royalties from a publication relating to health care. Dr. Strowd has received publishing royalties from a publication relating to health care.