Discontinuation Of Immunosuppression Research Articles

Pure Red Cell Aplasia - Post Major ABO Incompatible Allogenic Stem Cell Transplantation Role of Ibrutinib

Pure Red Cell Aplasia (PRCA) is a well-recognized complication of Major ABO-incompatible allogeneic stem cell transplantation. It is featured by anemia, Reticulocytopenia, and the absence of erythroblasts in a normal-appearing bone marrow biopsy. The mechanism for PRCA is presumed to be the persistence of recipient isoagglutinins, produced by residual host B lymphocytes or plasma cells, which probably interfere with the engraftment of donor erythroid cells. Several risk factors for PRCA have been reported, such as the presence of Anti-A Isoagglutininsbefore transplantation, reduced intensity conditioning, absence of Graft Versus Host Disease (GVHD), sibling donor and Cyclosporin A(CsA) as GVHD prophylaxis. PRCA is not a barrier to going ahead with Hematopoietic Stem Cell Transplantation (HSCT). There are many therapeutic options however few recover spontaneously, among the available options include high-dose steroids, Erythropoietin(EPO), Plasma exchange, Donor lymphocyte Infusion (DLI), treatment with Rituximab, Bortezomib, Daratumumab and tapering or discontinuation of immunosuppression. All these options have variable success in the literature ranging from 30% - 70%, Non-responders become red cell transfusion dependent and their quality of life is impaired. We are reporting a novel therapeutic option, Ibrutinib as an armamentarium in treating the PRCA post-HSCT, which works by blocking the Bruton Tyrosine Kinase (BTK) pathway thereby inhibiting the host B cell isoagglutinins production and good clinical response.

The co-occurrence of sarcoidosis and anti-PLA2R-associated membranous nephropathy in a patient with underlying genetic susceptibility

BackgroundSarcoidosis is a multisystemic inflammatory disease, characterized by the presence of non-caseating, epithelioid granulomas. Glomerular disease in patients with sarcoidosis is rare and membranous nephropathy (MN) is cited as the most common. The association between the two diseases remained unclear. This article reported a case of co-occurrence of sarcoidosis and anti-PLA2R-associated MN, to provide a possible relationship between these two entities.Case presentationA 61-year-old Chinese Han woman with a history of sarcoidosis was admitted to our hospital for nephrotic syndrome. Her sarcoidosis was diagnosed according to the adenopathy observed on the computed tomography scan and the biopsy of lymph nodes. The MN presented with nephrotic syndrome with a PLA2R antibody titer of 357RU/ml, and the final diagnosis was based on a renal biopsy. The patient’s sarcoidosis was remitted after treatment with prednisone. One year later MN was diagnosed, and she was treated with prednisone combined with calcineurin inhibitors, based on a full dose of renin-angiotensin system (RAS) inhibitor. The patient’s sarcoidosis had been in remission while the MN was recurrent, and her renal function deteriorated to end-stage renal disease 6 years later due to discontinuation of immunosuppression. A genetic test led to the identification of the HLA-DRB1*0301 and HLA-DRB1*150 genes associated with both sarcoidosis and MN, which provides a new possible explanation of the co-occurrence of these two diseases.ConclusionThis case suggested for the first time a potential genetic connection between idiopathic MN and sarcoidosis which needs further studies in the future.

Neurological Adverse Events Related to Immune Checkpoint Inhibitors: A Practical Review.

The increasing use of immune checkpoint inhibitors (ICI) in cancer therapy has brought attention to their associated neurotoxicities, termed neurological immune-related adverse events (n-irAEs). Despite their relatively rare incidence, n-irAEs pose a significant risk, potentially leading to severe, long-lasting disabilities or even fatal outcomes. This narrative review aims to provide a comprehensive overview of n-irAEs, focusing on their recognition and management. The review addresses a spectrum of n-irAEs, encompassing myositis, myasthenia gravis, various neuropathies, and central nervous system complications, such as encephalitis, meningitis, and demyelinating diseases. The key features of n-irAEs are emphasized in this review, including their early onset after initiation of ICIs, potential association with non-neurological irAEs and/or concurrent oncological response, the significance of ruling out other etiologies, and the expected improvement upon discontinuation of ICIs and/or immunosuppression. Furthermore, this review delves into considerations for ICI re-challenge and the intricate nature of n-irAEs within the context of pre-existing autoimmune and paraneoplastic syndromes. It underscores the importance of a multidisciplinary approach to diagnosis and treatment, highlighting the pivotal role of severity grading in guiding treatment decisions.

Lupus Nephritis Outcomes after Stopping Immunosuppression.

Background/Objectives: Immunosuppression (IS) is a standard therapy for lupus nephritis (LN). Data on the outcomes of patients with LN after the discontinuation of immunosuppression remain uncertain. This study aimed to evaluate the outcomes and results of patients with lupus nephritis (LN) who ceased immunosuppressive (IS) therapy. Methods: Records were obtained on the clinical and laboratory features of LN patients who were treated at our Lupus Unit. They included median values and ranges for various numerical variables such as patient age, disease duration, and treatment duration. Categorical variables such as gender, LN class, IS treatment type, and patient outcomes, which were categorized as either "stable" or "flare experienced", were presented as percentages and frequencies. A flare in LN was characterized by a two-fold increase in serum creatinine levels and a rise in proteinuria following the cessation of IS medication. Results: Outcomes were assessed for 45 patients with LN who ceased IS therapy after achieving remission. The patients' median age was 55 years (29-78). The median duration of treatment was 4 years (0.5-14). The LN histology distribution was class V = 24.4%, class IV = 17.8 %, class III = 17.8%, class III + IV = 15.6%, class III + V = 6.7%, class IV + V = 2.2%, and class II + IV and II = 2.2%. At the discontinuation of IS treatment, creatinine levels were elevated in 9/45 (20%) patients. Furthermore, 28.9% of patients relapsed after IS treatment discontinuation. Patients with anti-Smith antibodies (anti-Sm) were observed to have a higher occurrence of relapses, with six patients experiencing flare compared to four patients who remained stable (p = 0.03). Five (38.5%) of the patients with flares had high creatinine levels after IS discontinuation. Conclusions: Most of our patients maintained clinical remission and stable levels of LN parameters after IS treatment discontinuation. Those with a high serum creatinine level, ongoing proteinuria, depleted complement levels, and the presence of anti-Sm antibodies were more likely to experience flares after the discontinuation of IS therapy.

Mycophenolate and methotrexate are better tolerated than azathioprine in myasthenia gravis

Azathioprine is recommended as the first-line steroid-sparing immunosuppressive agent for myasthenia gravis. Mycophenolate and methotrexate are often considered as second-line choices despite widespread consensus on their efficacy. We aimed to gather real-world data comparing the tolerability and reasons for discontinuation for these agents, by performing a national United Kingdom survey of side effects and reasons for discontinuation of immunosuppressants in myasthenia gravis. Of 235 patients, 166 had taken azathioprine, 102 mycophenolate, and 40 methotrexate. The most common side effects for each agent were liver dysfunction for azathioprine (23 %), diarrhoea for mycophenolate (14 %), and fatigue for methotrexate (18 %). Women were generally more likely to experience side effects of immunosuppressants. Azathioprine was significantly more likely to be discontinued than mycophenolate and methotrexate due to side effects. There was no significant difference in treatment cessation due to lack of efficacy. This study highlights the significant side-effect burden of treatment for myasthenia gravis. Mechanisms to reduce azathioprine toxicity should be utilised, however mycophenolate and methotrexate appear to be good treatment choices if teratogenicity is not a concern. Women are disadvantaged due to higher frequency of side effects and considerations around pregnancy and breastfeeding. Treatments with improved tolerability are needed.

Severe Recurrence and Retinal Inflammatory Infiltration After Cessation of Immunosuppression for Multifocal Choroiditis and Panuveitis.

To describe a severe recurrence of intraocular inflammation following the cessation of immunosuppression, previously administered for multifocal choroiditis and panuveitis (MCP). Retrospective chart review. A 27-year-old woman with MCP initially was treated with intravenous and oral corticosteroids and photodynamic therapy because of an active macular neovascularization in both eyes. Mycophenolate was soon started and the recurrences during tapering of the oral corticosteroids in the first months were treated with periocular corticosteroids and anti-vascular endothelial growth factor injections as they became available. After a decade of immunosuppression without recurrences, the patient, having relocated, discontinued mycophenolate upon the advice of a new ophthalmologist who diagnosed her with punctate inner choroidopathy. This led to a severe recurrence in both eyes, characterized by new inflammatory lesions, ellipsoid zone loss, and widespread inflammatory cell infiltration into the outer retina. Intravitreal triamcinolone injections resulted in the resolution of sub- and intraretinal inflammatory lesions and ellipsoid zone defects. The abrupt discontinuation of immunosuppression in a patient with MCP was associated with a rebound phenomenon, characterized by multi-level inflammatory activity in the posterior pole. This rebound phenomenon may offer clues as to the inflammatory targets in MCP.

Flares of acute graft-versus-host disease: a Mount Sinai Acute GVHD International Consortium analysis

AbstractThe absence of a standardized definition for graft-versus-host disease (GVHD) flares and data on its clinical course are significant concerns. We retrospectively evaluated 968 patients across 23 Mount Sinai Acute GVHD International Consortium (MAGIC) transplant centers who achieved complete response (CR) or very good partial response (VGPR) within 4 weeks of treatment. The cumulative incidence of flares within 6 months was 22%, and flares were associated with a higher risk of nonrelapse mortality (NRM; adjusted hazard ratio [aHR], 4.84; 95% confidence interval [CI], 3.19-7.36; P < .001). Flares were more severe (grades 3/4, 41% vs 16%; P < .001) and had more frequent lower gastrointestinal (LGI) involvement (55% vs 32%; P < .001) than the initial GVHD. At CR/VGPR, elevated MAGIC biomarkers predicted the future occurrence of a flare, along with its severity and LGI involvement. In multivariate analyses, higher Ann Arbor (AA) biomarker scores at CR/VGPR were significant risk factors for flares (AA2 vs AA1: aHR, 1.81 [95% CI, 1.32-2.48; P = .001]; AA3 vs AA1: aHR, 3.14 [95% CI, 1.98-4.98; P < .001]), as were early response to initial treatment (aHR, 1.84; 95% CI, 1.21-2.80; P = .004) and HLA-mismatched unrelated donor (aHR, 1.74; 95% CI, 1.00-3.02; P = .049). MAGIC biomarkers also stratified the risk of NRM both at CR/VGPR and at the time of flare. We conclude that GVHD flares are common and carry a significant mortality risk. The occurrence of future flares can be predicted by serum biomarkers that may serve to guide adjustment and discontinuation of immunosuppression.

Successful use of tacrolimus for treatment-refractory neuroblastoma-associated opsoclonus-myoclonus-ataxia syndrome: A case series.

Opsoclonus-myoclonus-ataxia syndrome (OMAS) is an autoimmune central nervous system disorder, primarily manifesting as a paraneoplastic sequalae to neuroblastoma, and characterized by motor disorders and behavioral disturbances. OMAS is typified by aberrant B-cell and T-cell activation. Current treatment involves immunosuppression using corticosteroids, intravenous immunoglobulin, and rituximab. However, these approaches often lead to treatment-related toxicities and symptomatic recurrences with chronic neurocognitive impairment. We treated three children with refractory neuroblastoma-associated OMAS with tacrolimus, a T-cell-targeting calcineurin inhibitor, effectively controlling symptoms within a month and enabling the discontinuation of immunosuppression with minimal side effects. Tacrolimus shows promise as a therapeutic option for refractory OMAS.

Feasibility of discontinuing immunosuppression in children with idiopathic nephrotic syndrome.

Despite adverse events associated with the long-term use of immunosuppressants, their long-term discontinuation remains challenging in children with idiopathic nephrotic syndrome. Relapse and resumption of immunosuppressants after discontinuation and associated risk factors were analyzed. This single-center retrospective cohort study included children with frequently relapsing/steroid-dependent nephrotic syndrome (FRNS/SDNS) or steroid-resistant nephrotic syndrome (SRNS) who initiated immunosuppressant treatment between 2010 and 2020. Patients treated with immunosuppressants for less than two years, those with genetic SRNS, and those with continuation of immunosuppressants were excluded. Sixty-eight patients with FRNS/SDNS or SRNS discontinued immunosuppressants. Discontinuation of immunosuppressants was more frequently tried in patients with less relapse on initial immunosuppressants and less rituximab administration. Of 68 patients who discontinued immunosuppressants, 45 (66%) relapsed and 31 (46%) resumed immunosuppressants with a median follow-up of 39.8months (IQR 24.6-71.2months) after discontinuation. The relapse-free survival rates were 40.0%, 35.3%, and 35.3% in 1, 2, and 3years from discontinuation of immunosuppressants, respectively. Relapse on initial immunosuppressants (HR 2.038, 95%CI 1.006-4.128, P = 0.048) and the relapse-free interval before discontinuation of immunosuppressants (HR 0.971, 95%CI 0.944-0.998, P = 0.037) were significant risk factors associated with relapse after the discontinuation of immunosuppressants, adjusting for sex, age at immunosuppressant treatment initiation, SRNS, and rituximab use. Long-term discontinuation of immunosuppressants can be feasible in patients without a relapse on initial immunosuppressants, those with longer relapse-free interval before discontinuation of immunosuppressants, and those without a relapse for one year after discontinuation of immunosuppressants. Not applicable.

Withdrawal of immunosuppressants and low-dose steroids in patients with stable IgG4-RD (WInS IgG4-RD): an investigator-initiated, multicentre, open-label, randomised controlled trial

ObjectivesIgG4-related disease (IgG4-RD) is an immune-mediated, fibroinflammatory disease. Induction treatment with glucocorticoid (GC) is usually effective, but its tendency of relapse makes the strategy for maintenance treatment a challenge. The...

Post-Transplant Cyclophosphamide-Based Prophylaxis and Its Impact on the Immune Reconstitution and the Incidence of Infectious Complications

Introduction PTCY-based prophylaxis is becoming increasingly prevalent across allogeneic hematopoietic cell transplantation (allo-HCT) due to its efficacy on GVHD prevention. However, using PTCY has been associated with delayed engraftment, immune reconstitution, and high infectious complications. Although different studies have investigated how PTCY interacts with infectious risk after allo-HCT, whether the incidences of these complications differ depending on donor type has not been widely investigated. At our institution, PTCY-based prophylaxis has become our institutional prophylaxis irrespectively of the selected donor type. This study explores the incidences of infectious complications and immune cell reconstitution dynamics in patients undergoing allo-HCT with PTCY and according to the donor type selected. Methods This study included the 253 consecutive adults who underwent peripheral blood allo-HCT with PTCY at our institution between 2013 and 2021. Retrospective data was updated in June 2023. All patients received levofloxacin 500mg daily from day +1 until neutrophil engraftment. No patient received letermovir. Cumulative incidences (CI) analyses have been estimated considering death as competing event and reported at day +30, +100, +180, and 1-year. Infection density was calculated by dividing the number of infections of a patient by the observed time period after allo-HCT. Immune reconstitution was evaluated by the measurement of lmmunoglobulin (IgG), CD4+T-cell (CD4) and CD8+T-cells (CD8) levels in alive patients without relapse history. Results The median age was 53 years (range, 18-70 years), with 44 (17.6%) patients older than 65. Acute myeloid leukemia was the most common underlying diagnosis (38%), and 103 (41%) patients received myeloablative conditioning regimens. As reported in Table 1, 120 (47.4%) patients received grafts from HLA-matched donors, 84 (33.2%) from 9/10 HLA mismatched unrelated donors (MMUD) and 49 (19.4%) from haploidentical donors (haplo-HCT). To perform the statistical analysis, the study cohort was divided into 3 groups according to donor type. Baseline characteristics were balanced between these 3 groups, except for the proportion of patients with HCT-CI&amp;gt;3, higher in HLA-matched donor group (p=0.028). As shown in Table 1, 244 (96%) patients engrafted. The median of days to neutrophil and platelet engraftment, and the CIs of clinically relevant acute and chronic GVHD did not differ according to the donor type. Moreover, the duration of the immunosuppression and post-transplant outcomes were similar in all groups. Bacterial bloodstream infections (BSI) were predominantly diagnosed within the first 30 days post allo-HCT, and with a tend to higher incidence in allo-HCT performed from HLA-matched donors (p=0.07). CMV reactivation was the most frequent viral infection in all groups, occurring mostly between days +30 and +100, and with a higher CI in the MMUD group (p=0.033). CMV disease, grade 2-4 BK hemorrhagic cystitis, VHH6 reactivation/disease and fungal infection CIs were not prevalent post-transplant complications generally occurring during the first 100 days after allo-HCT, with comparable CI differences among the 3 groups. The CI of respiratory viral infections increased steadily during the first year after allo-HCT, with similar incidences among the 3 study groups. Infection density analysis showed comparable volume of infections complications in the 3 study groups. As shown in Figure 1, a higher infection density was observed during the first 100 days after allo-HCT (with approximately 1 or 2 number of infections occurring during that time period in most of the patients). After day +100, the number of infections progressively decreased during the post-transplant follow-up. Immune reconstitution was measured in 139 (55%) alive patients. IgG, CD4, and CD8 levels tended to normalize in most patients from day 180 onwards, with median days to normalization of 208, 216, and 203 days, respectively, and with no differences according to donor type. Conclusions Patients undergoing allo-HCT with PTCY-based prophylaxis have a relevant infectious density rate during the peri-engraftment phase with no differences according to donor type. Infectious complications decreased 6 months after allo-HCT, and in parallel with discontinuation of immunosuppression and immune reconstitution with no differences according to donor type.

Flares of Acute Graft-Versus-Host Disease: Mount Sinai Acute Gvhd International Consortium (MAGIC) Study

[Background] The current standard first-line treatment for acute graft-versus-host disease (GVHD), systemic high-dose steroids, induces clinical responses in a majority of patients. Flares of GVHD after initial improvement often occur during tapering or discontinuation of immunosuppression. There is no consensus regarding the definition of GVHD flare and little has been published regarding its natural history. [Methods] We retrospectively evaluated clinical data and blood samples from 968 allogeneic hematopoietic cell transplantation (HCT) recipients from 23 Mount Sinai Acute GVHD International Consortium (MAGIC) transplant centers who achieved complete response (CR) or very good partial response (VGPR) within 4 weeks of acute GVHD treatment between 2014 and 2021. VGPR was defined as the complete resolution of acute GVHD manifestations except residual stage 1 skin disease. Flares were defined as a recurrence of acute GVHD after achievement of CR/VGPR if (1) patients had an increased symptom severity of at least 1 organ stage; (2) received intensified treatment (increase in steroid dose ≥ 0.25 mg/kg or initiation of additional systemic immunosuppression); and (3) had no prior history of primary disease relapse or donor lymphocyte infusion preceding the flare. Serum samples obtained at the time of CR/VGPR and at the time of flares were analyzed for ST2 and REG3α concentrations that generated MAGIC algorithm probabilities (MAPs) resulting in previously validated Ann Arbor (AA) scores (1, 2, and 3). [Results] The median recipient age at HCT was 55 years (range: 0 to 79); 18.6% of patients had grades III-IV acute GVHD before CR/VGPR. The median maximum daily dose of corticosteroids before CR/VGPR was 1 mg/kg methylprednisolone equivalent (range, 0.1 to 3.2 mg/kg). Flares developed within 6 months following CR/VGPR in 210/968 (21.7%) patients with a median onset of 28 days (range: 2 to 448). Symptom severity at the onset of flare symptoms varied widely (grade I: 22%; grade II: 38%; grade III-IV: 41%) and the development of a flare was associated with a five-fold increase in NRM (hazard ratio [HR], 4.84 [95% CI, 3.19-7.36], P &amp;lt; 0.001) when considered as a time-dependent covariate in a multivariate regression model. The large majority of non-relapse deaths after flares (54/71, 76%) were due to acute GVHD or complications from its treatment. The AA scores at the time of first CR/VGPR successfully stratified patients for risk of six-month NRM (AA1: 5%, AA2: 11%, AA3: 34%, P &amp;lt; 0.001) (Figure A). Increasing AA score at CR/VGPR was also associated with significantly increased risk of GVHD flares (Figure B). Not only did the risk of flare increase with each rising AA score, but the number of patients with severe (grade III/IV) symptoms at flare onset also increased (AA1: 34%, AA2: 43%, AA3: 54%). We next generated a multivariate regression model of risk factors for the development of flares. High AA scores at the time of CR/VGPR (AA2: HR, 1.81 [95% CI, 1.32-2.48], P = 0.001; AA3: HR, 3.14 [95% CI, 1.98-4.98], P &amp;lt; 0.001), HCT from HLA mismatched unrelated donor (HR, 1.74 [95% CI, 1.00-3.02], P = 0.049), and interestingly, rapid achievement of CR/VGPR from the time of initial treatment (≤14 days) (HR, 1.84 [95% CI, 1.21-2.80], P = 0.004) were all identified as significant risk factors. Meanwhile, no other transplant, GVHD, or treatment characteristics associated with the development of flares including maximum GVHD severity, maximum steroid dose, and use of additional immunosuppressive agents other than steroids before CR/VGPR. AA scores measured at the onset of flare symptoms in 98 patients also predicted six-month NRM (AA1, 6%; AA2, 19%; AA3 42%, P = 0.01). [Conclusion] Despite advances in treatment, flares of GVHD symptoms following excellent (CR/VGPR) responses still occur in over one fifth of patients in current practice and are associated with a five-fold increase in six-month NRM. AA scores from serum biomarkers predict outcomes despite the absence of symptoms, suggesting that MAGIC biomarkers detect subclinical damage to GI crypts that can drive later recrudescence of clinical GVHD. Measurement of the MAP at the time of response to GVHD treatment may thus help to risk-stratify tapering strategies of immunosuppressive therapy.

Long-term Course of Kidney Function in Uterus Transplant Recipients Under Treatment With Tacrolimus and After Transplantectomy: Results of the First Clinical Cohort.

Chronic kidney disease is common after non-renal solid organ transplantation, mainly secondary to calcineurin inhibitors toxicity. Uterus transplantation (UTx) is an innovative treatment for women with absolute uterine factor infertility. UTx is exclusive because it is transient with the absence of lifelong immunosuppression and is performed in young healthy participants. Therefore, UTx provides a unique setting for evaluating the effect of time-limited calcineurin inhibitors treatment on recipients' kidney function. In the first UTx cohort worldwide, we studied kidney function using estimated glomerular filtration rate (eGFR) in 7 women over a median follow-up of 121 (119-126) mo. Median eGFR (mL/min/1.73 m2) of the cohort was 113 at UTx, which declined to 74 during month 3, 71 at months 10-12, 76 at hysterectomy (HE), and 83 at last follow-up. Median duration of tacrolimus exposure was 52 (22-83) mo, and median trough levels (µg/L) were 10 during month 3 and 5.8 at HE. Between UTx and month 3, decline in kidney function was observed in all 7 participants with a median eGFR slope for the whole cohort of -24 mL/min/1.73 m2, which declined further by -4 mL/min/1.73 m2 until months 10-12. Thereafter, eGFR slope improved in 3 participants, remained stable in 3, and worsened in 1 until HE/tacrolimus discontinuation, after which it improved in 2. Eventually, between UTx and last follow-up, 4 of 7 participants had a decline in their eGFR, the median annual eGFR slope being negative at -1.9 mL/min/1.73 m2/y for the whole group. Kidney function declined in all recipients early after UTx followed by a persistent long-term decrease in majority, despite transplantectomy and discontinuation of immunosuppression. Thus, UTx may incur an increased risk of chronic kidney disease even in this young and healthy population, highlighting the importance of close surveillance of kidney function and minimization of tacrolimus exposure.

Immunosuppression-Free Life after Pediatric Liver Transplant: A Case-Control Study from the Society of Pediatric Liver Transplant (SPLIT) Registry

To compare long-term outcomes of pediatric liver transplant (LT) recipients off immunosuppression (IS) with matched controls on IS using data from the Society of Pediatric Liver Transplant (SPLIT) registry. This was a retrospective case-control study. SPLIT participants <18years of age, ≥4years after isolated LT, and off IS for ≥1year (cases) were age- and sex-matched 1:2 to patients with the same primary diagnosis and post-LT follow-up duration (controls). Primary outcomes included retransplantation, allograft rejection, IS comorbidities, and prevalence of SPLIT-derived composite ideal outcome (c-IO) achieved at the end of the follow-up period. Differences were compared using multiple linear regression for continuous outcomes and logistic regression for dichotomous data. The study cohort was composed of 33 cases (42.4% male, 60.6% biliary atresia, median age at LT of 0.7 [P25, P75, 0.5, 1.6] years, median IS withdrawal time of 9 [P25, P75, 6, 12] years after LT) and 66 age- and sex-matched controls. No cases required retransplantation. Cases and controls had similar growth parameters, laboratory values, calculated glomerular filtration rates, rates of post-transplant lymphoproliferative disease, graft rejection, and attainment of c-IO. No differences in allograft rejection rates, IS complications, or c-IO prevalence were seen between SPLIT patients off IS and age- and sex-matched controls remaining on IS. Discontinuation of IS most commonly occurred in the context of rigorously designed IS withdrawal trials. The available sample size was small, affecting generalizability to the broader pediatric LT population.

#4760 LUPUS NEPHRITIS RELAPSE AFTER IMMUNOSUPPRESSION WITHDRAWAL: A SPANISH MULTICENTER STUDY

Abstract Background and Aims In lupus nephritis (LN), therapeutic schemas for remission induction are well known but data about duration of maintenance treatment are limited. There is no agreement between clinical practice guidelines about duration and withdrawal of therapy, and literature regarding this topic is scarce. Recently, a RCT has observed that immunosuppression discontinuation after 2‒3 years was related to LN relapse when compared with immunosuppression maintenance. However, immunosuppressive agents are related to severe adverse events and toxicity. We conducted this study with the aim to evaluate the incidence of LN relapse in a cohort of patients with discontinuation of immunosuppressive treatment after a first LN flare. We also aimed to determine factors associated to the presence of renal relapse in this population. Method Multicenter retrospective observational study including patients with biopsy proven LN who have received immunosuppressive treatment that was subsequently discontinued. Patients on prednisone at doses lower than 5 mg per day were allowed to be included. Patients were diagnosed between 1990 and 2018. The study was conducted in Spain. Relapse was defined according to Malvar et al criteria. Results 113 patients were included, mean age was 34.11 ±14.56 years-old and 85.8% were women. Serum creatinine at the time of LN diagnosis was 1.09±0.63 mg/dL, and proteinuria 3.16±2.53g/24h, ANA were positive in 85.84%, and anti-DNA Abs in 69.91%. Serum C3 and C4 levels were 72.51±44.06 and 13.04±11.27 respectively. 55.75% presented with class IV LN, 12.39% with class III or V LN, and 8.85% with class II. Mixed forms were less frequent. In a follow up period of 172.53±162.95 months, 17.7% (n = 20) presented a renal flare after immunosuppressive drugs withdrawal. Time from LN to relapse was 89.05±39.87 months, and time from immunosuppression discontinuation to relapse was 37.75±32.13 months. There were no differences in baseline characteristics between patients who relapsed and patients who did not, neither in histologic characteristics at the time of LN diagnostic biopsy except for glomerulosclerosis, that was less frequent in the relapse group (20% vs 34.41%, p = 0.0435). However, a tendency to a shorter time under immunosuppression in patients who relapsed was observed (73.55±79.06 vs 110.79±206.87 months). Data about treatment withdrawal in each group are summarized in Figure 1. Interestingly, there were no differences between both groups in steroids withdrawal (75% vs 78.49%,p = 0.7327) and hydroxychloroquine withdrawal (33.33% vs 21.74%, p = 0.3393). At the time of immunosuppression discontinuation, patients who relapsed presented lower serum C3 and C4 levels (78.79±24.89 vs 112.26±35.52, p = 0.0080 and 13.82±6.07 vs 23.09±12.56, p = 0.0333), but there were no differences in terms of renal function at this moment. At the end of follow up, patients who relapsed presented more albuminuria (227.87±259.79 vs 78.65±24.77, p = 0.0289) but creatinine levels were similar in both groups (0.84±0.30 vs 0.84±0.30, 0.5105). Only one patient died and two patients required renal replacement therapy, all in the no relapse group. Conclusion In a cohort of 113 patients with biopsy proven LN who were treated con immunosuppression and subsequently discontinued, 17.7% presented renal relapse at a mean time of 37 months after withdrawal. There was a tendency to a short time on immunosuppressive regimens in patients who relapsed. Also, lower serum C3 and C4 levels at the time of immunosuppression withdrawal were associated to renal relapse. At the end of a follow up of 14 years, patients who relapsed those who did not showed a similar maintained renal function but those who relapsed presented lower albuminuria.

Discontinuation of immunosuppression in patients with immune-mediated drug-induced liver injury or idiopathic autoimmune hepatitis: A case-control study.

Drug-induced liver injury (DILI) may present with autoimmune features and require immunosuppressive therapy (IST) to reach biochemical response. Discontinuation of IST without hepatitis relapse may be more frequent in these patients as compared to patients with classical autoimmune hepatitis (AIH). We aimed to determine baseline characteristics and outcome of patients with immune-mediated drug induced liver injury (IMDILI) with particular emphasis on IST during follow-up. We performed a single-center retrospective study of consecutive patients presenting at a tertiary care center between January 2005 and December 2019 either with IMDILI or with classical AIH, for whom full baseline characteristics and a close follow-up were available over a 12-month period. Overall, 31 patients (IMDILI n= 16, mean age 59[34-74] years; AIH n= 15, mean age 47 [15-61] years) were included, showing similar biochemical, serological, and histological characteristics. Incriminating drugs in IMDILI patients were mostly represented by nonsteroidal antiinflammatory drugs and sartans. Initial corticosteroids combined with IST led to biochemical response in all patients. Compared to idiopathic AIH, more patients with IMDILI were weaned off corticosteroids at the end of follow-up (11/16 [68.7%] vs 4/15 [26.6%], P< 0.02). At 1 year of follow-up, more patients in the IMDILI group compared to the classical AIH group were off any type of IST (13/16 [81%] vs 15/15 [100%], P= 0.08). Although presenting with similar baseline biochemical and histological characteristics as idiopathic AIH, patients with IMDILI may not require long-term IST.

From the Editor’s Desk…

From the Editor’s Desk…

An 8-month-old boy with infantile nephrotic syndrome caused by semaphorin 3B-associated membranous nephropathy.

We present a case of nephrotic syndrome caused by semaphorin 3B-associated membranous nephropathy. The patient was an 8-month-old male infant who presented with severe proteinuria and hypertension. He was treated with prednisolone (PSL) for nephrotic syndrome; however, remission was not achieved within 4weeks. He was diagnosed with steroid-resistant nephrotic syndrome and underwent kidney biopsy. Pathological examination revealed membranous nephropathy with IgG deposits on both the glomerular basement membrane (GBM) and the tubular basement membrane (TBM). He was treated with cyclosporine (CsA) in addition to PSL and achieved complete remission. However, frequent relapses occurred after the discontinuation or tapering of immunosuppressants. Two years after treatment initiation, a second biopsy was performed and showed worsening of the disease, which required treatment with several immunosuppressants to achieve complete remission. After that, we performed additional immunostaining for semaphorin 3B, which confirmed the diagnosis of semaphorin 3B-associated membranous nephropathy. Although extremely rare in infantile cases, semaphorin 3B-associated membranous nephropathy should be considered in the differential diagnosis, as strong treatment with immunosuppressants might be needed. In addition, mycophenolate mofetil showed an effective clinical response in this case, indicating that it can be considered for future treatment strategies.

Effect of Maintaining Immunosuppression After Kidney Allograft Failure on Mortality and Retransplantation.

We performed a single-center retrospective study of patients transplanted from October 2007 to May 2017 with AF. We collected data on demographics, immunosuppression, calculated panel reactive antibody (cPRA) levels, death, retransplantation, and dialysis. Cox regression models were used to evaluate factors associated with death and retransplantation. From October 2007 to May 2017, 1354 solitary ABO-compatible transplants were performed, of which 97 failed. Ten percent of patients received a preemptive retransplant. Among those who returned to dialysis (n = 87), 35% died, 25% received another transplant, and 30% remained on dialysis. After AF, 46% of patients discontinued immunosuppression. The cPRA was unchanged if immunosuppression was maintained, but immunosuppression discontinuation was associated with increased cPRA from a median (interquartile range) of 18 (0-99) to 96 (88.5-100.0; P = 0.003). Age at failure (hazard ratio, 1.1; confidence interval, 1.0-1.1) and cardiovascular disease were associated with death (hazard ratio, 2.9; confidence interval, 1.2-7.0) in multivariate analysis. Importantly, immunosuppression maintenance was not associated with increased death or retransplantation despite the increase in cPRA that occurred when immunosuppression was discontinued. Kidney transplant recipients with AF have a high mortality rate after dialysis initiation. Although immunosuppression withdrawal was associated with increased cPRA, it was not associated with reduced retransplantation. Therefore, it is reasonable to discontinue immunosuppression after AF despite sensitization if retransplantation is delayed.

Antibody response to a third SARS-CoV-2 vaccine dose in recipients of an allogeneic haematopoietic cell transplantation.

Allogeneic haematopoietic cell transplantation (allo-HCT) recipients show impaired antibody (Ab) response to a standard two-dose vaccination against severe acute respiratory syndrome coronavirus-2 and currently a third dose is recommended as part of the primary vaccination regimen. By assessing Ab titres 1 month after a third mRNA vaccine dose in 74 allo-HCT recipients we show sufficient neutralisation activity in 77% of the patients. Discontinuation of immunosuppression before the third vaccine led to serological responses in 50% of low responders to two vaccinations. Identifying factors that might contribute to better vaccine responses in allo-HCT recipients is critical to optimise current vaccination strategies.