Immunosuppressive Research Articles

A Scoping Review of Arthropod-Borne Flavivirus Infections in Solid Organ Transplant Recipients.

Arthropod-borne flaviviruses (ABFs), transmitted by mosquitoes or ticks, are increasing due to climate change and globalization. This scoping review examines the epidemiology, clinical characteristics, diagnostics, treatment, and outcomes of ABF infection in solid organ transplant recipients (SOTRs). A database search up to January 25, 2024, focused on ABFs such as West Nile virus (WNV), dengue virus (DENV), Japanese encephalitis virus (JEV), Powassan virus (POWV), yellow fever virus (YFV), and Zika virus (ZIKV), limited to SOTRs. We identified 173 WNV cases from 84 studies, with 28 donor-derived infections (DDIs). Common clinical features included fever (78.5%), altered mental status (65.1%), and weakness or paralysis (45.6%). Treatment involved reducing immunosuppression (IS) in 93 cases, with intravenous immunoglobulin (IVIG), interferon alfa-2b, and ribavirin used in 75 cases. Seven cases involved graft loss or rejection post-infection. WNV infection had a 23.7% mortality rate, with severe neurological complications in 43.9% For DENV infection, 386 cases from 47 studies were identified, including 14 DDI cases. Symptoms included fever (85%), myalgias (56.4%), and headache or retro-orbital pain (34.6%). Severe dengue occurred in 50 cases (13.0%). IVIG was administered in six cases. Reduction in IS was reported in 116 patients. DENV mortality rate was 4.9%. Additionally, 26 cases of less common ABFs such as JEV, POWV, YFV, and ZIKV were described. In summary, ABF infections among SOTRs are associated with higher morbidity and mortality compared to the general population, emphasizing the need for improved preventive strategies, timely diagnosis, and optimized management protocols.

Peripheral blood immune cells distribution in biopsy-proven myocarditis: etiology and prognostic correlates

Abstract Background Myocarditis is an inflammatory disease of the myocardium with viral or immune-mediated/autoimmune etiology. Definite etiological diagnosis relays on endomyocardial biopsy (EMB). High titre anti-heart autoantibodies (AHA) define severe autoimmune forms. Virus-negative myocarditis may require immunosuppression (IS) to reduce progression to dilated cardiomyopathy, heart transplant or death. Prognostic stratification is incomplete and IS is not always efficacious. Animal and human studies suggest a pathogenetic role of immune cells, but little is known on their peripheral distribution or prognostic role. Purpose Characterize EMB-proven myocarditis patients’ peripheral blood to identify new non-invasive etiological and prognostic biomarkers. Methods Seventy-eight EMB-proven myocarditis patients and 9 healthy controls (HC) were enrolled according to the Declaration of Helsinki and written informed consent was collected for each participant. Peripheral blood mononuclear cells were purified by Ficoll stratification and immune cells distribution was evaluated by flow cytometry. Variables were analysed by Mann-Whitney or Kruskall-Wallis and Dunn post-hoc tests clustering patients according to clinical features, EMB and AHA results. Results Compared to HC (figure 1), plasmacytoid dendritic cells were reduced in myocarditis patients: with autoimmune/lymphocytic forms (p=0.0091); without extra cardiac autoimmune diseases (AD, p=0.0075); in those unresponsive to IS (p=0.0379) or never treated because of spontaneous healing (p=0.0015). Moreover, several immunophenotypical features discriminated myocarditis type/IS-response from HC. Viral forms were characterized by reduced CD94+ NK cells and CCR2 over-expression in intermediate monocytes (p=0.029, p=0.013). Autoimmune cases were defined by: higher CD62L+ NK cells when AHA negative (p=0.019); increased Th1 if not requiring IS (p=0.03); higher γδ-TCR+ Th17 and reduced Treg cells if without other AD (both p=0.04), or higher CD4+/IL17+ cells with concurrent AD (p=0.02) and AHA positivity (p=0.036). Moreover, ongoing IS treatment influenced peripheral cells distribution: whole blood cell counts were more frequently altered and total NK cells were reduced (p=0.007); treg cells were reduced in patients actively treated but unresponsive to IS (p=0.036). Conclusion Biopsy-proven myocarditis patients showed a skewed peripheral blood distribution of either innate or adaptive immune cells according to different histology, etiology (viral vs autoimmune) and response to IS in autoimmune forms, unveiling potential new non-invasive immunological biomarkers for myocarditis. Figure: Plasmacytoid dendritic cells (pDCs) percentage was assessed by flow-cytometry and data were showed by boxplots clustering myocarditis patients for etiology (A), EMB histological result (B), presence of extracardiac AD (C) or IS response (D). Data were analysed by Kruskall-Wallis (graph bottom) and Dunn post-hoc tests.

Steroid-sparing strategy for the treatment of vasculitis associated with antineutrophil cytoplasmic antibodies

Glucocorticoids (GC) and immunosuppressants (IS) are traditional treatments for vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA), often resulting in the development of infections, diabetes mellitus and other adverse events (AEs). The development of a steroid-sparing strategy using biologic disease-modifying antirheumatic drugs (bDMARDs, including rituximab, etc.) and synthetic targeted drugs (avacopan) has radically improved the course of the disease. Currently, there are increasing number of basic and clinical trials of numerous bDMARDs that effectively reduce the number of AEs associated with GC and IS. The steroid-sparing therapeutic strategy not only shows considerable efficacy, but also opens up new perspectives for the treatment of patients with ANCA-associated systemic vasculitis.

T cell immuno-phenotyping : a source of predictive biomarkers for autoimmune hepatitis relapse

Relapse after immunosuppression (IS) treatment withdrawal is frequent in patients with Autoimmune Hepatitis (AIH), and non-invasive biomarkers predictive of this risk are lacking. We assessed the frequency of circulating T cell subsets as potential biomarkers of disease activity and predictor of the risk of relapse after IS withdrawal. Serum levels of the cytokine B-cell Activating Factor (BAFF) were also investigated. Blood samples from 58 patients with active AIH, 56 AIH patients in remission, and 31 patients with NASH were analyzed. The frequency of activated CD4+ T peripheral helper (TPH) cells (CD4+CD45RA-CXCR5-PD1+CD38+) and of activated CD8+ T cells (CD8+CD45RA-PD1+CD38+) were assessed by flow cytometry. BAFF levels were determined by ELISA. Activated TPH and CD8+ T cell frequencies were significantly increased in patients with active AIH compared to remission AIH or NASH (TPH: 0.88% of total CD3+ vs. 0.42% and 0.39% respectively, p < 0.0001; CD8+ subset: 1.42% vs. 0.09% and 0.11% p < 0.0001). Among patients in remission undergoing treatment withdrawal (n = 18), those with increased frequencies of activated TPH (> 0.5% of total CD3+) and/or activated CD8+ T cells (> 0.18% total CD3+) had a higher risk of relapse (80% vs. 15% after 2 years, p = 0.0071). High BAFF serum concentration (> 213pg/ml) was also associated to a higher risk of relapse (57% vs. 11%, p = 0.0452). In conclusion, high frequency of activated TPH and of activated CD8+, as well as high levels of BAFF, before IS discontinuation, were significantly associated to a greater risk of relapse during the first two years. Thus, they represent promising biomarkers to provide personalized clinical follow-up for patients with AIH.

Erosive Tarsal Conjunctival Lesions Following Immunogenic Events in Early Development of Ocular Graft-vs-Host Disease.

Ocular graft-versus-host disease (oGVHD) affects more than half of the patients following allogeneic hematopoietic stem cell transplantation (HSCT). The disease onset and the pathogenesis of oGVHD are not well understood. We hope to identify the triggers and explore the clinical signs and symptoms of oGVHD development at the early stages. The records of post-HSCT patients seen consecutively in a 1-year span in a single provider's clinic were reviewed. The history, symptoms, and clinical findings of the patients with erosive tarsal conjunctival lesions (ETCLs) were analyzed. Out of the 228 patients screened, 19 had clinically witnessed ETCL in at least one eye during the period. Twelve (63%) patients had a never-before-described nodular erosion on the subtarsal conjunctiva; seven (37%) had previously described pseudomembranous erosions. The ocular symptom onset was within 1 month after immunosuppression (IS) taper, vaccination, or donor lymphocyte infusion (DLI) in 16 of the 19 patients. While 16 (84%) patients reported painless mucous discharge, only 9 (47%) reported dryness as the initial symptom. Within 6 months, only 4 (21%) had discharge but 15 (82%) patients endorsed dryness. Subepithelial conjunctival fibrosis followed ETCL immediately in situ. Corneal punctate staining increased with time, while aqueous tear production decreased. The ETCL described is likely one of the earliest detectable findings of oGVHD and triggered by certain immunogenic events. The ocular symptoms of wet mucous discharge should be considered a warning sign for oGVHD onset, particularly when it occurs shortly after prominently immunogenic events.

Primary FSGS Patient Response to Immunosuppression (IS) and Risk of ESKD

Primary FSGS Patient Response to Immunosuppression (IS) and Risk of ESKD

Diverse Clinical and Immunological Profiles in Patients with IPEX Syndrome: a Multicenter Analysis from Turkey.

Immunodysregulation, Polyendocrinopathy, Enteropathy, and X-linked syndrome (IPEX), caused by pathogenic FOXP3 variants, is a rare autoimmune disorder with diverse clinical features, including early-onset diabetes, eczema, and enteropathy. Atypical cases show milder symptoms and unique signs, requiring different treatments. Therefore, there are ambiguities in the accurate diagnosis and management of IPEX. We sought to present clinical, genetic, and immunological assessments of 12 IPEX patients with long-term follow-up to facilitate the diagnosis and management of the disease. Clinical findings and treatment options of the patients were collected over time. Lymphocyte subpopulations, protein expressions, regulatory T (Treg) and circulating T follicular helper (cTFH) cells, and T-cell proliferation were analyzed. Predominant presentations included autoimmunity (91.6%), failure to thrive (66.7%), and eczema (58.3%). There were four classical and eight atypical IPEX individuals. Allergic manifestations were more common in atypical patients. Notably, chronic diarrhea demonstrated heightened severity compared to other manifestations. Four patients (33.3%) demonstrated eosinophilia, and nine (75%) showed high serum IgE levels. Most patients exhibited normal percentages of Treg cells with reduced CD25, FOXP3, and CTLA-4 expressions, corrected after hematopoietic stem cell transplantation (HSCT). Compared to healthy controls, the TH2-like skewing accompanied by reduced TH17-like responses was observed in cTFH and Treg cells of patients. Overall, nine patients (75%) received immunosuppressants (ISs), and six (50%) underwent HSCT, which was the only treatment revealing sustained control. Sirolimus was used in six patients and showed better control than other ISs. The first cohort from Turkey with long-term follow-up results, comparing typical and atypical cases, provides insights into the outcomes of different therapeutic modalities and T- cell subtype changes in IPEX syndrome.

Efficacy and safety of telitacicept, a BLyS/APRIL dual inhibitor, in the treatment of IgA nephropathy: a retrospective case-control study.

Telitacicept, a B lymphocyte stimulator/A proliferation-inducing ligand dual-target fusion protein, has recently been used in autoimmune diseases. We assessed the efficacy and safety of telitacicept in immunoglobulin A nephropathy (IgAN) patients. This study included 42 IgAN patients who received telitacicept treatment, forming the 'whole telitacicept group'. Among them, 20 patients who had not previously received corticosteroid (CS) therapy or immunosuppressive (IS) agents were categorized as the 'newly treated telitacicept subgroup'. Additionally, 28 patients who were selected to match historical controls received conventional IS therapy (CS therapy with/without IS agents) and were classified as the 'conventional IS group'. Telitacicept was partially used in combination with conventional IS therapy, including initial CS in different doses. Various indicators were compared at 4-week intervals up to 24weeks among the three groups. After 24weeks of treatment, the 24-hour proteinuria decreased from 1.70g [interquartile range (IQR) 1.05-2.58] to 0.21g (IQR 0.39-0.13) (P=.043) in the newly treated telitacicept subgroup, from 1.78g (IQR 0.97-2.82) to 0.44g (IQR 1.48-0.16) (P=.001) in the conventional IS group and from 1.07g (IQR 0.66-1.99) to 0.26g (IQR 0.59-0.17) (P=.028) in the whole telitacicept group. The estimated glomerular filtration rate (eGFR) increased from 76.58±30.26ml/min/1.73m2 to 80.30±26.76ml/min/1.73m2 (P=.016) in the newly treated telitacicept subgroup, from 72.73±33.41ml/min/1.73m2 to 84.08±26.81ml/min/1.73m2 (P=.011) in the conventional IS group and from 70.10±32.88ml/min/1.73m2 to 71.21±31.49ml/min/1.73m2 (P=.065) in the whole telitacicept group. During follow-up periods, the efficacy rates of the three groups did not show statistically significant differences and no serious adverse events were observed. Telitacicept may be a safe and effective treatment for IgAN, offering reductions in proteinuria and increases in eGFR similar to conventional IS therapy. After a 24-week follow-up, the incidence of adverse events was lower for telitacicept than for conventional IS therapy.

Perspective on oral medication adherence among patients with acute graft-versus-host disease: a qualitative descriptive study

PurposeDespite the importance of adherence to immunosuppressants (IMMs) after an allogeneic haematopoietic stem cell transplant (HSCT) for the treatment of acute graft-versus-host disease (aGvHD), no studies to date have reported the experiences of such patients concerning medication adherence (MA). Therefore, the aim of the study was to explore the perspective on MA to immunosuppressive oral therapy among allogeneic HSCT patients with aGvHD.MethodsA qualitative descriptive study following a reflexive thematic analysis methodological approach was performed involving a purposive sample of 16 patients with aGvHD who were being cared for in the outpatient setting of a bone marrow transplant centre and were willing to participate. Semi-structured audio-recorded interviews were conducted, transcribed verbatim and thematically analysed; member checking was performed. COnsolidated criteria for REporting Qualitative research (COREQ) and the ESPACOMP Medication Adherence Reporting Guideline were followed.ResultsParticipants aged 25–74 years and mostly males (62.5%) were recruited for this study; 56.2% developed grade I, 37.5% grade II and 6.3% grade III aGvHD; 56.2% were receiving treatment with both cyclosporine and prednisone. Patients' perspectives have been summarised into four themes, named: “Transiting from an external obligation to a habit”; “Being in the middle between the negative and positive effects of the IMMs”; “Failure to systematically respect the rules”; and “Adopting personal strategies to become adherent”. After difficulties with the perception of feeling obliged, patients became used to adhering to IMMs. Although there were failures in systematically taking the medication correctly and there were episodes of non-adherence, the adoption of personal strategies helped patients to become adherent to their medication schedules.ConclusionsMA in patients with aGvHD is a complex behaviour and is often a challenge. These results can help healthcare professionals and centres to understand how best to design tailored strategies and behavioural interventions to maximise patients’ MA to IMMs.

The evaluation of neurologists’ awareness on hepatitis B virus reactivation before launching immunosuppressive treatment

Background: Individuals encountering hepatitis B virus (HBV) are at risk of hepatitis B virus reactivation (HBVr) when exposed to immunosuppressive (IS) therapy. Here, we aimed to evaluate neurologists’ knowledge on HBVr in patients receiving IS treatment and draw attention to importance of the issue. Methods: Eighty-six physicians from neurology departments throughout Turkey between 1st March- 30th April 2020 were enrolled. Results: Of 86 physicians (average age 37.2±7.6 years), 34 (39.5%) were affiliated with university hospitals, 23 (26.7%) in training and research hospitals, and 29 (33.6%) in secondary healthcare centers. While 28 (32.5%) stated following a guideline, 58 (67.4%) declared following no guidelines. Physicians receiving postgraduate training on HBVr administered prophylaxis before IS treatment at a higher rate (p=0.04), and 69 (80.2%) considered all patients receiving any IS treatment should be screened for HBVr. To all participants, patients selected for screening should be tested for HBsAg; 83 (96.6%) and 29 (33.3%) stated patients should be tested for anti-HBs and anti-HBc IgG, respectively. Conclusion: Given our study findings, rate of screening performed by neurologists to give IS treatment for HBVr and their awareness level on the situation were not found to be sufficient. In addition, two more important factors required to be raised awareness were detected in our study: First, the rate of using anti-HBc in screening is low, and the awareness should be increased in this direction. Secondly, the risk of HBVr should be categorized in terms of IS treatment and host in our country where HBV infection is seen at a high rate, and determining the prophylactic approach is insufficient.

Post-Kidney Transplant Cancer: A Real-World Retrospective Analysis From a Single Italian Center.

We describe the epidemiology of cancer after kidney transplantation (KTx), investigating its risk factors and impact on therapeutic management and survival in KTx recipients (KTRs). The association between modification of immunosuppressive (IS) therapy after cancer and survival outcomes was analyzed. We collected data from 930 KTRs followed for 7 [1-19]years. The majority of KTRs received KTx from a deceased donor (84%). In total, 74% of patients received induction therapy with basiliximab and 26% with ATG. Maintenance therapy included steroids, calcineurin inhibitors, and mycophenolate. Patients with at least one cancer (CA+) amounted to 19%. NMSC was the most common tumor (55%). CA+ were older and had a higher BMI. Vasculitis and ADPKD were more prevalent in CA+. ATG was independently associated with CA+ and was related to earlier cancer development in survival and competing risk analyses (p = 0.01 and <0.0001; basiliximab 89 ± 4 vs. ATG 40 ± 4months). After cancer diagnosis, a significant prognostic impact was derived from the shift to mTOR inhibitors compared to a definitive IS drug suspension (p = 0.004). Our data confirm the relevance of cancer as a complication in KTRs with ATG as an independent risk factor. An individualized choice of IS to be proposed at the time of KTx is crucial in the prevention of neoplastic risk. Finally, switching to mTORi could represent an important strategy to improve patient survival.

Potential role of B- and NK-cells in the pathogenesis of pediatric aplastic anemia through deep phenotyping.

Pediatric patients with unexplained bone marrow failure (BMF) are often categorized as aplastic anemia (AA). Based on the accepted hypothesis of an auto-immune mechanism underlying AA, immune suppressive therapy (IST) might be effective. However, due to the lack of diagnostic tools to identify immune AA and prognostic markers to predict IST response together with the unequaled curative potential of hematopoietic stem cell transplantation (HSCT), most pediatric severe AA patients are momentarily treated by HSCT if available. Although several studies indicate oligoclonal T-cells with cytotoxic activities towards the hematopoietic stem cells, increasing evidence points towards defective inhibitory mechanisms failing to inhibit auto-reactive T-cells. We aimed to investigate the role of NK- and B-cells in seven pediatric AA patients through a comprehensive analysis of paired bone marrow and peripheral blood samples with spectral flow cytometry in comparison to healthy age-matched bone marrow donors. We observed a reduced absolute number of NK-cells in peripheral blood of AA patients with a skewed distribution towards CD56bright NK-cells in a subgroup of patients. The enriched CD56bright NK-cells had a lower expression of CD45RA and TIGIT and a higher expression of CD16, compared to healthy donors. Functional analysis revealed no differences in degranulation. However, IFN-γ production and perforin expression of NK-cells were reduced in the CD56bright-enriched patient group. The diminished NK-cell function in this subgroup might underly the auto-immunity. Importantly, NK-function of AA patients with reduced CD56bright NK-cells was comparable to healthy donors. Also, B-cell counts were lower in AA patients. Subset analysis revealed a trend towards reduction of transitional B-cells in both absolute and relative numbers compared to healthy controls. As these cells were previously hypothesized as regulatory cells in AA, decreased numbers might be involved in defective inhibition of auto-reactive T-cells. Interestingly, even in patients with normal distribution of precursor B-cells, the transitional compartment was reduced, indicating partial differentiation failure from immature to transitional B-cells or a selective loss. Our findings provide a base for future studies to unravel the role of transitional B-cells and CD56bright NK-cells in larger cohorts of pediatric AA patients as diagnostic markers for immune AA and targets for therapeutic interventions.

Comparison of the In Vitro Iron Bioavailability of Tempeh Made with Tenebrio molitor to Beef and Plant-Based Meat Alternatives.

Iron is an essential mineral that supports biological functions like growth, oxygen transport, cellular function, and hormone synthesis. Insufficient dietary iron can lead to anemia and cause fatigue, cognitive impairment, and poor immune function. Animal-based foods provide heme iron, which is more bioavailable to humans, while plant-based foods typically contain less bioavailable non-heme iron. Edible insects vary in their iron content and may have heme or non-heme forms, depending on their diet. Edible insects have been proposed as a protein source that could address issues of food insecurity and malnutrition in low resource contexts; therefore, it is important to understand the bioavailability of iron from insect-based foods. In this study, we used Inductively Coupled Plasma and Mass Spectrometry (IPC-MS) and Caco-2 cell culture models to compare the soluble and bioavailable iron among five different lab-produced tempeh formulations featuring Tenebrio molitor (mealworm) with their non-fermented raw ingredient combinations. Finally, we compared the iron bioavailability of a mealworm tempeh with two sources of conventional beef (ground beef and sirloin steaks) and two commercially available plant-based meat alternatives. The results show that while plant-based meat alternatives had higher amounts of soluble iron, particularly in the Beyond Burger samples, the fermented mealworm-based tempeh had greater amounts of bioavailable iron than the other samples within the set. While all the samples presented varying degrees of iron bioavailability, all products within the sample set would be considered good sources of dietary iron.

LCP-Tacrolimus Extended-Release (Envarsus XR) Use in Adolescent and Young Adult Solid Organ Transplant Recipients.

Limited published experience describes once daily, extended-release tacrolimus (LCP-Tac) use in pediatric solid organ transplantation (SOT), particularly nonrenal SOT. LCP-Tac can simplify immunosuppression (IS) regimens, minimize immediate release-tacrolimus (IR-Tac)-associated adverse effects, and promote adherence. This study describes the successful use of LCP-Tac in adolescent and young adult (AYA) SOT populations. A single-center, retrospective chart review of AYA SOT recipients (age < 25 years) converted from IR-Tac to LCP-Tac. Graft survival, biopsy-proven acute rejection (BPAR), infection rates, estimated glomerular filtration rate (eGFR), and pill burden were assessed at five time points postconversion (1, 3, 6, 12, and 24 months). Intrapatient variability of tacrolimus, as assessed by coefficient of variability (CV%), was also analyzed. Twenty-nine AYA SOT recipients (19 heart, 6 kidney, and 4 liver) were converted to LCP-Tac, with a median age of 17.4 years at conversion. Conversion, mainly due to perceived or identified medication nonadherence, occurred at a median of 5.4 years posttransplant. No graft loss occurred within 24 months of conversion, and BPAR incidence rate was consistent with previous reports for these populations. Only one patient experienced CMV infection. Renal function remained stable postconversion. Successful conversion from IR-Tac to LCP-Tac was demonstrated in AYA heart, kidney, and liver transplant recipients. These AYA SOT recipients experienced reduced pill burden and improved tacrolimus trough concentration variability. However, the impact on medication adherence warrants further investigation. Future research should explore the targeted use of LCP-Tac to enhance IS tolerability and medication adherence in young SOT populations.

Extended survival of 9- and 10-gene-edited pig heart xenografts with ischemia minimization and CD154 costimulation blockade-based immunosuppression

BackgroundXenotransplantation has made significant advances recently using pigs genetically engineered to remove carbohydrate antigens, either alone or with addition of various human complement, coagulation, and anti-inflammatory ‘transgenes’. Here we evaluated results associated with gene-edited (GE) pig hearts transplanted in baboons using an established costimulation-based immunosuppressive regimen and a cold-perfused graft preservation technique. MethodsEight baboons received heterotopic abdominal heart transplants from 3-GE (GalKO.β4GalNT2KO.hCD55, n=3), 9-GE (GalKO.β4GalNT2KO.GHRKO.hCD46.hCD55. TBM.EPCR.hCD47.HO-1, n=3) or 10-G (9-GE+CMAHKO, n=2) pigs using Steen’s cold continuous perfusion for ischemia minimization. Immunosuppression (IS) included induction with anti-thymocyte globulin and αCD20, ongoing αCD154, MMF, and tapered corticosteroid. ResultsAll three 3-GE grafts functioned well initially, but failed within 5 days. One 9-GE graft was lost intraoperatively due to a technical issue and another was lost at POD 13 due to antibody mediated rejection (AMR) in a baboon with a strongly positive pre-operative cross-match. One 10-GE heart failed at POD113 with combined cellular and antibody mediated rejection. One 9-GE and one 10-GE hearts had preserved graft function with normal myocardium on protocol biopsies, but exhibited slowly progressive graft hypertrophy until elective necropsy at POD393 and 243 respectively. Elevated levels of IL-6, MCP-1, C-reactive protein, and human thrombomodulin were variably associated with conditioning, the transplant procedure, and clinically significant postoperative events. ConclusionRelative to reference genetics without thrombo-regulatory and anti-inflammatory gene expression, 9- or 10-GE pig hearts exhibit promising performance in the context of a clinically applicable regimen including ischemia minimization and αCD154-based IS, justifying further evaluation in an orthotopic model.

When is the right time to change therapy? An observational study of the time to response to immunosuppressive drugs in systemic lupus erythematosus

ObjectivesTo analyse the response to immunosuppressants (IS) in extrarenal flares of SLE to determine the most appropriate timing during follow-up for a change in therapeutic strategy.MethodsObservational cohort study including a...

Immunosuppressives discontinuation after renal response in lupus nephritis: predictors of flares, time to withdrawal and long-term outcomes.

The optimal duration of immunosuppressive (IS) treatment for lupus nephritis (LN) remains uncertain. We assessed the prevalence and predictors of IS tapering and discontinuation (D/C) in LN patients. Data from 137 inception cohort LN patients were analyzed. We examined determinants of flares during tapering and after IS D/C, D/C achievement and time to D/C, and adverse long-term outcomes applying logistic and linear regression models. IS tapering was attempted in 111 (81%) patients, and D/C was achieved in 67.5%. Longer time to achieve complete renal response (CR) (OR : 1.07, p= 0.046) and higher SLEDAI-2K at tapering initiation (OR : 2.57, p= 0.008) were correlated with higher risk of renal flares during tapering. Persistent hydroxychloroquine use (≥2/3 of follow-up) (OR : 0.28, p= 0.08) and lower SLEDAI-2K 12 months before IS D/C (OR : 1.70, p= 0.013) decreased the risk of post-D/C flares. Adverse outcomes (>30% eGFR decline, chronic kidney disease, end-stage renal disease, death) at the end of follow-up (median124 months) were more frequent in patients with flares during IS tapering (53% vs 16%, p< 0.0038) but did not differ between IS D/C achievers and non-achievers. In proliferative LN, differences mirrored those in entire cohort, except for time to D/C, which occurred 20 months earlier in membranous vs proliferative LN (β-coef=-19.8, p= 0.014). Earlier CR achievement and lower SLEDAI-2K at tapering initiation prevent flares during IS tapering, while persistent hydroxychloroquine use and lower SLEDAI-2K 12 months before IS D/C prevent post-D/C flares. Flares during tapering increase the risk of unfavorable long-term outcomes. Earlier IS D/C is feasible in membranous LN.

The Effect of Nutritional Status in the Treatment of Periprosthetic Joint Infections in Total Hip Arthroplasty

BackgroundPeriprosthetic joint infections (PJIs) continue to be a complication that plagues arthroplasty. Albumin is a surrogate marker for nutrition as well as chronic inflammation, and hypoalbuminemia increases the risk of complications in arthroplasty. Patients with PJI are at increased risk for malnutrition and complications. This study’s objective was to analyze patients who underwent treatment of PJI following total hip arthroplasty and investigate the outcome with regards to albumin levels. MethodsOverall, 48 patients who underwent surgery for a total hip PJI at 1 institution were reviewed. Albumin and C-reactive protein were recorded preoperatively and 2 to 3 weeks postoperatively. Treatment failure was determined by further surgical treatment for PJI or repeat infection, as determined by Musculoskeletal Infection Society guidelines. ResultsA debridement, antibiotics, and implant retention procedure was performed in 39 patients, and explant with the placement of an antibiotic spacer was performed in 9. Preoperative mean albumin levels were significantly decreased in patients who failed to clear their infection compared to patients who remained infection-free (2.5 versus 3.3, P < .001). Postoperative albumin levels decreased in this same population (2.6 versus 3.8, P < .001). C-reactive protein was elevated in patients who failed to clear their infection preoperatively (19.9 versus 7.5, P < .001) and postoperatively (7.0 versus 1.7, P < .001). The average time to repeat surgical treatment for their PJI was 9 months ConclusionsLower albumin levels are observed in patients with PJI who failed to remain infection-free after surgery. Albumin is a surrogate marker for nutrition, and low albumin is associated with poor immune function. Hypoalbuminemia is found with chronic inflammation as well as malnutrition. Nutritional reserves are diverted to the acute inflammatory response during an infection, which can lead to a deficient state. Further research may develop treatments to alter this modifiable risk factor. Level of EvidenceLevel 4.

COVID-19 severity, breakthrough infections and vaccine safety in young individuals with autoimmune diseases: insights from the COVAD study

Notwithstanding the wealth of literature on COVID-19, studies focusing on young adults with autoimmune diseases (AD) are lacking. To determine early (within 7 days) and late (after 7 days) anti-SARS-CoV-2 vaccine-related adverse events (AEs), post-vaccine disease flares, COVID-19 severity and breakthrough infections (B-INFs) in young people with rheumatic diseases (RMDs) and non-rheumatic autoimmune diseases (nr-ADs) compared to healthy controls (HC). Data were captured through the international COVID-19 vaccination in autoimmune diseases (COVAD) 1 and 2 questionnaires. Of 20,685 complete responses, we identified 6010 from patients aged 18–35 years (1692 RMD, 400 nrADs, 3918 HC) who received up to 4 vaccine doses. BNT162b2 was the most frequently administered vaccine and prior to vaccination, 7% of people with nrAD were taking immunosuppressants (IS) versus 80% in RMDs. Early mild AEs were more frequent in RMDs (93%) and nr-ADs (92%) compared to HC (85%). The frequency of late mild AEs was < 20% in all groups. Severe AEs were rare. SARS-CoV-2 infection rates were similar across all groups, however, RMD patients reported a single episode of infection more frequently than nrADs and HC, while nrADs reported multiple infections more frequently than RMD. Self-reported disease flares were reported by 10% or RMD and 7% of nrAD patients. Our study reinforces the safety of anti-SARS-CoV-2 vaccine also in young people with ADs, but it also highlights that among young individuals the number and clinical picture of SARS-CoV-2 infections is affected more by the type of AD rather than by coexisting IS therapy.

Multifocal Cryptococcus Neoformans Osteomyelitis in a Kidney Transplant Recipient

Cryptococcal infections are notoriously difficult to diagnose and have been associated with high morbidity and mortality. Cryptococcus neoformans presenting as osteomyelitis is an unexpected clinical scenario in the transplant ward. A young male who underwent spousal kidney donor transplantation 16 months ago presented with painful and ulcerated soft tissue in upper and lower limbs which were diagnosed as cryptococcus osteomyelitis. He was managed with surgical debridement, liposomal amphotericin B, flucytosine and reduction in maintenance immunosuppression (IS). To our knowledge this is the first reported case of multifocal cryptococcus osteomyelitis in a kidney transplant recipient.