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Objective: To develop a guideline for selecting biomarkers in the diagnosis and assessment in patients with axial spondyloarthritis (axSpA). Method: A joint effort was carried out by the core team, the literature review team and the multidisciplinary voting panel to formulate recommendations regarding biomarkers in axSpA, using an evidence-based and consensus-based strategy. Certainty of evidence and strength of recommendation were determined, and levels of agreement within the voting panel were calculated. Results: A total of 20 recommendations were formulated in this guideline, with levels of agreement ranging from 6.48 to 9.71. The two strong recommendations, HLA-B27 testing in patients suspected of axSpA and regular-interval monitoring of CRP/ESR represent the status quo of axSpA evaluation, while the 13 conditional recommendations represent the promising biomarkers with clinical utility in diagnosis, disease activity assessment, prediction of radiographic progression and therapeutic responses. This guideline does not dictate clinical choices of tests on axSpA, and decisions should be made based on comprehensive consideration of costs, accessibility, patients' values and willingness as well as the objective of testing in the local context. Conclusion: This guideline addresses the interpretation of the clinical significance of biomarkers in axSpA, and the biomarkers endorsed in this guideline composed a clinical toolkit for healthcare professionals to choose from. [ABSTRACT FROM AUTHOR]

Simple Summary: B-cell acute lymphoblastic leukemia is a complex blood cancer that primarily affects children. Predicting treatment response is challenging due to the variability of the disease. In our study, we classified patients into three groups based on their DNA content (hyperploid, normoploid, and hypoploid). We then analyzed the markers present on leukemia cells using flow cytometry to identify potential differences between these groups. We found that hypoploid patients had a lower percentage of cells in the S phase of the cell cycle and showed higher levels of the HLA-DR marker, along with the co-expression of CD34 and CD22. These findings provide insights that could contribute to a better understanding and management of this disease in the future. Background/Objectives: B-cell acute lymphoblastic leukemia (B-ALL) presents a challenge in hematological malignancies due to its heterogeneity, which impacts treatment outcomes. Stratification based on the DNA index (DNAi) categorizes patients into favorable prognosis (hyperploid), standard prognosis (normoploid), and uncertain or poor prognosis (hypoploid) groups. In this study, we explored whether specific immunophenotypic markers are associated with each DNAi-based group and their potential connection to prognostic categories, aiming to provide new insights that may contribute to a better understanding of prognosis in B-ALL. Methods: In this study, we utilized flow cytometry to analyze immunophenotypic markers and combined this with DNA index (DNAi) measurements to stratify pediatric B-ALL patients into distinct risk categories. Our methodology focused on accurately classifying patients into hyperploid, normoploid, and hypoploid groups based on their DNA content, facilitating a comparative analysis of immunophenotypic characteristics across these groups. Results: Our analysis revealed that hypoploid B-ALL patients displayed a significantly lower percentage of cells in the S phase of the cell cycle compared to normoploid and hyperploid groups. Additionally, distinct immunophenotypic profiles were observed in hypoploid patients, characterized by higher expression levels of HLA-DR and a notable co-expression of CD34 and CD22. Conclusions: This study found that hypoploid B-ALL patients have distinct characteristics, such as lower S-phase cell percentages and specific immunophenotypic profiles, including higher HLA-DR expression and CD34/CD22 co-expression. These differences across DNA index-based prognostic categories warrant further research to explore their potential prognostic significance. [ABSTRACT FROM AUTHOR]

Objective Individuals positive for anti-cyclic-peptide-antibodies (anti-CCP) and musculoskeletal complaints (MSK-C) are at risk for developing rheumatoid arthritis (RA). In this study we aimed to investigate factors involved in arthritis progression. Methods Anti-CCP2-positive individuals with MSK-C referred to a rheumatologist were recruited. Individuals lacked arthritis at clinical and ultrasound examination and were followed for ≥3 years or until clinical arthritis diagnosis. Blood samples from inclusion were analysed for nine ACPA reactivities (citrullinated α-1-enolase, fibrinogen, filaggrin, histone, vimentin and tenascin peptides); 92 inflammation-associated proteins; and HLA-shared epitope alleles. Cox regression was applied to the data to identify independent predictors in a model. Results Two hundred and sixty-seven individuals were included with median follow-up of 49 months (interquartile range [IQR]: 22–60); 101 (38%) developed arthritis after a median of 14 months (IQR: 6–27). The analysis identified that presence of at least one ACPA reactivity (hazard ratio [HR] 8.0; 95% CI: 2.9, 22), ultrasound-detected tenosynovitis (HR 3.4; 95% CI: 2.0, 6.0), IL-6 levels (HR 1.5; 95% CI: 1.2, 1.8) and IL-15 receptor α (IL-15Rα) levels (HR 0.6; 95% CI: 0.4, 0.9) are significant independent predictors for arthritis progression in a prediction model (Harrell's C 0.76 [ s. e. 0.02], AUC 0.82 [95% CI: 0.76, 0.89], cross-validated AUC 0.70 [95% CI: 0.56, 0.85]). Conclusion We propose a high RA risk phase characterized by presence of ACPA reactivity, tenosynovitis, IL-6 and IL-15Rα and suggest that these factors need to be further investigated for their biological effects and clinical values, to identify individuals at particular low risk and high risk for arthritis progression. [ABSTRACT FROM AUTHOR]

Objective: Primary antiphospholipid syndrome (PAPS) is a rare autoimmune disease characterized by the presence of antiphospholipid antibodies and the occurrence of thrombotic events and pregnancy complications. Our study aimed to identify novel genetic susceptibility loci associated with PAPS. Methods: We performed a genome‐wide association study comprising 5,485 individuals (482 affected individuals) of European ancestry. Significant and suggestive independent variants from a meta‐analysis of approximately 7 million variants were evaluated for functional and biological process enrichment. The genetic risk variability for PAPS in different populations was also assessed. Hierarchical clustering, Mahalanobis distance, and Dirichlet Process Mixtures with uncertainty clustering methods were used to assess genetic similarities between PAPS and other immune‐mediated diseases. Results: We revealed genetic associations with PAPS in a regulatory locus within the HLA class II region near HLA‐DRA and in STAT1‐STAT4 with a genome‐wide level of significance; 34 additional suggestive genetic susceptibility loci for PAPS were also identified. The disease risk allele near HLA‐DRA is associated with overexpression of HLA‐DRB6, HLA‐DRB9, HLA‐DQA2, and HLA‐DQB2 in immune cells, vascular tissue, and nervous tissue. This association is independent of the association between PAPS and HLA‐DRB1*1302. Functional analyses highlighted immune‐related pathways in PAPS‐associated loci. The comparison with other immune‐mediated diseases revealed a close genetic relatedness to neuromyelitis optica, systemic sclerosis, and Sjögren syndrome, suggesting co‐localized causal variations close to STAT1‐STAT4, TNPO3, and BLK. Conclusion: This study represents a comprehensive large‐scale genetic analysis for PAPS and provides new insights into the genetic basis and pathophysiology of this rare disease. [ABSTRACT FROM AUTHOR]

The article offers update on the curation of genetic associations with rheumatologic autoimmune diseases to improve patient outcomes. Topics discussed include monogenic autoimmune and/or autoinflammatory conditions, development of a framework for curation of HLA disease associations, development of a methodology for curation of complex, multigenic diseases, and curation of disease-associated somatic variants.

Objectives: Nasal polyposis (NP) is a common and recurrent condition of the sinonasal cavity which has significant impact on patients' quality of life. NP pathophysiology involves a complex interplay of genetic, environmental, and immunological factors. Several studies have explored the association between human leukocyte antigen (HLA) class II alleles and NP, but the results have been conflicting. The aim of this meta-analysis is to investigate the association between HLA class II alleles, specifically HLA-DQA1, HLA-DQB1, and HLA-DRB1and NP risk. Methods: A systematic review was conducted using electronic databases, including PubMed, Google Scholar, and Cochrane Library, to identify studies investigating the association between HLA class II alleles and NP. Eligible studies were identified by specific inclusion and exclusion criteria. The odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association between HLA class II alleles and NP risk. A random-effects model was used to calculate the pooled OR and corresponding 95% CI, and a study required a heterogeneity assessment value I 2 < 25% to be considered for analysis. Study design: Meta-analysis. Results: A total of four studies were included in this meta-analysis, involving a total of 258 NP alleles and 802 control alleles. The analysis indicated that DQA1*0201 (OR = 3.08, 95% CI [1.70, 5.59]) and DRB1*7 (OR = 2.04, 95% CI [1.14, 3.66]) were significantly associated with increased risk of NP. The analysis of the NP risk alleles DQA1*0201 and DRB1*7 had an I2 < 0% representing low heterogeneity. Sensitivity analysis with LFK indices showed minor asymmetry in either allele. Conclusions: This meta-analysis provides evidence that the HLA-DQA1*0201 and HLA-DRB1*7 alleles are risk factors for the development of NP. These findings could contribute to a better understanding of the genetic predisposition of NP and may have implications for the development of novel approaches for the prevention and treatment of this condition. [ABSTRACT FROM AUTHOR]

To examine the frequency of recurrence and identify risk factors for recurrence in patients with acute anterior uveitis (AAU). Retrospective cohort study from a single tertiary ophthalmic clinical center. All subjects with AAU identified from a database of Inflammatory Eye Disease presenting to Te Whatu Ora (Auckland, New Zealand) between 2008 and 2021. Data were collected retrospectively from chart review and electronic patient records for all patients during the study period. Rates of recurrence were reported using the Kaplan–Meier estimator. Multivariate analysis of risk factors for recurrence was calculated using a marginal Cox regression model. The primary outcome measure was disease recurrence. Secondary outcome measure was moderate vision loss (≤20/50). A total of 2763 eyes of 2092 subjects with AAU were studied, with a median follow-up time of 8.9 years and a total follow-up of 19 794.9 eye-years. Recurrence occurred in the ipsilateral eye in 1258 eyes (45.5%) and in the contralateral eye in 522 eyes (27.3%). Rates of ipsilateral recurrence over 10 years were 38.1% for idiopathic disease, 43.2% for human leukocyte antigen B27 (HLA-B27)/inflammatory arthritis, and 44.9% for viral uveitis. On multivariate analysis, the following were associated with increased risk of ipsilateral recurrence: older age (P < 0.001), Māori ethnicity (P = 0.006), Asian ethnicity (P < 0.001), HLA-B27/inflammatory arthritis (P < 0.001), and viral uveitis (P = 0.018). There was no association with gender, smoking, bilateral disease, or hypertensive uveitis. Rates of contralateral eye involvement were significantly lower than ipsilateral eye recurrence. Contralateral recurrence at 10 years was 15.2% in idiopathic uveitis, 37.6% in HLA-B27/inflammatory arthritis, and 2.0% in viral uveitis. Risk factors identified for contralateral eye involvement were Māori ethnicity (P = 0.003), Pasifika (Pacific Islanders) ethnicity (P = 0.021), and HLA-B27/inflammatory arthritis (P < 0.001). Moderate vision loss (≤20/50) was present in 411 eyes (14.9%) at final follow-up and was more common if time to first recurrence was shorter (P < 0.001). Approximately half of patients with AAU will develop recurrence in the ipsilateral eye, and one-quarter will have recurrence in the contralateral eye. Patients with viral disease have the highest risk of ipsilateral recurrence and lowest risk of contralateral recurrence. Patients with risk factors for recurrence should be managed and counseled appropriately to minimize the risk of visual loss and complications of uveitis. Proprietary or commercial disclosure may be found after the references. [ABSTRACT FROM AUTHOR]

Purpose: This review primarily discusses the current research advance of predictive biomarkers for melanoma immunotherapy. The aim of the present review is to summarize the biomarkers and evaluate the advantages and disadvantages. Methods: All reference can be found through Pubmed. This review mainly focuses on three main directions: tumor-related factors, host factors, and the tumor microenvironment. In the end, there exhibits some unusual aspects of predictive biomarkers and forecasts the future model. Results: The mainsteam of predictive biomarkers focuses on PD-L1, TMB, gene mutations, immune cells, IDO1, LDH, tertiary lymphoid structures (TLS), HLA-DR, tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), and Extracellular vesicles (EVs). Conclusion: The current research advance of predictive biomarkers for melanoma immunotherapy can be mainly divided into three parts: tumor-related factors, host factors, and the tumor microenvironment. The predictive biomarkers include PD-L1, TMB, gene mutations, immune cells, IDO1, LDH, TLS, HLA-DR, TAMs, TILs, and EVs. A model based on multiple biomarkers is expected to become the answer to predicting prognosis. [ABSTRACT FROM AUTHOR]

The article explores the unconventional role of microRNA (miRNA) in enhancing the human leukocyte antigen class I (HLA-I) antigen processing pathway by interacting with a silencer. Through experiments and in silico analyses, miR-155-5p was found to bind to the 3' untranslated region (3'UTR) of TAP-binding protein (tpn), leading to increased HLA-I surface expression in melanoma cells. The study also highlights the clinical relevance of miR-155-5p and its impact on immune cell infiltration, providing new insights into miRNA functions and silencers. The findings suggest a novel mechanism where miRNAs activate target transcription by binding to silencers, ultimately enhancing downstream pathways and antigen presentation. [Extracted from the article]

Simple Summary: The restoration of HLA-class-I expression in lung cancer cells may reverse immune evasion, enhance cytotoxic T-cell activity, and improve immune checkpoint inhibitors' therapeutic efficacy. In the current study, we provide experimental evidence that autophagy blockage either at the late stage (chloroquine and bafilomycin) or early stage of the autophagic process (ULK1 inhibitors and MAP1LC3A silencing) can up-regulate the expression of HLA-class-I molecules in the A549 and H1299 NSCLC cell lines and their CD133+ stem cells. This upregulation enhances the cytotoxic activity of activated CD8+ T-cells, in particular after pre-incubation with anti-PD-L1 monoclonal antibodies. The restoration of HLA-class-I-mediated antigen presentation with autophagy blockers in lung cancer is a promising avenue that urgently requires further exploration in clinical trials. Background/Objectives: Immune checkpoint inhibitors have an established role in non-small cell lung cancer (NSCLC) therapy. The loss of HLA-class-I expression allows cancer cell evasion from immune surveillance, disease progression, and failure of immunotherapy. The restoration of HLA-class-I expression may prove to be a game-changer in current immunotherapy strategies. Autophagic activity has been recently postulated to repress HLA-class-I expression in cancer cells. Methods: NSCLC cell lines (A549 and H1299) underwent late-stage (chloroquine and bafilomycin) and early-stage autophagy blockage (ULK1 inhibitors and MAP1LC3A silencing). The HLA-class-I expression was assessed with flow cytometry, a Western blot, and RT-PCR. NSCLC tissues were examined for MAP1LC3A and HLA-class-I expression using double immunohistochemistry. CD8+ T-cell cytotoxicity was examined in cancer cells pre-incubated with chloroquine and anti-PD-L1 monoclonal antibodies (Moabs); Results: A striking increase in HLA-class-I expression following incubation with chloroquine, bafilomycin, and IFNγ was noted in A549 and H1299 cancer cells, respectively. This effect was further confirmed in CD133+ cancer stem cells. HLA-class-I, β2-microglobulin, and TAP1 mRNA levels remained stable. Prolonged exposure to chloroquine further enhanced HLA-class-I expression. Similar results were noted following exposure to a ULK1 and a PIKfyve inhibitor. Permanent silencing of the MAP1LC3A gene resulted in enhanced HLA-class-I expression. In immunohistochemistry experiments, double LC3A+/HLA-class-I expression was seldom. Pre-incubation of H1299 cancer cells with chloroquine and anti-PD-L1 MoAbs increased the mean % of apoptotic/necrotic cells from 2.5% to 18.4%; Conclusions: Autophagy blockers acting either at late or early stages of the autophagic process may restore HLA-class-I-mediated antigen presentation, eventually leading to enhanced immunotherapy efficacy. [ABSTRACT FROM AUTHOR]

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide. In this retrospective cohort study, we aimed to assess the effects of various MEFV genotypes on the clinical characteristics of the patients, with a special focus on the joint involvement. In total, 782 patients with FMF were categorized into 3 groups according to the MEFV mutation; Group 1: Patients homozygous for M694V; Group 2: Patients carrying other pathogenic MEFV variants in exon 10 in homozygous or compound heterozygous states; and Group 3: FMF patients with other variants or without mutations. Clinical and demographic findings were compared between groups. Among the 782 FMF patients, total frequency of arthritis was 237 (30.3%): 207 (26.4%) were acute monoarthritis and 67 (8.5%) were chronic arthritis. Both the frequency of arthritis (acute and/or chronic) (40.4% vs. 24.8% vs. 26.7%; p:0.001) and acute monoarthritis (35.4% vs. 20% vs. 23.7%; p:0.001) were significantly higher in Group 1 than in the other groups. FMF patients with chronic arthritis showed a distinct juvenile idiopathic arthritis (JIA) distribution pattern with a more frequent enthesitis-related arthritis (ERA) subtype (43.2%). HLA-B27 was positive in 24% of the ERA patients. Conclusion: Homozygous M694V mutation is associated with a more frequent and longer acute monoarthritis comparing to other MEFV genotypes. In addition, the risk of chronic arthritis seems not related to the MEFV mutations. However, FMF patients with chronic arthritis show a distinct ILAR JIA distribution pattern with a more frequent ERA and undifferentiated arthritis subtype. What is known: • Homozygous M694V mutation is associated with a more frequent and longer acute monoarthritis What is new: • FMF patients with chronic arthritis show a distinct ILAR JIA distribution pattern with a more frequent ERA subtype • ERA patients with negative HLA-B27 antigen should also be assessed for polyserositis episodes of FMF, especially in countries with high FMF carrier frequency [ABSTRACT FROM AUTHOR]

Research progress from the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) pilot award program was presented and discussed at the GRAPPA 2023 annual meeting. Topics included identification of protein biomarkers associated with enthesitis in psoriatic arthritis (PsA), the role of HLA-B27 on gut microbial dysbiosis in PsA, single-cell profiling of synovial fluid vs psoriatic skin lesions in PsA, and the role of mechanotransduction in hyperactivation of transforming growth factor-β via αVβ6 integrin in psoriatic epidermis. [ABSTRACT FROM AUTHOR]

Objective: HLA‐DR–expressing fibroblast‐like synoviocytes (FLS) are a prominent cell type in synovial tissue in chronic inflammatory forms of arthritis. FLS‐derived extracellular matrix (ECM) proteins, including fibronectin‐1 (FN1), contain immunogenic CD4+ T cell epitopes in patients with postinfectious Lyme arthritis (LA). However, the role of FLS in presentation of these T cell epitopes remains uncertain. Methods: Primary LA FLS and primary murine FLS stimulated with interferon gamma (IFNγ), Borrelia burgdorferi, and/or B burgdorferi peptidoglycan (PG) were assessed for properties associated with antigen presentation. HLA‐DR–presented peptides from stimulated LA FLS were identified by immunopeptidomics analysis. OT‐II T cells were co‐cultured with stimulated murine FLS in the presence of cognate ovalbumin antigen to determine the potential of FLS to act as inducible antigen presenting cells (APCs). Results: FLS expressed HLA‐DR molecules within inflamed synovial tissue and tendons from patients with postinfectious LA in situ. Major histocompatibility complex (MHC) class II and co‐stimulatory molecules were expressed by FLS following in vitro stimulation with IFNγ and B burgdorferi and presented both foreign and self‐MHC‐II peptides, including an immunogenic T cell epitope derived from Lyme autoantigen FN1. Stimulated FLS induced proliferation of naive OT‐II CD4+ T cells that were dependent on OT‐II antigen and CD40. Stimulation with B burgdorferi PG enhanced FLS‐mediated T cell activation. Conclusion: MHC‐II+ FLS are inducible APCs that can induce CD4+ T cell activation in an antigen‐ and CD40‐dependent manner. Activated FLS can also present ECM‐derived Lyme autoantigens, implicating FLS in amplifying tissue‐localized autoimmunity in LA. [ABSTRACT FROM AUTHOR]

It has been demonstrated previously that human leukocyte antigen class I (HLA-I) and class II (HLA-II) alleles may modulate JAK2 V617F and CALR mutation (CALRmut)-associated oncogenesis in myeloproliferative neoplasms (MPNs). However, the role of immunogenetic factors in MPNs remains underexplored. We aimed to investigate the potential involvement of HLA genes in CALRmut+ MPNs. High-resolution genotyping of HLA-I and -II loci was conducted in 42 CALRmut+ and 158 JAK2 V617F+ MPN patients and 1,083 healthy controls. A global analysis of the diversity of HLA-I genotypes revealed no significant differences between CALRmut+ patients and controls. However, one HLA-I allele (C*06:02) showed an inverse correlation with presence of CALR mutation. A meta-analysis across independent cohorts and healthy individuals from the 1000 Genomes Project confirmed an inverse correlation between the presentation capabilities of the HLA-I loci for JAK2 V617F and CALRmut-derived peptides in both patients and healthy individuals. scRNA-Seq analysis revealed low expression of TAP1 and CIITA genes in CALRmut+ hematopoietic stem and progenitor cells. In conclusion, the HLA-I genotype differentially restricts JAK2 V617F and CALRmut-driven oncogenesis potentially explaining the mutual exclusivity of the two mutations and differences in their presentation latency. These findings have practical implications for the development of neoantigen-based vaccines in MPNs. [ABSTRACT FROM AUTHOR]

Platelet transfusion refractoriness (PTR) is a conditioikb1n where platelet counts fail to increase adequately in several transfusions, often found in hemato-oncological situations. PTR poses life-threatening risks to patients, especially in cases when the platelet is very low, and transfusion is life-saving. It can be differentiated into immune or non-immune causes. While non-immune causes predominate, immune factors, particularly anti-HLA antibodies, are also notable in many cases. Accurately determining if platelet transfusion failure originates from an immune or non-immune cause is vital due to differing treatments, particularly the need for HLA-compatible platelets with immune causes. Yet, a lack of consensus exists regarding the diagnostic methods and treatment modalities. Therefore, this review aims to explore the origins, mechanisms, diagnostic criteria, and management approaches concerning PTR. PLAIN LANGUAGE SUMMARY TITLE: Platelet Transfusion Failure PLAIN LANGUAGE SUMMARY: Platelet transfusion refractoriness (PTR) is when platelet levels do not rise enough after several transfusions, often seen in malignancy and blood disorder. It's risky, especially when patients urgently need platelets to survive. PTR can happen because of immune or non-immune reasons. While non-immune causes are more common, immune factors, like anti-HLA antibodies, are also important. Figuring out if PTR is from an immune or non-immune cause is crucial because treatments differ, especially needing matching platelets for immune causes. But, there is still no agreement on how to diagnose and treat PTR. This review looks at why it happens, how to diagnose it, and ways to manage it. [ABSTRACT FROM AUTHOR]

PurposeMethodsResultsConclusionWe compared the distribution of the HLA-B27 allele among Ethiopian patients with acute anterior uveitis (AAU) and controls without that disease.The clinical features of patients were collected from their medical records. HLA-B27 genotyping was performed for 64 patients, with AAU using the real-time polymerase chain reaction (RT-PCR), and the results were compared to those from a panel of 192 healthy, unrelated volunteer control participants (refraction patients and volunteers) free of signs of anterior uveitis. Other outcomes were assessed comparing HLA-B27 positive vs. negative patients.The histocompatibility antigen HLA-B27 was identified in 6 out of 64 (9.4%) AAU patients, compared with 1.0% in controls (Odds Ratio = 9.8, 95% CI (1.93, 50.01)). Sub-group analysis of the cases revealed that patients with HLA-B27 positivity had a higher incidence of ocular hypertension (Odds Ratio = 5.93, 95% CI (1.29, 27.2)).The antigen HLA-B27 was represented ~10-fold more frequently in the patient group than in the control group. HLA-B27 allele distribution in both cases and controls is lower than in reports from Caucasian and Asian populations, but similar to South Africa. [ABSTRACT FROM AUTHOR]

Keloid disorder is a morbid and disfiguring benign fibroproliferative disease with a higher incidence in groups with darker skin pigmentation. Predicting keloidogenesis in patients is difficult with treatment primarily aimed at preventing further scar expansion and improving aesthetics without addressing their unknown underlying pathophysiology. We aimed to identify potential genetic predispositions to keloid scarring in the literature. A search was conducted on 21 August 2023, by the first and second authors independently from 1985 to August 2023 using PubMed, MEDLINE, Embase, Web of Science, Scopus and CINAHL. The following MeSH terms were used: 'Keloid', 'Risk' and 'Genetic'. Two researchers independently searched for studies based on titles and abstracts and screened filtered articles by reviewing full text. If no agreement could be reached, a third senior author designated whether the article should be included. We used the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses 2020 statement as the basis of our organisation. Human studies with genetic analysis to determine an association of a protein or gene to keloidogenesis were selected for inclusion. Studies in languages other than English, reviews, conference articles, and book chapters were excluded. Fifty studies met inclusion criteria. The human leukocyte antigen (HLA) system was broadly implicated, and the DRB1*15 allele was associated with an increased risk of keloid in three separate ethnic groups. Some HLA Class I alleles were associated with keloid in one population but not in others. Additionally, polymorphisms in the E3 ubiquitin‐protein ligase (NEDD4) signal cascade and vitamin D receptor (VDR) have been implicated in diverse groups. No current genetic test can predict keloid risk. Our review identified candidate predisposing genes, including NEDD4, VDR and components of the HLA system. Further studies in heterogeneous populations are needed to identify reliable screening targets. [ABSTRACT FROM AUTHOR]

d 14.2% for HLA-B*51. Furthermore, the frequencies for the two mentioned allelic groups in the studied ethnicities showed significant differences (P<0.05). Conclusions Although HLA-B*35 and HLA-B*51 exhibited the highest frequencies at the HLA-B gene locus in the overall population and the ethnic groups, the differences in the frequencies among the ethnicities were significant. This study highlights the high genetic diversity of HLA-B within the studied ethnic groups. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this cross-sectional study was to investigate if serum levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and CC chemokine ligand 17 (CCL17) correlate with disease activity in axial spondyloarthritis (axSpA) and peripheral spondyloarthritis (pSpA) patients. Patients and methods: The cross-sectional study was conducted with 80 individuals (48 females, 32 males; mean age: 47.7±11.5 years) between March 2021 and September 2021. Of the participants, 20 were axSpA, 20 were pSpA, and 20 were active rheumatoid arthritis patients, and the remaining 20 were healthy controls. Age, sex, body mass index, disease duration, comorbid diseases, smoking status, medical treatments, C-reactive protein (CRP) level and human leukocyte antigen B27 (HLA-B27) positivity were recorded. Serum GM-CSF and CCL17 levels were analyzed by ELISA. Ankylosing Spondylitis Disease Activity Score with CRP (ASDAS-CRP) was used to evaluate the disease activity of patients with spondyloarthritis. Functional status of spondyloarthritis patients was evaluated by Bath Ankylosing Spondylitis Functional Index (BASFI). Results: While the serum GM-CSF levels were similar in the axSpA and pSpA groups, they were significantly higher than the healthy control group (p=0.021 and p=0.009, respectively). There was a significant correlation between GM-CSF levels and ASDAS-CRP (r=0.545, p=0.013) and BASFI (r=0.546, p=0.013) in the axSpA group. In active axSpA patients, the cut-off value for GM-CSF was 15.89 pg/mL (sensitivity 50%, specificity 100%). No differences were detected in serum CCL17 levels among the groups. Conclusion: The results suggest that serum GM-CSF levels may be used as a new marker for the evaluation of disease activity in axSpA, and GM-CSF might be a therapeutic target. [ABSTRACT FROM AUTHOR]

Purpose: To quantitatively analyze choroidal and retinal vascular changes in HLA-B27-associated anterior uveitis. Study Design: A retrospective study. Methods: Medical records of 51 eyes with unilateral HLA-B27-associated anterior uveitis, their fellow eyes and 47 sex and age-matched healthy eyes were retrospectively reviewed. Their choroidal and retinal vasculature were analyzed using swept-source (SS) optical coherence tomography (OCT) and OCT angiography (OCTA) scans. Results: Deep capillary plexus (DCP) vessel density (VD) (p < 0.001), choroidal vascularity index (CVI) (p = 0.012), and choriocapillary flow deficit (CCFD) (p < 0.001) of uveitic and fellow eye group were significantly higher than those of control group. On the contrary, superficial capillary plexus (SCP) VD (p < 0.001) of uveitic and fellow eye group were significantly lower than of control group. The vascular parameters of uveitis and fellow eye group showed no significant difference between uveitic and resolution period. Conclusion: Certain choroidal and retinal vascular parameters were significantly changed in both HLA-B27-associated anterior uveitis without posterior segment involvement and the quiet fellow eyes, suggesting their possible effects as a systemic inflammatory disorder. [ABSTRACT FROM AUTHOR]

Simple Summary: Treatment personalization is essential in the era of precision medicine. Biomarkers are necessary to predict clinical outcomes and guide treatment selection to improve efficacy and reduce toxicity. Genomic human leukocyte antigen-class I (HLA-I) has been shown to correlate with outcomes among non-small cell lung cancer (NSCLC) patients treated with immunotherapy. Here, we investigate whether the HLA genotype is predictive of outcomes in regard to the combination of immunotherapy with chemotherapy. We found that the HLA-I supertypes HLA-A01 and -A03, but not HLA homozygosity, overall correlated with survival in NSCLC patients treated with immunochemotherapy. While further validation is needed, these results highlight the potential and variability of the HLA genotyping as a biomarker for immunotherapy delivery. Introduction: Maximal heterozygosity on the human leukocyte antigen (HLA) loci has been found to be associated with improved survival and development of immune-related adverse events (irAEs) among NSCLC patients treated with immunotherapy. Here, we investigated the effect of germline HLA-I/-II on clinical outcomes among NSCLC patients treated with first-line pembrolizumab in combination with chemotherapy. Method: We prospectively recruited patients with NSCLC who were commencing first-line pembrolizumab in combination with chemotherapy. DNA from white blood cells was used for high-resolution HLA-I/II typing. Results: Of the 65 patients recruited, 53 complied with the inclusion criteria. We did not find an association between HLA-I/-II homozygosity and clinical outcome among the studied population. However, the presence of HLA-A01 was associated with unfavourable PFS (HR = 2.32, 95%CI 1.13–4.77, p = 0.022) and worsening OS (HR = 2.86, 95%CI 1.06–7.70, p = 0.038). The presence of HLA-B27 was associated with improved PFS (HR = 0.35, 95%CI 0.18–0.71, p = 0.004) and trends toward improving OS. None of the HLA-I supertypes were associated with the development or worsening of irAEs. Conclusions: The absence of association between genomic HLA-I/-II homozygosity and clinical outcome among patients with advanced NSCLC treated with pembrolizumab in combination with chemotherapy might reflect a diminished role for HLA molecules among patients with low or no PD-L1. HLA-A01 and HLA-B27 might have a role in predicting clinical outcomes among this cohort of patients. Further studies are needed to explore biomarkers for this group of patients. [ABSTRACT FROM AUTHOR]

Objectives To explore differences in axial spondyloarthritis (axSpA) clinical phenotype around the world in a large sample of patients included in the International Map of Axial Spondyloarthritis (IMAS). Method IMAS was a cross-sectional online survey (2017–2022) of 5557 unselected axSpA patients from 27 countries. We analysed across five geographic regions the age at symptom onset, diagnostic delay, gender, HLA-B27, family history, extra-musculoskeletal manifestations, presence of comorbidities, disease activity (BASDAI), level of spinal stiffness and treatments. Results Of 5557 IMAS participants, 3493 were from Europe, 770 from North America, 600 from Asia, 548 from Latin America and 146 from South Africa. Age at symptom onset ranged between 25 and 30 years and was higher in Latin America. Diagnostic delay was longest in South Africa and lowest in Asia. The lowest HLA-B27 positivity was observed in Latin America and the highest in Asia. Extra-musculoskeletal manifestations were the lowest in Europe. Mean disease activity (BASDAI) was 5.4, with highest values in South Africa and lowest in Asia. Most of the patients had used NSAIDs for their condition and less than half had ever taken conventional synthetic DMARDS; both were more frequent in Latin America and South Africa. Almost half of the patients had ever taken biologic DMARDs, more frequent use being in the Americas. Conclusion There is great heterogeneity of axSpA clinical phenotype presentation around the world. AxSpA manifests differently in different regions, so further understanding of these differences of phenotypes is needed to achieve early diagnosis and initiation of optimal disease treatment in axSpA in the different regions. [ABSTRACT FROM AUTHOR]

Objectives: To assess the link between the administration of biologic disease-modifying antirheumatic drugs (bDMARDs) and the risk of malignancy in human leukocyte antigen B27 (HLA-B27)-positive patients with ankylosing spondylitis (AS) experiencing sustained inflammation. Methods: Between 2006 and 2021, 1445 HLA-B27-positive patients with AS were retrospectively evaluated. Among them, 112 patients required bDMARD therapy. The study compared conventional therapy with bDMARDs and investigated the risk factors for developing malignancies. Results: During 8253 patient-years of follow-up, 38 (2.6%) patients developed various malignancies, including lung, liver, breast, and colon cancer. The risk of malignancy was significantly higher in the bDMARD-treated group compared to PS-matched groups receiving conventional synthetic DMARDs (csDMARD) and non-steroidal anti-inflammatory drugs. The cumulative risk of malignancies increased significantly after 6 years of follow-up. All patients who developed malignancy after bDMARD therapy received tumor necrosis factor-α inhibitors. Requiring bDMARD therapy, requiring bDMARDs in combination with csDMARD therapy, and being diagnosed with AS after 30 years of age were independent risk factors for developing malignancy. Conclusions: HLA-B27-positive AS patients with sustained inflammation requiring biologic therapy, particularly if diagnosed after age 30, may have an increased risk of malignancy. Regular cancer screenings are advisable for these patients while undergoing biologic treatment. [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) is genetically a distinct tumor compared to cutaneous melanoma (CM), and due to its low mutational burden, it is far less perceptible to the immune system. Thus, treatments that have revolutionized the treatment of CM remain widely inefficient in metastatic UM or only demonstrate effectiveness in a small subpopulation of patients. To this end, the therapeutic benefit of immune checkpoint blockade is very limited and may come at the expense of severe immune-related adverse events that could potentially affect all organ systems. Notably, tebentafusp, an entirely novel class of anti-cancer drugs, has received official authorization for the treatment of metastatic UM. It is the first agent that demonstrated a survival advantage in a randomized controlled trial of metastatic UM patients. Despite the survival benefit and approval, the restriction of tebentafusp to HLA-A*02:01-positive patients and the low objective response rate indicate the persistent need for additional therapies. Thus, liver-directed therapies are commonly used for tumor control of hepatic metastases and represent a central pillar of the daily management of liver-dominant disease. Further, promising data from targeted therapies independent of MEK-inhibitors, such as the combination of darovasertib and crizotinib, raise hope for additional options in metastatic UM in the future. This narrative review provides a timely and comprehensive overview of the current treatment landscape for metastatic UM. [ABSTRACT FROM AUTHOR]

The functional outcomes and restoration of form after vascularized composite allotransplantation (VCA) have exceeded the results that could be achieved with current autologous surgical techniques. However, the longevity of VCA grafts has been limited due to the development of donor-specific antibodies (DSAs), and chronic rejection and graft failure occur despite long-term immunotherapy. Furthermore, despite widespread consensus that these non-life-saving transplants are beneficial for select patients, the application of VCA is limited by the need for lifelong immunosuppression. Therefore, attempts to achieve drug-free tolerance through safe and effective therapies are critical. This review highlights recent publications regarding alloantibody-mediated rejection (AMR) in various VCAs with a focus on the critical need for novel tolerance-inducing strategies. The development and implementation of effective methods of inducing tolerance, such as the use of anti-CD3 immunotoxins, could drastically improve VCA graft outcomes and recipient quality of life. [ABSTRACT FROM AUTHOR]

In human leukocyte antigen (HLA)-mismatched allogeneic stem cell transplantation settings, donor-specific anti-HLA antibodies (DSAs) can independently lead to graft failure, including both primary graft rejection and primary poor graft function. Although several strategies, such as plasma exchange, intravenous immunoglobulin, rituximab, and bortezomib, have been used for DSA desensitization, the effectiveness of desensitization and transplantation outcomes in some patients remain unsatisfactory. In this review, we summarized recent research on the prevalence of anti-HLA antibodies and the underlying mechanism of DSAs in the pathogenesis of graft failure. We mainly focused on desensitization strategies for DSAs, especially novel methods that are being investigated in the preclinical stage and those with promising outcomes after preliminary clinical application. [ABSTRACT FROM AUTHOR]

Spondyloarthritis refers to a broad group of conditions that include ankylosing spondylitis, psoriatic arthritis, reactive arthritis, and enteropathic arthritis associated with Crohn’s disease or ulcerative colitis. They have been classified by the ASAS group (ASsessment in Ankylosing Spondylitis) into axial spondyloarthritis and peripheral spondyloarthritis. Common features include the absence of autoantibodies, genetic predisposition, and clinical aspects such as axial joint involvement, peripheral manifestations, and extra-articular involvement. However, the pathogenic mechanisms remain complex and incompletely elucidated, despite the fact that the specialized literature has described several pathways that act in synergy: genetic predisposition, environmental factors (infections and mechanical stress), or innate and acquired immune mechanisms. Finally, an inflammatory response is triggered by the recruitment of a large number of inflammatory cells and the release of innate cytokines in the affected areas: joints or periarticular or extraarticular tissues. The current article aims to update and systematize the knowledge accumulated so far on this topic, focusing on the mechanisms that have been involved in the onset, progression, and severity of ankylosing spondylitis.

Introduction: An inverse relationship has been identified between tacrolimus serum concentrations and donor-derived cell-free DNA (dd-cfDNA) levels after lung transplant, but limited data exists on this relationship in the kidney transplant population. Project Aim: The purpose of this evaluation was to examine the relationship between high tacrolimus variability and elevated dd-cfDNA levels in kidney and simultaneous pancreas-kidney transplant recipients at a single center. Design: Single-center, retrospective, descriptive comparative evaluation of kidney and pancreas-kidney transplant recipients who received longitudinal ddcfDNA surveillance. Intrapatient tacrolimus variability was assessed using the coefficient of variation (%CV) measured between 1 and 12 months posttransplant. Pediatrics, retransplant or multiorgan transplant recipients, and pregnant recipients were excluded. Results: One hundred fifteen recipients with 518 dd-cfDNA levels and 3028 tacrolimus troughs were assessed. Pancreas-kidney recipients had significantly higher median dd-cfDNA (0.29% vs. 0.18%, P =.034) and were excluded from analysis. Ninety-nine kidney transplant recipients were included for analysis. Recipients with tacrolimus %CV ≥30 (N = 66) had significantly higher median dd-cfDNA than %CV <30 (0.22% vs. 0.17%, P =.031). Tacrolimus %CV ≥30 demonstrated higher median peak dd-cfDNA than %CV <30, though this was not statistically significant (0.36% vs. 0.28%, P =.058). Conclusion: These data demonstrated that high intrapatient tacrolimus variability may be associated with elevated dd-cfDNA in the first year after kidney transplant. [ABSTRACT FROM AUTHOR]

Background: Enthesitis-related arthritis (ERA) is a subtype of juvenile idiopathic arthritis with high disease burden. The objectives of this study were to explore the prevalence of HLA-B27, clinical characteristics, and treatment outcomes in children with ERA and compare the differences between HLA-B27 positive and negative patients. Methods: A retrospective cohort study at a pediatric rheumatology clinic in a tertiary referral hospital in Bangkok, Thailand, including ERA patients with at least 6 months of follow-up (July 2011-April 2022) was performed. Data were collected from medical records from diagnosis to recent follow-up, assessing disease activity and treatment outcomes, with an analysis comparing HLA-B27 positive and negative patients. Descriptive statistics were used for data analysis. Results: There were 59 ERA patients with mean age ± SD at diagnosis 11.2 ± 2.5 years, 53 males (89.8%), and positive HLA-B27 in 38 patients (64.4%). The HLA-B27 positive group had significantly higher levels of inflammatory markers at initial diagnosis (p = 0.001), lower baseline hemoglobin (p = 0.001) and hematocrit (p = 0.002), higher disease activity assessed by the Juvenile Spondyloarthritis Disease Activity score at 6 and 12 months of follow-up (p = 0.028 and 0.040, respectively), increased utilization of bridging systemic corticosteroids (60.5% vs. 14.3%, p = 0.001) and anti-TNF (39.5% vs. 9.5%, p = 0.018), and longer duration of methotrexate (median[IQR] 1.7[1.1–3.1] vs. 1.3[0.6–1.9] years, p = 0.040). The HLA-B27 negative group had more prevalent hip arthritis than the positive group at initial diagnosis (66.7% vs. 28.9%, p = 0.005) and during the course of the disease (71.4% vs. 36.8%, p = 0.011). Conclusion: Most of the ERA patients tested positive for HLA-B27. Throughout the follow-up period, these patients demonstrated greater disease activity, greater use of corticosteroids and anti-TNF, and longer duration of methotrexate to control the disease. Key points: • HLA-B27 was tested positive in nearly two-thirds of enthesitis-related arthritis (ERA) patients. • ERA patients with positive HLA-B27 had significantly higher levels of inflammatory markers with lower hemoglobin and hematocrit at initial diagnosis, increased disease activity assessed by the Juvenile Spondyloarthritis Disease Activity (JSpADA) score at 6 and 12 months of follow-up, greater utilization of bridging systemic corticosteroids and anti-TNF, and longer duration of methotrexate use. • ERA patients with negative HLA-B27 had more prevalent hip arthritis at initial diagnosis and during disease course. • Application of the Assessment of SpondyloArthritis international Society (ASAS) classification for adult spondyloarthritis in ERA patients who entered adulthood showed the predominance of peripheral spondyloarthritis in more than half of the patients. [ABSTRACT FROM AUTHOR]

Simple Summary: The human leukocyte antigen (HLA) system is crucial for immune responses against infections and cancer. Certain HLA class Ia molecules, like HLA-B27 and HLA-B57, are linked to both viral control (e.g., HIV, HCV) and development of autoimmune diseases (e.g., Spondylarthritis and psoriasis, respectively). Here we explore the use of HLA class I molecules as therapeutics in an "open format" (peptide free) construct, designed to activate immune cells through the interaction of LILRB and KIR receptors. The study identified IOS-1002, a modified version of HLA-B57:01:01 molecule fused to an IgG4 engineered to enhance stability and manufacturability. The research described in this manuscript highlights IOS-1002's unique mechanism of action, which includes binding to LILRB1, LILRB2, KIR3DL1 and CD64 receptors leads to the stimulation of multiple effector cells from both the innate and adaptive immune system. IOS-1002 is a first-in-class, multi-target, and multi-functional agent, currently being evaluated in a first-in-human phase I trial for various solid tumor indications. HLA-B27 and HLA-B57 are associated with autoimmunity and long-term viral control and protection against HIV and HCV infection; however, their role in cancer immunity remains unknown. HLA class I molecules interact with innate checkpoint receptors of the LILRA, LILRB and KIR families present in diverse sets of immune cells. Here, we demonstrate that an open format (peptide free conformation) and expression- and stability-optimized HLA-B57-B2m-IgG4_Fc fusion protein (IOS-1002) binds to human leukocyte immunoglobulin-like receptor B1 and B2 (LILRB1 and LILRB2) and to killer immunoglobulin-like receptor 3DL1 (KIR3DL1). In addition, we show that the IgG4 Fc backbone is required for engagement to Fcγ receptors and potent activation of macrophage phagocytosis. IOS-1002 blocks the immunosuppressive ITIM and SHP1/2 phosphatase signaling cascade, reduces the expression of immunosuppressive M2-like polarization markers of macrophages and differentiation of monocytes to myeloid-derived suppressor cells, enhances tumor cell phagocytosis in vitro and potentiates activation of T and NK cells. Lastly, IOS-1002 demonstrates efficacy in an ex vivo patient-derived tumor sample tumoroid model. IOS-1002 is a first-in-class multi-target and multi-functional human-derived HLA molecule that activates anti-tumor immunity and is currently under clinical evaluation. [ABSTRACT FROM AUTHOR]

Introduction: To assess differences in the diagnosis journey and access to care in a large sample of patients with axial spondyloarthritis (axSpA) from around the world, included in the International Map of Axial Spondyloarthritis (IMAS). Methods: IMAS was a cross-sectional online survey (2017–2022) of 5557 unselected patients with axSpA from 27 countries. Across five worldwide geographic regions, the patient journey until diagnosis and healthcare utilization in the last 12 months prior to survey were evaluated. Univariable and multivariable linear regression was used to analyze factors associated with higher healthcare utilization. Results: Of 5557 participants in IMAS, the diagnosis took an average of 7.4 years, requiring more than two visits to HCPs (77.7% general practitioner and 51.3% rheumatologist), and more than two diagnostic tests [67.5% performed human leukocyte antigen B27 (HLA-B27), 64.2% x-ray, and 59.1% magnetic resonance imaging (MRI) scans]. North America and Europe were the regions with the highest number of healthcare professional (HCP) visits for diagnosis, while the lowest number of visits was in the Asian region. In the previous 12 months, 94.9% (n = 5272) used at least one healthcare resource, with an average of 29 uses per year. The regions with the highest healthcare utilization were Latin America, Europe, and North America. In the multiple linear regression, factors associated with higher number of healthcare utilization were younger age (b = – 0.311), female gender (b = 7.736), higher disease activity (b = 1.461), poorer mental health (b = 0.624), greater functional limitation (b = 0.300), greater spinal stiffness (b = 1.527), and longer diagnostic delay (b = 0.104). Conclusion: The diagnosis of axSpA usually takes more than two visits to HCPs and at least 7 years. After diagnosis, axSpA is associated with frequent healthcare resource use. Younger age, female gender, higher disease activity, poorer mental health, greater functional limitation, greater spinal stiffness, and longer diagnostic delay are associated with higher healthcare utilization. Europe and North America use more HCP visits and diagnostic tests before and after diagnosis than the other regions. [ABSTRACT FROM AUTHOR]

Objectives GCA can be confirmed by temporal artery biopsy (TAB) but false negatives can occur. GCA may be overdiagnosed in TAB-negative cases, or if neither TAB nor imaging is done. We used HLA genetic association of TAB-positive GCA as an 'unbiased umpire' test to estimate historic overdiagnosis of GCA. Methods Patients diagnosed with GCA between 1990 and 2014 were genotyped. During this era, vascular imaging alone was rarely used to diagnose GCA. HLA region variants were jointly imputed from genome-wide genotypic data of cases and controls. Per-allele frequencies across all HLA variants with P  < 1.0 × 10−5 were compared with population control data to estimate overdiagnosis rates in cases without a positive TAB. Results Genetic data from 663 GCA patients were compared with data from 2619 population controls. TAB-negative GCA (n  = 147) and GCA without TAB result (n  = 160) had variant frequencies intermediate between TAB-positive GCA (n  = 356) and population controls. For example, the allele frequency of HLA-DRB1*04 was 32% for TAB-positive GCA, 29% for GCA without TAB result, 27% for TAB-negative GCA and 20% in population controls. Making several strong assumptions, we estimated that around two-thirds of TAB-negative cases and one-third of cases without TAB result may have been overdiagnosed. From these data, TAB sensitivity is estimated as 88%. Conclusions Conservatively assuming 95% specificity, TAB has a negative likelihood ratio of around 0.12. Our method for utilizing standard genotyping data as an 'unbiased umpire' might be used as a way of comparing the accuracy of different diagnostic pathways. [ABSTRACT FROM AUTHOR]

This article, published in the International Journal of Rheumatic Diseases, provides a comprehensive analysis of the clinical application of JAK inhibitors in SAPHO syndrome. SAPHO syndrome is a rare autoimmune inflammatory disease characterized by skin lesions, bone and joint lesions, and peripheral tissue damage. The study includes a retrospective analysis of 10 SAPHO syndrome patients, detailing their clinical data and treatment outcomes. The most common symptoms observed in these patients were sternoclavicular pain and swelling, joint pain in limbs, palmoplantar pustulosis, and severe acne. The article also includes clinical scores and radiographic images to support the findings. The study suggests that JAK inhibitors may be an effective treatment option for SAPHO syndrome, but emphasizes the importance of personalized treatment for optimal outcomes. [Extracted from the article]

Objective: Upadacitinib improved the signs and symptoms of non‐radiographic axial spondyloarthritis (nr‐axSpA) versus placebo over 14 weeks in the primary analysis of the SELECT‐AXIS 2 nr‐axSpA study. Here, we evaluated the efficacy and safety of upadacitinib through 1 year in patients with nr‐axSpA in SELECT‐AXIS 2. Methods: Patients aged at least 18 years diagnosed with nr‐axSpA who fulfilled the 2009 Assessment of SpondyloArthritis International Society (ASAS) classification criteria and were receiving stable background therapy were randomized to upadacitinib 15 mg once daily or placebo for the 52‐week double‐blind period. Efficacy was assessed using non‐responder imputation incorporating multiple imputation (NRI‐MI) and as‐observed analyses for binary endpoints, and mixed‐effects model repeated measures for continuous endpoints. Results: Of 314 randomized patients, 259 (upadacitinib, n = 129; placebo, n = 130) completed 52 weeks of treatment. More patients receiving upadacitinib versus placebo achieved ≥40% improvement in ASAS at week 52 (63% vs 43%, NRI‐MI; nominal P < 0.001). Similar treatment effects were observed for the achievement of axSpA Disease Activity Score inactive disease (33% v 11%, NRI‐MI; nominal P < 0.001). Overall, patients receiving upadacitinib versus placebo showed greater improvement in disease activity, inflammation, pain, function, enthesitis, and quality of life through 52 weeks. Adverse events were generally comparable between the treatment groups. No opportunistic infections, malignancies, major adverse cardiovascular events, venous thromboembolic events, inflammatory bowel disease, or deaths were reported in those receiving upadacitinib. Conclusion: Treatment with upadacitinib showed sustained efficacy versus placebo with no new safety findings identified through 1 year. These results support the continued favorable benefit–risk profile of upadacitinib treatment for nr‐axSpA. [ABSTRACT FROM AUTHOR]

Gliomas are primary brain tumors that arise from neural stem cells, or glial precursors. Diagnosis of glioma is based on histological evaluation of pathological cell features and molecular markers. Gliomas are infiltrated by myeloid cells that accumulate preferentially in malignant tumors, and their abundance inversely correlates with survival, which is of interest for cancer immunotherapies. To avoid time-consuming and laborious manual examination of images, a deep learning approach for automatic multiclass classification of tumor grades was proposed. As an alternative way of investigating characteristics of brain tumor grades, we implemented a protocol for learning, discovering, and quantifying tumor microenvironment elements on our glioma dataset. Using only single-stained biopsies we derived characteristic differentiating tumor microenvironment phenotypic neighborhoods. The study was complicated by the small size of the available human leukocyte antigen stained on glioma tissue microarray dataset — 206 images of 5 classes — as well as imbalanced data distribution. This challenge was addressed by image augmentation for underrepresented classes. In practice, we considered two scenarios, a whole slide supervised learning classification, and an unsupervised cell-to-cell analysis looking for patterns of the microenvironment. In the supervised learning investigation, we evaluated 6 distinct model architectures. Experiments revealed that a DenseNet121 architecture surpasses the baseline's accuracy by a significant margin of 9% for the test set, achieving a score of 69%, increasing accuracy in discerning challenging WHO grade 2 and 3 cases. All experiments have been carried out in a cross-validation manner. The tumor microenvironment analysis suggested an important role for myeloid cells and their accumulation in the context of characterizing glioma grades. Those promising approaches can be used as an additional diagnostic tool to improve assessment during intraoperative examination or subtyping tissues for treatment selection, potentially easing the workflow of pathologists and oncologists. [ABSTRACT FROM AUTHOR]

Background: Uveitis, characterized by inflammation of the iris, ciliary body, and choroid, presents a significant global clinical challenge, contributing substantially to visual impairment. Risk factors include autoimmune diseases and immune cell dysfunctions, yet many remain unidentified. Immune cells, notably T cells, B cells, and monocytes, play pivotal roles in uveitis pathogenesis. While biologic agents show promise, comprehensive studies on immune cell types in ocular diseases are lacking. Genome-wide association studies (GWAS) and Mendelian randomization MR) present promising avenues to elucidate genetic susceptibilities and causal relationships between immune cell traits and uveitis risk. Methods: Two-sample MR analysis was used to evaluate the causal relationship between 731 immune cells and uveitis, and genome-wide significance analysis was performed for genetic variation in 731 immune cells traits (P < 5 x 10-8). Immune characteristics include median fluorescence intensity (MFI), relative cell counts (RC), absolute cell counts (AC), and morphological parameters (MP), which were determined by published GWAS, and public data from the IEU Open GWAS database. The main analysis method of MR is inverse variance weighting IVW). Heterogeneity and horizontal pleiotropy were also assessed. Results: 5 immunophenotypes, including CD62L-DC %DC, IgD+ CD38dim %B cell, CD3 on CM CD4+T cell, CD3 on CD45RA-CD4 +T cell, and CD3 on CD39+ CD4+ Treg may increase the risk of uveitis. 5 immunophenotypes, including CD11b on CD33dim HLA DR-Myeloid cell, HLA DR on CD33dim HLA DR+ CD11b-myeloid cell, CD14-CD16 + %monocyte, HLA DR on CD14-CD16 + monocyte and PDL-1 on CD14-CD16 + monocyte was negatively associated with the risk of uveitis. Among them, HLA DR on CD14-CD16 + monocyte (OR=0.921, 95%CI =0.875-0.970, P=0.001) and HLA DR on CD33dim HLA DR+ CD11b- (OR=0.879, 95%CI = 0.833- 0.927, P=0.00) were negatively associated with the risk of uveitis in bi-direction. Conclusion: These results indicate that 10 immune cells traits are significantly associated with the risk of developing uveitis and 2 of them were strongly associated with uveitis bi-directionally, after excluding the effects of confounding factors such as some immune diseases, which provided new ideas and therapeutic targets for the study of immune mechanism of uveitis. [ABSTRACT FROM AUTHOR]

Background: Mucosal-associated invariant T (MAIT) cells assume pivotal roles in numerous autoimmune inflammatory maladies. However, scant knowledge exists regarding their involvement in the pathological progression of oral lichen planus (OLP). The focus of our study was to explore whether MAIT cells were altered across distinct clinical types of OLP. Methods: The frequency, phenotype, and partial functions of MAIT cells were performed by flow cytometry, using peripheral blood from 18 adults with non-erosive OLP and 22 adults with erosive OLP compared with 15 healthy adults. We also studied the changes in MAIT cells in 15 OLP patients receiving and 10 not receiving corticosteroids. Surface proteins including CD4, CD8, CD69, CD103, CD38, HLA-DR, Tim-3, Programmed Death Molecule-1 (PD-1), and related factors released by MAIT cells such as Granzyme B (GzB), interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-17A, and IL-22 were detected. Results: Within non-erosive OLP patients, MAIT cells manifested an activated phenotype, evident in an elevated frequency of CD69+ CD38+ MAIT cells (p < 0.01). Conversely, erosive OLP patients displayed an activation and depletion phenotype in MAIT cells, typified by elevated CD69 (p < 0.01), CD103 (p < 0.05), and PD-1 expression (p < 0.01). Additionally, MAIT cells exhibited heightened cytokine production, encompassing GzB, IFN-γ, and IL-17A in erosive OLP patients. Notably, the proportion of CD103+ MAIT cells (p < 0.05) and GzB secretion (p < 0.01) by MAIT cells diminished, while the proportion of CD8+ MAIT cells (p < 0.05) rose in OLP patients with corticosteroid therapy. Conclusions: MAIT cells exhibit increased pathogenicity and pro-inflammatory capabilities in OLP. Corticosteroid therapy influences the expression of certain phenotypes and functions of MAIT cells in the peripheral blood of OLP patients. [ABSTRACT FROM AUTHOR]

Simple Summary: High-dose post-transplant cyclophosphamide is effective in preventing graft-versus-host disease (GVHD) but is associated with adverse outcomes such as delayed engraftment, infections, and cardiac issues. This pilot study evaluated the efficacy and toxicity of reduced-dose PTCY (40 mg/kg/day) in patients undergoing HLA-matched allogeneic hematopoietic stem cell transplantation (alloHSCT). Neutrophil and platelet engraftment occurred at medians of 15 and 16 days, respectively. At day 100, the incidences of grade II–IV and III–IV acute GVHD were 18.2% and 4.5%, respectively, with no cases of grade IV acute GVHD or steroid-refractory disease. One-year incidence of moderate-severe chronic GVHD was 6.4%. Both incidences, acute GVHD and chronic GVHD, are similar to our previous experience with higher doses of PTCY. Two-year overall survival and relapse-free survival were 77.1% and 58.3%. There were low incidences of infections and only one early cardiac event. These results suggest that reduced-dose PTCY provides adequate immunosuppression with a low toxicity profile. PTCY 50 mg/kg/day on days +3/+4 is an excellent strategy to prevent GVHD. However, its use is associated with adverse outcomes such as delayed engraftment, increased risk of infection, and cardiac complications. This pilot study evaluates the efficacy and toxicity of a reduced dose of PTCY (40 mg/kg/day) combined with tacrolimus in 22 peripheral blood HLA-matched alloHSCT patients. At day +100, the cumulative incidences of grade II–IV and III–IV acute GVHD were 18.2% and 4.5%, respectively. No grade IV acute GVHD or steroid-refractory disease was observed. The cumulative incidences of all-grade and moderate-severe chronic GVHD at 1-year were 11.4% and 6.4%, respectively. No patient died from transplant-related complications. Two-year OS and RFS were 77.1% and 58.3%, respectively. All patients engrafted, with neutrophil and platelet recovery occurring at a median of 15 (IQR 14–16) and 16 days (IQR 12–23), respectively. The cumulative incidences of bloodstream bacterial infections, polyomavirus BK hemorrhagic cystitis, HHV6 reactivation, CMV reactivation, and fungal infections were 13.6%, 9.1%, 9.1%, 4.6%, and 6%, respectively. Only one early cardiac event was observed. These results suggest that PTCY 40 mg/kg/day on a +3/+4 schedule provides adequate immunosuppression to allow for engraftment and prevent clinically significant GVHD with a low toxicity profile. [ABSTRACT FROM AUTHOR]

Potential kidney transplant patients with HLA-specific antibodies have reduced access to transplantation. Their harmful effects are mediated by the Fc portion of IgG, including activation of the complement system and Fc receptor-initiated cytotoxic processes by circulating leucocytes. Avoiding antibody incompatibility is the conventional approach, but for some patients this can mean extended waiting times, or even no chance of a transplant if there are no alternative, compatible donors. For these cases, pretransplant antibody removal may provide access to transplantation. Plasmapheresis is currently used to achieve this, with acceptable outcome results, but the process can take days to reduce the antibody levels to a safe level, so has limited use for deceased donors. There is now an alternative, in the form of an IgG-digesting enzyme, Imlifidase, which can be administered for in vivo IgG inactivation. Imlifidase cleaves human IgG, separating the antigen-binding part, F(ab')2 from Fc. Typically, within six hours of dosing, most, if not all, of the circulating IgG has been inactivated, allowing safe transplantation from a previously incompatible donor. For deceased donor transplantation, where minimizing cold ischaemia is critical, this six-hour delay before implantation should be manageable, with the compatibility testing processes adjusted to accommodate the treatment. This agent has been used successfully in phase 2 clinical trials, with good short to medium term outcomes. While a donation rate that matches demand may be one essential answer to providing universal access to kidney transplantation, this is currently unrealistic. IgG inactivation, using Imlifidase, is, however, a realistic and proven alternative. [ABSTRACT FROM AUTHOR]

We aimed to examine the drug retention rate (DRR) of the interleukin-17 inhibitor ixekizumab in a real-world monocentric cohort of psoriatic arthritis (PsA) patients and to assess the predictors of drug discontinuation. Consecutive PsA patients who underwent treatment with ixekizumab from October 2019 to February 2023 were enrolled in this observational, retrospective, monocentric study. Clinical records were assessed at baseline and throughout the follow-up period. We collected sociodemographic data, smoking habits, body mass index, the presence of Human Leukocyte Antigen B27, comorbidities, disease involvement and duration, previous therapy, discontinuation of ixekizumab, reasons for discontinuation, and adverse events (AEs). DRR was evaluated as time to drug discontinuation and assessed through Kaplan–Meier curves. Baseline factors predicting drug discontinuation were investigated through logistic regression models. Eighty PsA patients were included in this study. Ixekizumab was administered at a dose of 160 mg by subcutaneous injection at baseline, followed by 80 mg every four weeks thereafter. Ixekizumab had a 38-month-cumulative DRR of 43.8%, accounting for both inefficacy and AEs. When considering only inefficacy, the DRR was 62.6%. Comorbidities (p = 0.665), obesity (p = 0.665), smoking (p = 0.884), disease duration ≤ 2 years (p = 0.071), axial (p = 0.131) and skin involvement (p = 0.460), and previous therapies, including conventional synthetic (p = 0.504) and biological (p = 0.474) Disease-Modifying Antirheumatic Drugs (bDMARDs), as well as the number of previous bDMARDs or targeted synthetic Disease-Modifying Antirheumatic Drugs (tsDMARDs), did not significantly affect the DRR (p = 0.349). Multivariate analysis found no independent predictors of drug discontinuation. The most frequent AEs leading to discontinuation were skin reactions; no severe infections were observed. In our real-world study, comorbidities, disease duration, and previous therapies did not affect the DRR of ixekizumab. Ixekizumab had a favorable safety profile, with no severe AEs observed. [ABSTRACT FROM AUTHOR]

Objective: We previously reported that CD14+ dendritic‐shaped cells exhibit a dendritic morphology, engage in pseudo‐emperipolesis with lymphocytes, and express CD90 in the perivascular areas of rheumatoid arthritis (RA) synovial tissues. However, it remains unclear whether these CD14highCD90intermediate(int) cells function as dendritic cells. In this study, we investigated the dendritic cell–differentiation potential of CD14highCD90int cells. Methods: The localization and number of CD14highCD90int cells in RA synovial tissues and peripheral blood were examined. The dendritic cell–differentiation potential of CD14highCD90int cells was examined by measuring interleukin‐6 and tumor necrosis factor‐α levels in the supernatant and CD83 and human leukocyte antigen (HLA)‐DR expression in the cells after induction of dendritic cell differentiation. Synovial cells were co‐cultured with lymphocytes, and the activation of these cells was examined. Results: CD14highCD90int cells were abundant in RA synovial tissues, including the sublining layer and the pannus areas. Patients with untreated and active RA had significantly higher percentages of CD14highCD90int cells in the peripheral blood and synovial tissues. In RA synovial cells, inflammatory cytokine levels increased with dendritic cell–differentiation culture, but CD83 and HLA‐DR expression were significantly increased in the CD14highCD90int cell group. When co‐cultured with lymphocytes, cell numbers and inflammatory cytokine levels significantly increased in both groups of synovial cells after dendritic cell induction. Conclusion: CD14+ cells migrate and spread from the circulating blood to RA synovial tissues while expressing CD90, and CD14highCD90int cells in contact with lymphocytes differentiate into HLA‐DR+ dendritic cells, which contribute to chronic inflammation in RA. [ABSTRACT FROM AUTHOR]

Background: Juvenile idiopathic arthritis (JIA) is a chronic inflammatory joint disease with a complex etiology. It is characterised by symptoms such as swelling, exudates, soreness, and reduced mobility. Early diagnosis and treatment are crucial to improving long-term prognosis and preventing complications. Case presentation: A 5-year-old girl with polyarticular seronegative, human leukocyte antigen B27 (HLA-B27)-positive JIA previously under the care of another medical centre was admitted for evaluation of disease activity and possible reintroduction of treatment. The patient's history began at the age of 14 months when symptoms of inflammation of the small joints of the hands appeared. On physical examination pain and swelling of the proximal interphalangeal joints of the hands were detected. Laboratory tests revealed low inflammatory indices. Rheumatoid factor, anti-citrullinated protein antibodies, and a genetic test for HLA-Cw6 were negative. An ultrasound of the hands confirmed the presence of arthritis. Furthermore, a magnetic resonance imaging (MRI) scan and a computed tomography (CT) scan were performed, revealing sacroiliitis. The treatment initially included two disease-modifying drugs -- methotrexate and sulphasalazine with folic acid shielding. Subsequently, due to the poor response to treatment, the child was qualified for biological treatment with adalimumab, achieving a significant improvement in clinical condition and imaging findings. Follow-up hospital admissions confirmed the stabilisation of the patient's condition and the absence of disease progression. Conclusion: This case emphasises the importance of early diagnosis and an individualised therapeutic approach in the treatment of JIA. Biological therapy with adalimumab, combined with conventional drugs, proved effective in controlling the disease's symptoms and improving the patient's quality of life. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to research the frequency of Human Leukocyte Antigen (HLA)-B27 antigen positivity and relationship between HLA-B27 positivity and other autoantibodies and between HLA-B27 positivity and treatment in patients diagnosed with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Material and Method: The study is a retrospective study. Patients diagnosed with RA and AS as a result of the examinations performed at Physical Medicine and Rehabilitation outpatient clinic between January 2017 and September 2022 were retrospectively screened, and patients whose HLA-B27 antigen was tested were included in study. Results: A total of 569 patients, 199 with RA and 370 with AS were included in study. While HLA-B27 was positive in 11% of patients with RA, it was 37.5% in patients with AS and there was a significant difference between the groups. When we analyzed the correlation of autoantibodies with HLA-B27, we found that HLA-B27 was not correlated with RF, Anti-cyclic citrullinated peptides (Anti-CCP) or Anti-nuclear antibody (ANA). When we analyzed the relationship between HLA-B27 and the treatment method, there was no significant relationship between HLA-B27 and treatment method. Conclusion: While HLA-B27 was found to be 5% positive in the general population in the literature, we found 11% in 199 patients with RA. This study is important because it shows that HLA-B27 positivity is not very common in patients diagnosed with AS recently contrary to popular belief. More studies are needed to evaluate HLA-B27 frequency in RA and AS. [ABSTRACT FROM AUTHOR]

Background and Objectives This study looked at the frequency of HLA alleles and their genetic diversity in specific Iranian ethnic groups. This is important for the successful transplantation of hematopoietic stem cells. Materials and Methods In this descriptive study, HLA-DRB1 alleles were determined in low resolution level for donors using the PCR-SSP method. By using the HLA lab data and the stem cell donors' information in Iranian Blood Transfusion Organization, the ethnic and HLA information from the Gilak (n = 510, 24.70%), Lur (n = 465, 22.53%), Kurd (n = 719, 34.84%), and Arab (n = 370, 17.93%) ethnicities were collected and analyzed. The relationship between alleles and ethnicity was examined, and a statistically significant relationship (p < 0.05) between the frequency of alleles in the studied ethnic groups was evaluated using the chi-square test. Results The low frequency allelic groups related to HLA-DRB1 were HLA-DRB1*09 (0.6%), HLADRB1*12 (0.8%), and HLA-DRB1*08 (1.6%). Allelic groups with higher frequency included HLA-DRB1*11 (22.7%), HLA-DRB1*03 (11.8%), HLA-DRB1*15 (11.7%), and HLADRB1*04 (11.1%). Among the allelic groups of HLA-DRB1, the frequency of 9 HLA-DRB1 allelic groups showed significant differences in the studied populations. Conclusions The frequency of several allelic groups showed significant differences among Iranian ethnicities. Identifying similarities and differences in the frequency of HLA alleles among Iranian ethnicities can help not only expand the pool of donors in registries but also assist in planning for providing of hematopoietic stem cell donors for patients from different Iranian ethnic groups. [ABSTRACT FROM AUTHOR]

Spondylarthritis (SpA) is a chronic inflammatory condition that encompasses damage to the axial or peripheral skeleton, accompanied by specific extra-articular symptoms. Within this group, Ankylosing Spondylitis stands out as the hallmark member. Although the heritability of Ankylosing Spondylitis is estimated to be over 95%, only a portion of the heritability has been explained, with HLA-B27 accounting for 20.1% of it; therefore, ongoing research endeavors are currently concentrated on investigating the potential participation of different entities in the development of the disease. Genome-wide association studies have led to significant advances in our understanding of the genetics of SpA. In this descriptive review, we delve into the pathogenesis of Spondylarthritis beyond HLA-B27. We summarize the latest research on the potential participation of various entities in the development of the disease, including other genetic loci, immune dysregulation, microbiota, and environmental factors. The multifactorial nature of SpA and the complex interplay of genetic, immunological, and environmental factors are being increasingly recognized; therefore, it is of paramount importance to consider a holistic approach to comprehend the pathogenesis of SpA in order to identify novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Histocompatibility testing is pivotal in any renal transplantation workup, aimed at enhancing prospective donor recipient compatibility and improving transplant outcomes. The evolution and advancement of histocompatibility testing, particularly HLA typing, have significantly improved its precision. This study outlines the historical progression from serologic to DNA-based HLA typing, emphasizing the role of HLA proteins in immune response. Anti-HLA antibodies, targeting HLA proteins, pose challenges in renal transplantation. Monitoring and managing these antibodies are critical for renal transplant success. Complement-dependent cytotoxicity crossmatch and flow cytometry crossmatch are essential techniques for assessing donor–recipient compatibility. Panel-reactive antibody assesses antibodies against a panel of donor antigens, often HLA. Higher PRA levels (percentage) complicate donor matching, requiring specialized protocols. Virtual crossmatch evaluates recipient anti-HLA antibodies against potential donors through synthetic beads. This approach predicts crossmatch outcomes by comparing antibody profiles, offering a valuable tool for the risk assessment of renal transplantation. Despite advancements, a comprehensive understanding of alloreactive immune responses requires a combination of assays, emphasizing the importance of a multifaceted approach in histocompatibility testing. This is an attempt to compile the relevant information, providing a basis for comparison in a clear and foundational format for histocompatibility testing laboratories. [ABSTRACT FROM AUTHOR]

Various aspects of the concept of Vyadhikshamatva have been thoroughly explored, highlighting its profound significance in resisting disease manifestation, particularly in the context of Ankylosing spondylitis. Investigated the relationship between HLA-B27 and Ankylosing spondylitis (AS) by examining current knowledge and hypotheses Furthermore, efforts were made to portray the influence of prakruti (constitution) and balam (strength) on disease manifestation and progression. Ayurvedic literature along with contemporary research works was analyzed for correlating various aspects like vyadhikshamatva,oja (The final essence of all body elements), and balam along with their influence on the defensive mechanism of the body. A thorough literature search was conducted to explore the strong association between HLA-B27 and AS by examining various hypotheses like the Arthritogenic peptide hypothesis, the Misfolding hypothesis, the Surface Homodimer hypothesis, and the β2 microglobulin hypothesis that attempts to explain the pathogenic role of HLA-B27 in AS. Alongside classical Ayurvedic texts, databases like PubMed and Scopus were searched using keywords such as Immunity, Ankylosing spondylitis, Vyadhikshamatva, HLA-B27, Balam, and Autoimmune disorder with the help of Boolean operators. The review highlighted the critical role of Vyadhikshamatva in disease prevention, particularly in influencing the manifestation of conditions like AS despite genetic predisposition (HLA-B27). Further, the understanding of the Ayurvedic concepts can clearly explain the conflict that has arisen in the determination of the positive HLAB27 gene in Ankylosing Spondylitis as a definite diagnosing criteria. This comprehensive understanding will uplift the need for personalized medicine in disease management. Further research must be needed to understand the interaction between genetic factors (HLAb27), individual constitution, and their vyadikshamatva. [ABSTRACT FROM AUTHOR]

Background: A 10-day dexamethasone regimen has emerged as the internationally adopted standard-of-care for severe COVID-19 patients. However, the immune response triggered by SARS-CoV-2 infection remains a complex and dynamic phenomenon, leading to various immune profiles and trajectories. The immune status of severe COVID-19 patients following complete dexamethasone treatment has yet to be thoroughly documented. Results: To analyze monocyte HLA-DR expression (mHLA-DR) and CD4 + T lymphocyte count (CD4) in critically ill COVID-19 patients after a dexamethasone course and evaluate their association with 28-day ICU mortality, adult COVID-19 patients (n = 176) with an ICU length of stay of at least 10 days and under dexamethasone treatment were included. Associations between each biomarker value (or in combination) measured at day 10 after ICU admission and 28-day mortality in ICU were evaluated. At day 10, the majority of patients presented decreased values of both parameters. A significant association between low mHLA-DR and 28-day mortality was observed. This association remained significant in a multivariate analysis including age, comorbidities or pre-existing immunosuppression (adjusted Hazard ratio (aHR) = 2.86 [1.30–6.32], p = 0.009). Similar results were obtained with decreased CD4 + T cell count (aHR = 2.10 [1.09–4.04], p = 0.027). When combining these biomarkers, patients with both decreased mHLA-DR and low CD4 presented with an independent and significant elevated risk of 28-day mortality (i.e., 60%, aHR = 4.83 (1.72–13.57), p = 0.001). Conclusions: By using standardized immunomonitoring tools available in clinical practice, it is possible to identify a subgroup of patients at high risk of mortality at the end of a 10-day dexamethasone treatment. This emphasizes the significance of integrating immune monitoring into the surveillance of intensive care patients in order to guide further immumodulation approaches. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to assess whether circulating histone‐specific T cells represent tools for precision medicine in systemic lupus erythematosus (SLE). Methods: Seroprevalence of autoantibodies and HLA‐DR beta (DRB) 1 profile were assessed among 185 patients with SLE and combined with bioinformatics and literature evidence to identify HLA–peptide autoepitope couples for ex vivo detection of antigen‐specific T cells through flow cytometry. T cell differentiation and polarization was investigated in patients with SLE, patients with Takayasu arteritis, and healthy controls carrying HLA‐DRB1*03:01 and/or HLA‐DRB1*11:01. SLE Disease Activity Index 2000 and Lupus Low Disease Activity State were used to estimate disease activity and remission. Results: Histone‐specific CD4+ T cells were selectively detected in patients with SLE. Among patients with a history of anti‐DNA antibodies, 77% had detectable histone‐specific T cells, whereas 50% had lymphocytes releasing cytokines or upregulating activation markers after in vitro challenge with histone peptide antigens. Histone‐specific regulatory and effector T helper (Th) 1‐, Th2‐, and atypical Th1/Th17 (Th1*)‐polarized cells were significantly more abundant in patients with SLE with quiescent disease. In contrast, total Th1‐, Th2‐, and Th1*‐polarized and regulatory T cells were similarly represented between patients and controls or patients with SLE with active versus quiescent disease. Histone‐specific effector memory T cells accumulated in the blood of patients with quiescent SLE, whereas total effector memory T cell counts did not change. Immunosuppressants were associated with expanded CD4+ histone‐specific naive T (TN) and terminally differentiated T cells. Conclusion: Histone‐specific T cells are selectively detected in patients with SLE, and their concentration in the blood varies with disease activity, suggesting that they represent innovative tools for patient stratification and therapy. [ABSTRACT FROM AUTHOR]

Introduction: The transplantation of highly sensitized patients remains a major obstacle. Immunized patients wait longer for a transplant if not prioritized, and if transplanted, their transplant outcome is worse. Case Presentation: We report a successful AB0- and HLA-incompatible living donor kidney transplantation in a 35-year-old female patient with systemic lupus erythematosus (SLE) and antiphospholipid syndrome. The patient had a positive T- and B-cell complement-dependent cytotoxicity (CDC) crossmatch and previous graft loss due to renal vein thrombosis. We treated the patient with intravenous immunoglobulins, rituximab, horse anti-thymocyte globulin, daratumumab, and imlifidase, besides standard immunosuppression. All IgG antibodies were sensitive to imlifidase treatment. Besides donor-specific HLA antibodies, anti-dsDNA antibodies and antiphospholipid antibodies were cleaved. The patient initially had delayed graft function. Two kidney biopsies (day 7 and day 14) revealed acute tubular necrosis without signs of HLA antibody-mediated rejection. On posttransplant day 30, hemodialysis was stopped, and creatinine levels declined over the next weeks to a baseline creatinine of about 1.7 mg/dL after 12 months. Conclusion: In this case, a novel multimodal treatment strategy including daratumumab and imlifidase enabled successful kidney transplantation for a highly immunized patient with antiphospholipid antibodies. [ABSTRACT FROM AUTHOR]