Immuno

Living therapies, including chimeric antigen receptor T (CAR-T) cells, oncolytic viruses (OVs), and bacteria-based platforms, are emerging as promising approaches in cancer treatment because they can directly target tumors and modulate anti-tumor immunity. This narrative review summarizes current knowledge on these therapies, focusing on their mechanisms of action, therapeutic applications, major limitations, and recent advances in genetic engineering, synthetic biology, and delivery systems. CAR-T cell therapy has shown substantial clinical success in hematological malignancies through the genetic redirection of T cells against tumor-associated antigens, although its efficacy in solid tumors remains limited by antigen heterogeneity and the immunosuppressive tumor microenvironment (TME). OVs selectively infect and lyse malignant cells while also stimulating local and systemic immune responses, and engineered OVs may further enhance therapeutic activity by reshaping the TME. Bacteria-based therapies exploit the natural tumor-targeting ability of selected strains, particularly in hypoxic regions, to deliver therapeutic agents and activate immune responses. Despite encouraging progress, safety concerns, immune-related barriers, and tumor complexity remain major challenges. Overall, integrating living therapies with modern biotechnological advances and existing treatment modalities may support more personalized and synergistic strategies for cancer management. Full article

Extracellular vesicles (EVs) are lipid bilayer-bound structures capable of transporting molecular markers from their cell of origin and are secreted by multiple cell types, including malignant cells. EVs have emerged as promising tools for developing less invasive diagnostic approaches. In B-cell acute lymphoblastic leukemia (B-ALL), immunophenotypic characterization of extracellular vesicle-enriched populations (EVEPs) in peripheral blood (PB) may provide complementary information for disease detection and monitoring. This exploratory study aimed to characterize EVEPs obtained from PB and bone marrow (BM) of adult patients with B-ALL and to compare them with the clinical immunophenotype (CIP). A total of 12 individuals were initially recruited (eight with B-ALL, one with T-ALL, and three healthy controls). The study focused on the eight B-ALL patients and three controls, while the T-ALL sample was used as a specificity control. EVEPs were isolated by differential centrifugation and analyzed by flow cytometry and confocal microscopy, primarily evaluating CD3 and CD19 expression. EVEPs derived from PB samples of patients with B-ALL showed a higher percentage of marker-positive events by flow cytometry (CD45, CD34, CD19, CD20, and CD10), consistent with the leukemic phenotype identified in the CIP. Additionally, CD3⁺CD19⁺ EVEPs were occasionally detected. These findings suggest that EVEPs partially reflect the leukemic immunophenotype and may serve as a complementary source of biological information. The detection of CD3⁺CD19⁺ events highlights complex cellular interactions within the leukemic niche and warrants further investigation. Full article

Cutaneous leishmaniasis remains a therapeutic challenge due to toxicity, parasitic resistance, and the limitations of conventional drugs. In this context, combination therapies using natural immunomodulatory compounds have emerged as a promising alternative. This study evaluated the antileishmanial, cytotoxic, and immunomodulatory effects of gallic acid (GA) combined with paromomycin sulfate (PAR) using in vitro models. IC₅₀ values were determined in promastigote and amastigote forms of Leishmania (Viannia) guyanensis, and CC₅₀ values were assessed in RAW 264.7 macrophages. Peripheral blood mononuclear cells (PBMCs) from healthy volunteers (n = 13) were stimulated with GA, PAR, GA + PAR, or controls to evaluate lymphoproliferation and cytokine production. GA showed higher activity against intracellular amastigotes (IC₅₀ = 11.4 µM), while GA + PAR also demonstrated activity (IC₅₀ = 20.5 µM). PAR alone showed limited efficacy. The combination exhibited limited antiparasitic activity, with effects mainly at higher concentrations and without consistent superiority over GA monotherapy. Immunologically, GA + PAR displayed a balanced cytokine profile without inducing excessive proliferation. These findings suggest a complementary immunomodulatory effect, although further studies are needed to confirm its therapeutic relevance. Full article

Foot-and-Mouth Disease (FMD) is caused by the FMD virus. Indirect Sandwich Enzyme-Linked Immunosorbent Assay (IS-ELISA) was standardized to characterize the FMD serotype “O” virus. Total protein content in the guinea pig serum (whole serum), ammonium sulfate precipitated guinea pig serum (ASPGPS) protein and ion-exchange-based purified guinea pig serum (IEGPS) protein was measured as 52 µg/mL, 24 µg/mL and 10 µg/mL respectively. The whole serum of guinea pigs and rabbits showed the 1:32 and 1:64 anti-FMD serotype “O” virus neutralizing antibody titers, while the anti-FMD serotype “O” virus neutralizing antibody titer was 1:128 in the IEGPS proteins. IEGPS protein with 1:128 neutralizing antibody titers were used as capture/trapping antibodies in the standardization of the assay. The IEGPS protein 1:1000 diluted with 10 µg/mL of protein content was found to be optimum for capture/trapping antibodies. To cover residual blank spaces, different available blocking buffers were evaluated and Skimmed Milk Solution 5% in Phosphate-Buffered Saline (PBS5%) proved best amongst blocking buffers. Coating of 1:1000 diluted IEGPS at 37 °C for 1 h followed by storage at 4 °C for overnight was best for incubation time. FMD serotype “O” virus 1:100 diluted was optimum in IS-ELISA. Similarly rabbit anti-FMD serotype “O” virus specific immune serum 1:10,000 diluted and goat anti-rabbit IgG horseradish peroxidase conjugate 1:4000 diluted were found to be optimum during the standardization of the assay. Lastly ELISA plates proved to be best amongst the available plates for assay. In each experiment, the plateau region, test background and plate background were recorded. Lastly it became possible for the establishment of an optimized and potentially cost-effective IS-ELISA requiring further diagnostic validation in research and diagnostic laboratories in the country. Full article

Gabapentin is widely used for epilepsy and neuropathic pain. Beyond neurological indications, preclinical evidence suggests that gabapentin may exert anti-inflammatory effects that have not been systematically reviewed. A systematic review (2015–2025) was performed, resulting in thirteen in vitro and in vivo studies evaluating gabapentin’s impact on inflammatory signaling pathways, cytokine production, immune cell activity, and tissue inflammation. Outcomes included molecular pathways, inflammatory mediators, histopathological changes, and functional inflammatory measures. Risk of bias and study quality were assessed using the SYRCLE RoB tool for in vivo studies and the SciRAP approach for in vitro studies. Gabapentin demonstrated potential modulation of inflammatory responses in neuropathic pain, neuroinflammation, uveitis, and sepsis models through inhibition of MAPK and NF-κB signaling, reduction in pro-inflammatory cytokines, modulation of PPAR signaling pathways, and activation of Nrf2/HO-1 pathway. Gabapentin’s pharmacological actions extend beyond neuronal excitability to include modulation of inflammatory pathways, supporting a broader biological role for gabapentin. Although preclinical data support gabapentin’s potential anti-inflammatory properties, further targeted experimental and clinical studies are warranted to confirm these findings. Full article

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, with blast TBI (bTBI) particularly affecting military personnel and individuals exposed to explosive environments, yet there are no available curative treatments to date. While adrenergic receptor antagonists have shown promise in reducing neuroinflammation and improving TBI mortality rates, systemic administration of these drugs can have deleterious effects including bradycardia and hypotension. Here, we introduce a polymeric nanoparticle system for the delivery of adrenergic receptor antagonists, which allows for size-based targeting of the injured blood–brain barrier (BBB). These nanoparticles consist of chitosan-coated polylactic co-glycolic acid encapsulating the β-adrenergic receptor antagonist propranolol and/or the α-adrenergic receptor antagonist phenoxybenzamine. Particles designed with a 200 nm hydrodynamic diameter showed a 20–24% increase in permeability on an in vitro contact co-culture BBB model exposed to a 23 or 35 PSI acoustic blast when compared to uninjured controls, whereas 100 nm particles show no difference, suggesting blast injury induces BBB damage that enables the accumulation of larger particles. Treatment of blast-injured human brain microvascular cells with our nanoformulation reduced extracellular inflammatory cytokine levels and reduced the expression of pro-inflammatory markers in microglia. Moreover, these particles mitigated the upregulation of extracellular TNFα induced by free phenoxybenzamine in injured and uninjured microglia, suggesting nanoparticle drug encapsulation can reduce adverse drug reactions in the brain. Together, these findings provide proof-of-concept for size-based targeting and the potential anti-inflammatory effects of CS-PLGA nanoparticles containing adrenergic receptor antagonists for treatment of TBI and bTBI. Full article

Chronic pain is increasingly understood as a neuroimmune disorder rather than a purely neuronal condition, in which immune mediators and immune-like signaling within the nervous system regulate nociceptive gain across peripheral tissues, dorsal root ganglia (DRG), spinal cord, and supraspinal networks. Seminal and recent syntheses show that microglia, macrophages, cytokines/chemokines, and innate immune sensors can initiate and maintain maladaptive plasticity and central sensitization, helping explain the frequent clinical dissociation between structural pathology, systemic inflammatory markers, and pain severity. However, immune biology is bidirectional: alongside pronociceptive pathways, a growing literature describes active “pain-resolving” programs that terminate sensitization and restore homeostasis, including regulatory T cell (Treg)–IL-10 signaling and specialized pro-resolving mediators (SPMs). A structured search of PubMed/MEDLINE, supplemented by Europe PMC and PubMed Central, was performed, and citation chasing through broad scholarly indices was used to identify high-impact reviews, meta-analyses, and translational mechanistic studies. Systematic biomarker syntheses in low back pain, neck pain, and fibromyalgia indicate modest and heterogeneous systemic inflammatory signals, underscoring the need for mechanistic endotyping and stage-specific interventions. Based on this evidence, a clinically oriented framework is presented that distinguishes immune-driven pain amplification from impaired resolution and outlines practical implications for assessment, biomarker interpretation, and precision-oriented trial design. Full article

Both plants and animals have developed a sophisticated two-tiered innate immune system. This involves an initial recognition of microbial patterns conserved on the cell surface (PAMP-triggered immunity) and a subsequent more specific intracellular recognition of pathogenic effectors or their activities (effector-triggered immunity). A common fundamental feature is the use of NLR-like intracellular receptors to detect insider threats. Both plant NLRs (receptors containing nucleotide-binding domains and leucine-rich repeats) and animal NLRs (NOD-like receptors) share a modular tripartite architecture, typically featuring a central nucleotide-binding domain (NBD/NOD) and C-terminal leucine-rich repeats (LRRs). The NBD/NOD is crucial for facilitating the exchange of ADP/ATP, acting as a molecular switch to promote oligomerization and activation of NLRs in both kingdoms. In this review, we summarize the similarities and differences between plant and animal molecular perception and immunity mechanisms. Additionally, we highlight the fact that some human pathogens can infect plants, and crucially, some plant pathogens are capable of causing disease in humans. This suggests conserved molecular strategies to invade and manipulate host cells belonging to different biological kingdoms, uncovering that plant and human pathology may benefit from future investigations in their respective fields. Full article

This manuscript presents an updated version of PEPlife, a manually curated database that provides extensive information on peptide half-life. The updated version, PEPlife2, contains 4500 total entries, including 2300 newly curated entries and 2200 entries from the previous PEPlife database. These entries correspond to 1673 unique peptide sequences and 257 unique protein sequences where different entries may refer to the same peptide/protein sequence, the half-life of which was evaluated using different experimental assays. Each entry contains detailed information, including experimental methods used to determine half-life, chemical modifications, biological activity, routes of administration, and other relevant data. In addition to unmodified peptide sequences, PEPlife2 includes cyclic peptides and chemically modified peptides, such as those with N- and C-terminal modifications. To provide structural insights, peptide and protein structures were sourced from the Protein Data Bank (PDB) or predicted using PEPstrMOD. PEPlife2 integrates advanced analytical tools including BLAST (version 2.7.1), Smith–Waterman and CLUSTALW. This database provides a valuable resource for peptide and protein therapeutics research, particularly in the design of immunotherapeutics and vaccines. Full article

Hypersensitivity reactions to iodinated contrast media (ICM) are traditionally categorized as immediate or delayed reactions, involving IgE-mediated pathways, non–IgE-dependent mast cell or complement activation, or T cell–mediated immune mechanisms. However, we observed that some individuals develop systemic inflammatory responses that do not fit these established categories. We describe here a case series of three patients who developed cytokine release syndrome (CRS)-like reactions following iodinated contrast administration, which were initially difficult to distinguish from sepsis and were only recognized after recurrent episodes. Clinical presentation, laboratory findings, cytokine profiles, allergy investigations, and treatment outcomes were reviewed. All patients developed fever, rigors, and hypotension within 5 to 70 h after exposure, accompanied by leukocytosis and markedly elevated inflammatory markers despite negative microbiological investigations. Serum tryptase levels remained within the normal range with no significant rise, while cytokine analyses demonstrated elevations of pro-inflammatory interleukin-6 and other cytokines in patients 1 and 3 where samples were available. Standard corticosteroid premedication did not prevent recurrence, and one patient developed systemic symptoms following intradermal testing. All patients improved with high-dose systemic corticosteroids and supportive care. These findings suggest that ICM may induce a cytokine-mediated inflammatory phenotype distinct from classical hypersensitivity reactions, highlighting the importance of early clinical recognition to guide diagnosis and management. Full article

Inflammatory bowel disease (IBD) is a chronic, immune-mediated gastrointestinal disorder. Although genetic susceptibility contributes to disease risk, it cannot explain the rapidly rising incidence, implicating environmental drivers. Diet has emerged as a key factor, especially the growing global consumption of ultra-processed foods (UPFs), characterised by extensive use of industrial food additives. While epidemiological studies increasingly associate UPF consumption with IBD risk, the underlying biological mechanisms remain insufficiently integrated. This review examines how UPF consumption contributes to IBD pathogenesis and whether dietary modification offers a more comprehensive therapeutic approach than immune inhibition alone. The evidence demonstrates that UPFs, particularly their additive components, disrupt gut homeostasis through converging mechanisms that closely align with IBD pathogenesis. By promoting dysbiosis, impairing mucus and epithelial barrier integrity, inducing endoplasmic reticulum stress, and activating inflammatory pathways such as the NLRP3 inflammasome, food additives sustain the self-perpetuating cycle of intestinal inflammation characteristic of IBD. Although immune dysregulation is central to disease expression, evidence indicates that it is largely driven by upstream disturbances in the gut environment. Current immune-targeted therapies control symptoms but do not address these upstream drivers. In contrast, dietary modulation, particularly reducing UPF exposure, offers a system-level strategy to restore gut homeostasis and complement existing treatments. Together, these findings support a shift in IBD research and management toward targeting upstream drivers of inflammation to improve long-term disease control and ultimately mitigate the growing global burden of IBD. Full article

Antibodies are highly specialized glycoproteins produced by B cells in response to antigenic stimulation. They are a major component of the adaptive immune system and play a key role in host defenses by detecting, neutralizing, and eliminating foreign antigens. Over the years, their roles have transcended mere immune biomarkers due to their unique specificity, affinity maturation, and structural versatility, making them indispensable tools in biomedical research, including vaccine design, therapeutic development, and diagnostics. In this work, we examine the structural and functional basis of antibody bioactivity while highlighting key engineering strategies, including Fc modification, glycosylation engineering, and the development of novel antibody formats. We also considered the application of engineered antibodies in infectious disease and cancer prevention and treatment, focusing on current challenges, and proposing emerging directions that position antibody engineering as a transformative approach in future biomedical research and innovation. Full article

Kidney disease is an alarming universal health concern and a leading cause of morbidity and mortality. About 861 million individuals around the world suffer from kidney complications. However, current treatment alternatives are limited. These limitations underscore the urgent need for new therapeutic approaches. Autophagy is a dynamic and cellular housekeeping mechanism. The use of conditional autophagy-related gene knockouts in kidney cells has led to a better understanding of autophagy’s significance. Basal autophagy in the kidney serves as a quality control mechanism, vital for cellular metabolism and organelle homeostasis. Under stressful conditions, kidney cells adapt their autophagic activity. This process is intricately controlled by signaling pathways that control autophagic flux, with sirtuins, AMP-activated protein kinase (AMPK), and mammalian target of rapamycin (mTOR) acting as key regulators. Additionally, autophagy plays a role in the natural aging process of renal tissue. Small-molecule natural products have demonstrated efficacy in regulating autophagy and mitigating kidney damage in several experimental studies. However, specific mechanisms by which small molecules regulate autophagy across different renal disorders have yet to be fully understood. This study shows that the recent advancements in using small molecules in autophagy research have reignited interest in the related signaling pathways and their role in the pathophysiology of renal diseases. Further research on autophagy and its regulatory signaling networks could provide new therapeutic targets for small-molecule intervention in renal disorders. Full article

Melanoma is characterized by a high mutational burden making it an established model for studying tumor neoantigens and developing strategies for personalized immunotherapy. In this study, a reproducible bioinformatics pipeline was developed and implemented for the identification and prioritization of candidate neoantigens derived from non-synonymous somatic mutations in melanoma, using genomic data from the MSK-IMPACT cohort (mel-mskimpact-2020; n = 696) and comparative reference information from TCGA-SKCM. From the somatic mutation annotation file (MAF), 16,311 non-synonymous mutations were filtered, from which 50,480 mutant 8–11-mer peptides were generated using a sliding-window approach centered on the mutated position. Peptide–HLA class I binding affinity was predicted using MHCflurry 2.0 across six representative alleles (HLA-A*02:01, HLA-A*24:02, HLA-B*35:01, HLA-B*39:05, HLA-C*04:01, and HLA-C*07:02). Candidate prioritization was initially based on predicted binding percentile (rank ≤ 2), identifying 12,209 peptide–HLA combinations with high predicted binding affinity. To refine candidate selection, additional computational analyses were incorporated, including proteasomal cleavage prediction using NetChop 3.1 and estimation of T-cell epitope immunogenicity using the Immune Epitope Database (IEDB) immunogenicity predictor. Furthermore, a direct comparison between mutant (MUT) and corresponding wild-type (WT) peptides was performed using Δaffinity and Δrank metrics to evaluate the predicted impact of somatic mutations on HLA binding. The analysis revealed a predominance of peptides associated with the HLA-B locus, particularly the allele HLA-B*35:01, among the interactions with the lowest predicted binding percentiles. Several high-ranking peptide candidates were derived from genes with known roles in melanoma biology, including PLCG2, GATA3, AKT1, PTEN, PTCH1, and SMO. Overall, the integrative computational framework implemented in this study enables the systematic prioritization of candidate neoantigens derived from non-synonymous mutations in melanoma. This pipeline provides a reproducible strategy for exploring tumor neoantigen repertoires and may serve as a foundation for subsequent experimental validation and for studies related to neoantigen-based immunotherapies and immunopeptidomics. Full article

Nanomaterials (NMs) are increasingly utilized in drug delivery, diagnostic imaging, and therapeutic applications. However, their widespread use raises concerns regarding potential neurotoxicity, particularly for metal and metal oxide nanoparticles. Accumulating evidence indicates that these nanoparticles induce neurotoxicity through interconnected mechanisms, including excessive reactive oxygen species generation, activation of neuroinflammatory pathways, mitochondrial dysfunction, and disruption of blood–brain barrier integrity. These molecular events collectively lead to synaptic impairment, neuronal apoptosis, and progressive cognitive and behavioral deficits, with toxicity severity influenced by dose, exposure duration, and age. Given that in vitro models often fail to capture complex systemic interactions such as nanoparticle biodistribution, blood–brain barrier dynamics, and neuroimmune responses, this review places particular emphasis on in vivo studies to provide a more physiologically relevant understanding of nanoparticle-induced neurotoxicity. Importantly, a growing body of in vivo evidence demonstrates that natural bioactive compounds can mitigate these effects by targeting key pathogenic pathways, including oxidative stress, inflammation, and mitochondrial dysfunction, while preserving neuronal integrity. These findings highlight the therapeutic potential of natural bioactives as protective agents against nanoparticle-induced neurotoxicity and as candidates for broader neuroprotective strategies. This review summarizes the mechanistic basis of metal and metal oxide nanoparticle neurotoxicity and critically evaluates the protective role of natural bioactive compounds, with a focus on evidence derived from animal models. Full article

Peri-implantitis is a chronic inflammatory condition driven by dysregulated host immune responses, yet clinical risk assessment continues to rely on routinely collected clinical indicators. Clinical prediction models, including machine learning-based and conventional approaches, have been proposed to integrate these indicators for peri-implantitis risk stratification, but their conceptualization of immunopathological risk has not been systematically examined. This systematic review and functional meta-synthesis were conducted according to PRISMA 2020. Six eligible studies were included, comprising 1316 patients and 2438 dental implants. Four studies employed machine learning-based models, and two used conventional clinical prediction approaches. A functional meta-synthesis was performed to interpret how models integrate clinical predictors as surrogate manifestations of immune dysregulation. Additionally, an exploratory random-effects meta-analysis of area under the receiver operating characteristic curve (AUC) values was conducted where applicable. Discriminative performance ranged from moderate to high across studies, with overlapping AUC estimates between modeling paradigms. Despite methodological differences, both machine learning and conventional models converged on shared immunopathological constructs related to inflammatory burden, prior periodontal disease, plaque-related factors, and host systemic conditions. These findings support the clinical utility of immunopathologically informed prediction models for peri-implantitis and highlight the need for future studies incorporating external validation. Full article

Neuroinflammation is a central hallmark of numerous neurological disorders, including Alzheimer’s disease, Parkinson’s disease, traumatic brain injury, and spinal cord damage. Its persistent and dysregulated nature not only accelerates neuronal loss but also impedes endogenous repair, posing a major challenge for effective therapeutic intervention. Recent advances in nanobiotechnology have opened transformative opportunities to modulate neuroinflammation with unprecedented precision while simultaneously supporting neural regeneration. This review highlights emerging nanomaterial-based strategies including lipid-based, polymeric, inorganic nanoparticles designed to traverse the blood–brain barrier (BBB), deliver anti-inflammatory agents, modulate immune cell behavior, and attenuate glial activation. Extending beyond nanoparticle-based delivery systems, recent advances also emphasize the integration of nanomaterials into biomimetic architectures to provide structural and functional cues for neural repair. We further summarize how these functional nanostructured scaffolds, such as extracellular matrix (ECM) mimetic, nanofibrous and conductive hydrogels, are being leveraged in neural tissue engineering to direct stem cell fate, promote axonal outgrowth, and rebuild damaged neuroarchitectures. Moreover, pharmacokinetics, biodistribution, safety, clinical trials, regulatory considerations and limitations of nanotherapeutics in neurodegenerative diseases are discussed. By outlining the current progress, mechanistic insights, and translational challenges, this review underscores the potential of nanobiotechnology-enabled therapeutics to revolutionize the treatment of neuroinflammatory conditions and advance next-generation neural repair technologies. Full article

In the post-pandemic era, monitoring adaptive immunity of the population to emerging SARS-CoV-2 variants remains an important public health priority. To address this need, we developed a test that can simultaneously assess the neutralization ability of three SARS-CoV-2 variants. A panel of lentiviral pseudoviruses, each bearing the S-protein of different SARS-CoV-2 variants (Wuhan-Hu-1, BA.1, and XBB.1.5) and expressing a unique fluorescent protein (Clover, mRhubarb713, or mRuby3) was generated and used to transduce hACE2-overexpressing cells. The percentage of infected target cells for each variant was quantified via flow cytometry. Co-infection led to a minor reduction in the percentage of infected cells compared to mono-infection controls, confirming the robustness of the assay. We then applied the test to the analysis of human sera samples, which were collected in the Sirius Federal Territory (Russian Federation) and revealed the following: (1) sera collected in 2021 neutralized the Wuhan-Hu-1 variant and demonstrated cross-specificity to the BA.1 variant, but not to the XBB.1.5 variant; (2) sera collected after the Omicron emergence point neutralized Wuhan-Hu-1 and BA.1, and possessed a weak ability to neutralize the XBB.1.5. This assay provides a valuable tool for efficient profiling of humoral immunity and monitoring its development in response to ongoing viral diversity. Full article

The primary objective is to determine predictors of pulmonary hypertension (PH) development in patients with centromere antibody (ACA) positive systemic sclerosis (SSc) and to assess survival in patients with and without PH. This was a retrospective cohort study that included both prevalent and incident SSc patients with ACA. Clinical characteristics, mortality and immunomodulatory use were compared between SSc-ACA+ patients with and without PH. Univariable and multivariable logistic regression models, along with a univariable Cox proportional hazards model, were used to assess predictors and survival of PH, respectively. Of 146 SSc-ACA+ patients, 25 (17.1%) developed PH. Patients with PH had more frequent obstructive sleep apnea (36% vs. 12%), heart failure (44% vs. 7.4%), arrhythmias (32% vs. 12%), valvular heart disease (VHD) (32% vs. 8.3%), and chronic kidney disease (36% vs. 12%) than those without PH. In the multivariable logistic regression analysis, VHD was associated with an increased risk of PH development (OR = 7.79), while immunomodulatory use before PH was associated with a reduced risk of PH (OR = 0.34). Patients with PH who received immunomodulatory therapy had a better survival than those with PH without immunomodulatory treatment (p = 0.0008). PH is associated with high mortality in patients with SSc-ACA+. Immunomodulatory use may lower the incidence and mortality of PH in patients with SSc-ACA+ disease. Further randomized studies are needed to confirm this assumption. Full article