Giant cell arteritis (GCA) is the most common vasculitis among elderly people. The clinical spectrum of the disease is heterogeneous, with a classic/cranial phenotype, and another extracranial or large vessel phenotype as the two more characteristic patterns. Permanent visual loss is the main short-term complication. Glucocorticoids (GC) remain the cornerstone of treatment. However, the percentage of relapses with GC alone is high, and the rate of adverse events affects more than 80% of patients, so it is necessary to have alternative therapeutic options, especially in patients with worse prognostic factors or high comorbidity. MTX is the only DMARD that has shown to reduce the cumulative dose of GC, while tocilizumab is the first biologic agent approved due to its ability to decrease the relapse rate and lower the cumulative GC doses. However, apart from the IL-6 pathway, there are other pro-inflammatory cytokines and growth factors involved in the typical intima hyperplasia and vascular remodeling of GCA. Among them, the more promising targets in GCA treatment are the IL12/IL23 axis antagonists, IL17 inhibitors, modulators of T lymphocytes, and inhibitors of either the JAK/STAT pathway, the granulocyte-macrophage colony-stimulating factor, or the endothelin, all of which are updated in this review.

Galectin-1 (Gal1) plays a regulatory role in the immune system. We have recently validated that Gal1 serum (sGal1) levels are increased in rheumatoid arthritis (RA) patients compared to healthy donors (HDs); however, there is no information on Gal1 in spondyloarthritis (SpA). Objective: To compare Gal1 levels in patients with SpA versus RA as a diagnostic biomarker. Methods: We studied sGal1 levels in HD (n = 52), SpA (n = 80) and RA patients (n = 64) who were randomly divided into discovery and validation sets. Synovial fluid (SF) from osteoarthritis (OA) (n = 28), peripheral SpA (n = 28) and RA (n = 28) were studied. In SpA patients, we analyzed the association between clinical parameters and sGal1 levels. Results: sGal1 levels were significantly lower in patients with SpA with respect to RA and similar to those of the HD. A cut-off of 20.50 ng/mL (sGal1) allowed one to differentiate RA patients from SpA and HD (Odd Ratio (OR) 8.23 and 12.64, respectively). Gal1 SF levels in SpA were slightly lower than OA patients and significantly lower than RA patients. No correlation was observed between sGal1 levels and clinical parameters in SpA patients. Conclusion: Gal1 could act as a diagnostic biomarker of RA and would allow one to distinguish SpA and RA patients.

Few studies have considered immune-mediated inflammatory disorders (IMID) together, which is necessary to adequately understand them given they share common mechanisms. Our goal was to investigate the expression of vasoactive intestinal peptide (VIP) and its receptors VPAC1 and VPAC2 in selected IMID, analyze the effect of biological therapies on them, and identify miRNA signatures associated with their expression. Serum VIP levels and mRNA of VPAC and miRNA expression in peripheral blood mononuclear cells were analyzed from 52 patients with psoriasis, rheumatoid arthritis, Graves’ disease, or spondyloarthritis and from 38 healthy subjects. IMID patients showed higher levels of VIP and increased expression of VPAC2 compared to controls (p < 0.0001 and p < 0.0192, respectively). Receiver operating characteristic curve analysis showed that the levels of VIP or VPAC2 expression were adequate discriminators capable of identifying IMID. Treatment of IMID patients with anti-TNFα and anti-IL12/23 significantly affected serum VIP levels. We identified miRNA signatures associated with levels of serum VIP and VPAC2 expression, which correlated with IMID diagnosis of the patients. The results indicate that the expression of VIP/VPAC2 is able of identify IMIDs and open up a line of research based on the association between the VIP/VPAC axis and miRNA signatures in immune-mediated diseases.

Pro-inflammatory CD4⁺CD28⁻ T cells are characteristic of immunosenescence, but also of several autoimmune/inflammatory diseases. Vasoactive intestinal peptide (VIP) acts as an anti-inflammatory and immunomodulatory mediator on these cells. Our objective was to study the mutual influence between senescent Th cells and VIP axis in early arthritis (EA), comparing with non-EA donors. We characterized the correlation between senescent Th cells and clinic parameters of EA as well as the behavior of senescent Th biomarkers by real-time PCR. Clinical data were systematically recorded at baseline and after 6 months of follow-up. The number of CD4⁺CD28⁻ T cells measured by sorting is higher in patients who initially meet ACR classification criteria for rheumatoid arthritis (RA) compared to those who were classified as undifferentiated arthritis (UA). A slight positive correlation between EA CD4⁺CD28⁻ T cells and CRP or ESR and a negative correlation with bone mineral density were found. Th senescent biomarkers in EA CD4⁺CD28⁻ T cells were similar to donors, however some of them increased after 6 months of follow-up. VPAC receptors were analyzed by real-time PCR and immunofluorescence, and CD4⁺CD28⁻ T cells showed higher expression of VPAC₂ and lower of VPAC₁, VPAC₂ showing a significant increased expression in EA cells. Sorted CD4⁺CD28⁻ T cells were in vitro expanded in presence of VIP, wherein VIP increased senescent biomarker CD27, while it diminished CD57 or NKG2 senescent biomarkers. Our study demonstrates for the first time the existence of a link between senescent Th cells and the VIP axis.

Galectin-1 and -9 (Gal1/9) are essential mediators of immune-inflammatory responses, which makes these proteins potential biomarkers for immune-mediated diseases (IMIDs), such as rheumatoid arthritis (RA), psoriasis (PS), psoriatic arthritis (PsA), inflammatory bowel disease, and systemic lupus erythematosus (SLE). Our aim was to evaluate plasma Gal1/9 differences between IMID patients and healthy donors (HD). We analyzed 980 plasma samples divided into two analytical cohorts (600 discovery group and 380 validation group). Generalized linear models estimated Gal1/9 levels, adjusting for sex, age, storage time, and plate variability. In the overall IMID group, plasma Gal1 levels were comparable to those of HD, while Gal9 levels were significantly elevated. Levels varied across individual diseases: SLE patients consistently showed the highest Gal1/9 levels compared to both HD and other IMIDs, and RA patients had elevated Gal9 levels versus HD. Both Gal1 and Gal9 plasma levels correlated positively with higher disease activity, and Gal1 was higher in patients with longer disease duration. After adjustment for these confounders, SLE and RA patients maintained the highest Gal9 levels compared to HD. Our study demonstrates that Gal1 and Gal9 are differentially expressed across IMIDs, with particularly elevated levels in SLE, and both galectins are associated with disease activity.

The aim of this study was to identify single-nucleotide polymorphisms (SNPs) in bone remodeling-related genes associated with disease severity and bone mineral density (BMD) in early arthritis (EA) patients. For this purpose, the genotyping of 552 SNPs located in gene regions of semaphorins 4b, 4d, 4f, DKK1, 2 and 3, sclerostin, OPG, RANK and RANKL was performed using Immunochip from Illumina Inc. in 268 patients from the Princesa Early Arthritis Register Longitudinal (PEARL) study. Measurements of BMD and disease activity were chosen as outcome variables to select SNPs of interest. The relationships of SNPs with the BMD of the forearm, lumbar spine and hip (Hologic-4500 QDR) were analyzed by linear regression adjusted for age, sex, body mass index and presence of anti-citrullinated peptide antibodies (ACPAs). The association of each SNP with activity variables was analyzed by linear regression, logistic regression or ordered logistic regression according to the variable, and multivariate models were adjusted for potentially confounding variables, such as age, sex and presence of ACPAs. These analyses showed that four SNPs located in the genes coding for RANK (TNFRSF11A) and OPG (TNFRSF11B) were significantly associated with clinical variables of severity. SNP rs1805034 located in exon 6 of TNFRSF11A, which causes a non-synonymous (A/V) mutation, showed significant association with BMD and therefore may be considered as a possible biomarker of severity in RA patients. SNPs in the OPG gene showed an association with serum OPG levels and predicted disease activity after two years of follow-up.