Optimising psoriatic arthritis therapy with immunological methods to increase standard evaluation: the protocol of an open-label multicentre, parallel-group, two-arm randomised controlled study evaluation precision medicine approach in the treatment of psoriatic arthritis

Introduction: Psoriatic arthritis (PsA) affects around 150 000 people in the UK of whom around 50% require treatment with biologics. The most used biologics for PsA target tumour necrosis factor (TNF) or interleukin-17A (IL-17A). About 50% of patients respond to each, but it is not currently possible to predict response for individual patients, necessitating sequential treatment steps. A recent proof of concept study in PsA suggested that using peripheral immunophenotype to choose therapy could improve time to treatment response. This study will test the hypothesis, within an open-label parallel-group biomarker-stratified multicentre randomised controlled trial, which the baseline proportion of CD4+T cells with an activated type 17 immunophenotype (Th17 levels) predicts response to IL-17A or TNF inhibitors in PsA. Additional analyses will identify if the model can be refined by combining additional clinical and immunophenotypic factors. Statistical modelling will be used to predict the likely effectiveness of these approaches compared with standard care. Methods and analysis: Patients with PsA eligible to start their first biologic as part of standard care are recruited and baseline blood tests are taken for immunophenotyping. Participants are stratified equally by Th17 levels and randomised 1:1 to receive either TNF (adalimumab) or IL-17A (secukinumab) inhibitors. The primary analysis will establish the interaction between baseline immunophenotype and treatment on the primary outcome (achievement of minimal disease activity criteria at week 24). In secondary analysis, modelling will identify if this prediction model can be optimised further by incorporating clinical phenotypes and additional immunophenotyping techniques. Ethics and dissemination: Ethical approval for the study was granted by the North West Preston Research Ethics Committee (ref 21/NW/0016). Dissemination will be via conference presentations and peer-reviewed publications, aiming to impact on treatment guidelines. Trial registration number ISRCTN17228602

RA-MAP, molecular immunological landscapes in early rheumatoid arthritis and healthy vaccine recipients

Rheumatoid arthritis (RA) is a chronic inflammatory disorder with poorly defined aetiology characterised by synovial inflammation with variable disease severity and drug responsiveness. To investigate the peripheral blood immune cell landscape of early, drug naive RA, we performed comprehensive clinical and molecular profiling of 267 RA patients and 52 healthy vaccine recipients for up to 18 months to establish a high quality sample biobank including plasma, serum, peripheral blood cells, urine, genomic DNA, RNA from whole blood, lymphocyte and monocyte subsets. We have performed extensive multi-omic immune phenotyping, including genomic, metabolomic, proteomic, transcriptomic and autoantibody profiling. We anticipate that these detailed clinical and molecular data will serve as a fundamental resource offering insights into immune-mediated disease pathogenesis, progression and therapeutic response, ultimately contributing to the development and application of targeted therapies for RA.</p

Maternal killer-cell immunoglobulin-like receptors and paternal human leukocyte antigen ligands in recurrent pregnancy loss cases in Turkey

Objective: The survival of a semi-allogeneic fetus depends on several immunological mechanisms, and it has been suggested that recurrent pregnancy loss (RPL) could develop as a result of one or more immunological abnormalities. Methods: Compatibility between partners for human leukocyte antigen (HLA) genotypes and the relationships between maternal killer-cell immunoglobulin-like receptor (KIR) and paternal HLA-Bw4/Bw6 and HLA-C1/C2 supra-groups were investigated in 25 couples with RPL in comparison to healthy couples with children. HLA and KIR genotyping was performed using polymerase chain reaction with sequence-specific primers and/or sequence-specific oligonucleotides. Results: HLA class I incompatibility between partners, especially in HLA-B alleles, was more common in the RPL group (p=0.01). HLA-C2 homozygosity was more frequent in the male partners of RPL couples than in other groups (p=0.03). The KIR2DL5 gene frequency was significantly higher in both the female and male partners of RPL couples, whereas the KIR2DS3 gene frequency in male partners of RPL couples was significantly reduced (p=0.03). The presence of KIR2DL3 in women with RPL was correlated with the presence of HLA-C2 alleles in their spouses (p=0.03). Conclusion: Our data from a Turkish population suggest that male HLA-C2 homozygosity may play an important role in RPL. Additionally, an incidental match between male HLA-C2 and female HLA-C1 ligand KIR receptors might perturb the balance between activatory and inhibitory KIR-ligand interactions during pregnancy in couples affected by RPL. The roles of orphan KIR2DL5 and orphan KIR2DS3 in RPL remain obscure

Killer cell immunoglobulin-like receptor genotypes in the Turkish population

One hundred eighty-seven healthy and unrelated volunteers from various regions of Turkey were selected for the study. Killer-cell immunoglobulin-like receptors (KIR) genotyping was performed by polymerase chain reaction using commercial sequence-specific oligonucleotide probe (SSOP) kits. Gene frequencies of the Turkish population were determined by direct counting of the positive and negative loci. The genotype data is publicly available in the Allele Frequencies Net Database under the population name "Turkey KIR pop 3" number "3399"

Effects of azithromycin on intracellular cytokine responses and mucocutaneous manifestations in Behcet's disease

Summary. Objective: The aim of this study was to investigate the effects of azithromycin on mucocutaneous manifestations and ex vivo intracellular cytokine responses in patients with Behçet's disease (BD). Methods: Ten BD patients with active manifestations and nine healthy controls (HCs) were included in the study. Patients were treated with azithromycin (1500 mg/week) for four weeks. Clinical and immunological responses were evaluated in the pre- and post-azithromycin treatment periods. Peripheral blood mononuclear cells (PBMCs) of patients and controls were stimulated by Streptococcus sanguinis, lipopolysaccharide (LPS), lipoteichoic acid (LTA), and heat shock protein-60 (HSP-60) for three hours. Ex vivo intracellular interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) levels were measured. Results: Follicular lesions and genital ulcers completely healed, and the number of oral ulcers decreased after treatment (P = 0.000). The stimulated intracellular IFN-γ response to S. sanguinis was higher in BD patients (5.75%) than in HCs (3.9%) before treatment (P = 0.05). Likewise, the pretreatment IFN-γ response was significantly higher than the post-treatment response (1.95%). In BD patients, pretreatment stimulated intracellular IFN-γ responses to LTA (5.8%) were also higher than post-treatment responses (3.15%), but the difference did not reach statistical significance (P = 0.07). Conclusions: Azithromycin treatment decreased the mucocutaneous manifestations in BD patients and suppressed the intracellular IFN-γ responses of PBMCs to S. sanguinis ex vivo, which suggests this treatment has an immunomodulatory effect

Annexin-A1: the culprit or the solution?

Annexin-A1 has a well-defined anti-inflammatory role in the innate immune system, but its function in adaptive immunity remains controversial. This glucocorticoid-induced protein has been implicated in a range of inflammatory conditions and cancers, as well as being found to be overexpressed on the T cells of patients with autoimmune disease. Moreover, the formyl peptide family of receptors, through which annexin-A1 primarily signals, have also been implicated in these diseases. In contrast, treatment with recombinant annexin-A1 peptides resulted in suppression of inflammatory processes in murine models of inflammation. This review will focus on what is currently known about annexin-A1 in heath and disease and discuss the potential of this protein as a biomarker and therapeutic target

Nesfatin-1 treatment preserves antioxidant status and attenuates renal fibrosis in rats with unilateral ureteral obstruction

Background: Nesfatin-1 (NES-1), an anorexigenic peptide, was reported to have anti-inflammatory and anti-apoptotic actions in several inflammation models. Methods: To elucidate potential renoprotective effects of NES-1, unilateral ureteral obstruction (UUO) was induced in male Sprague Dawley rats by ligating left ureters. The rats were injected intraperitoneally with either saline (SL) or NES-1 (10 µg/kg/day) for 7 or 14 days (n = 8 in each group). On the 7th or 14th day, obstructed kidneys were removed for the isolation of leucocytes for flow-cytometric analysis and the assessments of biochemical and histopathological changes. Results: Opposite to glutathione levels, renal myeloperoxidase activity in the SL-treated UUO group was significantly increased compared with the sham-operated group, while NES-1 treatment abolished the elevation. The percentages of CD8+/CD4+ T-lymphocytes infiltrating the obstructed kidneys were increased in the SL-treated groups but treatment with NES-1 did not prevent lymphocyte infiltration. Elevated tumour necrosis factor-alpha (TNF-α) levels in SL-treated UUO group were decreased with NES-1. Although total degeneration scores were similarly increased in all UUO groups, tubular dilatation scores were significantly increased in UUO groups and lowered by NES-1 only in the 7-day treated group. Elevated interstitial fibrosis scores in the SL-treated groups were decreased in both 7- and 14-day NES-1 treated groups, while alpha-smooth muscle actin (α-SMA) and apoptosis scores were depressed in both NES-1 treated groups. Conclusion: The present data demonstrate that UUO-induced renal fibrosis is ameliorated by NES-1, which appears to involve the inhibition of neutrophil infiltration and thereby amelioration of oxidative stress and inflammation. These data suggest that NES-1 may have a regulatory role in protecting the kidneys against obstruction-induced renal injury