Genetic Associations in Ankylosing Spondylitis

Ankylosing spondylitis is a common inflammatory arthritis that is characterised by inflammation of the spine and sacroiliac joints. The genetic association between AS and the MHC Class I gene B27 is one of the strongest disease associations known, however the evidence points to AS being an oligogenic disease. The aim of this study was to investigate several candidate genes that may contribute to the susceptibility to AS. The MHC Class II region is a highly polymorphic area where associations with particular alleles and other autoimmune diseases have been previously demonstrated. This study investigated the distribution of the MHC Class II DRbeta1 alleles and the DRbeta1*04 subtypes in a large well defined group of AS patients in comparison to both normal healthy controls and HLA B27 positive healthy controls all from the West of Scotland. A significant increase in the distribution of the DRbeta1*01 alleles was seen in the AS patients in comparison to both control populations. No significant differences were seen in the distribution of the DRbeta1*04 subtypes between the AS patients and the B27 positive controls. The TNF genes lie within the MHC Class III region on chromosome six in close proximity to the B27 gene. There are several polymorphic sites within the TNF genes, some of which have been linked to differences in production of the TNF proteins. TNF is an important pro-inflammatory cytokine and it has been suggested that increased levels of TNF could contribute to disease pathogenesis. Six different polymorphic sites were investigated in total. A significant increase in the 1* allele at the -308 site within the TNF promoter was seen in the AS patients compared to the B27 positive controls. Other associations were seen at other sites between the patients and the normal population but they would appear to be linked to the presence of B27 and not to the disease. None of the associations demonstrated would appear to be with any of the alleles linked to increased production of TNF. Recent whole genome screens have highlighted areas other than the MHC that may have a role to play in susceptibility to disease. One in particular is on chromosome two where the IL-1 genes lie. The IL-1 genes are also important pro-inflammatory cytokines where particular alleles have been associated with other autoimmune diseases. Three sites were investigated, one within the IL-1 alpha gene, one within the IL-1 beta gene and the third within the natural antagonist IL-1 receptor antagonist. No associations were seen in the IL-1 alpha or IL-1 beta, however a significant increase in the carriage of the 2* allele of the IL-1 receptor antagonist 86 base pair variable number tandem repeat was demonstrated in the AS patients compared to B27 positive controls. This allele has previously been shown to predispose to increased levels of the anti-inflammatory IL-I receptor antagonist. Overall this study has demonstrated three different associations at three different loci, one within the MHC class II region, one within the MHC class III and one within the IL-1 region. This study has also demonstrated the possible existence of extended haplotypes that could cross the TNF locus into the MHC Class II region that would incorporate the HLA B27 gene. Large family studies would be required to confirm this finding. In conclusion none of the associations demonstrated in this study are with any of the alleles that have previously been linked to increased pro-inflammatory cytokines. In fact it could be hypothesised that the associations demonstrated in this study could in theory lead to a reduced pro-inflammatory response

Essential role for proteinase-activated receptor-2 in arthritis

Using physiological, pharmacological, and gene disruption approaches, we demonstrate that proteinase-activated receptor-2 (PAR-2) plays a pivotal role in mediating chronic inflammation. Using an adjuvant monoarthritis model of chronic inflammation, joint swelling was substantially inhibited in PAR-2-deficient mice, being reduced by more than fourfold compared with wild-type mice, with virtually no histological evidence of joint damage. Mice heterozygous for PAR-2 gene disruption showed an intermediate phenotype. PAR-2 expression, normally limited to endothelial cells in small arterioles, was substantially upregulated 2 weeks after induction of inflammation, both in synovium and in other periarticular tissues. PAR-2 agonists showed potent proinflammatory effects as intra-articular injection of ASKH95, a novel synthetic PAR-2 agonist, induced prolonged joint swelling and synovial hyperemia. Given the absence of the chronic inflammatory response in the PAR-2-deficient mice, our findings demonstrate a key role for PAR-2 in mediating chronic inflammation, thereby identifying a novel and important therapeutic target for the management of chronic inflammatory diseases such as rheumatoid arthritis

Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression.

Immune checkpoint blockade with therapeutic anti-cytotoxic T lymphocyte-associated antigen (CTLA)-4 (Ipilimumab) and anti-programmed death (PD)-1 (Nivolumab and Pembrolizumab) antibodies alone or in combination has shown remarkable efficacy in multiple cancer types, concomitant with immune-related adverse events, including arthralgia and inflammatory arthritis (IA) in some patients. Herein, using Nivolumab (anti-PD-1 antagonist)-responsive genes along with transcriptomics of synovial tissue from multiple stages of rheumatoid arthritis (RA) disease progression, we have interrogated the activity status of PD-1 pathway during RA development. We demonstrate that the expression of PD-1 was increased in early and established RA synovial tissue compared to normal and OA synovium, whereas that of its ligands, programmed death ligand-1 (PD-L1) and PD-L2, was increased at all the stages of RA disease progression, namely arthralgia, IA/undifferentiated arthritis, early RA and established RA. Further, we show that RA patients expressed PD-1 on a majority of synovial tissue infiltrating CD4+ and CD8+ T cells. Moreover, enrichment of Nivolumab gene signature was observed in IA and RA, indicating that the PD-1 pathway was downregulated during RA disease progression. Furthermore, serum soluble (s) PD-1 levels were increased in autoantibody positive early RA patients. Interestingly, most of the early RA synovium tissue sections showed negative PD-L1 staining by immunohistochemistry. Therefore, downregulation in PD-1 inhibitory signaling in RA could be attributed to increased serum sPD-1 and decreased synovial tissue PD-L1 levels. Taken together, these data suggest that agonistic PD1 antibody-based therapeutics may show efficacy in RA treatment and interception

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Prevention and early treatment of the long-term physical effects of COVID-19 in adults: design of a randomised controlled trial of resistance exercise. CISCO-21

No abstract available