Association between interleukin-12 p40 subunit and risk of primary Sjögren's syndrome: a Mendelian randomization study.

OBJECTIVES: Interleukin-12 (IL-12) signalling was proposed in the immunopathogenesis of primary Sjögren's disease. The efficacy of therapies targeting this pathway is currently unclear. Herein, we investigated the associations between circulating proteins involved in the IL-12 and IL-23 signalling pathways on primary Sjögren's disease using mendelian randomization. METHODS: We selected SNPs from protein quantitative trait loci of IL12A, IL12B, IL12Rß1, IL12Rß2, and IL23R to examine the association between alterations in their levels and risk of primary Sjögren's disease. Genetic association data for proteins were taken from studies ranging from 3,301-54 306 in sample size, and from 3,232 cases of primary Sjögren's disease and 17 481 controls. The Wald ratio or inverse variance weighted methods estimated causal effects. We applied colocalization and pleiotropy-robust methods as sensitivity analyses for confounding. RESULTS: There was a negative association between genetically predicted IL-12p40 (encoded by IL12B) and primary Sjögren's disease. In the two independent exposure datasets odds ratio (OR) 0.79 (95% confidence interval [CI] 0.68-0.93; P-value = 0.004) and OR 0.86 (95% CI 0.78-0.95; P-value = 0.003) per standard deviation decrease in genetically predicted IL-12p40. Neither IL-12Rß2 and IL-23R met the threshold P-value after MR analyses (P-value < 0.01) for colocalization assessment. No variants for the IL12A gene met prerequisite thresholds for weak instrument bias. CONCLUSION: This study provides genetic evidence that IL-12p40 has a causal role in primary Sjögren's disease pathogenesis. Our data suggest that decreasing levels of IL-12p40 may be deleterious. We would not suggest selecting this drug target as a therapeutic option.

A review of the advances in understanding the genetic basis of spondylarthritis and emerging clinical benefit.

Spondyloarthropathies (SpA), including ankylosing spondylitis (AS) and psoriatic arthritis (PsA), have been shown to have a substantial genetic predisposition based on heritability estimates derived from family studies and genome-wide association studies (GWAS). GWAS have uncovered numerous genetic loci associated with susceptibility to SpA, with significant associations to human leukocyte antigen (HLA) genes, which are major genetic risk factors for both AS and PsA. Specific loci differentiating PsA from cutaneous-only psoriasis have been identified, though these remain limited. Further research with larger sample sizes is necessary to identify more PsA-specific genetic markers. Current research focuses on translating these genetic insights into clinical applications. For example, polygenic risk scores are showing promise for the classification of disease risk and diagnosis and future research should focus on refining these risk assessment tools to improve clinical outcomes for individuals with SpA. Addressing these challenges will help integrate genetic testing into patients care and impact clinical practice.

Aspirin and Ticagrelor Versus Aspirin and Clopidogrel or Prasugrel and the Effect on Staphylococcal-associated Infections: A Real-world Study.

PURPOSE: Antiplatelet therapy is used for the primary and secondary prevention of thrombotic diseases such as acute coronary syndrome (ACS). These patients are more vulnerable to infections, as such, strategies are required to mitigate these risks. METHODS: We conducted a retrospective cohort study using TriNetX, a global federated health research network that includes both inpatient and outpatient electronic medical records from health care organizations worldwide. Patients ≥18 years old, after ACS, who were placed on aspirin and ticagrelor were compared with patients placed on aspirin and clopidogrel or prasugrel. Patients were identified using International Statistical Classification of Diseases and Related Health Problems terminology codes. After propensity score matching (1:1), a total of 239,358 patients were identified in each cohort. The primary outcomes of interest investigated were rates of (1) acute and subacute infective endocarditis, (2) sepsis of unknown origin, (3) staphylococcus arthritis, (4) cellulitis and acute lymphangitis, (5) Staphylococcus aureus bacteremia, and (6) staphylococcal pneumonia after initiation of treatment. Outcomes were analyzed at 1, 3, and 5 years. FINDINGS: At 5 years, a combination of aspirin and ticagrelor, compared with a combination of aspirin and clopidogrel or prasugrel, was associated with significantly reduced rates of (1) acute and subacute endocarditis (hazard ratio [HR] plus 95% CI) (HR = 0.85; 0.77-0.945; P = 0.030), (2) sepsis of unknown origin (HR = 0.89; 95% CI, 0.86-0.91; P < 0.0001), (3) cellulitis and acute lymphangitis (HR = 0.89; 95% CI, 0.87-0.92; P < 0.0001, and (4) Staphylococcus aureus bacteremia (HR = 0.72; 95% CI, 0.61-0.85; P = 0.0007). However, a combination of aspirin and clopidogrel was associated with a marinally lower risk of staphylococcal pneumonia (HR = 1.04; 95% CI, 1.01-1.062; P < 0.0001). IMPLICATIONS: A combination of aspirin and ticagrelor is associated with a lower rate of a variety of bacterial infections. This combination warrants further investigation in in-vitro studies to tease out mechanisms and through clinical randomized trials in groups who have ACS and are at high infection risk.

British Axial Spondyloarthritis Inception Cohort (BAxSIC): a protocol for a multicentre real-world observational cohort study of early axial spondyloarthritis.

Objectives: Timely diagnosis remains a challenge in axial SpA (axSpA). In addition, data are scarce on the impact of diagnostic delay and disease progression in affected individuals. The British Axial Spondyloarthritis Inception Cohort (BAxSIC) study aims to investigate the impact of newly diagnosed axSpA, the natural history of the disease and the effect of diagnostic delay on disease outcomes. Methods: BAxSIC is a prospective, multicentre, observational study. Eligible participants are adults (≥16 years of age), with a physician-confirmed diagnosis of axSpA in the 6 months prior to study entry, recruited from secondary and tertiary rheumatology centres in the UK. Participants will be followed up for 3 years, with in-person visits at baseline and 24 months. In addition, patient self-reported assessments will be recorded remotely via the online electronic case report form (eCRF) at 6, 12, 18, 30 and 36 months. Results: The first patient was enrolled in BAxSIC in June 2023. Recruitment is currently ongoing and is planned to end in June 2026. Initial results will be available in 2027. Since opening, the trial has undergone two protocol amendments. Conclusion: The BAxSIC study is the first inception cohort designed to investigate the impact of diagnostic delay on clinical presentation and long-term functional outcomes in patients with axSpA in the UK. With an innovative, patient-led virtual longitudinal data collection model, data generated from this study will help inform and improve the care of people newly diagnosed with axSpA. Trial registration: ClinicalTrials.gov (http://clinicaltrials.gov), NCT05676775.

Metabolic syndrome and psoriatic arthritis: the role of weight loss as a disease-modifying therapy.

Psoriatic arthritis (PsA) is an inflammatory joint and entheseal disease associated with significant personal and public health burden. PsA has a prevalence of up to 1%, affecting ~20% of people suffering with psoriasis. PsA is frequently accompanied by metabolic syndrome (MetS), and both conditions are characterised by a chronic pro-inflammatory state, with several key cytokines in PsA (interleukin (IL)-17 and IL-23) also elevated in those with MetS. This narrative review aims to provide an update on MetS in PsA, focusing on its prevalence, pathogenesis, prognosis, treatment interactions and future therapeutic options. MetS is particularly prevalent in PsA compared to other inflammatory arthritides. Cohort studies indicate a higher risk of PsA in individuals with obesity, while Mendelian randomization studies link childhood obesity, insulin resistance, and dyslipidaemia to PsA. Weight loss interventions have been shown to reduce disease activity in PsA. Additionally, MetS negatively impacts the efficacy of tumour necrosis factor inhibitor (TNFi) drugs in treating PsA. Drugs given for PsA may also affect the conditions constituting MetS. Leflunomide has been shown to reduce body weight but also increase blood pressure. TNFi drugs lead to weight gain but reduce cardiovascular risk. Janus kinase inhibitors increase lipid levels and cardiovascular risk among high-risk groups. Anti-IL-17 and anti-IL-12/IL-23 drugs may cause a short-term increase in cardiovascular risk, although the long-term effects have yet to be established. Weight loss represents an unexplored avenue for disease modification in PsA, alongside a plethora of general health benefits. Dietary and exercise modifications are the cornerstone of weight management but vary substantially across individuals. Novel therapies to treat weight loss, such as glucagon-like peptide 1 agonists and sodium-glucose cotransporter 2 inhibitors, may prove useful alongside disease-modifying therapies for those with PsA and MetS and should be investigated as potential therapeutic adjuncts.

What effects do obesity and related health problems have on psoriatic arthritis? Psoriatic arthritis (PsA) is a condition that causes joint pain and swelling, which can lead to permanent damage to the joints over time. This condition affects 1 in 100 people and 1 in 5 people with psoriasis. Metabolic syndrome (MetS) is a condition where a person has a combination of high body fat, high blood pressure, high blood sugar and/or high cholesterol. MetS is more common in someone with PsA. If a person has MetS, they are more likely to get PsA. If a person with PsA has MetS, they have worse joint problems and their joint problems do not improve as much with certain treatments. Many of the drugs given for PsA can affect MetS. This can include increasing or decreasing body weight, increasing blood pressure and increasing or decreasing the risk of having a heart attack or stroke. Different medications affect these risks in different ways. Weight loss helps people with PsA improve their joint problems. However, some people find losing weight harder than others. Medications that can help people lose weight, could be useful to improve joint problems in PsA. Future studies should see if these medications can be useful in people with PsA and MetS.

Use of Mendelian randomization to assess the causal status of modifiable exposures for rheumatic diseases.

The explosion in Mendelian randomization (MR) publications is hard to ignore and shows no signs of slowing. Clinician readers, who may not be familiar with jargon-ridden methods, are expected to discern the good from the many low-quality studies that make overconfident claims of causality or stretch the plausibility of what MR can investigate. We aim to equip readers with foundational concepts, contextualized using examples in rheumatology, to appraise the many MR papers that are or will appear in their journals. We highlight the importance of assessing whether exposures are under plausibly specific genetic influence, whether the hypothesized causal pathways make biological sense, and whether results stand up to replication and use of control outcomes. Quality of research can vary substantially using MR as with any design, and all methods have inherent limitations. MR studies have provided and can still contribute valuable insights in the context of evidence triangulation.

Genetically Proxied Interleukin-13 Inhibition Is Associated With Risk of Psoriatic Disease: A Mendelian Randomization Study.

OBJECTIVE: Inhibitors of the interleukin 13 (IL-13) pathway, such as dupilumab, are licensed for atopic dermatitis and asthma. Adverse events resembling psoriatic disease after dupilumab initiation have been reported, but evidence is limited to case reports with uncertain causality. We aimed to investigate whether genetically mimicked IL-13 inhibition (IL-13i) is associated with risk of psoriatic arthritis (PsA) and psoriasis. METHODS: We instrumented IL-13i using a protein-coding variant in the IL13 gene, rs20541, that is associated with circulating eosinophil count (biomarker of IL-13i) at genome-wide significance in a study of 563,946 individuals. Outcome genetic data were taken from studies of PsA, psoriasis, and related spondyloarthritis traits in up to 10,588 cases and 209,287 controls. Colocalization analysis was performed to examine genetic confounding. We additionally used circulating IgE as a biomarker to test whether associations were replicated, both in the test and in an independent genetic dataset. We also replicated analyses using individual-level data from the UK Biobank. RESULTS: Genetically proxied IL-13i was associated with increased risk of PsA (odds ratio [OR] 37.39; 95% confidence interval [95% CI] 11.52-121.34; P = 1.64 × 10-9) and psoriasis (OR 20.08; 95% CI 4.38-92.01; P = 1.12 × 10-4). No consistent associations were found for Crohn disease, ulcerative colitis, ankylosing spondylitis, or iritis. Colocalization showed no strong evidence of genetic confounding for psoriatic disease. Results were replicated using circulating IgE for the exposure, using independent outcome data and using individual-level data. CONCLUSION: We provide supportive genetic evidence that IL-13i is linked to increased risk of PsA and psoriasis. Physicians prescribing IL-13 inhibitors should be vigilant for these adverse events.

Vitamin D, chronic pain, and depression: linear and non-linear Mendelian randomization analyses.

Vitamin D deficiency has been linked to various chronic pain conditions. However, randomized trials of vitamin D supplementation have had mixed results. In contrast, systematic reviews of randomized trials indicate a protective effect of vitamin D supplementation on depression. We undertake a Mendelian randomization investigation in UK Biobank, a study of UK residents aged 40-65 at recruitment. We perform linear and non-linear Mendelian randomization analyses for four outcomes: fibromyalgia, clinical fatigue, chronic widespread pain, and probable lifetime major depression. We use genetic variants from four gene regions with known links to vitamin D biology as instruments. In linear analyses, genetically-predicted levels of 25-hydroxyvitamin D [25(OH)D], a clinical marker of vitamin D status, were not associated with fibromyalgia (odds ratio [OR] per 10 nmol/L higher 25(OH)D 1.02, 95% confidence interval [CI] 0.93, 1.12), clinical fatigue (OR 0.99, 95% CI 0.94, 1.05), chronic widespread pain (OR 0.95, 95% CI 0.89, 1.02), or probable lifetime major depression (OR 0.97, 95% CI 0.93, 1.01). In non-linear analyses, an association was observed between genetically-predicted 25(OH)D levels and depression in the quintile of the population with the lowest 25(OH)D levels (OR 0.75, 95% CI 0.59, 0.94); associations were null in other strata. Our findings suggest that population-wide vitamin D supplementation will not substantially reduce pain or depression; however, targeted supplementation of deficient individuals may reduce risk of depression.

Role of Anti-Inflammatory Diet and Fecal Microbiota Transplant in Psoriatic Arthritis.

PURPOSE: Psoriatic arthritis (PsA) is a chronic inflammatory condition with complex and heterogenous manifestations. Although a myriad of treatment options including biologic medications are available to alleviate symptoms and slow disease progression, there is currently no cure for this condition. There has been a recent emergence of understanding about the relationship between the gut microbiome and immune-mediated inflammatory diseases. This has generated interest in the potential role of dietary interventions, particularly anti-inflammatory diets, and fecal microbiota transplant (FMT) as novel therapeutic approaches. The purpose of this narrative review is to examine the role of an anti-inflammatory diet and FMT in turn and whether their combination may offer alternate approaches for the management of PsA. METHODS: Our non-systematic narrative review was informed by a literature search using PubMed and Google Scholar using the terms anti-inflammatory diet, FMT, nutrition supplements, and PsA. Preclinical studies and non-English language articles were excluded when synthesizing the narrative review. FINDINGS: Current randomized controlled trials (RCTs) and observational evidence suggest that a hypocaloric diet or Mediterranean diet can help achieve weight loss among PsA patients who are overweight or obese, which in turn reduces inflammation and improves disease activity. However, there is no strong data to support the beneficial effects of intermittent fasting, vitamin supplements, turmeric supplements, probiotics, or omega-3 fatty acid supplements in PsA. Current evidence on the use of FMT in PsA is limited as only one small RCT has been conducted which did not demonstrate efficacy for improving clinical symptoms. IMPLICATIONS: Clinicians can consider recommending hypocaloric or Mediterranean diets as an adjunct to standard management of PsA, possibly under the guidance of a dietician. Further research is needed to explore the beneficial effects of the synergistic role of combining an anti-inflammatory diet with FMT in PsA.

Denosumab, for osteoporosis, reduces the incidence of type 2 diabetes, risk of foot ulceration and all-cause mortality in adults, compared with bisphosphonates: An analysis of real-world, cohort data, with a systematic review and meta-analysis.

AIM: To evaluate the impact of denosumab on (i) the incidence of type 2 diabetes (T2D), and (ii) long-term health outcomes (microvascular [neuropathy, retinopathy, nephropathy] and macrovascular [cardiovascular disease, cerebrovascular accident] complications, and all-cause mortality) in patients with T2D, before (iii) combining results with prior studies using meta-analysis. METHODS: A retrospective analysis of data in a large global federated database (TriNetX; Cambridge, MA) was conducted from 331 375 patients, without baseline T2D or cancer, prescribed either denosumab (treatment, n = 45 854) or bisphosphonates (control, n = 285 521), across 83 healthcare organizations. Propensity score matching (1:1) of confounders was undertaken that resulted in 45 851 in each cohort. Secondary analysis further evaluated the impact of denosumab on long-term health outcomes in patients with T2D. Additionally, we systematically searched prior literature that assessed the association between denosumab and T2D. Estimates were pooled using random-effects meta-analysis. Risk of bias and evidence quality were assessed using Cochrane-endorsed tools. RESULTS: Denosumab (vs. bisphosphonates) was associated with a lower risk of incident T2D over 5 years (hazard ratio 0.83 [95% confidence interval {CI} 0.78-0.88]). Secondary analysis showed significant risk reduction in all-cause mortality (0.79 [0.72-0.87]) and foot ulceration (0.67 [0.53-0.86]). Also, pooled results from four studies (three observational, one randomized controlled trial) following meta-analysis showed a reduced relative risk (RR [95% CI]) for incident T2D in patients prescribed denosumab (0.83 [0.79-0.87]) (I2 = 10.76%). CONCLUSIONS: This is the largest cohort study to show that denosumab treatment is associated with a reduced RR of incident T2D, as well as an associated reduced RR of all-cause mortality and microvascular complications, findings that may influence guideline development in the treatment of osteoporosis, particularly in patients who are at a high risk of T2D.

Insomnia and short sleep duration, but not chronotype, is associated with chronic widespread pain: Mendelian randomization study.

OBJECTIVES: Sleep disturbance has been associated with chronic widespread pain (CWP), but their causal relationship remains unclear. We aimed to examine the causal relationship and direction between CWP and sleep traits, namely insomnia, sleep duration and chronotype, using Mendelian Randomization. METHOD: We used genetic association data from ~0.5 million individuals and up to 1.8 million controls from the UK Biobank (UKB). All traits were defined predominantly by self-report. Short sleep duration was defined as average ≤6 hours per 24 hours. Chronotype refers to the inclination to sleep at certain times where some wake and go to bed early ('morning' person), and others wake and go to sleep later ('evening' person). To permit use of the largest available genetic association data, we used the Causal Analysis Using Summary Effect estimates (CAUSE) method, which allows for sample overlap. RESULTS: Insomnia (OR 1.009, 95% credible interval 1.005, 1.014; p = 0.018 that the causal model is a better fit than non-causal model) and short sleep duration (OR 1.060, 95%CrI 1.038, 1.083; p = 0.040) were causally associated with increased risk of CWP, with limited evidence for reverse causation. There was no evidence in support of long sleep duration or chronotype being associated with CWP. CONCLUSIONS: This study suggest that insomnia and short sleep duration (≤6 hours) are associated with an increased risk of CWP. Improving short sleep duration and insomnia, rather than chronotype, may be effective in reducing the risk of CWP, although these results should be replicated in epidemiological and interventional studies.

Genetically proxied IL-6 receptor inhibition is associated with increased risk of atopic dermatitis.

BACKGROUND: Dermatitis has been reported after initiation of IL-6 receptor (IL-6R) inhibitors (IL-6Ri), while genetic association studies of atopic dermatitis (AD) have implicated IL-6R pathway signaling. However, causality remains unclear. As the indications for IL-6Ri expand, so do the clinical importance of determining whether there is mechanistic evidence linking it to AD. OBJECTIVE: Our aim was to examine the association between IL-6Ri and risk of AD. METHODS: To genetically mimic IL-6Ri, we selected single-nucleotide polymorphisms within or near the IL6R gene associated with C-reactive protein at genome-wide significance among 343,524 individuals. Genetic data were obtained from 10,788 individuals with AD and 30,047 controls of European ancestry. We used inverse variance-weighted and pleiotropy-robust methods and examined genetic confounding using colocalization. Analyses were replicated by using 13,473 Finnish and 2,385 East Asian individuals with AD. The results from 3 independent analyses were pooled by meta-analysis. RESULTS: Genetically proxied IL-6Ri was associated with increased risk of AD (odds ratio [OR] = 1.78 per 4.4-mg/L reduction in C-reactive protein level [95% CI = 1.28-2.48] [P = 6.5 × 10-4]). The results were replicated using Finnish outcome data (OR = 2.07 [95% CI = 1.58-2.72] [P = 1.57 × 10-7]) and Eastern Asian data (OR = 1.68 [95% CI = 1.12-2.54] [P = .013]). Meta-analysis of 3 independent populations (OR = 1.89 [95% CI = 1.57-2.28] [P = 2.68 × 10-11]) showed no evidence of heterogeneity (P = .65). We found no statistical evidence for pleiotropy or genetic confounding. CONCLUSION: This genetic investigation provides consistent evidence (across independent multiancestry populations) that IL-6R signaling is causally implicated in AD susceptibility. Clinicians should remain vigilant for adverse effects resembling AD when using IL-6R inhibitors for immune-mediated inflammatory diseases.

Modifiable risk factors and inflammation-related proteins in polymyalgia rheumatica: genome-wide meta-analysis and Mendelian randomisation.

OBJECTIVE: Polymyalgia rheumatica (PMR) is an age-related inflammatory disease of unknown cause. We aimed to identify potentially modifiable risk factors and therapeutic targets for preventing or treating PMR. METHODS: We meta-analysed genetic association data from 8,156 cases of PMR (defined using diagnostic codes and self-report) and 416,495 controls of European ancestry from the UK Biobank and FinnGen. We then performed Mendelian randomization analyses to estimate the association between eight modifiable risk factors (using data from up to 1.2 million individuals) and 65 inflammation-related circulating proteins (up to 55,792 individuals), using the inverse variance weighted and pleiotropy robust methods. RESULTS: We identified three novel genome-wide significant loci in the IL1R1, NEK6 and CCDC88B genes and confirmation of previously described associations with HLA-DRB1 and ANKRD55. Genetically predicted smoking intensity (OR 1.32; 95%CI 1.08-1.60; p = 0.006) and visceral adiposity (OR 1.22; 95%CI 1.10-1.37; p = 3.10x10-4) were associated with PMR susceptibility. Multiple circulating proteins related to IL-1 family signaling were associated with PMR. IL-1 receptor-like 2, also known as IL-36 receptor (OR 1.25; p = 1.89x10-32), serum amyloid A2 (OR 1.06, 9.91x10-10) and CXCL6 (OR 1.09, p = 4.85x10-7) retained significance after correction for multiple testing. CONCLUSION: Reducing smoking and visceral adiposity at a population level might reduce incidence of PMR. We identified proteins that may play causal roles in PMR, potentially suggesting new therapeutic opportunities. Further research is needed before these findings are applied to clinical practice.

Obesity is a risk factor for poor response to treatment in early rheumatoid arthritis: a NORD-STAR study.

OBJECTIVE: This report from the NORD-STAR (Nordic Rheumatic Diseases Strategy Trials and Registries) trial aimed to determine if obesity is associated with response to conventional and biological antirheumatic treatment in early rheumatoid arthritis (RA). METHODS: This report included 793 participants with untreated early RA from the randomised, longitudinal NORD-STAR trial, all of whom had their body mass index (BMI) assessed at baseline. Obesity was defined as BMI ≥30 kg/m2. All participants were randomised 1:1:1:1 to one of four treatment arms: active conventional treatment, certolizumab-pegol, abatacept and tocilizumab. Clinical and laboratory measurements were performed at baseline and at 8, 12, 24 and 48-week follow-up. The primary endpoint for this report was response to treatment based on Clinical Disease Activity Index (CDAI) and Simple Disease Activity Index (SDAI) remission and Disease Activity Score with 28 joints using C-reactive protein (DAS28-CRP) <2.6 stratified by BMI. RESULTS: Out of 793 people included in the present report, 161 (20%) had obesity at baseline. During follow-up, participants with baseline obesity had higher disease activity compared with those with lower BMI, despite having similar disease activity at baseline. In survival analyses, obesity was associated with a lower likelihood of achieving response to treatment during follow-up for up to 48 weeks (CDAI remission, HR 0.84, 95% CI 0.67 to 1.05; SDAI, HR 0.77, 95% CI 0.62 to 0.97; DAS28-CRP <2.6, HR 0.78, 95% CI 0.64 to 0.95). The effect of obesity on response to treatment was not influenced by the treatment arms. CONCLUSION: In people with untreated early RA followed up for up to 48 weeks, obesity was associated with a lower likelihood of good treatment response, irrespective of the type of randomised treatment received. TRIAL REGISTRATION NUMBER: NCT01491815.