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.

Risk of diabetic retinopathy and diabetic macular oedema with sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists in type 2 diabetes: a real-world data study from a global federated database.

AIMS/HYPOTHESIS: A protective role of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP1-ra) in the development of diabetic retinopathy and diabetic macular oedema has been described in some recent studies, which may extend beyond glycaemic control. We aimed to review the clinical impact of SGLT2i and GLP1-ra therapy on the risk of diabetic retinopathy and diabetic macular oedema in individuals with type 2 diabetes taking insulin. METHODS: This is a retrospective cohort analysis of approximately two million people with type 2 diabetes receiving insulin across 97 healthcare organisations using a global federated health research network (TriNetX, Cambridge, USA). Two intervention cohorts (SGLT2i + insulin, n=176,409; GLP1-ra + insulin, n=207,034) were compared against a control cohort (insulin with no SGLT2i/GLP1-ra, n=1,922,312). Kaplan-Meier survival analysis was performed and estimated HRs were reported for each outcome. Propensity score was used to 1:1 match for age, sex, ischaemic heart disease, hypertension, microvascular complications, chronic kidney disease, HbA1c, BMI and use of pioglitazone, lipid modifying agents, antilipemic agents, ACE inhibitors, angiotensin II inhibitors and metformin. A sub-analysis comparing the two intervention cohorts was also performed. RESULTS: SGLT2i with insulin was associated with a reduced HR (95% CI) for diabetic macular oedema compared with the control cohort (0.835; 0.780, 0.893), while GLP1-ra with insulin demonstrated a lack of signal with no statistical significance to the HR (1.013; 0.960, 1.069). SGLT2i with insulin was not associated with a clinically significant increase in the risk of developing diabetic retinopathy (1.076; 1.027, 1.127), while GLP1-ra with insulin increased diabetic retinopathy risk (1.308; 1.261, 1.357). Compared with SGLT2i with insulin, GLP1-ra with insulin was associated with higher risk of diabetic retinopathy (1.205; 1.153, 1.259) and diabetic macular oedema (1.130; 1.056, 1.208). CONCLUSIONS/INTERPRETATION: Our study suggests that the combination of SGLT2i and insulin is associated with lower risk of developing diabetic macular oedema. However, the use of GLP1-ra was associated with an increased risk of diabetic retinopathy in individuals with type 2 diabetes also taking insulin. A comparative analysis showed favourable outcomes with SGLT2i and insulin in the development of diabetic macular oedema and diabetic retinopathy. RCTs using dedicated  retinal imaging are required to determine the causal relationship with these therapies.

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.

Exploring the unifying concept of Spondyloarthritis: a latent class analysis of the REGISPONSER registry.

OBJECTIVES: The aim of our study is to identify the potential distinct phenotypes within a broad Spondyloarthritis (SpA) population. METHODS: We conducted a cross-sectional study using the REGISPONSER registry with data from 31 specialist centres in Spain including patients with SpA who fulfilled the European Spondyloarthropathy Study Group (ESSG) criteria. A latent class analysis (LCA) was performed to identify the latent classes underlying SpA according to a set of predefined clinical and radiographic features, independently of expert opinion. RESULTS: In a population of 2319 SpA patients, a 5 classes LCA model yielded the best fit. Classes named 'axial with spine involvement' and 'axial with isolated SIJ involvement" show a primarily axial SpA phenotype defined by inflammatory back pain and high HLA-B27 prevalence. Patients in class 'axial + peripheral' show similar distribution of manifest variables to previous classes but also have a higher likelihood of peripheral involvement (peripheral arthritis/dactylitis) and enthesitis, therefore representing a mixed (axial and peripheral) subtype. Classes 'Peripheral + psoriasis' and 'Axial + peripheral + psoriasis' are indicative of peripheral SpA (and/or PsA) with high likelihood of psoriasis, peripheral involvement, dactylitis, nail disease, and low HLA-B27 prevalence, while class 'Axial + peripheral + psoriasis' also exhibits increased probability of axial involvement both clinically and radiologically. CONCLUSION: The identification of 5 latent classes in the REGISPONSER registry with significant overlap between axial and peripheral phenotypes is concordant with a unifying concept of SpA. Psoriasis and related features (nail disease and dactylitis) influence the phenotype of both axial and peripheral manifestations.

Socioeconomic deprivation is associated with reduced response and lower treatment persistence with TNF inhibitors in rheumatoid arthritis.

OBJECTIVE: To investigate the association between socioeconomic deprivation and outcomes following TNF inhibitor (TNFi) treatment. METHODS: Individuals commencing their first TNFi in the British Society for Rheumatology Biologics Register for RA (BSRBR-RA) and Biologics in RA Genetics and Genomics Study Syndicate (BRAGGSS) cohort were included. Socioeconomic deprivation was proxied using the Index of Multiple Deprivation and categorized as 20% most deprived, middle 40% or 40% least deprived. DAS28-derived outcomes at 6 months (BSRBR-RA) and 3 months (BRAGGSS) were compared using regression models with the least deprived as referent. Risks of all-cause and cause-specific drug discontinuation were compared using Cox models in the BSRBR-RA. Additional analyses adjusted for lifestyle factors (e.g. smoking, BMI) as potential mediators. RESULTS: 16 085 individuals in the BSRBR-RA were included (mean age 56 years, 76% female), of whom 18%, 41% and 41% were in the most, middle and least deprived groups, respectively. Of 3459 included in BRAGGSS (mean age 57, 77% female), proportions were 22%, 36% and 41%, respectively. The most deprived group had 0.3-unit higher 6-month DAS28 (95% CI 0.22, 0.37) and were less likely to achieve low disease activity (odds ratio [OR] 0.76; 95% CI 0.68, 0.84) in unadjusted models. Results were similar for 3-month DAS28 (ß = 0.23; 95% CI 0.11, 0.36) and low disease activity (OR 0.77; 95% CI 0.63, 0.94). The most deprived were more likely to discontinue treatment (hazard ratio 1.18; 95% CI 1.12, 1.25), driven by ineffectiveness rather than adverse events. Adjusted estimates were generally attenuated. CONCLUSION: Socioeconomic deprivation is associated with reduced response to TNFi. Improvements in determinants of health other than lifestyle factors are needed to address socioeconomic inequities.

Diagnostic delay is associated with uveitis and inflammatory bowel disease in AS: a study of extra-musculoskeletal manifestations in SpA.

OBJECTIVES: To examine the prevalence of extra-musculoskeletal manifestations (EMM) and the association between diagnostic delay and their incidence in AS and PsA. METHODS: This was a retrospective, cohort study comprising two single centre cohorts in Europe and one multicentre cohort in Latin America (RESPONDIA). Crude prevalence of EMMs (uveitis, IBD and psoriasis) was calculated across geographic area and adjusted by direct standardization. Cox proportional hazard analysis was performed to assess the association between diagnostic delay and EMM incidence. RESULTS: Of 3553 patients, 2097 had AS and 1456 had PsA. The overall prevalence of uveitis was 22.9% (95% CI: 21.1, 24.8) in AS and 3.8% (95% CI: 2.9, 5.0) in PsA; 8.1% (95% CI: 7.0, 9.4) and 2.1% (1.3, 2.9), respectively, for IBD; and 11.0% (95% CI: 9.7, 12.4) and 94.6% (93.0, 95.9), respectively, for psoriasis. The EMM often presented before the arthritis (uveitis 45.1% and 33.3%, and IBD 37.4% and 70%, in AS and PsA, respectively). In the multivariable model, longer diagnostic delay (≥5 years) associated with more uveitis (hazard ratio [HR] 4.01; 95% CI: 3.23, 4.07) and IBD events (HR 1.85; 95% CI: 1.28, 2.67) in AS. Diagnostic delay was not significantly associated with uveitis (HR 1.57; 95% CI: 0.69, 3.59) or IBD events (HR 1.59; 95% CI: 0.39, 6.37) in PsA. CONCLUSION: EMMs are more prevalent in AS than PsA and often present before the onset of the articular disease. A longer diagnostic delay is associated with the 'de novo' appearance of uveitis and IBD in AS, highlighting the need to enhance diagnostic strategies to shorten the time from first symptom to diagnosis in SpA.

The synergistic impact of type 2 diabetes and MASLD on cardiovascular, liver, diabetes-related and cancer outcomes.

BACKGROUND AND AIMS: We examined the impact of a co-diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D) on patient outcomes. METHODS: Using TriNetX, a global federated research network (n = 114 million), we undertook two retrospective cohort studies, using time-to-event analysis. Analysis 1 compared MASLD with T2D to MASLD alone; analysis 2 compared T2D with MASLD to T2D alone. Propensity score matching using greedy nearest neighbour (calliper .1) balanced the cohorts (1:1) for significant covariates. Primary outcomes were cardiovascular, liver, diabetes-related, and cancer events over 5 years. RESULTS: Analysis 1 (n = 95 275): a co-diagnosis of T2D significantly increased the risk of ischaemic heart disease (IHD) (HR 1.39; CI: 1.34, 1.44), ischaemic stroke (HR 1.45; CI: 1.35, 1.56), heart failure (HR 1.42; CI: 1.36, 1.49), atrial fibrillation (HR 1.09; CI: 1.03, 1.16), hepatocellular carcinoma (HR 1.96; CI: 1.69, 2.27), pancreatic cancer (HR 1.25; CI: 1.06, 1.48) and liver-related complications over 5 years from MASLD diagnosis. Analysis 2 (n = 15 208): a co-diagnosis of MASLD significantly increased risk of all-cause mortality (HR 1.11; CI: 1.02, 1.22), IHD (HR 1.181; CI: 1.08, 1.29), hepatocellular (HR 50.31; CI: 6.94, 364.72), pancreatic (HR 1.78; CI: 1.12, 2.84), breast (HR 1.43; CI: 1.09, 1.88) and renal cancer (HR 2.01; CI: 1.24, 3.26), and diabetic neuropathy (HR 1.17; CI: 1.09, 1.27) over 5 years from metformin initiation. CONCLUSIONS: T2D significantly potentiates the risk of cardiovascular, malignancy and liver-related outcomes in people with MASLD. The effect of MASLD on people with T2D, although less dramatic, still potentiated risk of death, IHD, malignancy and peripheral neuropathy.

Effect of combination pioglitazone with sodium-glucose cotransporter-2 inhibitors or glucagon-like peptide-1 receptor agonists on outcomes in type 2 diabetes: A systematic review, meta-analysis, and real-world study from an international federated database.

AIMS: To evaluate the efficacy and cardiovascular outcomes of combination pioglitazone with either a glucagon-like peptide-1 receptor agonist (GLP-1RA) or a sodium-glucose cotransporter-2 (SGLT2) inhibitor in individuals with type 2 diabetes (T2D) by conducting a systematic review, meta-analysis, and analysis of a large international real-world database. METHODS: We searched MEDLINE, SCOPUS and Web of Science to identify relevant articles for inclusion (PROSPERO [CRD: 42023483126]). Nineteen studies assessing pioglitazone + SGLT2 inhibitors or GLP-1RAs versus controls were identified, 16 of which were randomized controlled trials. Risk of bias was assessed using Cochrane-endorsed tools and quality of evidence was assessed using GRADE. We additionally performed a retrospective cohort study of all individuals aged 18 years or over with T2D, using the TriNetX platform. We included propensity-score-matched individuals who were treated for at least 1 year with pioglitazone and a GLP-1RA or pioglitazone and an SGLT2 inhibitor, compared against GLP-1RA and SGLT2 inhibitor monotherapy. Outcomes were all-cause mortality, heart failure, chronic kidney disease and composite stroke and transient ischaemic attack. RESULTS: The average follow-up in the included studies ranged from 24 to 52 weeks. Combination of pioglitazone with a GLP-1RA reduced glycated haemoglobin (HbA1c) and weight greater than in controls: mean differences -1% (95% confidence interval [CI] -1.27, -0.74) and -1.19 kg (95% CI -1.80, -0.58), respectively. There was no statistically significant difference in systolic blood pressure (SBP) or mortality between groups: mean difference - 1.56 mmHg (95% CI -4.48, 1.35; p = 0.30) and relative risk (RR) 0.29 (95% CI 0.07-1.15; p = 0.08), respectively. Combination of pioglitazone with SGLT2 inhibitors reduced HbA1c, weight and SBP to a greater extent than control treatment: mean differences -0.48% (95% CI -0.67, -0.28), -2.3 kg (95% CI -2.72, -1.88) and -2.4 mmHg (95% CI -4.1, -0.7; p = 0.01), respectively. There was no statistically significant difference in mortality between groups (RR 1.81, 95% CI 0.30-10.97; p = 0.52). The included trials demonstrated a reduction in risk of heart failure with combination treatment. Similarly, from the real-world database (n = 25 230 identified), pioglitazone and SGLT2 inhibitor combination therapy was associated with reduced risk of heart failure compared to monotherapy alone (hazard ratio 0.50, 95% CI 0.38-0.65; p < 0.001). CONCLUSION: Both our systematic review/meta-analysis and the real-world dataset show that combination of pioglitazone with either GLP-1RAs or SGLT2 inhibitors is associated with increased weight loss and reduced risk of heart failure compared with monotherapy.

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.

SGLT2i and GLP-1 RA therapy in type 1 diabetes and reno-vascular outcomes: a real-world study.

AIMS/HYPOTHESIS: Insulin is the primary treatment for type 1 diabetes. However, alternative glucose-lowering therapies are used adjunctively, but importantly are off-label in type 1 diabetes. Little work has previously been undertaken to evaluate safety with long-term efficacy and cardio-renal benefits of such therapies. We sought to investigate the real-world impact of sodium-glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy in individuals with type 1 diabetes in relation to effect on blood glucose levels, adverse events and cardio-renal outcomes. METHODS: We performed a retrospective cohort study of all patients aged 18 or over with type 1 diabetes on the TriNetX platform, a global collaborative network providing access to real-time, anonymised medical records. We included patients who had been treated with an SGLT2i or GLP-1 RA for at least 6 months and analysed the efficacy, safety and cardio-renal outcomes 5 years after initiation of therapy. RESULTS: We identified 196,691 individuals with type 1 diabetes, 13% of whom were treated with adjunctive glucose-lowering therapy in addition to insulin. Included in the core analysis were 1822 patients treated with a GLP-1 RA and 992 individuals treated with an SGLT2i. Both agents provided clinically meaningful reductions in HbA1c (-2.6 mmol/mol [-0.2%] with SGLT2i and -5.4 mmol/mol [-0.5%] with GLP-1 RA). The SGLT2i treated cohort showed preservation of eGFR over a 5-year period compared with the GLP-1 RA treated cohort (+3.5 ml/min per 1.73 m2 vs -7.2 ml/min per 1.73 m2, respectively), including patients with established chronic kidney disease (CKD). The SGLT2i treated cohort experienced higher rates of diabetic ketoacidosis (DKA) (RR 2.08 [95% CI 1.05, 4.12] p=0.0309) and urinary tract infection/pyelonephritis (RR 2.27 [95% CI 1.12, 4.55] p=0.019) compared with the GLP-1 RA treated cohort. However, the SGLT2i treated cohort were less likely to develop heart failure (RR 0.44 [95% CI 0.23, 0.83] p=0.0092), CKD (RR 0.49 [95% CI 0.28, 0.86] p=0.0118) and be hospitalised for any cause (RR 0.59 [95% CI 0.46, 0.76] p≤0.0001) when compared with the GLP-1 RA treated cohort. CONCLUSIONS/INTERPRETATION: Both SGLT2is and GLP-1 RAs have potential benefits as adjunctive agents in type 1 diabetes. SGLT2is provide cardio-renal benefits, despite an increase in the risk of DKA and urinary tract infection compared with GLP-1 RA therapy. Long-term evaluation of the efficacy and safety of these adjunctive therapies is required to guide their use in individuals with type 1 diabetes.

2022 EULAR recommendations for screening and prophylaxis of chronic and opportunistic infections in adults with autoimmune inflammatory rheumatic diseases.

OBJECTIVES: To develop EULAR recommendations for screening and prophylaxis of chronic and opportunistic infections in patients with autoimmune inflammatory rheumatic diseases (AIIRD). METHODS: An international Task Force (TF) (22 members/15 countries) formulated recommendations, supported by systematic literature review findings. Level of evidence and grade of recommendation were assigned for each recommendation. Level of agreement was provided anonymously by each TF member. RESULTS: Four overarching principles (OAP) and eight recommendations were developed. The OAPs highlight the need for infections to be discussed with patients and with other medical specialties, in accordance with national regulations. In addition to biologic/targeted synthetic disease-modifying antirheumatic drugs (DMARDs) for which screening for latent tuberculosis (TB) should be performed, screening could be considered also before conventional synthetic DMARDs, glucocorticoids and immunosuppressants. Interferon gamma release assay should be preferred over tuberculin skin test, where available. Hepatitis B (HBV) antiviral treatment should be guided by HBV status defined prior to starting antirheumatic drugs. All patients positive for hepatitis-C-RNA should be referred for antiviral treatment. Also, patients who are non-immune to varicella zoster virus should be informed about the availability of postexposure prophylaxis should they have contact with this pathogen. Prophylaxis against Pneumocystis jirovecii seems to be beneficial in patients treated with daily doses >15-30 mg of prednisolone or equivalent for >2-4 weeks. CONCLUSIONS: These recommendations provide guidance on the screening and prevention of chronic and opportunistic infections. Their adoption in clinical practice is recommended to standardise and optimise care to reduce the burden of opportunistic infections in people living with AIIRD.

ASAS-EULAR recommendations for the management of axial spondyloarthritis: 2022 update.

OBJECTIVES: To update the Assessment of SpondyloArthritis international Society (ASAS)-EULAR recommendations for the management of axial spondyloarthritis (axSpA). METHODS: Following the EULAR Standardised Operating Procedures, two systematic literature reviews were conducted on non-pharmacological and pharmacological treatment of axSpA. In a task force meeting, the evidence was presented, discussed, and overarching principles and recommendations were updated, followed by voting. RESULTS: Five overarching principles and 15 recommendations with a focus on personalised medicine were agreed: eight remained unchanged from the previous recommendations; three with minor edits on nomenclature; two with relevant updates (#9, 12); two newly formulated (#10, 11). The first five recommendations focus on treatment target and monitoring, non-pharmacological management and non-steroidal anti-inflammatory drugs (NSAIDs) as first-choice pharmacological treatment. Recommendations 6-8 deal with analgesics and discourage long-term glucocorticoids and conventional synthetic disease-modifying antirheumatic drugs (DMARDs) for pure axial involvement. Recommendation 9 describes the indication of biological DMARDs (bDMARDs, that is, tumour necrosis factor inhibitors (TNFi), interleukin-17 inhibitors (IL-17i)) and targeted synthetic DMARDs (tsDMARDs, ie, Janus kinase inhibitors) for patients who have Ankylosing Spondylitis Disease Activity Score ≥2.1 and failed ≥2 NSAIDs and also have either elevated C reactive protein, MRI inflammation of sacroiliac joints or radiographic sacroiliitis. Current practice is to start a TNFi or IL-17i. Recommendation 10 addresses extramusculoskeletal manifestations with TNF monoclonal antibodies preferred for recurrent uveitis or inflammatory bowel disease, and IL-17i for significant psoriasis. Treatment failure should prompt re-evaluation of the diagnosis and consideration of the presence of comorbidities (#11). If active axSpA is confirmed, switching to another b/tsDMARD is recommended (#12). Tapering, rather than immediate discontinuation of a bDMARD, can be considered in patients in sustained remission (#13). The last recommendations (#14, 15) deal with surgery and spinal fractures. CONCLUSIONS: The 2022 ASAS-EULAR recommendations provide up-to-date guidance on the management of patients with axSpA.

Assessment and diagnosis of the acute hot joint: a systematic review and meta-analysis.

OBJECTIVES: Prompt diagnosis of septic arthritis (SA) in acute native hot joints is essential for avoiding unnecessary antibiotics and hospital admissions. We evaluated the utility of synovial fluid (SF) and serum tests in differentiating causes of acute hot joints. METHODS: We performed a systematic literature review of diagnostic testing for acute hot joints. Articles were included if studying ≥1 serum or SF test(s) for an acute hot joint, compared with clinical assessment and SF microscopy and culture. English-language articles only were included, without date restriction. The following were recorded for each test, threshold and diagnosis: sensitivity, specificity, positive/negative predictive values and likelihood ratios. For directly comparable tests (i.e. identical fluid, test and threshold), bivariate random-effects meta-analysis was used to pool sensitivity, specificity, and areas under the curves. RESULTS: A total of 8443 articles were identified, and 49 were ultimately included. Information on 28 distinct markers in SF and serum, differentiating septic from non-septic joints, was extracted. Most had been tested at multiple diagnostic thresholds, yielding a total of 27 serum markers and 156 SF markers. Due to heterogeneity of study design, outcomes and thresholds, meta-analysis was possible for only eight SF tests, all differentiating septic from non-septic joints. Of these, leucocyte esterase had the highest pooled sensitivity [0.94 (0.70, 0.99)] with good pooled specificity [0.74 (0.67, 0.81)]. CONCLUSION: Our review demonstrates many single tests, individually with diagnostic utility but suboptimal accuracy for exclusion of native joint infection. A combination of several tests with or without a stratification score is required for optimizing rapid assessment of the hot joint.

Angiotensin receptor blockade is associated with increased risk of giant cell arteritis.

OBJECTIVES: Angiotensin II is implicated in GCA pathology. We examined whether the use of angiotensin receptor blockers (ARBs) is associated with GCA risk compared with angiotensin-converting enzyme inhibitors (ACEis) or other antihypertensives. METHODS: We performed a matched cohort study including adults who were initiators of antihypertensives in UK primary care data between 1995 and 2019. Treatment-naïve individuals without prior GCA or PMR were categorized into three groups-ARB initiators, ACEi initiators, or other antihypertensive initiators (beta-blockers, calcium channel blockers, diuretics or alpha-adrenoceptor blockers)-and followed for up to 5 years. Incident GCA was defined using validated Read codes, with age of onset ≥50 years and two or more glucocorticoid prescriptions. Inverse probability-weighted Cox models were used to model outcome risk, adjusting for lifestyle parameters, comorbidities and comedications. RESULTS: Among >1 million new starters of antihypertensives (81 780 ARBs, 422 940 ACEis and 873 066 other antihypertensives), the incidence rate of GCA per 10 000 patient-years was 2.73 (95% CI 2.12, 3.50) in the ARB group, 1.76 (95% CI 1.25, 2.39) in the ACEi group and 1.90 (95% CI 1.37, 2.56) in the other antihypertensives group. The hazard of GCA was higher in ARB initiators [hazard ratio (HR) 1.55; 95% CI 1.16, 2.06] than initiators of ACEis, but similar between initiators of other antihypertensives and ACEis (HR 1.08; 95% CI 0.87, 1.35). CONCLUSIONS: Initiation of ARBs is associated with a higher risk of GCA compared with ACEis or other antihypertensives. Mechanistic studies of angiotensin receptor biology will provide further clarity for our findings.

The predictive accuracy of cardiovascular risk prediction tools in inflammatory arthritis and psoriasis: an observational validation study using the Clinical Practice Research Datalink.

OBJECTIVES: Cardiovascular risk prediction tools developed for the general population often underperform for individuals with rheumatoid arthritis (RA), and their predictive accuracy are unclear for other inflammatory conditions that also have increased cardiovascular risk. We investigated performance of QRISK-3, Framingham Risk Score (FRS) and Reynolds Risk Score (RRS) in RA, psoriatic disease (psoriatic arthritis (PsA) and psoriasis) and ankylosing spondylitis (AS). We considered osteoarthritis as a non-inflammatory comparator. METHODS: We utilised primary care records from the Clinical Practice Research Datalink (CPRD) Aurum database to identify individuals with each condition and calculated 10-year cardiovascular risk using each prediction tool. Discrimination and calibration of each tool in each disease was assessed. RESULTS: Time-dependent AUC for QRISK3 was 0.752 for RA (95% CI 0.734-0.777), 0.794 for AS (95% CI 0.764-0.812), 0.764 for PsA (95% CI 0.741-0.791),0.815 for psoriasis (95% CI 0.789-0.835), and 0.698 for osteoarthritis (95% CI 0.670-0.717) indicating reasonably good predictive performance. AUC for FRS were similar, and slightly lower for RRS. FRS was reasonably well calibrated for each condition but underpredicted risk for patients with RA. RRS tended to underpredict CVD risk, whilst QRISK3 overpredicted CVD risk, especially for the most high-risk individuals. CONCLUSIONS: CVD risk for individuals with RA, AS and psoriatic disease were generally less accurately predicted using each of the 3 CVD risk prediction tools than reported accuracies in the original publications. Individuals with osteoarthritis also had less accurate predictions suggesting inflammation is not the sole reason for underperformance. Disease specific risk prediction tools may be required.

Association between psoriatic disease and lifestyle factors and comorbidities: cross-sectional analysis and Mendelian randomization.

OBJECTIVES: To examine associations between PsA and psoriasis vs lifestyle factors and comorbidities by triangulating observational and genetic evidence. METHODS: We analysed cross-sectional data from the UK Biobank (1836 PsA, 8995 psoriasis, 36 000 controls) to describe the association between psoriatic disease and lifestyle factors (including BMI and smoking) and 15 comorbidities [including diabetes and coronary artery disease (CAD)] using logistic models adjusted for age, sex and lifestyle factors. We applied bidirectional Mendelian randomization (MR) to genome-wide association data (3609 PsA and 7804 psoriasis cases, up to 1.2 million individuals for lifestyle factors and 757 601 for comorbidities) to examine causal direction, using the inverse-variance weighted method. RESULTS: BMI was cross-sectionally associated with risk of PsA (OR 1.31 per 5 kg/m2 increase; 95% CI 1.26, 1.37) and psoriasis (OR 1.23; 1.20, 1.26), with consistent MR estimates (PsA OR 1.38; 1.14, 1.67; psoriasis OR 1.36; 1.18, 1.58). In both designs, smoking was more strongly associated with psoriasis than PsA. PsA and psoriasis were cross-sectionally associated with diabetes (OR 1.35 and 1.39, respectively) and CAD (OR 1.56 and 1.38, respective). Genetically predicted glycated haemoglobin (surrogate for diabetes) increased PsA risk (OR 1.18 per 6.7 mmol/mol increase; 1.02, 1.36) but not psoriasis. Genetic liability to PsA (OR 1.05; 1.003, 1.09) and psoriasis (OR 1.03; 1.001, 1.06) were associated with increased risk of CAD. CONCLUSION: Observational and genetic evidence converge to suggest that BMI and glycaemic control are associated with increased psoriatic disease risk, while psoriatic disease is associated with increased CAD risk. Further research is needed to understand the mechanism of these associations.

Outcomes following switching from etanercept originator to etanercept biosimilar in 1024 RA patients: A matched-analysis of the BSRBR-RA.

OBJECTIVES: Adults with RA are being switched from etanercept originator to biosimilar in non-medical/cost-saving switching. This analysis aims to investigate outcomes in these patients, including (a) drug survival and (b) disease activity at six and 12-month, compared with those who remain on originator. METHODS: Using BSRBR-RA, those who switched directly from etanercept originator to biosimilar were identified and matched to patients receiving originator, based on gender, age, disease duration, originator start year. Drug survival was calculated; Cox-proportional hazard models assessed differences in drug persistence between those who switched versus remaining on originator. Change in DAS28 after six and 12-months was compared between cohorts. Multiple imputation was used. RESULTS: 1024 adults with RA switching from etanercept originator to biosimilar were included, with a matched cohort of patients remaining on originator. Patients who switched onto a biosimilar product were no more likely to discontinue etanercept treatment versus those who remained on originator; hazard ratio 1.06 (95%CI 0.89-1.26), with 65% of patients remaining on treatment at three years. Ninety-five (9%) patients switched back to originator within the first year. After six and 12-months, biosimilar patients were no more likely to have a worsening of DAS28 (>0.6units) compared with those who remained on originator. CONCLUSIONS: This is the largest matched comparative effectiveness analysis showing patients switched from etanercept originator to biosimilar appear to do just as well with regards to disease activity and drug persistence compared with those who remained on originator. These data will be reassuring to clinicians and patients regarding non-medical switching.

Etanercept originator versus etanercept biosimilar for the treatment of rheumatoid arthritis as a first biologic: results from the BSRBR-RA.

OBJECTIVES: Etanercept biosimilars show comparable efficacy to their originators among biologic-naïve patients with RA in randomized controlled trials. Nationwide guidelines have obligated prescribing of etanercept biosimilars from 2016, resulting in significant cost savings. This analysis aimed to compare the effectiveness of etanercept originator vs etanercept biosimilar amongst biologic-naïve RA patients treated in routine clinical practice in the UK. METHODS: Biologic-naïve RA patients starting etanercept in the British Society for Rheumatology Biologics Register in Rhematoid Arthritis (BSRBR-RA) cohort study from 2010 were included. Data collected at start of therapy includes patient demographics and disease activity. Follow-up data includes changes in disease activity and anti-rheumatic therapy. Six- and 12-month primary outcomes include DAS for 28-joints (DAS28) remission, EULAR response and minimal clinically important difference in function. Etanercept drug survival was assessed using Kaplan-Meier and Cox regression, including reasons for treatment withdrawal. Multiple imputation accounted for missing data. Propensity-decile adjustment was used to account for confounding by indication. RESULTS: A total of 1806 biologic-naïve RA patients started etanercept: 1009 originator, 797 biosimilar. At 6 and 12 months, the proportion of patients achieving DAS28 remission and EULAR response were similar between treatments. During follow-up, 19% of originator patients switched onto etanercept biosimilar. Patients were censored at time of switch. Patients on originator were no more likely to stop therapy vs biosimilar; 71% of originator and 76% of biosimilar patients remained on therapy at 1 year. CONCLUSIONS: In one of the largest analyses of patients with RA, biologic-naïve RA patients treated with etanercept originator showed similar outcomes vs biosimilar using real-world data. Drug survival, and disease activity after 6 and 12 months of therapy, was similar between cohorts.

Childhood, adolescent, and adulthood adiposity are associated with risk of PCOS: a Mendelian randomization study with meta-analysis.

STUDY QUESTION: What is the influence of body composition during childhood, adolescence, and adulthood, as well as metabolic parameters, on incident polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Excess body fat, even during childhood/adolescence, and metabolic parameters, suggestive of hyperinsulinaemia/insulin resistance, significantly impact the risk of PCOS in a linear fashion. WHAT IS KNOWN ALREADY: Observational and Mendelian randomization (MR) data have demonstrated an association between adulthood overweight/obesity and development of PCOS. However, the contribution of body composition in childhood/adolescence to incident PCOS is unclear, as is the influence of childhood overweight/obesity. STUDY DESIGN, SIZE, DURATION: We conducted a systematic review and meta-analysis and integrated our results with a previously published systematic review. Two blinded investigators screened abstracts published between November 2010 and May 2021. Furthermore, we incorporated summary statistics from genome-wide association study (GWAS) data in subjects of European ancestry. Adult overweight was defined as BMI ≥ 25 kg/m2 and obesity as BMI ≥ 30 kg/m2; in Asian subjects, overweight was defined as BMI ≥ 23 kg/m2 and obesity as BMI ≥ 25 kg/m2. PARTICIPANTS/MATERIALS, SETTING, METHODS: We utilized meta-analysis and MR together to allow synthesis of genetic and observational data. For the systematic review, the search revealed 71 studies, of which 63 were included in meta-analysis by calculating odds ratios (ORs) using the random-effects model. Furthermore, we conducted a two-sample MR study of GWAS data to determine the impact of childhood and adult body size (defined categorically by BMI and childhood body size proportions), abnormal body composition and metabolic parameters (higher fasting serum insulin or lower sex hormone-binding globulin (SHBG) concentration) on the odds of incident PCOS via the inverse-variance weighted method. MAIN RESULTS AND THE ROLE OF CHANCE: Significant associations were shown between body composition and PCOS incidence. From the systematic review/meta-analysis, women with overweight (OR 3.80, 2.87-5.03), obesity (OR 4.99, 3.74-6.67), and central obesity (OR 2.93, 2.08-4.12) had increased odds of PCOS. For adolescents with overweight and/or obesity, the PCOS odds were greater than for adults. From MR, for every standard deviation increase in BMI (4.8 kg/m2), the odds of PCOS increased by 2.76 (2.27-3.35). Childhood body size had an independent effect on PCOS odds after adjusting for adult body size (OR: 2.56, 1.57-4.20). Genetically determined body fat percentage (OR 3.05, 2.24-4.15), whole body fat mass (OR 2.53, 2.04-3.14), fasting serum insulin (OR 6.98, 2.02-24.13), and SHBG concentration (OR 0.74, 0.64-0.87) were all significantly associated with PCOS in a linear relation. LIMITATIONS, REASONS FOR CAUTION: The meta-analysis included studies which were cross-sectional and retrospective, limiting our ability to determine causality. MR was limited by interrogating subjects only of European ancestry and including cases classified by either self-diagnosis or diagnostic criteria. WIDER IMPLICATIONS OF THE FINDINGS: Our study demonstrates for the first time a critical role of the impact of excess childhood/adolescent adiposity on the pathophysiology of adult PCOS. Our results, driven by genetically determined childhood/adolescent body composition, higher BMI, hyperinsulinaemia, and lower SHBG, clearly favour obesity driving the metabolic, but not reproductive, PCOS phenotype. Overall, effective weight maintenance, even from the early years, is likely to reduce the risk of this reproductive endocrine disorder. STUDY FUNDING/COMPETING INTEREST(S): S.S.Z. was funded by a National Institute for Health and Care Research (NIHR) Academic Clinical Lectureship. U.A. is chair of the NIHR Steering Committee Trial-CASSANDRA-DN. No other authors declare any sources of funding or relevant conflicts of interest. The authors declare that the research was conducted in the absence of any commercial or financial relations that could be construed as a potential conflict of interest. TRIAL REGISTRATION NUMBER: N/A.