Metabolic Induction of Trained Immunity through the Mevalonate Pathway.

Innate immune cells can develop long-term memory after stimulation by microbial products during infections or vaccinations. Here, we report that metabolic signals can induce trained immunity. Pharmacological and genetic experiments reveal that activation of the cholesterol synthesis pathway, but not the synthesis of cholesterol itself, is essential for training of myeloid cells. Rather, the metabolite mevalonate is the mediator of training via activation of IGF1-R and mTOR and subsequent histone modifications in inflammatory pathways. Statins, which block mevalonate generation, prevent trained immunity induction. Furthermore, monocytes of patients with hyper immunoglobulin D syndrome (HIDS), who are mevalonate kinase deficient and accumulate mevalonate, have a constitutive trained immunity phenotype at both immunological and epigenetic levels, which could explain the attacks of sterile inflammation that these patients experience. Unraveling the role of mevalonate in trained immunity contributes to our understanding of the pathophysiology of HIDS and identifies novel therapeutic targets for clinical conditions with excessive activation of trained immunity.

Association of Low-Dose Colchicine With Incidence of Knee and Hip Replacements : Exploratory Analyses From a Randomized, Controlled, Double-Blind Trial.

BACKGROUND: Osteoarthritis is a major contributor to pain and disability worldwide. Given that inflammation plays an important role in the development of osteoarthritis, anti-inflammatory drugs may slow disease progression. OBJECTIVE: To examine whether colchicine, 0.5 mg daily, reduces incident total knee replacements (TKRs) and total hip replacements (THRs). DESIGN: Exploratory analysis of the LoDoCo2 (Low-Dose Colchicine 2) randomized, controlled, double-blind trial. (Australian New Zealand Clinical Trials Registry: ACTRN12614000093684). SETTING: 43 centers in Australia and the Netherlands. PATIENTS: 5522 patients with chronic coronary artery disease. INTERVENTION: Colchicine, 0.5 mg, or placebo once daily. MEASUREMENTS: The primary outcome was time to first TKR or THR since randomization. All analyses were performed on an intention-to-treat basis. RESULTS: A total of 2762 patients received colchicine and 2760 received placebo during a median follow-up of 28.6 months. During the trial, TKR or THR was performed in 68 patients (2.5%) in the colchicine group and 97 (3.5%) in the placebo group (incidence rate, 0.90 vs. 1.30 per 100 person-years; incidence rate difference, -0.40 [95% CI, -0.74 to -0.06] per 100 person-years; hazard ratio, 0.69 [CI, 0.51 to 0.95]). In sensitivity analyses, similar results were obtained when patients with gout at baseline were excluded and when joint replacements that occurred in the first 3 and 6 months of follow-up were omitted. LIMITATION: LoDoCo2 was not designed to investigate the effect of colchicine in osteoarthritis of the knee or hip and did not collect information specifically on osteoarthritis. CONCLUSION: In this exploratory analysis of the LoDoCo2 trial, use of colchicine, 0.5 mg daily, was associated with a lower incidence of TKR and THR. Further investigation of colchicine therapy to slow disease progression in osteoarthritis is warranted. PRIMARY FUNDING SOURCE: None.

Therapy with JAK inhibitors or bDMARDs and the risk of cardiovascular events in the Dutch rheumatoid arthritis population.

OBJECTIVE: Caution has been advocated recently when using Janus kinase inhibitors (JAKi) in rheumatoid arthritis (RA) patients with an unfavorable cardiovascular risk profile. We aimed to compare the incidences in cardiovascular events between JAKi or bDMARDs in a large population of RA patients. METHODS: RA patients starting a new bDMARD or JAKi between August 1st 2018 and January 31st 2022 have been selected from IQVIA's Dutch Real-World Data Longitudinal Prescription database, covering about 63% of outpatient prescriptions in the Netherlands. Study outcome was a cardiovascular event, defined as the start of platelet aggregation inhibitors during study period. The incidence densities of cardiovascular events were compared between JAKi and bDMARDs using multilevel Poisson regression, adjusted for exposition time and confounders. RESULTS: 15 191 unique patients were included, with 28 481 patient-years on treatment with either JAKi (2,373) or bDMARDs (26 108). Most patients were female (72%) and median age was 62 years. We found 36 cardiovascular events (1.52 events/100 patient years) during therapy with JAKi and 383 events (1.47 events/100 patient years) during therapy with bDMARDs, respectively, resulting in an adjusted incidence rate ratio (IRR) of 0.99 for JAKi compared with bDMARDs (95% confidence interval (CI), 0.70-1.41). Sub-analyses in patients >65 years, by sex, or separately for tofacitinib and baricitinib, yielded similar results. CONCLUSION: In a large Dutch general RA population, the risk of cardiovascular events seems not different between JAKi users and those using bDMARDs, although a small increase in higher risk patients cannot be excluded.

Shared decision making in routine clinical care of patients with rheumatoid arthritis: an assessment of audio-recorded consultations.

OBJECTIVES: Although shared decision making (SDM) is advocated in rheumatoid arthritis (RA) treatment, it is largely unclear when, how and to what extent SDM is applied in routine clinical care of patients with RA. This study aimed to investigate the level of SDM in RA treatment from an observer perspective and to assess associations between the level of SDM and characteristics of the clinician, patient and consultation. METHODS: The level of SDM was investigated by scoring audio-recordings of 168 routine consultations with unique patients with the observer patient involvement (OPTION) scale (scale 0-100, higher OPTION scores indicating higher levels of SDM). Associations between the level of SDM and characteristics of the clinician, patient and consultation were assessed using multilevel modelling. Statistical significance was set at p<0.05. RESULTS: The mean OPTION score was 28.3 (SD=15.1). The multilevel model included four characteristics: clinician age, patient age, consultation duration and type of treatment decision. There were significant, positive associations between the level of SDM and the consultation duration (b=0.63, 95% CI 0.16 to 1.11), decision for stopping and/or starting medication (b=14.30, 95% CI 5.62 to 22.98), decision for adjusting medication doses (b=8.36, 95% CI 3.92 to 12.81) and decision for administering single dose glucocorticoids (b=15.03, 95% CI 9.12 to 20.93). Thus, a higher level of SDM was significantly associated with a longer consultation duration and the type of treatment decision. No other significant associations were found. CONCLUSIONS: Overall, the level of SDM in RA treatment leaves room for improvement. To foster SDM in routine clinical care, training programmes on patient-centred communication skills may be helpful.

Transgenic mice expressing human IL-32 develop adipokine profiles resembling those of obesity-induced metabolic changes.

Low-grade inflammation is associated with the development of insulin resistance in obese individuals. The present study aims to provide additional evidence strengthening the role of interleukin (IL)-32 in this key process. Using an IL-32 transgenic (IL-32tg) mouse model, we observed that IL-32tg fed a normal diet had greater body weight, due to greater accumulation of white adipose tissue (WAT) along with larger sized adipocytes. This led to metabolic consequences, with significant higher leptin levels and a trend towards hyperinsulinemia, indicating a phenotype resembling the metabolic syndrome. Adipocytes of IL-32tg mice were more prone to induce a pro-inflammatory response locally, which would be expected when predisposed to insulin resistance and type2 diabetes mellitus (T2D). In conclusion, our study provides novel evidence of a direct contribution of IL-32 to pathophysiological perturbations within the adipose tissue, possibly contributing to the metabolic syndrome that precedes frank insulin resistance and T2D. Future research should focus on the role of IL-32 in the obesity epidemic.

Low disease activity (DAS28≤3.2) reduces the risk of first cardiovascular event in rheumatoid arthritis: a time-dependent Cox regression analysis in a large cohort study.

OBJECTIVE: Systemic inflammation appears to contribute to the excess risk of cardiovascular disease (CVD) in rheumatoid arthritis (RA). The objective of this study was to investigate the effect of different levels of disease activity over time, particularly low disease activity and remission, on CVD risk in patients with RA. METHODS: Data from the Nijmegen early RA inception cohort were used. The primary outcome was first CVD events within the first 10 years of follow-up. Cut points of the DAS28 for remission (<2.6) and low (≤3.2), moderate (3.2-5.1) and high (>5.1) disease activity were used. The effect of disease activity on CVD risk was analysed using Cox-proportional hazards regression with DAS28 as a time-dependent covariate and also conventionally with time-averaged DAS28 as the primary dependent variable. RESULTS: Low DAS28 (≤3.2) was significantly associated with a reduced risk of CVD (HR 0.65, 95% CI 0.43 to 0.99) compared with DAS28 >3.2, both when included as a time-dependent covariate and as time-averaged DAS28 ≤3.2 (HR 0.52, 95% CI 0.33 to 0.81). Remission had a modest, non-significant protective effect against CVD (HR 0.67, 95% CI 0.43 to 1.07). CONCLUSION: Results of this study suggest that low disease activity is sufficient to achieve a protective effect against CVD in RA. Apparently, remission defined as DAS28 <2.6 has no additional protective effect against CVD compared with low disease activity. Our results strengthen the use of tight control strategies in daily clinical practice to achieve low stable disease activity or remission in patients with RA as soon as possible.

The effect of disease duration and disease activity on the risk of cardiovascular disease in rheumatoid arthritis patients.

OBJECTIVE: Disease duration and disease activity may be associated with an increased risk of cardiovascular disease (CVD) in rheumatoid arthritis (RA). The objectives of this study were to investigate (1) the relationship between duration of inflammation and the development of CVD in RA patients and (2) the relationship between RA disease activity over time and CVD in patients with RA. METHODS: RA patients with a follow-up of ≥6 months in the Nijmegen early RA cohort without prior CVD were included. Disease activity over time was calculated using the time-averaged  28 joint disease activity score (DAS28) for each patient. Kaplan-Meier survival analysis and Cox proportional hazards regression were used for the analyses. RESULTS: During follow-up of the 855 patients that were included, 154 CV events occurred. The course of hazards over time did not indicate a change in the risk of CVD over the course of RA (disease duration), which is also reflected by the absence of a deflection in the survival curves. The survival distributions did not differ between patients with a disease duration of <10 years or >10 years (Log-rank test: p=0.82). Time-averaged DAS28 was significantly associated with CVD (p=0.002) after correction for confounders. CONCLUSIONS: Disease duration does not appear to independently affect the risk of CVD. The risk of CVD in RA patients was not increased after 10 years of disease duration compared with the first 10 years. Disease activity over time may contribute to the risk of CVD.

Intramuscular methylprednisolone administration in hand osteoarthritis patients: a feasibility study to inform a randomized controlled trial.

Background: Inflammation is thought to play an important role in hand osteoarthritis (HOA), which is associated with pain and increased limitation of hand function. Objectives: To explore the acceptability of therapy with intramuscular methylprednisolone in HOA among health-care providers (HCPs) and HOA patients. Additionally, the response to a single methylprednisolone injection was investigated. Design: We adopted a mixed-methods design. Methods: In a qualitative study, we asked HCPs and patients for their acceptability of intramuscular methylprednisolone. A prospective observational study was performed afterward in HOA patients who received a single 120-mg intramuscular methylprednisolone injection as part of off-label administration. Average pain, functional impairment, and occurrence of adverse events were assessed at baseline and at 4, 8, and 12 weeks after the injection. Results: Fourteen HCPs and 15 patients participated in the first part of the study. They considered intramuscular methylprednisolone potentially effective, yet expressed concerns about the risk for long-term adverse events. Among the 22 HOA patients who received intramuscular methylprednisolone, 13 patients reported 44 adverse events, with half of them occurring within the first 4 weeks after injection and being classified as nonserious. Mean hand pain decreased the most 4 weeks after injection and this effect persisted till week 12, though less pronounced. Similar results were seen with HOA-related functional impairment, which improved the most at week 4 and to a lesser extent at week 12. Conclusion: We found a good acceptability of intramuscular methylprednisolone treatment among HCPs and HOA patients, as well as a potential to reduce pain and improve hand function with a good safety profile for as long as 12 weeks after a single administration.

Use of methylprednisolone in the muscle for hand osteoarthritis patients: a feasibility study to inform a randomized controlled trial Hand osteoarthritis is very common among adults and older people, and being characterized by high levels of pain, stiffness and decreased function of the hand. Therapeutic options for hand osteoarthritis are limited. Methylprednisolone is sometimes used in clinical practice with good results. However, these results are mainly based on the experience of the physicians and do not rely on properly performed studies. That is why we intend to finally perform such a study. But before starting that, we wanted to see if patients with hand osteoarthritis and healthcare providers would accept the idea of injecting methylprednisolone into the buttocks muscle for the treatment of hand osteoarthritis. That is why we performed interviews with patients and healthcare providers, which brought up six factors to think about when discussing this therapeutic option: how well it works, how safe it is, the overall situation of the patient, how it's given, use of shared decision-making and logistics aspects. Next to this, we examined the effect of methylprednisolone over time on pain and function of the hands, as well as the frequency and nature of side effects. We found a decrease in hand pain and an improvement in hand function persisting for 12 weeks after just one methylprednisolone injection. Half of the patients reported side effects, but they all were non-serious. Eventually, we concluded that the use of methylprednisolone as an injection in the buttocks muscle for the treatment of hand osteoarthritis is accepted by both patients and health-care providers, and could be a safe and helpful therapy. The results will be used in the next study designed to assess the effect and safety of this therapy in a much larger group of patients with hand osteoarthritis.

Does Adding Single-Nucleotide Polymorphisms to Risk Algorithms Improve Cardiovascular Disease Risk Prediction in Rheumatoid Arthritis? An Internal and External Validation of a Clinical Risk Score.

OBJECTIVE: Current risk algorithms do not accurately predict cardiovascular disease (CVD) risk in rheumatoid arthritis (RA). An area of interest is that of single-nucleotide polymorphisms (SNPs), of which several have been associated with CVD in the general population. We investigated whether these SNPs are associated with CVD in RA and whether SNPs could improve CVD risk prediction in RA. METHODS: Sixty SNPs were genotyped in 353 patients with RA. Logistic and Cox regression analyses were performed to identify SNPs that were associated with CVD (n = 99). A prediction model with clinical variables was made. SNPs were added to investigate the additional predictive value. Both models were internally validated. External validation was done in a separate cohort (n = 297). RESULTS: rs3184504, rs4773144, rs12190287, and rs445925 were significantly associated with new CVD. The clinical prediction model consisted of age, sex, body mass index, systolic blood pressure, high-density lipoprotein cholesterol (HDLc), and creatinine, with an area under the curve (AUC) of 0.74 (P = 0.03). Internal validation resulted in an AUC of 0.76 (P < 0.01). A new model was made including SNPs and resulted in a model with rs17011666 and rs801426, age, total cholesterol, and HDLc, which performed slightly better with an AUC of 0.77 (P < 0.01). External validation resulted in a good fit for the clinical model, but a poor fit for the SNP model. CONCLUSION: Several SNPs were associated with CVD in RA. Risk prediction slightly improved after adding SNPs to the models, but the clinical relevance is debatable. However, larger studies are needed to determine more accurately the additional value of these SNPs to CVD risk prediction algorithms.

Towards a role of interleukin-32 in atherosclerosis.

BACKGROUND: IL-32 has been previously shown to promote inflammation in rheumatoid arthritis patients and to contribute to IL-1ß-induced ICAM-1 as well as other proinflammatory cytokines synthesis in human umbilical endothelial cells (HUVECs). Given the high rate of atherosclerosis in RA, these observations suggest that IL-32 may be involved in the inflammatory pathways of atherosclerosis. METHODS: mRNA and protein levels of IL-32 were determined in human atherosclerotic arterial vessel wall tissue by quantitative real-time PCR and immunohistochemistry. HUVEC and M1/M2 macrophages were stimulated with proinflammatory cytokines and TLR ligands to assess IL-32 mRNA induction. Human THP1 macrophages were transduced with AdIL-32γ, to investigate induction of several proatherosclerotic mediators. Finally, aortas from IL-32γ transgenic mice were studied and compared with aortas from age-matched wild-type mice. RESULTS: IL-32 expression was detectable in human atherosclerotic arterial vessel wall, with the expression of IL-32ß and IL-32γ mRNA significantly enhanced. TLR3-ligand Poly I:C in combination with IFNγ were the most potent inducers of IL-32 mRNA expression in both HUVEC and M1/M2 macrophages. Adenoviral overexpression of IL-32γ in human THP1 macrophages resulted in increased production of CCL2, sVCAM-1, MMP1, MMP9, and MMP13. The IL-32γ transgenic mice chow a normal fat diet exhibited vascular abnormalities resembling atherosclerosis. CONCLUSIONS: IL-32 acts as a proinflammatory factor and may be implicated in the inflammatory cascade contributing to atherosclerosis. By promoting the synthesis of matrix metalloproteinases, it may further contribute to plaque instability. Further studies are warranted to investigate whether IL-32 may serve as a potential therapeutic target in fighting atherosclerosis.

Day-to-day fluctuations of fatigue severity in individuals with knee osteoarthritis: an ecological momentary assessment approach.

Objective: The variable course of fatigue adds to the disease burden of patients with OA yet it has been poorly understood. This study aimed to describe within-person fluctuations of fatigue severity and explore its associations with pain, positive affect, negative affect, sleep, and perceived exertion of physical activity. Methods: Individuals with chronic knee pain or a clinical diagnosis of knee OA ≥40 years of age completed daily assessments about fatigue, pain, positive affect, negative affect, sleep, perceived exertion of physical activity (numeric rating scale 0-10), and overwhelming fatigue (yes/no) on a smartphone over 14 days. Within-person fluctuations of fatigue severity were described by the probability of acute changes (PACs) and s.d.s. Associations with pain, positive affect, negative affect, sleep, and perceived exertion of physical activity were explored using multilevel models. Results: Forty-nine individuals were included (mean age 63.4 years; 82% female). PACs and s.d.s of within-person daily fatigue fluctuations ranged from 0.00 to 0.80 and 0.35 to 2.95, respectively. Within-person associations of fatigue severity were moderate for positive affect [ß = -0.57 (95% CI -0.67, -0.47)], weak for pain [ß = 0.41 (95% CI 0.29, 0.53)] and negative affect [ß = 0.40 (95% CI 0.21, 0.58)], and negligible for sleep [ß = -0.13 (95% CI -0.18, -0.08)] and perceived exertion of physical activity [ß = 0.18 (95% CI 0.09, 0.26)]. Conclusion: Some individuals showed almost stable day-to-day levels of fatigue severity, whereas others experienced a substantial number of clinically relevant fluctuations. To reduce the burden of daily fatigue fluctuations, our results suggest that pain, positive and negative affect rather than sleep and perceived exertion of physical activity should be considered as potential targets.

Atherogenic index and high-density lipoprotein cholesterol as cardiovascular risk determinants in rheumatoid arthritis: the impact of therapy with biologicals.

Cardiovascular (CV) diseases are a serious concern in rheumatoid arthritis (RA), accounting for approximately one-third to one-half of all RA-related deaths. Besides the attempts to identify new risk factors, the proper management of traditional CV risk factors such as dyslipidemia should become a priority in the periodic evaluation of every RA patient. Atherogenic index has been suggested to be less susceptible to disease activity variation during large periods of time, making him more attractive to be used in CV risk prediction in this group of patients as compared to individual lipids concentrations. Nevertheless, inflammation may negatively impact HDL antiatherogenic properties, suggesting that HDL function assessment is of particular importance when predicting CV risk in these patients. A tight control of inflammation becomes therefore crucial for a successful CV risk management. The present paper debates these hypotheses focusing on the effects of therapy with biologicals on the above mentioned parameters.

Safety of JAK inhibitors: focus on cardiovascular and thromboembolic events.

INTRODUCTION: To date, four Janus kinase inhibitors (JAKis) are licensed for the treatment of rheumatoid arthritis (RA) and/or psoriatic arthritis (PsA) in North America and/or Europe: tofacitinib, baricitinib, upadacitinib, and filgotinib. Most DMARDs have cardioprotective potential, yet for some of them, including JAKi, the modulatory effect on cardiovascular risk remains undetermined. Since their commercialization, the risk of venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE) is taking on a relevant role in RA patients. AREAS COVERED: In this article, we will review the effect of JAKi on CV risk and atherosclerosis process as major contributor to MACE. Furthermore, we will present the effect of JAKi on thromboembolic risk. EXPERT OPINION: Although the effect of JAKi on CV and thrombosis is one of the most relevant topic regarding RA patients, it is necessary to underline that these patients have an increased risk of these comorbidities due to the inflammation process, and further study are needed in order to understand the real role of JAKi in controlling or inducing these complications.

Diagnostic parameters of cellular tests for Lyme borreliosis in Europe (VICTORY study): a case-control study.

BACKGROUND: Cellular tests for Lyme borreliosis might be able to overcome major shortcomings of serological testing, such as its low sensitivity in early stages of infection. Therefore, we aimed to assess the sensitivity and specificity of three cellular tests. METHODS: This was a nationwide, prospective, multiple-gate case-control study done in the Netherlands. Patients with physician-confirmed Lyme borreliosis, either early localised or disseminated, were consecutively included as cases at the start of antibiotic treatment. Controls were those without Lyme borreliosis from the general population (healthy controls) and those with potentially cross-reactive conditions (eg, autoimmune disease). We used three cellular tests for Lyme borreliosis (Spirofind Revised, iSpot Lyme, and LTT-MELISA) as index tests, and standard two-tier serological testing (STTT) as a comparator. Clinical data from Lyme borreliosis patients were collected at baseline and at 12 weeks after inclusion, and blood samples were obtained at baseline, 6 weeks, and 12 weeks. Control participants underwent clinical and laboratory assessments at baseline only. FINDINGS: Cases comprised 271 patients with Lyme borreliosis (of whom 245 had early-localised Lyme borreliosis and 26 had disseminated disease) and controls comprised 228 participants without Lyme borreliosis from the general population and 41 participants with potentially cross-reactive conditions. Recruitment occurred between May 14, 2018, and March 16, 2020. The specificity of STTT in healthy controls (216 of 228 samples [94·7%, 95% CI 91·5-97·7]) was higher than that of the cellular tests: Spirofind (140 of 171 [81·9%, 76·1-87·2]), iSpot Lyme (32 of 103 [31·1%, 21·5-40·3]) and LTT-MELISA (100 of 190 [52·6%, 44·9-60·3]). Cellular tests had varying sensitivities: Spirofind (88 of 204 [43·1%, 36·4-50·4]), iSpot Lyme (51 of 94 [54·3%, 44·5-63·7]), and LTT-MELISA (66 of 218 [30·3%, 23·8-36·7]). The Spirofind and iSpot Lyme outperformed STTT for sensitivity, but were similar to the C6-ELISA (C6-ELISA: 135 of 270 [50·0%, 44·5-55·5]; STTT: 76 of 270 [28·1%, 23·0-33·6]). INTERPRETATION: The cellular tests for Lyme borreliosis used in this study have a low specificity compared with serological tests, which leads to a high number of false-positive test results. We conclude that these cellular tests are unfit for clinical use at this stage. FUNDING: Netherlands Organization for Health Research and Development, AMC Foundation (Amsterdam UMC), and Ministry of Health of the Netherlands.

Cardiovascular effects of approved drugs for rheumatoid arthritis.

The risk of cardiovascular disease is increased in patients with rheumatoid arthritis compared with the general population owing to the influence of traditional and non-traditional risk factors. Inflammation has a pivotal contribution and can accelerate the atherosclerotic process. Although dampening inflammation with DMARDs should theoretically abrogate this process, evidence suggests that these drugs can also promote atherosclerosis directly and indirectly, hence adding to an increased cardiovascular burden. However, the extent and direction of the effects largely differ across drugs. Understanding how these drugs influence endothelial damage and vascular repair mechanisms is key to understanding these outcomes. NSAIDs and glucocorticoids can increase the cardiovascular risk. Conversely, conventional, biologic and targeted DMARDs control inflammation and reduce this risk, although some of these drugs can also aggravate traditional factors or thrombotic events. Given these data, the fundamental objective for clinicians should be disease control, in an individualized approach that considers the most appropriate drug for each patient, taking into account joint and cardiovascular outcomes. This Review provides a comprehensive analysis of the effects of DMARDs and other approved drugs on cardiovascular involvement in rheumatoid arthritis, from a clinical and mechanistic perspective, with a roadmap to inform the research agenda.

Angiotensin-Inhibiting Drugs Do Not Impact Disease Activity in Patients with Rheumatoid Arthritis: A Retrospective Cross-Sectional Study.

OBJECTIVES: Besides their proven effectivity in decreasing the risk of cardiovascular events, angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II type 1 receptor blockers (ARBs) are likely to possess anti-inflammatory properties as well. This study aims to investigate whether the use of ACEi and ARBs additionally lowers disease activity in patients with rheumatoid arthritis (RA). METHODS: In this cross-sectional study, we used ARBs or ACEi to study RA patients who had at least one DAS28-CRP measurement during a one-year period. A control group of RA patients without ACEi/ARBs was randomly selected. The primary outcome was the difference between the DAS28-CRP scores of ACEi/ARBs users and controls. The secondary outcomes were the differences between administered dosages of csDMARDs and bDMARDs for users and controls, respectively; these were expressed in defined daily dose (DDD). Confounders were included in the multiple regression analyses. RESULTS: A total of 584 ACEi/ARBs users and 552 controls were finally examined. Multiple linear regression analyses showed no association between the use of ACEi or ARBs and the DAS28-CRP scores (ACEi factor 1.00, 95% CI 0.94-1.06; ARBs 1.02, 95% CI 0.96-1.09), nor with the dosage of csDMARDs (ACEi 0.97, 95% CI 0.89-1.07; ARBs 0.99, 95% CI 0.90-1.10). Furthermore, the use of ACEi was not associated with reduced dosages of bDMARDs (OR 1.14, 95% CI 0.79-1.64), whereas ARBs users tended to use less bDMARDs (1.46, 95% CI 0.98-2.18, p = 0.06). CONCLUSION: In this study, the use of either ACEi or ARBs in RA patients had no impact on disease activity as measured by the DAS28-CRP. A trend towards lower bDMARD dosages was observed in ARBs users, but the significance of this finding is still unclear.

Atorvastatin is unlikely to prevent rheumatoid arthritis in high risk individuals: results from the prematurely stopped STAtins to Prevent Rheumatoid Arthritis (STAPRA) trial.

OBJECTIVES: Persons at high risk of rheumatoid arthritis (RA) might benefit from a low-risk pharmacological intervention aimed at primary prevention. Previous studies demonstrated disease-modifying effects of statins in patients with RA as well as an association between statin use and a decreased risk of RA development. A randomised, double-blind, placebo-controlled trial investigated whether atorvastatin could prevent arthritis development in high-risk individuals. METHODS: Arthralgia patients with anticitrullinated protein antibody (ACPA) >3 xULN or ACPA and rheumatoid factor, without (a history of) arthritis, were randomised to receive atorvastatin 40 mg daily or placebo for 3 years. The calculated sample size was 220 participants. The primary endpoint was clinical arthritis. Cox regression analysis was used to determine the effect of atorvastatin on arthritis development. RESULTS: Due to a low inclusion rate, mainly because of an unwillingness to participate, the trial was prematurely stopped. Data of the 62 randomised individuals were analysed. Median follow-up was 14 (inner quartiles 6-35) months. Fifteen individuals (24%) developed arthritis: 9/31 (29%) in the atorvastatin group; 6/31 (19%) in the placebo group: HR 1.40, 95% CI 0.50 to 3.95. CONCLUSIONS: In this small set of randomised high-risk individuals, we did not demonstrate a protective effect of atorvastatin on arthritis development. The main reason for the low inclusion was unwillingness to participate; this may also impede other RA prevention trials. Further research to investigate and solve barriers for prevention trial participation is needed.

Younger age and female gender are determinants of underestimated cardiovascular risk in rheumatoid arthritis patients: a prospective cohort study.

BACKGROUND: Rheumatoid arthritis (RA) patients have an increased cardiovascular (CV) risk. Here, we aimed to investigate whether gender and age are contributing to the misclassification of CV risk in RA patients. METHODS: Prospectively collected data on cardiovascular risk factors and incident events from the Nijmegen inception cohort were analyzed, with up to 10 years follow-up. Original as well as the EULAR-modified (M)_SCORE algorithms were used to calculate CV risk. Patients were stratified in deciles according to predicted risk; the Hosmer-Lemeshow test was used to check concordance between observed and predicted risk, in subgroups of gender and age. RESULTS: There were 863 RA patients included with 128 incident CV events. When using SCORE in the whole group, there was evidence of a discrepancy between the predicted and observed CV risk (H-L test p < 0.003), mainly present in the female subgroup (H-L test p < 0.001). Interestingly, 36% of females who developed an event belonged to the low CV risk group, whereas this was just 10% in RA males. When analyzing the subgroups based on age, a discrepancy was present only in the youngest patients (H-L test p < 0.001 in patients < 55 years) consisting of an underestimation of CV risk (5.3% predicted vs. 8.0% observed). Similar results were obtained when the M_SCORE was applied. CONCLUSION: CV risk is especially underestimated in female and younger RA patients. This suggests that modifying the weight for the female gender and/or younger age in currently used CV risk algorithms might improve their predictive value in RA, contributing to better CV risk management.