Male rheumatoid arthritis patients at substantially higher risk for cardiovascular mortality in comparison to women.

BACKGROUND: Patients with rheumatoid arthritis (RA) are at an increased risk for developing cardiovascular diseases. While advice regarding cardiovascular risk screening and management in RA patients has been incorporated in several guidelines in recent years, its implementation and adherence is still poor. OBJECTIVES: To assess the cardiovascular disease risk in new diagnosed RA patients and evaluate whether advice to initiate preventive medical treatment of high risk patients was followed. METHODS: All patients with a recent diagnosis of RA, aged 40-70 years, were screened between May 2019 and December 2022 for cardiovascular diseases and risk factors within the first year after diagnosis at the outpatient rheumatology clinic, as part of standard care. Screening included a physical examination with blood pressure measurement, and laboratory tests with lipid profile tests. All patients and their general practitioner (GP) received an overview with their cardiovascular risk profile and a calculated 10-year cardiovascular mortality risk. Cardiovascular risk was defined as low (<1%), intermediate (1-5%), high (5-10%) and very high (>10%). The national pharmacy network was consulted to check whether or not patients started preventive medication after screening. RESULTS: A total of 125 RA patients was included in this study. The mean age was 56 years and 78% was female. Median RA disease duration at screening was 6 months. Six patients (5%) indicated to have been screened before, and used antihypertensive medication. During screening, hypertension was found in 57% of male patients and 43% of female patients and dyslipidemia was found in 36% in male and 32% in female patients. 46% of male patients and 21% of female patients currently smoked. A high or very high 10-year cardiovascular mortality risk was found in 50% of male patients, but in only 4% of female patients. Only 26% of (very) high risk patients started antihypertensive or statin medication after screening. CONCLUSIONS: An increased cardiovascular disease risk is often present in newly diagnosed RA patients, especially male patients, with a large proportion having undiagnosed and untreated hypertension and hypercholesterolemia. Even with structural screening and informing of the patients and GPs, treatment of cardiovascular risk factors in high risk patients remains insufficient. CV risk screening needs to be part of standard care for RA patients, with clear agreement on the responsibilities between primary and secondary care. Awareness of the importance of CVD risk screening needs to improve among both RA patients themselves and the GPs to ultimately reduce the cardiovascular burden of our patients. Obviously, a better collaboration between GPs and rheumatologists is urgently needed to lower the cardiovascular burden of our patients.

Adherence to etanercept therapy in rheumatoid arthritis patients during 3 years of follow-up.

OBJECTIVES: To determine the percentage non-adherence to etanercept in patients with rheumatoid arthritis during three years of follow-up. METHODS: During study visits in this prospective cohort study, blood samples were taken to determine serum etanercept concentrations using ELISA and patients were asked if they had missed an etanercept dose, at which date and for what reason. Non-adherence was defined as serum etanercept concentration <0.1 µg/mL and no valid reason to miss the prescribed etanercept dose. RESULTS: In total, 292 consecutive patients treated with etanercept were included. Most patients had a valid reason to miss their etanercept dose (25/37). In total 12 out of 292 patients (4.1%, 95% confidence interval 2.2-7.2) were non-adherent during the 3 year period. In a small percentage of patients (3.4%, 95% confidence interval 0.8-10.4) who failed to respond to etanercept therapy, according to their rheumatologist, this was associated with inadequate exposure to etanercept and thus non-adherence. CONCLUSION: In this study, adherence to etanercept therapy was measured using serum etanercept concentration. In most patients an absent etanercept concentration was due to a medical reason. Furthermore, the majority of patients were adherent to etanercept therapy and had adequate drug exposure. In total, only 12 out of 292 patients (4.1%) were non-adherent during 3 years of follow-up. These findings highlight that only a small minority of patients are non-adherent to etanercept treatment, especially compared to adherence rates of other drugs. However, physicians should be aware that in patients failing to respond to treatment, non-adherence is a possible cause.

TWEAK and its receptor Fn14 in the synovium of patients with rheumatoid arthritis compared to psoriatic arthritis and its response to tumour necrosis factor blockade.

OBJECTIVE: To investigate the expression of tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor inducible 14 (Fn14) in the inflamed synovium of patients with arthritis, as TWEAK blockade has been observed to have a beneficial effect in an animal model of rheumatoid arthritis (RA). METHODS: Synovial tissue (ST) biopsies were obtained from 6 early, methotrexate-naive patients with RA as well as 13 patients with RA and 16 patients with psoriatic arthritis (PsA) who were matched for treatment and disease duration. Serial ST samples were obtained from a separate cohort of 13 patients with RA before and after infliximab treatment. TWEAK and Fn14 expression was evaluated by immunohistochemistry and digital image analysis. RESULTS: TWEAK and Fn14 were clearly expressed in ST of patients with RA and PsA. TWEAK expression was significantly higher in RA (sub)lining samples compared to PsA (p = 0.005 and p = 0.014, respectively), but Fn14 expression was comparable. Double immunofluorescence showed TWEAK and Fn14 expression on fibroblast-like synoviocytes and macrophages, but not T cells. Of interest, persistent TWEAK and Fn14 expression was found after anti-TNF therapy. CONCLUSIONS: TWEAK and Fn14 are abundantly expressed in the inflamed synovium of patients with RA and PsA. This raises the possibility that blocking TWEAK/Fn14 signalling could be of therapeutic benefit in inflammatory arthritis.

A prospective, randomised, placebo-controlled study to identify biomarkers associated with active treatment in psoriatic arthritis: effects of adalimumab treatment on synovial tissue.

OBJECTIVE: To determine which of the changes in synovial tissue correlates best with clinical response associated with effective therapy (adalimumab) to facilitate the planning of future studies with therapeutic agents for psoriatic arthritis (PsA). METHODS: A total of 24 patients with active PsA were randomised to receive adalimumab (n = 12) or placebo (n = 12) for 4 weeks. Synovial biopsies were obtained before and after 4 weeks of treatment. Immunohistochemical analysis was performed to characterise the cell infiltrate, expression of cytokines and matrix metalloproteinases (MMPs) and vascularity. Sections were analysed by digital image analysis. Statistical analysis was performed using covariance analysis. RESULTS: The mean Disease Activity Score in 28 joints (DAS28) after 4 weeks was 1.92 units lower (95% confidence interval (CI) 1.07 to 2.77) after adalimumab therapy compared with placebo. Paired pretreatment and post-treatment synovial samples were available from 19 patients. Many cell types were reduced after adalimumab treatment compared to placebo. After applying a ranked analysis of covariance (ANCOVA) model to correct for baseline imbalances, a significant effect of treatment was observed on CD3-positive cells: there was a median reduction of 248 cells/mm(2) after adalimumab versus placebo treatment (p = 0.035). In addition, the expression of MMP13 was significantly reduced after active treatment: the integrated optical density (IOD)/mm(2) was 18 190 lower after adalimumab treatment as compared to placebo (p = 0.033). CONCLUSION: Adalimumab therapy in PsA is associated with a marked reduction in T cell infiltration and MMP13 expression in synovial tissue, suggesting that these parameters could be used as biomarkers that are sensitive to change after active treatment in small proof of concept studies in PsA.

[Arthritis psoriatica]. / Arthritis psoriatica.

The symptoms ofpsoriatic arthritis vary from arthralgia and enthesitis to chronic erosive and mutilating arthritis, and are seen in 6-39% of all psoriasis patients. Because of increasing awareness of the clinical signs of psoriatic arthritis among both dermatologists and rheumatologists, the diagnosis ofpsoriatic arthritis is made more often; this is important since earlier diagnosis and treatment can avoid irreversible joint destruction. The overlap between the immunological mechanisms in the pathogenesis ofpsoriasis and psoriatic arthritis has led to the identification of common therapeutic targets, of which tumour-necrosis factor (TNF) is the most important. The successful treatment of psoriasis patients with TNF-a-blocking agents has not only brought about a marked improvement in the quality of life of many patients but has also improved the insight into the pathogenesis, for example by demonstrating that the role of acquired immunity is much more important than was previously thought. The Dutch Society of Dermatology and Venereology and the Dutch Society of Rheumatology have drawn up guidelines for the treatment of patients with psoriasis and psoriatic arthritis using these so-called biologics.

Detailed analysis of the cell infiltrate and the expression of mediators of synovial inflammation and joint destruction in the synovium of patients with psoriatic arthritis: implications for treatment.

BACKGROUND: The synovial tissue is a primary target of many inflammatory arthropathies, including psoriatic arthritis (PsA). Identification of proinflammatory molecules in the synovium may help to identify potentially therapeutic targets. OBJECTIVE: To investigate extensively the features of cell infiltration and expression of mediators of inflammation and joint destruction in the synovium of patients with PsA compared with patients with rheumatoid arthritis matched for disease duration and use of drugs. METHODS: Multiple synovial tissue biopsy specimens were obtained by arthroscopy from an inflamed joint in 19 patients with PsA (eight oligoarthritis, 11 polyarthritis) and 24 patients with rheumatoid arthritis. Biopsy specimens were analysed by immunohistochemistry to detect T cells, plasma cells, fibroblast-like synoviocytes, macrophages, proinflammatory cytokines, matrix metalloproteinases and tissue inhibitor metalloproteinase-1, adhesion molecules and vascular markers. Stained sections were evaluated by digital image analysis. RESULTS: The synovial infiltrate of patients with PsA and rheumatoid arthritis was comparable with regard to numbers of fibroblast-like synoviocytes and macrophages. T cell numbers were considerably lower in the synovium of patients with PsA. The number of plasma cells also tended to be lower in PsA. The expression of tumour necrosis factor alpha (TNFalpha), interleukin (IL) 1beta, IL6 and IL18 was as high in PsA as in rheumatoid arthritis. The expression of matrix metalloproteinases, adhesion molecules and vascular markers was comparable for PsA and rheumatoid arthritis. CONCLUSION: These data show increased proinflammatory cytokine expression in PsA synovium, comparable to results obtained for rheumatoid arthritis, and support the notion that, in addition to TNFalpha blockade, there may be a rationale for treatments directed at IL1beta, IL6 and IL18.

A randomised, double blind, placebo controlled, multicentre trial of combination therapy with methotrexate plus ciclosporin in patients with active psoriatic arthritis.

OBJECTIVES: To evaluate the safety and efficacy of adding ciclosporin A (CSA) to the treatment of patients with psoriatic arthritis (PsA) demonstrating an incomplete response to methotrexate (MTX) monotherapy. METHODS: In a 12 month, randomised, double blind, placebo controlled trial at five centres in three countries, 72 patients with active PsA with an incomplete response to MTX were randomised to receive either CSA (n = 38) or placebo (n = 34). Patients underwent full clinical and radiological assessment and, in addition, high resolution ultrasound (HRUS) was performed at one centre. An intention to treat (last observation carried forward) analysis was employed. RESULTS: Some significant improvements were noted at 12 months in both groups. However, in the active but not the placebo arm there were significant improvements in swollen joint count, mean (SD), from 11.7 (9.7) to 6.7 (6.5) (p<0.001) and C reactive protein, from 17.4 (14.5) to 12.7 (14.3) mg/l (p<0.05) as compared with baseline. The Psoriasis Area and Severity Index (PASI) score improved in the active group (2 (2.3) to 0.8 (1.3)) as compared with placebo (2.2 (2.7) to 1.9 (2.8)), p<0.001, and synovitis detected by HRUS (33 patients, 285 joints) was reduced by 33% in the active group compared with 6% in the placebo group (p<0.05). No improvement in Health Assessment Questionnaire or pain scores was detected. CONCLUSIONS: Synovitis detected by HRUS was significantly reduced. Combining CSA and MTX treatment in patients with active PsA, and a partial response to MTX, significantly improves the signs of inflammation but not pain or quality of life.