Non-Invasive Assessment of Micro- and Macrovascular Function after Initiation of JAK Inhibitors in Patients with Rheumatoid Arthritis.

BACKGROUND: Janus kinase (JAK) inhibitors constitute a novel class of oral biologic disease-modifying antirheumatic drugs for patients with rheumatoid arthritis (RA). However, their use has been associated with increased risk of major cardiovascular events. We investigated whether treatment with JAK inhibitors exerts significant alterations in the micro- and microvasculature in RA patients. METHODS: Thirteen patients with RA initiating treatment with JAK inhibitors were prospectively studied. Eventually, data from 11 patients who completed the study were analyzed. Procedures were performed at baseline and 3 months after treatment. Nailfold videocapillaroscopy was applied to detect alterations of the dermal capillary network. Participants underwent 24 h ambulatory blood pressure monitoring (Mobil-O-Graph device) for the assessment of blood pressure (both brachial and aortic) and markers of large artery stiffening [pulse wave velocity (PWV), augmentation index] throughout the whole 24 h and the respective day- and nighttime periods. Carotid intima-media thickness was assessed with ultrasound. RESULTS: Three-month treatment with JAK inhibitors was not associated with any differences in brachial and aortic blood pressure, arterial stiffness, and carotid atherosclerosis, with the only exception of nighttime PWV, which was significantly elevated at follow-up. However, three-month treatment with JAK inhibitors induced significant microvascular alterations and increased the total number of capillaroscopic abnormalities. CONCLUSIONS: Three-month treatment with JAK inhibitors may exert significant effects on microcirculation as assessed with nailfold videocapillaroscopy, whereas macrovascular structure and function appears largely unaffected. Further research toward this direction may add substantial information to the available literature regarding cardiovascular aspects of JAK inhibitors in RA.

Circulating levels of galectin-3 and coronary microvascular perfusion in rheumatoid arthritis patients with suppressed inflammation.

OBJECTIVE: Cardiovascular manifestations are the leading cause of mortality in rheumatoid arthritis (RA). Galectin-3, a lectin protein with major role in cellular, inflammatory, and fibrotic processes, has been introduced as a novel cardiac biomarker. We hypothesized that patients with RA present increased levels of galectin-3, and investigated potential associations with arterial stiffness and coronary microvascular dysfunction. METHODS: This cross-sectional study enrolled RA patients and non-RA individuals without cardiovascular comorbidities. Galectin-3 and high-sensitivity C-reactive protein (hsCRP) were measured with enzyme-linked immunosorbent assay (ELISA) in serum samples. Subendocardial viability ratio (SEVR), an index of microvascular myocardial perfusion, and pulse wave velocity (PWV), the gold-standard measure of vascular stiffness, were estimated with applanation tonometry. RESULTS: Cardiovascular risk factors and hsCRP were comparable between patients (n = 24) and controls (n = 24). However, galectin-3 was increased [6.9 (6.7) vs 4.6 (4.7)] ng/dl, p = 0.015], and coronary microvascular perfusion was decreased (142.6 ± 22.8 vs 159.7 ± 23.2%, p = 0.028) in RA patients compared to controls, whereas PWV did not significantly differ. Galectin-3 correlated with both PWV and SEVR in univariate analysis. However, after adjustment for cardiovascular risk factors and subclinical inflammation, these associations were rendered non-significant. CONCLUSION: Galectin-3 appears increased in RA, even among patients with suppressed inflammation in the absence of cardiovascular comorbidities. The observed association of galectin-3 with coronary microvascular perfusion in our study was non-significant after adjustment for cardiovascular risk factors and inflammation. The potential role of galectin-3 as a cardiac biomarker in RA warrants further investigation. Key Points • Galectin-3 has emerged as a novel cardiac biomarker but remains understudied in RA. • Patients with RA present elevated levels of galectin-3 and impaired coronary microvascular perfusion compared to non-RA individuals. • These differences were observed in patients with suppressed inflammation, even in the absence of CVD. • The association of galectin-3 with coronary microvascular impairment in RA warrants further investigation.

Peripheral nailfold capillary microscopic abnormalities in rheumatoid arthritis are associated with arterial stiffness: Results from a cross-sectional study.

Vascular injury eventually resulting in the establishment of cardiovascular disease is a serious complication in rheumatoid arthritis (RA). Nailfold videocapillaroscopy (NVC) is a non-invasive imaging modality that enables the quantitative and qualitative assessment of the peripheral microvasculature. Nevertheless, capillaroscopic patterns remain inadequately defined in RA, especially regarding their clinical significance as potential markers of systemic vascular impairment. Consecutive RA patients underwent NVC using a standardized protocol, to assess the following parameters: capillary density, avascular areas, capillary dimensions, microhemorrhages, subpapillary venous plexus, and presence of ramified, bushy, crossed and tortuous capillaries. Carotid-femoral pulse wave velocity (PWV) and pulse pressure were measured as well-acknowledged markers of large artery stiffening. The vast majority of our cohort (n = 44) presented a combination of non-specific and abnormal capillaroscopic parameters. Capillary ramification was associated with both PWV and pulse pressure, even after adjustment for cardiovascular risk factors and systemic inflammation. Our study highlights the high prevalence of a wide range of capillaroscopic deviations from the normal patterns in RA. Furthermore, it provides for the first time evidence of an association between structural disorders of the microcirculation and markers of macrovascular dysfunction, suggesting that NVC might have a role as an index of generalised vascular impairment in RA.

Study of Peripheral Microcirculation Assessed by Nailfold Video-Capillaroscopy and Association with Markers of Endothelial Dysfunction and Inflammation in Rheumatoid Arthritis.

Rheumatoid Arthritis (RA) is a chronic systemic autoimmune disease that primarily affects synovial joints and is associated with increased cardiovascular (CV) mortality and morbidity. This association is only partially attributed to the presence of classic CV disease risk factors, and is strongly associated with characteristics of disease itself namely systemic chronic inflammation and autoimmune activation. Growing evidence suggests that microvascular endothelial dysfunction contributes to the initiation and progression of vascular disease. Nailfold capillaroscopy is a non-invasive method that evaluates the morphology and the structure of nailfold capillaries. Extension of this method is the Nailfold Videocapillaroscopy (NVC), which provides the possibility of combining functional and anatomical study of peripheral microcirculation. The present cross-sectional study aims to evaluate using NVC the peripheral microcirculation in adult patients with RA and investigate the associations between structural and functional indices of digital capillaries with markers of atherosclerosis.

A rare case of POEMS syndrome presenting as essential thrombocythemia.

Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS) is a rare paraneoplastic syndrome, and its diagnosis is based on a series of clinical and laboratory findings. We present the case of a 46-year-old woman who was previously diagnosed with essential thrombocythemia. The patient complained about dyspnea on exertion, nausea, burning of the lower limbs, weight loss, recurrent episodes of lower back pain and polymenorrhea. Physical examination revealed hyperpigmentation, livedo reticularis of the lower limbs, sclerodermoid changes and plectrodactyly. A computed tomography-guided bone biopsy revealed the presence of plasmacytoma, and based on a combination of clinical features such as polyneuropathy, a diagnosis of POEMS syndrome has been established. The diagnosis of POEMS syndrome demands a high index of suspicion, especially in cases of peripheral neuropathy, peripheral edema or organomegaly of unknown origin. Since the syndrome can be fatal, early diagnosis is pivotal for patients' survival and quality of life.

Nailfold Videocapillaroscopy for the Evaluation of Peripheral Microangiopathy in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic and refractory autoimmune joint disease that affects multiple organs. Several methods have been applied for the study of microvascular endothelial dysfunction, which is considered an important component of vascular disease in RA. Implementation of nailfold videocapillaroscopy (NVC) represents a viable choice, as the skin is an easily accessible window for the non-invasive, real-time assessment of subtle microcirculation abnormalities. Although NVC is routinely used in the rheumatology field, especially for the diagnostic workout of Raynaud's phenomenon, accumulating evidence suggests a role in the evaluation of systemic vasculopathy associated with autoimmune rheumatic disorders. The current paper aims to provide an overview of NVC as a valuable clinical aid for the assessment of peripheral microcirculation in RA. Previous studies characterizing the capillaroscopic pattern in RA are summarized, along with associations with disease-related characteristics. Most available reports have mainly focused on the descriptions of non-specific morphological alterations that may reflect endothelial injury over the course of the disease. Still, the exact pattern of structural and functional capillaroscopic alterations and their clinical significance in RA remains a subject of ongoing research.

JAK Inhibition in Patients with Rheumatoid Arthritis: Haemodynamic Effects and Impact on Micro- and Macrovascular Function. Study Design and Rationale.

Rheumatoid arthritis (RA) is characterised by increased rates of cardiovascular disease (CVD), which represents the leading cause of death. Patients with RA presents increased prevalence of hypertension, which substantially contributes to the increased CVD burden associated with the disease. A solid pathophysiological background supports the presence of microvascular dysfunction in RA even in the absence of established CVD, while macrovascular dysfunction in the form of large artery stiffening has been further described. Janus kinase (JAK) inhibitors constitute a novel class of disease-modifying anti-rheumatic drugs (DMARDs) for the management of rheumatoid arthritis (RA). However, the vascular effects of JAK inhibitors in RA patients remain largely understudied. More recent evidence suggests higher risk of major adverse cardiovascular events with JAK inhibition compared to treatment with a TNF inhibitor, and calls for more careful consideration of potential negative effects on the cardiovascular system. The present prospective observational cohort study aims to investigate the impact of JAK inhibitors on ambulatory blood pressure and haemodynamic profile, as well as markers of micro- and macrovasculopathy among patients with RA.

Monitoring and Managing Cardiovascular Risk in Immune Mediated Inflammatory Diseases.

Cardiovascular disease (CVD) is common in immune-mediated inflammatory diseases (IMIDs) and it is predominately attributed to the interplay between chronic inflammation and traditional CVD risk factors. CVD has significant impact on the survival of patients with IMIDs as it is associated with increased morbidity and mortality. Despite recommendations for monitoring and managing CVD in patients with IMIDs, the individual CVD risk assessment remains problematic as CVD risk calculators for the general population consistently underestimate the risk in patients with IMIDs. Application of new technologies utilizing artificial intelligence techniques have shown promising potential for tailoring predictive medicine to the individual patient, but further validation of their role in clinical decision-making is warranted. In the meantime, individuals with IMIDs should be encouraged to adopt behavioral interventions targeting at modifiable lifestyle CVD risk factors, whereas rheumatologists need to be well aware of the unfavorable effects of antirheumatic medication on various CVD risk factors and outcomes. In the current paper, we aim to provide an overview of current and emerging strategies for mitigating CVD risk in patients with IMIDs, based on a practical approach.

The Effects of Nebivolol and Irbesartan on Ambulatory Aortic Blood Pressure and Arterial Stiffness in Hemodialysis Patients with Intradialytic Hypertension.

BACKGROUND: Intradialytic hypertension occurs in 5-15% of hemodialysis patients and is associated with increased cardiovascular risk, but the responsible mechanisms remain unknown. This study examined the effects of nebivolol and irbesartan on ambulatory central blood pressure (BP), arterial stiffness, and wave-reflection parameters in patients with intradialytic hypertension. METHODS: This is a prespecified analysis of a single-blind, randomized, cross-over study in 38 hemodialysis patients with intradialytic hypertension. Patients were randomized to nebivolol 5 mg followed byirbesartan 150 mg, or vice versa. In a non-randomized manner, the first half of the patients (n = 19) received a single drug dose 1 h prior to dialysis session and the remaining received the drugs for a whole week before the evaluation. Ambulatory central BP, arterial stiffness, and wave-reflection parameters were estimated with Mobil-O-Graph NG device, during a midweek dialysis day. RESULTS: Intake of a single dose of nebivolol or irbesartan resulted in lower postdialysis central systolic BP (c-SBP) (baseline: 140.9 ± 15.4; nebivolol: 130.3 ± 19.5, p = 0.009; irbesartan: 127.3 ± 24.4 mm Hg, p = 0.007). Single-dose nebivolol also produced marginally lower 24-h c-SBP (p = 0.064) and lower 24-h central diastolic BP (c-DBP) (p = 0.029). Weekly administration of both drugs reduced postdialysis c-SBP (baseline: 144.1 ± 15.3; nebivolol: 131.8 ± 14.1, p = 0.014; irbesartan: 126.4 ± 17.8, p = 0.001) and 24-h c-SBP and c-DBP (baseline: 135.5 ± 10.3/91.9 ± 9.2; nebivolol: 126.4 ± 8.4/86.6 ± 7.2, p < 0.001/p = 0.002; irbesartan: 128.7 ± 11.6/87.0 ± 9.4, p = 0.061/p = 0.051 mm Hg). Single-dose intake of both drugs did not affect heart rate-adjusted augmentation index [AIx(75)], but decreased postdialysis pulse wave velocity (PWV). Importantly, weekly administration of both drugs reduced 24-h PWV (baseline: 10.0 ± 2.5; nebivolol: 9.7 ± 2.5, p = 0.012; irbesartan: 9.7 ± 2.7, p = 0.041). In between drug-group comparisons, no significant differences were noted. CONCLUSIONS: This is the first randomized evaluation on the effects of pharmacological interventions on central BP and PWV in patients with intradialytic hypertension. Weekly administration of both nebivolol and irbesartan reduced 24-h central BP and PWV, but not AIx(75).

The Beneficial Hemodynamic Actions of SGLT-2 Inhibitors beyond the Management of Hyperglycemia.

Type 2 diabetes mellitus (DM) is a public health burden and its co-existence with hypertension is long established in the context of the metabolic syndrome. Both DM and hypertension are major risk factors, for end-stage renal disease, cardiovascular events and mortality. Strict blood pressure (BP) control in diabetics has been associated with a cardiovascular and renal risk decrease. Inhibitors of the sodium-glucose co-transporter 2 (SGLT-2) in the proximal tubule is a relatively novel class of agents for the treatment of type 2 DM. Inhibition of SGLT-2 co-transporter combines proximal tubule diuretic and osmotic diuretic action leading to glucose reabsorption reduction and mild natriuretic and diuretic effects. On this basis, several studies showed that treatment with SGLT-2 inhibitors can effectively decrease hyperglycemia but also increase BP control and reduce renal outcomes and cardiovascular mortality. Based on such evidence, the recent guidelines for the management of type 2 DM now suggest that SGLT-2 inhibitors should be preferred among oral agents in combination with metformin, in patients at increased cardiovascular risk, chronic kidney disease or heart failure. This review summarizes the existing data from studies evaluating the effect of SGLT-2 inhibitors on BP, and its potential value for cardio- and nephroprotection.

Lung Ultrasound-Guided Dry-Weight Reduction in Hemodialysis Patients Does Not Affect Short-Term Blood Pressure Variability.

BACKGROUND: Increased short-term blood pressure (BP) variability (BPV) in hemodialysis is associated with increased cardiovascular and all-cause mortality. Studies on the impact of BP-lowering interventions on BPV are scarce. This study examined the effect of dry-weight reduction with a lung ultrasound-guided strategy on short-term BPV in hemodialysis patients with hypertension. METHODS: This is a prespecified analysis of a randomized clinical trial in 71 hemodialysis patients with hypertension, assigned in a 1:1 ratio in the active group, following a strategy for dry-weight reduction guided by pre-hemodialysis lung ultrasound and the control group following standard-of-care treatment. All patients underwent 48-hour ambulatory BP monitoring at baseline and after 8 weeks. BPV was calculated with validated formulas for the 48-hour interval and the 2 daytime and nighttime periods. RESULTS: Dry-weight changes were -0.71 ± 1.39 in active vs. +0.51 ± 0.98 kg in the control group (P < 0.001), generating a between-group difference of 5.9/3.5 mm Hg (P < 0.05) in 48-hour BP at study end. All brachial BPV indices [SD, weighted SD, coefficient of variation, and average real variability (ARV)] did not change significantly from baseline to study end in the active [systolic blood pressure (SBP)-ARV: 12.58 ± 3.37 vs. 11.91 ± 3.13, P = 0.117; diastolic blood pressure (DBP)-ARV: 9.14 ± 1.47 vs. 8.80 ± 1.96, P = 0.190] or control (SBP-ARV: 11.33 ± 2.76 vs. 11.07 ± 2.51, P = 0.544; DBP-ARV: 8.38 ± 1.50 vs. 8.15 ± 1.49, P = 0.295) group (between-group comparison P = 0.211/0.117). Aortic BPV indices followed a similar pattern. Likewise, no significant changes in BPV indices for the daytime and nighttime periods were noted in both groups during follow-up. CONCLUSIONS: This study is the first to evaluate the effects of a nonpharmacological intervention on short-term BPV in hemodialysis, showing no effect of dry-weight reduction on BPV, despite BP decrease.

The effects of nebivolol and irbesartan on postdialysis and ambulatory blood pressure in patients with intradialytic hypertension: a randomized cross-over study.

OBJECTIVES: Intradialytic hypertension is estimated at 5-15% of hemodialysis patients and is associated with poor prognosis. Studies on therapeutic interventions for this entity are extremely few. We aimed to evaluate the effects of nebivolol and irbesartan on peridialytic, intradialytic, and ambulatory BP in patients with intradialytic hypertension. METHODS: This is a pilot randomized-cross-over study in 38 hemodialysis patients (age: 60.4 ±â€Š11.1 years, men: 65.8%) with intradialytic hypertension (intradialytic SBP rise ≥10 mmHg at ≥4 over six consecutive sessions]. After baseline evaluation, patients were randomly assigned to nebivolol 5 mg and subsequently irbesartan 150 mg, or vice versa. Nineteen patients received a single drug-dose 1 h before hemodialysis and 19 received the drug for a week before evaluation. A 2-week wash-out period took place before the initiation of the second drug. Patients had three respective 24-h ambulatory BP measurements starting before a midweek session. RESULTS: In total, 20 (52.6%) patients received nebivolol first and 18 (47.4%) received irbesartan. Patients receiving a single dose of either drug had lower postdialysis BP (baseline: 160.2 ±â€Š17.8/93.2 ±â€Š13.6 mmHg; nebivolol: 148.0 ±â€Š20.8/84.5 ±â€Š13.1 mmHg, P = 0.013/P = 0.027; irbesartan 142.9 ±â€Š29.9/87.2 ±â€Š18.1 mmHg, P = 0.003/P = 0.104 for SBP and DBP, respectively). The 24-h BP presented a trend towards reduction, but was significant only for 24-h DBP in the nebivolol arm. Patients on weekly administration of either drug had lower postdialysis BP (baseline: 162.5 ±â€Š16.8/95.4 ±â€Š12.7 mmHg; nebivolol: 146.7 ±â€Š16.3/91.8 ±â€Š12.2 mmHg, P = 0.001/P = 0.235; irbesartan: 146.0 ±â€Š23.9/85.8 ±â€Š12.9 mmHg, P = 0.004/ P = 0.007, respectively), lower intradialytic BP and lower 24-h BP (baseline: 148.3 ±â€Š12.6/90.2 ±â€Š9.0 mmHg; nebivolol: 139.2 ±â€Š10.6/85.0 ±â€Š7.7 mmHg, P < 0.001/P = 0.001; irbesartan: 142.4 ±â€Š16.4/85.1 ±â€Š9.9 mmHg, P = 0.156/P = 0.030). No significant differences were observed in comparisons between the two drugs, with the exception of heart rate, being lower with nebivolol. CONCLUSION: Both nebivolol and irbesartan reduced postdialysis and 24-h BP in patients with intradialytic hypertension. Weekly administration had greater effect and nebivolol was numerically slightly more potent than irbesartan.

A Comparative Study of Short-Term Blood Pressure Variability in Hemodialysis Patients with and without Intradialytic Hypertension.

BACKGROUND: Short-term blood pressure (BP) variability (BPV) is associated with increased cardiovascular risk in hemodialysis. Patients with intradialytic hypertension have high risk of adverse outcomes. Whether BPV is increased in these patients is not clear. The purpose of this study was to compare short-term BPV in patients with and without intradialytic hypertension. METHODS: Forty-one patients with and 82 patients without intradialytic hypertension (intradialytic SBP rise ≥10 mm Hg to > 150 mm Hg) matched in a 1: 2 ratio for age, sex, and hemodialysis vintage were included. All subjects underwent 48-h ambulatory BP monitoring during a regular hemodialysis and the subsequent interdialytic interval. Brachial and aortic BPV were calculated with validated formulas and compared between the 2 groups during the 48-h and the 44-h periods and during the 2 daytime and nighttime periods respectively. RESULTS: During 48-h or 44-h periods and daytime or nighttime, brachial SBP/DBP and aortic SBP/DBP were significantly higher in cases than in controls. All brachial SBP/DBP BPV indexes [SD, weighted SD (wSD), coefficient-of-variation (CV) and average-real-variability (ARV)] were not significantly different between groups during the 48- or 44-h periods (48-h: SBP-ARV 11.59 ± 3.05 vs. 11.70 ± 2.68, p = 0.844, DBP-ARV: 8.60 ± 1.90 vs. 8.90 ± 1.63, p = 0.357). Analysis stratified by day or night between days 1 and 2 revealed, in general, similar results. No significant differences in dipping pattern were observed between groups. Analysis of aortic BPV had similar findings. CONCLUSIONS: BPV is similar between those with and without intradialytic hypertension. However, those with intradialytic hypertension have a sustained increase in systolic and diastolic BP during the entire interdialytic interval.

The optimal blood pressure target in diabetes mellitus: a quest coming to an end?

The presence of hypertension in patients with diabetes mellitus (DM) substantially increases cardiovascular risk. Blood pressure (BP) decrease in these individuals is associated with large reductions in cardiovascular morbidity and mortality, but the optimal BP levels in DM still remain a matter of important controversy. For almost 20 years, guidelines recommended an office BP target of <130/80 mmHg in diabetic individuals, following evidence from trials randomizing patients to diastolic BP levels. When the action-to-control-cardiovascular-risk-in-diabetes-blood-pressure (ACCORD-BP) study showed that systolic BP (SBP) <120 mmHg was associated with similar risk to SBP < 140 mmHg in type 2 DM, all guidelines stepped back to recommend a SBP < 140 mmHg, despite the obvious limitations of ACCORD-BP, including the surprisingly low event rate and the actual average BP of 133.5/70.5 mmHg in the "standard-target" arm. In contrast, the systolic-blood-pressure-intervention-trial (SPRINT) showed cardiovascular benefits in hypertensive patients without DM randomized to SBP<120 versus <140 mmHg and many believed that absence of between-group differences in ACCORD-BP was rather a matter of power and not of dissimilar cardiovascular profile of diabetic patients. In this regard, the American-College-of-Cardiology/American-Heart-Association 2017 BP guidelines advocated a BP target of <130/80 in all hypertensives, including those with DM. However, the 2018 American-Diabetes-Association recommendations were not in the same direction, suggesting BP goal <140/90 for most patients, with the exception of those with "high cardiovascular risk", where a <130/80 mmHg target may apply. This review presents the evidence from old and recent trials relevant to optimal BP levels in DM, aiming to shed light in this major clinical question.

The Road Not So Travelled: Should Measurement of Vitamin D Epimers during Pregnancy Affect Our Clinical Decisions?

Observational studies suggest an adverse effect of maternal hypovitaminosis D during pregnancy. However, intervention studies failed to show convincing benefit from vitamin D supplementation during pregnancy. With analytical advances, vitamin D can now be measured in ten forms-including as epimers-which were thought to be biologically inactive, but can critically impair immunoassays. The aim of this commentary is to highlight the potential clinical and analytical significance of vitamin D epimers in the interpretation of vitamin D roles in pregnancy. Epimers may contribute a considerable proportion of total vitamin D-especially in the neonate-which renders the majority of common assays questionable. Furthermore, epimers have been suggested to have activity in laboratory studies, and evidence suggests that the fetus contributes significantly to epimer production. Maternal epimer levels contribute significantly to predict neonate circulating 25-hydroxyvitamin D concentrations. In conclusion, the existence of various vitamin D forms (such as epimers) has been established, and their clinical significance remains obscure. These results underscore the need for accurate measurements to appraise vitamin D status, in order to understand the current gap between observational and supplementation studies on the field.