A Study on the Immunoregulatory Role of the PD1 Pathway in Juvenile Idiopathic Arthritis.

Objectives: To investigate the immunoregulatory role of the Programmed-cell-Death-protein-1 (PD1) pathway, an inhibitory immune checkpoint, in Juvenile Idiopathic Arthritis (JIA). Methods: The PD1 expression on CD4+ and CD8+ T-cells was determined by flow cytometry and the PD1 soluble form (sPD1) levels by ELISA, in peripheral blood (PB)/serum and synovial fluid (SF) samples of JIA patients and healthy controls (HCs). We searched for any association in-between the biomarkers and with JIA activity. Results: 101 Caucasian patients (69 female), aged 12 (8-15) years, and 20 HCs participated in this study. The PB PD1 expression on T-cells was higher in: a. JIA patients vs HCs (CD4: 1.24% vs 0.32%, p=0.007, CD8: 1.6% vs 0.4%, p=0.002). b. active vs inactive JIA (CD4: 1.44% vs 0.87%, p=0.072, CD8: 2.1% vs 0.93%, p=0.005). The SF PD1 expression on T-cells correlated strongly and positively with the disease activity (CD4: ρ=0.55, p=0.022, CD8: ρ=0.555, p=0.026). The SF PD1 expression on CD8 T-cells was higher in patients on-treatment vs those off-treatment (21.3% vs 5.83% p=0.004). The sPD1 levels were higher in the SF vs the serum (801pg/ml vs 367.2, p=0.013), without an association with disease activity. Conclusion: These results indicate an up-regulation of the PD1-pathway in JIA, at least quantitatively, especially in active disease. sPD1 is compartmentally produced at the inflamed joints. Further investigation in a larger sample of JIA patients may verify these observations and contribute to unravelling the precise role of the PD1 pathway in the pathogenesis and persistence of the joint inflammation.

Recurrent Stroke as a Presenting Feature of Takayasu Arteritis in an Adolescent: A Case Report and Literature Review.

Takayasu arteritis is a large vessel vasculitis, characterized by granulomatous inflammation of arterial vessels, that typically affects the aorta, its main branches and pulmonary arteries. Disease diagnosis is a challenge and requires awareness of the condition, as clinical signs can be not specific. We report a case of an adolescent with recurrent stroke diagnosed with Takayasu arteritis. A diagnosis of Takayasu arteritis was established due to angiographic findings in the magnetic resonance angiography in conjunction with systolic blood pressure discrepancy, arterial hypertension and increased acute phase reactants. Takayasu arteritis is a rare cause of ischemic stroke in children. However, stroke may be the first manifestation of the disease. Clinical experience and multidisciplinary approach, including aggressive treatment, is essential for the favourable outcome of the disease and the reduction of the associated morbidity and mortality.

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.

Association of Intradialytic Hypertension with Future Cardiovascular Events and Mortality in Hemodialysis Patients: Effects of Ambulatory Blood Pressure.

INTRODUCTION: Intradialytic hypertension (IDHTN) is associated with increased risk of adverse outcomes. Patients with IDHTN have higher 44-h blood pressure (BP) than patients without this condition. Whether the excess risk in these patients is due to the BP rise during dialysis per se or on elevated 44-h BP or other comorbid conditions is uncertain. This study evaluated the association of IDHTN with cardiovascular events and mortality and the influence of ambulatory BP and other cardiovascular risk factors on these associations. METHODS: 242 hemodialysis patients with valid 48-h ABPM (Mobil-O-Graph-NG) were followed for a median of 45.7 months. IDHTN was defined as: systolic BP (SBP) rise ≥10 mm Hg from pre- to post-dialysis and post-dialysis SBP ≥150 mm Hg. The primary endpoint was all-cause mortality; the secondary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, resuscitation after cardiac arrest, heart failure hospitalization, coronary or peripheral revascularization. RESULTS: Cumulative freedom from both the primary and secondary endpoint was significantly lower for IDHTN patients (logrank-p = 0.048 and 0.022, respectively), corresponding to higher risks for all-cause mortality (hazard ratio (HR) = 1.566; 95% confidence interval (CI) [1.001, 2.450]) and the composite cardiovascular outcome (HR = 1.675; 95% CI [1.071, 2.620]) in these individuals. However, the observed associations lost statistical significance after adjustment for 44-h SBP (HR = 1.529; 95% CI [0.952, 2.457] and HR = 1.388; 95% CI [0.866, 2.225], respectively). In the final model after additional adjustment for 44-h SBP, interdialytic weight gain, age, history of coronary artery disease, heart failure, diabetes, and 44-h pulse wave velocity, the association of IDHTN with the outcomes was also not significant and the respective HRs were 1.377 (95% CI [0.836, 2.268]) and 1.451 (95% CI [0.891, 2.364]). CONCLUSIONS: IDHTN patients had higher risk for mortality and cardiovascular outcomes but this risk is at least partly confounded by the elevated BP levels during the interdialytic period.

Cardiorespiratory fitness assessed with cardiopulmonary exercise testing in patients with juvenile idiopathic arthritis: a systematic review and meta-analysis.

OBJECTIVES: JIA is the most common type of arthritis in children and adolescents, causing joint damage, chronic pain and disability. Deconditioning is also prevalent in patients with JIA due to both inactivity and the disease progression, resulting in reduced cardiorespiratory fitness (CRF). We aimed to evaluate CRF of patients with JIA compared with healthy controls. METHODS: This is a systematic review and meta-analysis of studies using cardiopulmonary exercise testing (CPET) to examine differences in determinants of CRF between patients with JIA vs healthy controls. The primary outcome was peak oxygen uptake (VO2peak). Literature search involved PubMed, Web of Science and Scopus databases, manual search of article references and grey literature. Quality assessment was undertaken with Newcastle-Ottawa Scale. RESULTS: From 480 literature records initially retrieved, eight studies (538 participants) were included in final meta-analysis. VO2peak was significantly lower in patients with JIA compared with controls [weighted mean difference (WMD): -5.95 ml/kg/min (95% CI -9.26, -2.65)]. Exercise duration and VO2peak (% predicted) were found to be significantly impaired in patients with JIA compared with controls [standardized mean difference: -0.67 (95% CI -1.04, -0.29) and WMD: -11.31% (95% CI -20.09, -2.53), respectively], while no significant differences were found in maximum heart rate. CONCLUSION: VO2peak and other CPET variables were lower in patients with JIA compared with controls, indicating reduced CRF in the former. Overall, exercise programs for patients with JIA should be promoted as part of their treatment to improve physical fitness and reduce muscle atrophy. PROSPERO REGISTRATION: CRD42022380833.

Gender-Related Differences in the Levels of Ambulatory BP and Intensity of Antihypertensive Treatment in Patients Undergoing Peritoneal Dialysis.

Prior studies have shown that among patients with chronic kidney disease not yet on dialysis, the faster progression of kidney injury in men than in women is, at least partly, explained by sex differences in ambulatory blood pressure (BP) control. The present study aimed to investigate potential differences in the levels of ambulatory BP and intensity of antihypertensive treatment between men and women with end-stage kidney disease undergoing long-term peritoneal dialysis (PD). In a case-control design, 48 male PD patients were matched for age and heart failure status with 48 female patients in a 1:1 ratio. Ambulatory BP monitoring was performed with an oscillometric device, the Mobil-O-Graph (IEM, Stolberg, Germany). The BP-lowering medications actually taken by the patients were prospectively recorded. No gender-related differences were observed in 24 h systolic BP (129.0 ± 17.9 vs. 128.5 ± 17.6 mmHg, p = 0.890). In contrast, 24 h diastolic BP was higher in men than in women (81.5 ± 12.1 vs. 76.8 ± 10.3 mmHg, p = 0.042). As compared with women, men were being treated with a higher average number of antihypertensive medications daily (2.4 ± 1.1 vs. 1.9 ± 1.1, p = 0.019) and were more commonly receiving calcium-channel-blockers (70.8% vs. 43.8%, p = 0.007) and ß-blockers (85.4% vs. 66.7%, p = 0.031). In conclusion, the present study shows that among PD patients, the levels of ambulatory BP and intensity of antihypertensive treatment are higher in men than in women. Longitudinal studies are needed to explore whether these gender-related differences in the severity of hypertension are associated with worse cardiovascular outcomes for male patients undergoing PD.

Effect of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers on cardiovascular outcomes in dialysis patients: a systematic review and meta-analysis.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs) are recommended by guidelines as first-line antihypertensive therapies in the general population or in patients with earlier stages of kidney disease. However, the cardioprotective benefit of these agents among patients on dialysis remains uncertain. METHODS: We searched the MEDLINE, PubMed and Cochrane databases from inception through February 2022 to identify randomized controlled trials (RCTs) comparing the efficacy of ACEIs/ARBs relative to placebo or no add-on treatment in patients receiving dialysis. RCTs were eligible if they assessed fatal or non-fatal cardiovascular events as a primary efficacy endpoint. RESULTS: We identified five RCTs involving 1582 dialysis patients. Compared with placebo or no add-on treatment, the use of ACEIs/ARBs was not associated with a significantly lower risk of cardiovascular events {risk ratio [RR] 0.79 [95% confidence interval (CI) 0.57-1.11]}. Furthermore, there was no benefit in cardiovascular mortality [RR 0.82 (95% CI 0.59-1.14)] and all-cause mortality [RR 0.86 (95% CI 0.64-1.15)]. These results were consistent when the included RCTs were stratified by subgroups, including hypertension, ethnicity, sample size, duration of follow-up and quality. CONCLUSION: The present meta-analysis showed that among patients on dialysis, the use of ACEIs/ARBs is not associated with a significantly lower risk of cardiovascular events and all-cause mortality as compared with placebo or no add-on treatment.

Hypertension in Dialysis Patients: Diagnostic Approaches and Evaluation of Epidemiology.

Whereas hypertension is an established cardiovascular risk factor in the general population, the contribution of increased blood pressure (BP) to the huge burden of cardiovascular morbidity and mortality in patients receiving dialysis continues to be debated. In a large part, this controversy is attributable to particular difficulties in the accurate diagnosis of hypertension. The reverse epidemiology of hypertension in dialysis patients is based on evidence from large cohort studies showing that routine predialysis or postdialysis BP measurements exhibit a U-shaped or J-shaped association with cardiovascular or all-cause mortality. However, substantial evidence supports the notion that home or ambulatory BP measurements are superior to dialysis-unit BP recordings in diagnosing hypertension, in detecting evidence of target-organ damage and in prognosticating the all-cause death risk. In the first part of this article, we explore the accuracy of different methods of BP measurement in diagnosing hypertension among patients on dialysis. In the second part, we describe how the epidemiology of hypertension is modified when the assessment of BP is based on dialysis-unit versus home or ambulatory recordings.

Prevalence of Apparent Treatment-Resistant Hypertension in ESKD Patients Receiving Peritoneal Dialysis.

BACKGROUND: Apparent treatment-resistant hypertension (aTRH) is defined as failure to achieve adequate blood pressure (BP) control despite taking ≥3 antihypertensive medications from different categories or when taking ≥4 antihypertensives regardless of BP levels. METHODS: In this cross-sectional study, we estimated the prevalence of aTRH in 140 patients receiving long-term peritoneal dialysis (PD) in four centers of Northern Greece, using the "gold-standard" method of ambulatory BP monitoring for the assessment of BP control status. The presence of subclinical overhydration was evaluated with the method of bioimpedance spectroscopy (BIS). RESULTS: Incorporating the diagnostic threshold of 130/80 mmHg for 24-hour ambulatory BP, the prevalence of aTRH in the overall study population was 30%. Compared to patients without aTRH, those with aTRH tended to be older in age, had higher PD vintage, had higher dialysate-to-plasma creatinine ratio, had more commonly history of diabetes mellitus, and were more commonly current smokers. With respect to the volume status, the overhydration index in BIS was higher in those with versus without aTRH (2.0 ±â€…1.9 L vs. 1.1 ±â€…2.0 L, P < 0.05). The prevalence of volume overload, defined as an overhydration index in BIS > 2.5 L, was also higher in the subgroup of patients with aTRH (38.1% vs. 18.4, P = 0.01). CONCLUSION: The present study showed that among patients on PD, the prevalence of aTRH was 30%. However, 38% of PD patients with aTRH had subclinical overhydration in BIS, suggesting that the achievement of adequate volume control may be a therapeutic opportunity to improve the management of hypertension in this high-risk patient population.The present study showed that among patients on PD, the prevalence of aTRH was 30%. However, 38% of PD patients with aTRH had subclinical overhydration in BIS, suggesting that the achievement of adequate volume control may be a therapeutic opportunity to improve the management of hypertension in this high-risk patient population. CLINICAL TRIALS REGISTRATION: Trial Number NCT03607747.

Feeding during Dialysis Increases Intradialytic Blood Pressure Variability and Reduces Dialysis Adequacy.

Whether hemodialysis patients should be allowed or even encouraged to eat during dialysis remains a controversial topic. This cross-over study aimed to evaluate the impact of feeding during dialysis on intradialytic blood pressure (BP) profile and dialysis adequacy in 26 patients receiving thrice-weekly, in-center hemodialysis. Over three consecutive mid-week dialysis sessions, intradialytic BP was monitored using the Mobil-O-Graph device (IEM, Stolberg, Germany). Blood samples were also obtained for the determination of the urea reduction ratio (URR). At baseline, patients underwent dialysis without the provision of a meal. In phases A and B, a meal with either high-protein (1.5 gr/kg of body weight) or low-protein (0.7 gr/kg of body weight) content was administered 1 h after the initiation of dialysis. The sequence of meals (high-protein and low-protein or vice versa) was randomized. Average intradialytic systolic BP (SBP) was similar on all three occasions. However, compared with baseline, the standard deviation (SD) (11.7 ± 4.1 vs. 15.6 ± 7.6 mmHg, p < 0.01), coefficient of variation (CV) (9.5 ± 3.7% vs. 12.4 ± 6.0%, p < 0.01) and average real variability (ARV) (9.4 ± 3.9 vs. 12.1 ± 5.2 mmHg, p < 0.01) of intradialytic SBP were higher in phase A. Similarly, compared with the baseline evaluation, all three indices of intradialytic SBP variability were higher in phase B (SD: 11.7 ± 4.1 vs. 14.1 ± 4.5 mmHg, p < 0.05; CV: 9.5 ± 3.7% vs. 11.1 ± 3.8%, p < 0.05; ARV: 9.4 ± 3.9 vs. 10.9 ± 3.9 mmHg, p < 0.05). Compared with dialysis without a meal, the consumption of a high-protein or low-protein meal resulted in a lower URR (73.4 ± 4.3% vs. 65.7 ± 10.7%, p < 0.001 in phase A and 73.4 ± 4.3% vs. 67.6 ± 4.3%, p < 0.001 in phase B, respectively). In conclusion, in the present study, feeding during dialysis was associated with higher intradialytic SBP variability and reduced adequacy of the delivered dialysis.

Epidemiology of Hypertension among Patients on Peritoneal Dialysis Using Standardized Office and Ambulatory Blood Pressure Recordings.

INTRODUCTION: Prior studies conducted in peritoneal dialysis (PD) patients in the late 1990s provided considerably variable estimates of the prevalence and control of hypertension. The present study aimed to investigate the current state of hypertension management in this high-risk population. METHODS: In 140 stable PD patients, we performed standardized automated office blood pressure (BP) measurements and 24-h ambulatory BP monitoring (ABPM) using the Mobil-O-Graph device (IEM, Germany). Office and ambulatory hypertension was diagnosed in patients with office BP ≥140/90 mm Hg and 24-h BP ≥130/80 mm Hg, respectively. Patients treated with ≥1 BP-lowering medications were also classified as hypertensives. RESULTS: The prevalence of office and ambulatory hypertension was 92.9% and 95%, respectively. In all, 92.1% of patients were being treated with an average of 2.4 BP-lowering medications daily. Adequate BP control was achieved in 52.3% and 38.3% of hypertensives by office BP and ABPM, respectively. The agreement between these 2 techniques in the identification of patients with BP levels above the diagnostic thresholds of hypertension was moderate (k-statistic: 0.524). In all, 5% of patients were normotensives with both techniques, 31.4% had controlled hypertension, 5% had white-coat hypertension, 19.3% had masked hypertension, and 39.3% had sustained hypertension. Isolated nocturnal hypertension was detected in 23.6% of patients, whereas no patient had isolated daytime hypertension. CONCLUSION: Among PD patients, hypertension is highly prevalent and remains often inadequately controlled. The use of ABPM enables the better classification of severity of hypertension and identification of isolated nocturnal hypertension, which is a common BP phenotype in the PD population.

Sequence analysis in Familial Mediterranean Fever patients with no confirmatory genotype.

INTRODUCTION/OBJECTIVES: Familial Mediterranean Fever (FMF) is a genetic disorder of the innate immunity characterized by chronic inflammatory state. The diagnosis is mainly based on clinical criteria and supported by genotyping, especially in atypical phenotypes. The primary objective was to depict the Familial Mediterranean Fever (FMF) genotype of Greek patients and investigate the contribution of Next Generation Sequencing (NGS) beyond the contemporary techniques [(Polymerase Chain Reaction (PCR)/hybridization and Non-Isotopic RNase Cleavage Assay (NIRCA). The secondary objective was to unravel any associations between the mutated genes with the disease course and response to treatment. METHODS: In this single center, retrospective study 31 patients with clinical diagnosis with FMF, but non-conclusive genetic analysis with PCR/hybridization and NIRCA, underwent NGS genotyping. RESULTS: PCR/NIRCA detected ≥ 1 mutation in 25/31 patients, most frequently M694V (29%), while NGS in 26/31 (83.9%), most frequently R202Q (61.3%). NGS genetically confirmed the clinical diagnosis (heterozygosity to compound or complex genotype) in 19 (61.3%) patients of our cohort. R202Q was significantly more prevalent by NGS than by contemporary techniques (61.3 vs 12.9%, p = 0.0002) and was associated with FMF. Rare mutations were detected by NGS in 19.2% patients. CONCLUSION: NGS clarifies the genetic profile of patients with atypical phenotypes and supports therapeutic management decisions. NGS unveiled the frequent involvement of R202Q in the pathogenesis of our FMF patients.

Transient Severe Liver Injury: A Unique Presentation of COVID-19 Disease in a Pediatric Patient.

Liver dysfunction is highlighted by several studies as a relevant complication in the context of coronavirus disease 2019 (COVID-19). We present a pediatric patient with mild phenotype but transient severe liver injury. Hepatic damage should be considered even in mild cases of the disease to ensure prompt recognition and management.

Arterial stiffness in Familial Mediterranean Fever: correlations with disease-related parameters and colchicine treatment.

INTRODUCTION/OBJECTIVES: Familial Mediterranean Fever is the most common autoinflammatory disease. As chronic inflammation may result in increased arterial stiffness, we aimed to investigate indices of arterial stiffness in patients with Familial Mediterranean Fever and their associations with disease-related factors and colchicine treatment. METHOD: The study was conducted with 43 patients with Familial Mediterranean Fever, including 30 children, in attack free period and 42 healthy controls. Arterial stiffness was assessed by carotid-femoral pulse wave velocity and augmentation index. RESULTS: Patients with Familial Mediterranean Fever presented similar carotid-femoral pulse wave velocity values to controls, but significantly higher augmentation index values (patients versus controls, 19.76% and 9.96%, P < 0.05). Augmentation index, adjusted for age and sex, was associated with complete response compared with partial response to treatment (B = - 17.78, 95% CI - 31.17 to - 4.40, P < 0.05) and the presence of M694V.M680I genotype (B = - 16.75, 95% CI - 33.81 to 0.30, P = 0.05). Carotid-femoral pulse wave velocity presented an inverse relationship with colchicine treatment duration (B = - 0.003, 95% CI - 0.006 to - 0.00, P < 0.05). Pulse wave velocity values adjusted for age and systolic blood pressure were associated with attack frequency (B = 0.48, 95% CI 0.01 to 0.96, P < 0.05). Addition of colchicine treatment duration to the model attenuated the association between carotid-femoral pulse wave velocity and attack frequency supporting the protective role of colchicine. CONCLUSIONS: The normal values of carotid-femoral pulse wave velocity in Familial Mediterranean Fever patients may reflect the compliance to colchicine treatment, which seems to have a protective role against arterial stiffness. However, the increased values of augmentation index need further investigation. KEY POINTS: • FMF patients are prone to present increased cardiovascular risk possibly due to inflammation. • Colchicine treatment may have protective role against arterial stiffness in FMF. • The normal values of cf-PWV in FMF patients may reflect the compliance to colchicine.