Treatment experiences with focus on IL-6R inhibition in patients with VEXAS-syndrome and a case of remission with azacytidine treatment.

OBJECTIVES: The aim of the study was to evaluate the treatment response to Interleukin-6-receptor inhibitition (IL-6Ri), primarily tocilizumab, in patients with VEXAS. METHODS: Data were obtained from review of hospital based clinical records and included symptoms, laboratory data, transfusion history, pathology reports, imaging, and treatment. RESULTS: Fifteen patients were treated with tocilizumab intravenously. Two patients changed treatment to subcutaneous sarilumab. Three discontinued treatment due to treatment failure.Of the 10 patients with treatment-response and prednisone use prior to IL-6Ri one was tapered off prednisone, one used it intermittently, and seven patients could be reduced to 10 mg or less daily.Three patients exhibited a marked decrease in UBA1-levels during IL-6Ri which corresponded with symptom control and normalization of haemoglobin levels. However, in most a progressive marrow failure occurred as indicated by decreasing platelet levels, increasing MCV, and for some, declining haemoglobin levels and transfusion dependence in spite of control of the inflammatory symptoms and low c-reactive protein levels.One patient became refractory to both tocilizumab and sarilumab, and had previously failed conventional DMARDs, JAK-inhibition, TNFa-inhibition, and interleukin-1R-inhibiton. Treatment with 9 cycles of azacytidine resulted in complete symptom remission, discontinuation of prednisone, normalization of biochemical parameters and undetectable UBA1 mutation levels which has now lasted for 10 months since cessation of azacytidine. CONCLUSION: IL-6Ri induces control of inflammatory symptoms and allows decreased prednisone usage in a large subset of VEXAS patients. However, most experience progressive bone marrow failure during IL-6Ri.Azacytidine could be a promising treatment strategy and warrants further investigation.

A low dietary sodium dose is associated with a more pronounced aldosterone response in normotensive than in hypertensive individuals.

In this comprehensive meta-regression analysis encompassing 79 randomized controlled trials, we observed that in populations assigned to a high sodium intake level exceeding 94 mmol, there was no discernible link between plasma aldosterone levels and sodium intake. However, among populations with normal blood pressure subjected to a lower sodium intake, falling below 111 mmol (N = 1544), the association between sodium intake and plasma aldosterone levels manifested as a decrease of 192 pg/ml per 100 mmol of sodium (95% CI - 303 to - 81). In hypertensive populations (N = 1145), this association was less pronounced, with a reduction of 46 pg/ml per 100 mmol sodium, (95% CI - 112 to 20). Furthermore, in normotensive populations the plasma aldosterone increase associated with a decrease in sodium intake was 70 pg/ml per 100 mmol sodium (95% CI 27 to 113). In hypertensive populations, the observed increase was more modest, at 30 pg/ml per 100 mmol sodium, (95% CI 6.8 to 54). A limitation of this study lies in the absence of individual participant data. Our analysis included adjustments for potential effect-modifiers, encompassing bias estimation, which did not substantially alter these associations. One perspective of the present results may be to prompt a reconsideration of current sodium reduction recommendations.

Monotreatment With Conventional Antirheumatic Drugs or Glucocorticoids in Rheumatoid Arthritis: A Network Meta-Analysis.

Importance: This is the first network meta-analysis to assess outcomes associated with multiple conventional synthetic disease-modifying antirheumatic drugs and glucocorticoid. Objective: To analyze clinical outcomes after treatment with conventional synthetic disease-modifying antirheumatic drugs and glucocorticoid among patients with rheumatoid arthritis. Data Sources: With no time restraint, English language articles were searched in MEDLINE, Embase, Cochrane Central, ClinicalTrials.gov, and reference lists of relevant meta-analyses until September 15, 2022. Study Selection: Four reviewers in pairs of 2 independently included controlled studies randomizing patients with rheumatoid arthritis to mono-conventional synthetic disease-modifying antirheumatic drugs, glucocorticoid, placebo, or nonactive treatment that recorded at least 1 outcome of tender joint count, swollen joint count, erythrocyte sedimentation rate, and C-reactive protein level. Of 1098 assessed articles, 130 articles (132 interventions) were included. Data Extraction and Synthesis: The review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline, and data quality was assessed by the Cochrane risk of bias tool RoB 2. Data were extracted by a single author and checked independently by 2 authors. Data were analyzed using a random effect model, and data analysis was conducted from June 2021 to February 2023. Main Outcomes and Measures: A protocol with hypothesis and study plan was registered before data recording. The most complete of recorded outcomes (tender joint count) was used as primary outcome, with imputations based on other outcomes to obtain a full analysis of all studies. Absolute change adjusted for baseline disease activity was assessed. Results: A total of 29 interventions in 275 treatment groups among 132 randomized clinical trials (mean [range], 71.0% [27.0% to 100%] females in studies; mean [range] of ages in studies, 53 [36 to 70] years) were identified, which included 13 260 patients with rheumatoid arthritis. The mean (range) duration of RA was 79 (2 to 243) months, and the mean (range) disease activity score was 6.3 (4.0 to 8.8). Compared with placebo, oral methotrexate was associated with a reduced tender joint count by 5.18 joints (95% credible interval [CrI], 4.07 to 6.28 joints). Compared with methotrexate, glucocorticoid (-2.54 joints; 95% CrI, -5.16 to 0.08 joints) and remaining drugs except cyclophosphamide (6.08 joints; 95% CrI, 0.44 to 11.66 joints) were associated with similar or lower tender joint counts. Conclusions and Relevance: This study's results support the present role of methotrexate as the primary reference conventional synthetic disease-modifying antirheumatic drug.

Onset of Action of Selected Second-Generation Antipsychotics (Pines)-A Systematic Review and Meta-Analyses.

Recommendations for duration of treatment with antipsychotics before considering a switch vary from 2 to 8 weeks, although several studies suggest a rapid onset of action. The objective of this review was to estimate time to onset of action and time to maximum antipsychotic effect of asenapine, olanzapine, quetiapine, and zotepine (pines). We searched bibliographic databases for randomized, placebo-controlled trials in adults with schizophrenia estimating the antipsychotic effect of pines over time. Thirty-five studies including 6331 patients diagnosed with chronic schizophrenia were included. We estimated the standardized mean differences (SMD) of changes in symptom score from baseline to follow-up between intervention and placebo groups across studies using meta-analysis techniques. The summarized effect across all included pines administered as immediate-release formulations showed a statistically significant effect at week 1 (SMD, -0.20 [CI95% -0.28, -0.13]), which increased until week 3 (SMD, -0.42 [CI95% -0.50, -0.34]), after which the effect leveled off (week 6: SMD, -0.53 [CI95% -0.62, -0.44]). The sensitivity analyses of the individual pines confirm this finding, although data sparsity increases variability and limits conclusiveness of these analyses.

Influence of sodium intake and change in sodium intake on plasma-renin in man.

BACKGROUND: Low sodium intake stimulates the production and activity of renin. The aim is to analyse the association between a large range of sodium intake and the plasma renin activity (PRA). METHODS: We performed electronic searches for articles published between January 1st 1946 and March 18th 2020 and updated on January 21st 2021. Randomized controlled trials (RCTs) allocating participants to different sodium diets were included. Data were extracted from published reports. Meta-regression analyses of mean PRA versus mean sodium intake estimated by 24-hour urinary sodium excretion were performed. PROSPERO Registration number is CRD42020150355. FINDINGS: 93 RCTs (102 interventions) were identified. In populations with usual/high sodium intake PRA was not associated with sodium intake. In populations with low sodium intake this association was mean -2·91 ng/ml/h per 100 mmol sodium (95% CI: -5·41- -0·42) in 60 studies of normotensive populations (n = 1769) and -1·91 ng/ml/h per 100 mmol sodium (-3·24 - -0·58) in 42 studies of hypertensive populations (n = 1267). The association of the change in PRA with the change in sodium intake was 1·32 ng/ml/h per 100 mmol sodium (0·47-2·18) in normotensive populations and 0·82 ng/ml/h per 100 mmol sodium (0·39-1·24) in hypertensive populations. Contrasting over-all bias assessments and potential effect modifiers had no independent impact on the sodium-PRA relationship. The variability between studies was considerable (I2 > 90%). INTERPRETATION: The accelerating effect of sodium reduction on PRA towards a sodium intake of zero mmol/24 h probably explains the interstudy variability. Further studies are needed to test whether this stimulating effect on PRA reflects a physiological disadvantage potentially associated with increased mortality. FUNDING: None.

The effect of activated charcoal on drug exposure following intravenous administration: A meta-analysis.

Activated charcoal both reduces primary drug absorption and enhances drug elimination. However, the two mechanisms of action overlap and are indistinguishable from each other. In order to estimate the extend of enhanced elimination, we summarized the effect of activated charcoal on intravenously administered drugs, where reduced drug exposure can be attributed to enhanced elimination. We performed a meta-analysis of randomized controlled studies evaluating the effect of orally administered activated charcoal on the systemic exposure of intravenously administered drugs. We searched the bibliographic databases PubMed, Embase and Cochrane. Meta-regression analyses of selected physiochemical drug properties on the effect sizes of activated charcoal were performed. All but one of 21 included studies used multiple-dose activated charcoal (MDAC). MDAC reduced the median half-life of the intravenously administered study drugs by 45.7% (interquartile range: 15.3%-51.3%) and area under the concentration time curve by 47.0% (interquartile range: 36.4%-50.2%). MDAC significantly improved drug elimination across nine different intravenously administered drugs, but we were unable to identify factors allowing extrapolation to other drugs. The results offer a possible and plausible rationale for the previously observed effects of single-dose activated charcoal beyond the timeframe where ingested drug is present in the gastro-intestinal tract.

Effects of low sodium diet versus high sodium diet on blood pressure, renin, aldosterone, catecholamines, cholesterol, and triglyceride.

BACKGROUND: Recent cohort studies show that salt intake below 6 g is associated with increased mortality. These findings have not changed public recommendations to lower salt intake below 6 g, which are based on assumed blood pressure (BP) effects and no side-effects. OBJECTIVES: To assess the effects of sodium reduction on BP, and on potential side-effects (hormones and lipids) SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to April 2018 and a top-up search in March 2020: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions. The top-up search articles are recorded under "awaiting assessment." SELECTION CRITERIA: Studies randomizing persons to low-sodium and high-sodium diets were included if they evaluated at least one of the outcome parameters (BP, renin, aldosterone, noradrenalin, adrenalin, cholesterol, high-density lipoprotein, low-density lipoprotein and triglyceride,. DATA COLLECTION AND ANALYSIS: Two review authors independently collected data, which were analysed with Review Manager 5.3. Certainty of evidence was assessed using GRADE. MAIN RESULTS: Since the first review in 2003 the number of included references has increased from 96 to 195 (174 were in white participants). As a previous study found different BP outcomes in black and white study populations, we stratified the BP outcomes by race. The effect of sodium reduction (from 203 to 65 mmol/day) on BP in white participants was as follows: Normal blood pressure: SBP: mean difference (MD) -1.14 mmHg (95% confidence interval (CI): -1.65 to -0.63), 5982 participants, 95 trials; DBP: MD + 0.01 mmHg (95% CI: -0.37 to 0.39), 6276 participants, 96 trials. Hypertension: SBP: MD -5.71 mmHg (95% CI: -6.67 to -4.74), 3998 participants,88 trials; DBP: MD -2.87 mmHg (95% CI: -3.41 to -2.32), 4032 participants, 89 trials (all high-quality evidence). The largest bias contrast across studies was recorded for the detection bias element. A comparison of detection bias low-risk studies versus high/unclear risk studies showed no differences. The effect of sodium reduction (from 195 to 66 mmol/day) on BP in black participants was as follows: Normal blood pressure: SBP: mean difference (MD) -4.02 mmHg (95% CI:-7.37 to -0.68); DBP: MD -2.01 mmHg (95% CI:-4.37, 0.35), 253 participants, 7 trials. Hypertension: SBP: MD -6.64 mmHg (95% CI:-9.00, -4.27); DBP: MD -2.91 mmHg (95% CI:-4.52, -1.30), 398 participants, 8 trials (low-quality evidence). The effect of sodium reduction (from 217 to 103 mmol/day) on BP in Asian participants was as follows: Normal blood pressure: SBP: mean difference (MD) -1.50 mmHg (95% CI: -3.09, 0.10); DBP: MD -1.06 mmHg (95% CI:-2.53 to 0.41), 950 participants, 5 trials. Hypertension: SBP: MD -7.75 mmHg (95% CI:-11.44, -4.07); DBP: MD -2.68 mmHg (95% CI: -4.21 to -1.15), 254 participants, 8 trials (moderate-low-quality evidence).   During sodium reduction renin increased 1.56 ng/mL/hour (95%CI:1.39, 1.73) in 2904 participants (82 trials); aldosterone increased 104 pg/mL (95%CI:88.4,119.7) in 2506 participants (66 trials); noradrenalin increased 62.3 pg/mL: (95%CI: 41.9, 82.8) in 878 participants (35 trials); adrenalin increased 7.55 pg/mL (95%CI: 0.85, 14.26) in 331 participants (15 trials); cholesterol increased 5.19 mg/dL (95%CI:2.1, 8.3) in 917 participants (27 trials); triglyceride increased 7.10 mg/dL (95%CI: 3.1,11.1) in 712 participants (20 trials); LDL tended to increase 2.46 mg/dl (95%CI: -1, 5.9) in 696 participants (18 trials); HDL was unchanged -0.3 mg/dl (95%CI: -1.66,1.05) in 738 participants (20 trials) (All high-quality evidence except the evidence for adrenalin). AUTHORS' CONCLUSIONS: In white participants, sodium reduction in accordance with the public recommendations resulted in mean arterial pressure (MAP) decrease of about 0.4 mmHg in participants with normal blood pressure and a MAP decrease of about 4 mmHg in participants with hypertension. Weak evidence indicated that these effects may be a little greater in black and Asian participants. The effects of sodium reduction on potential side effects (hormones and lipids) were more consistent than the effect on BP, especially in people with normal BP.

Different Original and Biosimilar TNF Inhibitors Similarly Reduce Joint Destruction in Rheumatoid Arthritis-A Network Meta-Analysis of 36 Randomized Controlled Trials.

The effect of five approved tumour necrosis factor inhibitors (TNFi: infliximab, etanercept, adalimumab, certolizumab, and golimumab) on joint destruction in rheumatoid arthritis (RA) have been compared versus methotrexate (MTX) in randomized controlled trials (RCTs) but have not been compared directly to each other or to an otherwise untreated placebo control. The present analysis compares effects of standard doses, high doses, and low doses of TNFis on radiographic joint destruction in RA and relate these effects to MTX and placebo by means of a Bayesian network meta-analysis. We identified 31 RCTs of the effect of TNFis on joint destruction and 5 RCTs with controls, which indirectly could link otherwise untreated placebo controls to the TNFi treatments in the network. The previously untested comparison with placebo was performed to estimate not only the effect relative to another drug, but also the absolute attainable effect. Compared to placebo there was a highly significant inhibitory effect on joint destruction of infliximab, etanercept, adalimumab, certolizumab, and golimumab, which was about 0.9% per year as monotherapy and about 1.2% per year when combined with MTX. Although significantly better than MTX and placebo, golimumab seemed inferior to the remaining TNFis. There was no difference between original reference drugs (Remicade, Enbrel) and the almost identical copy drugs (biosimilars).

Dose-response relation between dietary sodium and blood pressure: a meta-regression analysis of 133 randomized controlled trials.

BACKGROUND: The projected reduced mortality effect of reduced sodium intake in model-based studies conflicts with the observed increased mortality associated with low sodium intake in population studies. This may reflect an overestimation of the dose-response relation between sodium reduction (SR) and blood pressure (BP) used in mortality modeling studies. OBJECTIVES: The present meta-regression analysis sought to estimate the dose-response relations between SR and BP in study groups with mean BP above or below the 75th percentile of the general population. METHODS: Based on a literature search from 1 January 1946 to 11 April 2018, we identified 133 randomized controlled trials allocating healthy or hypertensive individuals to SR or usual sodium intake. Multivariable regression analyses of the mean SR versus the mean blood pressure effect adjusted for effect modifiers were performed. RESULTS: In study groups with mean BP above the 75th percentile [131/78 mm Hg systolic BP (SBP)/diastolic BP (DBP)], there was strong evidence of a linear dose-response relation between SR and BP. For SBP, the dose-response relation was -7.7 mm Hg/100 mmol SR (95% CI: -10.4, -5.0), and for DBP it was -3.0 mm Hg/100 mmol SR (95% CI: -4.6, -1.4). In study groups with mean BP ≤ 131/78 mm Hg, the relation between SR and BP was weak. For SBP it was -1.46 mm Hg/100 mmol SR (95% CI: -2.7, -0.20) and for DBP it was: -0.07 mm Hg/100 mmol SR (95% CI: -1.5, 1.4). CONCLUSIONS: Only study groups with a BP in the highest 25th percentile of the population showed a clinically significant drop in BP with SR. The policy of lowering dietary sodium intake in the general population may need to be reframed to target patients with hypertension. This study was registered at PROSPERO 2015 as CRD42015017773.

[Increased mortality on a daily salt intake below six grammes].

Randomised controlled trials of healthy individuals show that the effect of reduced dietary salt intake (SR) on blood pressure (BP) is less than 1 mmHg. Still, health authorities use BP effects obtained in studies of participants with high BP to simulate reduced mortality in computer modeling studies. These simulations are in contrast to real data from observational studies, which show that a low salt intake is associated with an increased mortality of about 15% in healthy as well as in hypertensive individuals. Consequently, SR at the population level should not be a public health priority.

Conflicting Evidence on Health Effects Associated with Salt Reduction Calls for a Redesign of the Salt Dietary Guidelines.

Ninety-five percent of the World's populations have a mean salt intake between 6 and 12 g, which is much lower than the tolerated daily level of up to 55 g/d. In spite of this, the recommended upper level by many health institutions is as low as 5.8 g/day. When reviewing the evidence for an upper level of 5.8 g/day, it becomes apparent that neither the supporting studies selected by the health institutions, nor randomized controlled trials and prospective observational studies disregarded by the health institutions, document that a salt intake below this 5.8 g, has beneficial health effects. Although there is an association between salt intake and blood pressure, both in randomized controlled trials and in observational studies, this association is weak, especially in non-obese individuals with normal blood pressure. Furthermore a salt intake below 5.8 g is associated with the activation of the renin-angiotensin-aldosteron system, an increase in plasma lipids and increased mortality. A redesign of the salt dietary guidelines, therefore, seems to be needed.

U-shaped dietary sodium-associated incidence of chronic kidney disease cautions against salt overrestriction in hypertension.

In this population study salt intake is not associated with development of chronic kidney disease (CKD) in individuals with normal blood pressure, whereas in hypertensive individuals both low and high salt intakes are associated with increased incidence of CKD, similar to U-shaped associations between salt intake and mortality found in previous studies. The results contribute to the skepticism, which has questioned the present public health policy to reduce salt intake below 5.8 g.

Effects of low sodium diet versus high sodium diet on blood pressure, renin, aldosterone, catecholamines, cholesterol, and triglyceride.

BACKGROUND: In spite of more than 100 years of investigations the question of whether a reduced sodium intake improves health is still unsolved. OBJECTIVES: To estimate the effects of low sodium intake versus high sodium intake on systolic and diastolic blood pressure (SBP and DBP), plasma or serum levels of renin, aldosterone, catecholamines, cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to March 2016: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 3), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also searched the reference lists of relevant articles. SELECTION CRITERIA: Studies randomising persons to low-sodium and high-sodium diets were included if they evaluated at least one of the above outcome parameters. DATA COLLECTION AND ANALYSIS: Two review authors independently collected data, which were analysed with Review Manager 5.3. MAIN RESULTS: A total of 185 studies were included. The average sodium intake was reduced from 201 mmol/day (corresponding to high usual level) to 66 mmol/day (corresponding to the recommended level).The effect of sodium reduction on blood pressure (BP) was as follows: white people with normotension: SBP: mean difference (MD) -1.09 mmHg (95% confidence interval (CI): -1.63 to -0.56; P = 0.0001); 89 studies, 8569 participants; DBP: + 0.03 mmHg (MD 95% CI: -0.37 to 0.43; P = 0.89); 90 studies, 8833 participants. High-quality evidence. Black people with normotension: SBP: MD -4.02 mmHg (95% CI:-7.37 to -0.68; P = 0.002); seven studies, 506 participants; DBP: MD -2.01 mmHg (95% CI:-4.37 to 0.35; P = 0.09); seven studies, 506 participants. Moderate-quality evidence. Asian people with normotension: SBP: MD -0.72 mmHg (95% CI: -3.86 to 2.41; P = 0.65); DBP: MD -1.63 mmHg (95% CI:-3.35 to 0.08; P =0.06); three studies, 393 participants. Moderate-quality evidence.White people with hypertension: SBP: MD -5.51 mmHg (95% CI: -6.45 to -4.57; P < 0.00001); 84 studies, 5925 participants; DBP: MD -2.88 mmHg (95% CI: -3.44 to -2.32; P < 0.00001); 85 studies, 6001 participants. High-quality evidence. Black people with hypertension: SBP MD -6.64 mmHg (95% CI:-9.00 to -4.27; P = 0.00001); eight studies, 619 participants; DBP -2.91 mmHg (95% CI:-4.52, -1.30; P = 0.0004); eight studies, 619 participants. Moderate-quality evidence. Asian people with hypertension: SBP: MD -7.75 mmHg (95% CI:-11,44 to -4.07; P < 0.0001) nine studies, 501 participants; DBP: MD -2.68 mmHg (95% CI: -4.21 to -1.15; P = 0.0006). Moderate-quality evidence.In plasma or serum, there was a significant increase in renin (P < 0.00001), aldosterone (P < 0.00001), noradrenaline (P < 0.00001), adrenaline (P < 0.03), cholesterol (P < 0.0005) and triglyceride (P < 0.0006) with low sodium intake as compared with high sodium intake. All effects were stable in 125 study populations with a sodium intake below 250 mmol/day and a sodium reduction intervention of at least one week. AUTHORS' CONCLUSIONS: Sodium reduction from an average high usual sodium intake level (201 mmol/day) to an average level of 66 mmol/day, which is below the recommended upper level of 100 mmol/day (5.8 g salt), resulted in a decrease in SBP/DBP of 1/0 mmHg in white participants with normotension and a decrease in SBP/DBP of 5.5/2.9 mmHg in white participants with hypertension. A few studies showed that these effects in black and Asian populations were greater. The effects on hormones and lipids were similar in people with normotension and hypertension. Renin increased 1.60 ng/mL/hour (55%); aldosterone increased 97.81 pg/mL (127%); adrenalin increased 7.55 pg/mL (14%); noradrenalin increased 63.56 pg/mL: (27%); cholesterol increased 5.59 mg/dL (2.9%); triglyceride increased 7.04 mg/dL (6.3%).