Outcome of refractory to conventional and/or biologic treatment adult Still's disease following canakinumab treatment: Countrywide data in 50 patients.

OBJECTIVE: To assess the efficacy and safety of the IL-1b inhibitor canakinumab in all adults with refractory Still's disease identified from the National Organization For Medicines for off-label drug use. METHODS: In a retrospective longitudinal multicenter cohort of 50 patients (median age 39 years) with active Still's disease despite treatment with corticosteroids (n = 11), conventional and synthetic (n = 34) and/or biologic disease modifying anti-rheumatic drugs (n = 30), we assessed the efficacy of canakinumab 150-300 mg administered every 4 (n = 47) or 8 weeks (n = 3) as combination therapy or monotherapy (n = 7) during a median follow-up of 27 (3-84) months. RESULTS: Α complete response was initially observed in 78% of patients within 3 months (median), irrespective of age at disease onset. A partial response was evident in 20%. One patient had resistant disease. Treatment de-escalation was attempted in 15 of 39 complete responders and a complete drug discontinuation in 21 patients for 8 months (median). Eleven patients (22%) relapsed during treatment, one during de-escalation process, and 11 after treatment discontinuation. Overall, 9 of 11 relapses were successfully treated with canakinumab treatment intensification or re-introduction. At last visit, 18% of patients were off treatment due to remission and 26% due to disease activity. Canakinumab had a significant corticosteroid sparing effect allowing weaning in 21 of 41 cases. Infections (20%, severe 4%) and leucopenia (6%) led to treatment cessation in one patient. CONCLUSION: High rates of sustained remission were observed in this, largest so far, real-life cohort of adult patients with refractory Still's disease treated with canakinumab.

Nocebo phenomena may be enhanced in aging: Implications for clinical practice.

Nocebo effects, denoting unfavourable outcomes after a medical intervention because of negative expectations rather than a direct pharmacologic action, are an important cause of dropout from clinical trials and non-adherence to medication, and may be especially pertinent for older adults. Several characteristics of aging individuals and their medical care have a potential to augment nocebo susceptibility, such as depression and anxiety, neurodegenerative diseases and chronic pain states, adverse healthcare experiences, generic drug use, age-related stereotypes, and strained patient-physician communication. Nocebo-related research in older adults is hindered by under-representation in clinical trials, medical complexity of geriatric patients, and lack of validated tools to accurately assess susceptibility and efficacy of preventive efforts.

Correction: Chromatin structure, transcriptional activity and DNA repair efficiency affect the outcome of chemotherapy in multiple myeloma.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Treatment modalities and drug survival in a systemic sclerosis real-life patient cohort.

BACKGROUND: European data indicate that systemic sclerosis (SSc)-related death rates are increasing, thus raising concerns about SSc's optimal management. Herein, we describe current treatment modalities and drug survival in a real-life SSc cohort. METHODS: Details on immunosuppressive/antiproliferative (methotrexate, mycophenolate, cyclophosphamide, azathioprine, rituximab, tocilizumab) and vasoactive agent [(endothelin receptor antagonists (ERAs), sildenafil, iloprost, and calcium channel blockers (CCB)] administration during the disease course (11.8 ± 8.4 years, mean + SD) of 497 consecutive patients examined between 2016 and 2018 were retrospectively recorded. Drug survival was assessed by Kaplan-Meier analysis. RESULTS: Methotrexate was the most frequently administered immunosuppressive/antiproliferative agent (53% of patients), followed by cyclophosphamide (26%), mycophenolate (12%), and azathioprine (11%). Regarding vasoactive agents, CCB had been ever administered in 68%, ERAs in 38%, iloprost in 7%, and sildenafil in 7% of patients; 23% of patients with pulmonary fibrosis had never received immunosuppressive/antiproliferative agents, 33% of those with digital ulcers had never received ERAs, iloprost, or sildenafil, whereas 19% of all patients had never received either immunosuppressive/antiproliferative or other than CCB vasoactive agents. Survival rates of methotrexate, cyclophosphamide, and mycophenolate differed significantly, being 84/75%, 59/43%, and 74/63% at 12/24 months, respectively, with inefficacy being the most frequent discontinuation cause. Conversely, CCB, ERAs, and sildenafil had high and comparable retention rates of 97/91%, 88/86%, and 80/80%, respectively. CONCLUSIONS: Existing therapeutic limitations indicate that more evidence-based treatment is warranted for successful management of SSc. Vasculopathy seems to be managed more rigorously, but the low retention rates of immunosuppressive/antiproliferative drugs suggest that effective and targeted disease-modifying agents are warranted.

Secukinumab after anti-tumour necrosis factor-α therapy: a phase III study in active rheumatoid arthritis.

OBJECTIVE: To assess the efficacy and safety of secukinumab in patients with rheumatoid arthritis (RA) who failed to respond to tumour necrosis factor- α (TNF-α) inhibitors. METHOD: This phase III double-blind, double-dummy, placebo-controlled study (NCT01770379) randomized (1:1:1) patients to subcutaneous secukinumab 150 mg, secukinumab 75 mg, or placebo at baseline, weeks 1, 2, 3, and 4, and then every 4 weeks. American College of Rheumatology (ACR) 20 response at week 24 was the primary endpoint. Secondary outcomes included the 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP), Health Assessment Questionnaire Disability Index (HAQ-DI), and ACR50 at week 24. Long-term treatment was planned for 5 years. RESULTS: ACR20 response rates at week 24 for the secukinumab 150 mg and 75 mg groups were not statistically superior to placebo. None of the secondary endpoints was met for either secukinumab dose. Although not statistically significant, compared with placebo, numerically greater differences in least squares mean changes from baseline in HAQ-DI score and numerically higher ACR50 response rates were observed at week 24 in both secukinumab treatment groups. No new or unexpected adverse events were observed in this study compared with the large secukinumab safety database across psoriasis, psoriatic arthritis, ankylosing spondylitis, and other RA studies. CONCLUSIONS: Given that other second-line therapies have demonstrated efficacy in RA patients who failed to respond to TNF-α inhibitors, these findings may suggest that interleukin-17A inhibition with secukinumab does not provide additional benefit to these patients. This study further confirms the well-characterized safety profile of secukinumab.

Association of left ventricular structural and functional abnormalities with aortic and brachial blood pressure variability in hypertensive patients: the SAFAR study.

Both brachial blood pressure (BP) level and its variability (BPV) significantly associate with left ventricular (LV) structure and function. Recent studies indicate that aortic BP is superior to brachial BP in the association with LV abnormalities. However, it remains unknown whether aortic BPV better associate with LV structural and functional abnormalities. We therefore aimed to investigate and compare aortic versus brachial BPV, in terms of the identification of LV abnormalities. Two hundred and three participants who underwent echocardiography were included in this study. Twenty-four-hour aortic and brachial ambulatory BP was measured simultaneously by a validated BP monitor (Mobil-O-Graph, Stolberg, Germany) and BPV was calculated with validated formulae. LV mass and LV diastolic dysfunction (LVDD) were evaluated by echocardiography. The prevalence of LV hypertrophy (LVH) and LVDD increased significantly with BPV indices (P⩽0.04) in trend tests. After adjustment to potential confounders, only aortic average real variability (ARV), but not brachial ARV or weighted s.d. (wSD, neither aortic nor brachial) significantly associated with LV mass index (P=0.02). Similar results were observed in logistic regression. After adjustment, only aortic ARV significantly associated with LVH (odds ratio (OR) and 95% confidence interval (CI): 2.28 (1.08, 4.82)). As for LVDD, neither the brachial nor the aortic 24-hour wSD, but the aortic and brachial ARV, associated with LVDD significantly, with OR=2.28 (95% CI: (1.03, 5.02)) and OR=2.36 (95% CI: (1.10, 5.05)), respectively. In summary, aortic BPV, especially aortic ARV, seems to be superior to brachial BPV in the association of LV structural and functional abnormalities.

Association of consumption of dairy products and meat with retinal vessel calibers in subjects at increased cardiovascular risk.

BACKGROUND AND AIMS: Association of dairy products and meat consumption with macrocirculation is previously described, but such association with microcirculation is poorly investigated. We aimed to test the hypothesis that the consumption of high- and low-fat dairy products as well as red, white, and processed meat is associated with retinal vessel calibers in adults at an increased risk of cardiovascular disease (CVD). METHODS AND RESULTS: In consecutive subjects (n = 181, age: 51.3 ± 12.4 years, 51.4% women) without CVD and diabetes mellitus but with increased CVD risk, we obtained digital left and right retinal images. These images were assessed with validated software to determine central retinal arteriolar and venular equivalents and the arteriolar to venular ratio (CRAE, CRVE, and AVR, respectively). The consumption of dairy products and meat was assessed through 24-h recalls in all volunteers. After adjustment for potential confounders, the following findings were obtained: (i) low-fat milk and yogurt were positively associated with CRAE (b=0.145, p=0.031 left; b=0.141, p=0.038 right) and inversely associated with CRVE (b=-0.155, p=0.026 left; b=-0.146, p=0.041 right); (ii) low-fat cheese was positively associated with CRAE (b=0.164, p=0.011 left and b=0.155, p=0.017 right); and (iii) red meat was inversely associated with CRAE (b=-0.143, p=0.032 left; b=-0.114, p=0.050 right). High-fat milk, yogurt, and cheese or white and processed meat were not found to be associated with retinal vessel calibers. CONCLUSIONS: High consumption of low-fat milk, yogurt, and cheese and low consumption of red meat could be beneficial for retinal microvascular health. Prospective studies are needed to verify these findings.

Association of left ventricular diastolic dysfunction with 24-h aortic ambulatory blood pressure: the SAFAR study.

Aortic blood pressure (BP) and 24-h ambulatory BP are both better associated with target organ damage than office brachial BP. However, it remains unclear whether a combination of these two techniques would be the optimal methodology to evaluate patients' BP in terms of left ventricular diastolic dysfunction (LVDD) prevention. In 230 participants, office brachial and aortic BPs were measured by a validated BP monitor and a tonometry-based device, respectively. 24-h ambulatory brachial and aortic BPs were measured by a validated ambulatory BP monitor (Mobil-O-Graph, Germany). Systematic assessment of patients' LVDD was performed. After adjustment for age, gender, hypertension and antihypertensive treatment, septum and lateral E/Ea were significantly associated with office aortic systolic BP (SBP) and pulse pressure (PP) and 24-h brachial and aortic SBP and PP (P ⩽ 0.04), but not with office brachial BP (P ⩾ 0.09). Similarly, 1 standard deviation in SBP was significantly associated with 97.8 ± 20.9, 86.4 ± 22.9, 74.1 ± 23.3 and 51.3 ± 22.6 in septum E/Ea and 68.6 ± 2 0.1, 54.2 ± 21.9, 37.9 ± 22.4 and 23.1 ± 21.4 in lateral E/Ea, for office and 24-h aortic and brachial SBP, respectively. In qualitative analysis, except for office brachial BP, office aortic and 24-h brachial and aortic BPs were all significantly associated with LVDD (P ⩽ 0.03), with the highest odds ratio in 24-h aortic SBP. Furthermore, aortic BP, no matter in the office or 24-h ambulatory setting, showed the largest area under receiver operating characteristic curves (P ⩽ 0.02). In conclusion, 24-h aortic BP is superior to other BPs in the association with LVDD.

Increased DNA double-strand breaks and enhanced apoptosis in patients with lupus nephritis.

OBJECTIVE: DNA double-strand breaks (DSBs) lead to mutations, genomic instability and apoptotic death, whereas accumulation of apoptotic cells results in excessive autoantigen presentation and autoantibody formation. We aimed to measure DSB levels in lupus nephritis, a severe complication of the prototypic systemic autoimmune disease. METHODS: The intrinsic DNA damage and the apoptosis induction/DSB levels were evaluated in peripheral blood mononuclear cells of six patients and 10 healthy controls following exposure to genotoxic agents (melphalan, cisplatin) ex vivo. DSBs were assessed using immunofluorescence quantification of γH2AX foci and comet assay. RESULTS: Intrinsic DNA damage was increased in lupus versus control cells in both assays (Olive Tail Moment units of 15.8 ± 2.3 versus 3.0 ± 1.4 in comet, p < 0.01; % γH2AX-positive cells: 13.6 ± 1.8 versus 4.6 ± 0.9, p < 0.01, respectively). Melphalan or cisplatin doses as low as 9.9 ± 4.8 or 29.8 ± 8.3 µg/ml, respectively, were sufficient to induce apoptosis in lupus cells; control cells required doses of 32.3 ± 7.7 and 67.7 ± 5.5 µg/ml, respectively. Drug-induced DSB levels were increased in lupus versus control cells, with the area under the curve (AUC) for melphalan-induced DSBs being 3050 ± 610 (% γH2AX-positive staining cells) × (drug dose) in patients and 1580 ± 350 in controls (p < 0.05); the corresponding values for cisplatin-induced AUC were 13900 ± 1800 for lupus and 4500 ± 750 for controls (p < 0.01). Interestingly, within either lupus patients or controls examined, the accumulation of DSBs correlated with apoptosis degrees (all p < 0.01). Results in lupus cells were not associated with individual disease activity level or treatment modalities at the time of the study. CONCLUSION: These findings suggest a novel mechanism by which increased accumulation of DSBs may render cells more sensitive to apoptosis, thus contributing to the induction of systemic autoimmunity.

Cadherin-11 mRNA transcripts are frequently found in rheumatoid arthritis peripheral blood and correlate with established polyarthritis.

Rheumatoid arthritis (RA) synovial fibroblasts hyperexpress the mesenchymal cadherin-11, which is involved also in tumor invasion/metastasis, whereas anti-cadherin-11 therapeutics prevent and reduce experimental arthritis. To test the hypothesis that cadherin-11 is aberrantly expressed in RA peripheral blood, 100 patients (15 studied serially) and 70 healthy controls were analyzed by real-time reverse transcription-PCR. Cadherin-11 mRNA transcripts were detected in 69.2% of moderately/severely active RA, versus 31.8% of remaining patients (p=0.001), versus 17.1% of controls (p<0.0001). Notably, cadherin-11 positivity correlated significantly and independently only with established (>1year) polyarthritis (>4 swollen tender joints), by multivariate logistic regression analysis including various possible clinical/laboratory factors. Rare cells of undefined nature, detected by flow cytometry following CD45(-) enrichment, strongly expressed surface cadherin-11 (estimated 10-50cells/ml of blood) in 5/6 patients with polyarticular established disease versus 1/6 patients with early RA. Studies on the potential pathogenic role of circulating cells expressing cadherin-11 in RA are warranted.

Chromatin structure, transcriptional activity and DNA repair efficiency affect the outcome of chemotherapy in multiple myeloma.

BACKGROUND: Melphalan is one of the most active chemotherapeutic agents in the treatment of multiple myeloma (MM). However, the mechanism underlying differential patient responses to melphalan therapy is unknown. METHODS: Chromatin structure, transcriptional activity and DNA damage response signals were examined following ex vivo treatment with melphalan of both malignant bone marrow plasma cells (BMPCs) and peripheral blood mononuclear cells (PBMCs) of MM patients, responders (n=57) or non-responders (n=28) to melphalan therapy. PBMCs from healthy controls (n=25) were also included in the study. RESULTS: In both BMPCs and PBMCs, the local chromatin looseness, transcriptional activity and repair efficiency of the transcribed strand (TS) were significantly higher in non-responders than in responders and lowest in healthy controls (all P<0.05). Moreover, we found that melphalan-induced apoptosis inversely correlated with the repair efficiency of the TS, with the duration of the inhibition of mRNA synthesis, phosphorylation of p53 at serine 15 and apoptosis rates being higher in responders than in non-responders (all P<0.001). CONCLUSIONS: Our findings provide a mechanistic basis for the link between DNA repair efficiency and response to melphalan therapy. Interestingly, the observation of these phenomena in PBMCs provides a novel approach for the prediction of response to anti-myeloma therapy.

Baseline osteocalcin levels and incident diabetes in a 3-year prospective study of high-risk individuals.

AIM: Experimental evidence suggests that osteocalcin is a key messenger that affects both adipocytes and insulin-producing ß cells. Epidemiological cross-sectional studies have shown a negative association between plasma levels of osteocalcin and glucose. For this reason, the hypothesis that lower baseline osteocalcin plasma levels are associated with diabetes was prospectively tested. METHODS: The study population consisted of individuals at high risk for type 2 diabetes who were screened for participation in the Greek arm of a European type 2 diabetes prevention study (the DE-PLAN study). All participants were free of diabetes at baseline and underwent a second evaluation 3 years later. Diabetes status was defined according to an oral glucose tolerance test. RESULTS: A total of 307 subjects were included in the present analysis. The population, including 154 men (50.3%), was middle-aged (54.4 ± 10.2 years) and overweight (BMI: 29.5 ± 4.9 kg/m(2)). At baseline, mean total plasma osteocalcin was lower in those with impaired fasting glucose and/or impaired glucose tolerance compared with those with normal glucose tolerance (6.0 ± 3.1 ng/mL vs. 7.3 ± 4.0 ng/mL, respectively; P = 0.01). After 3 years, 36 subjects had developed diabetes. In the prospective evaluation, there was no association between baseline osteocalcin levels and diabetes (OR: 1.04 per 1 ng/mL, 95% CI: 0.93-1.15; P = 0.49) on multivariable logistic regression analysis, nor was there any correlation with changes in plasma glucose after 3 years (r = 0.09, P = 0.38). CONCLUSION: Our prospective results show that lower levels of circulating osteocalcin do not predict future diabetes development and, in contrast to most cross-sectional published data so far, suggest that this molecule may not be playing a major role in glucose homoeostasis in humans.

Progressive changes in chromatin structure and DNA damage response signals in bone marrow and peripheral blood during myelomagenesis.

The molecular pathways implicated in multiple myeloma (MM) development are rather unknown. We studied epigenetic and DNA damage response (DDR) signals at selected model loci (N-ras, p53, d-globin) in bone marrow plasma cells and peripheral blood mononuclear cells (PBMCs) from patients with monoclonal gammopathy of undetermined significance (MGUS; n=20), smoldering/asymptomatic MM (SMM; n=29) and MM (n=18), as well as in healthy control-derived PBMCs (n=20). In both tissues analyzed, a progressive, significant increase in the looseness of local chromatin structure, gene expression levels and DNA repair efficiency from MGUS to SMM and finally to MM was observed (all P<0.002). Following ex vivo treatment with melphalan, a gradual suppression of the apoptotic pathway occurred in samples collected at different stages of myelomagenesis, with the severity and duration of the inhibition of RNA synthesis, p53 phosphorylation at serine15 and induction of apoptosis being higher in MGUS than SMM and lowest in MM patients (all P<0.0103). Interestingly, for all endpoints analyzed, a strong correlation between plasma cells and corresponding PBMCs was observed (all P<0.0003). We conclude that progressive changes in chromatin structure, transcriptional activity and DDR pathways during myelomagenesis occur in malignant plasma cells and that these changes are also reflected in PBMCs.

Effect of supine versus sitting position on noninvasive assessment of aortic pressure waveform: a randomized cross-over study.

Biomarkers derived noninvasively from the aortic blood pressure (BP) waveform provide information regarding cardiovascular (CV) risk independently of brachial BP (bBP). Although body position has significant impact on the assessment of bBP, its effect on aortic hemodynamics remains unknown. This study investigated the changes in both brachial and aortic hemodynamics, between the supine and sitting position. In this randomized cross-over study, the bBP and the aortic pressure waveform were assessed after a 5 min rest (sitting and supine in randomized order); aortic BP, pulse pressure (PP) amplification, augmentation index (AIx) and subendocardial viability index (SEVR) were assessed. Sixty-one subjects were examined (36 males, mean age 50±12 years). Mean BP did not differ between the sitting and supine position (110.8±13.7 vs 110.9±14.9, respectively, P=0.945). However, significant difference between the sitting and supine position in brachial PP (45.9±16.0 vs 52.6±15.6, respectively, P<0.001), aortic PP (36.7±15.2 vs 43.1±13.9, P<0.001), PP amplification (1.28±0.1 vs 1.23±0.1, P<0.001), AIx (26.9±11.9 vs 31.1±10.2, P<0.001) and SEVR (179.6±25.7 vs 161.2±25.8, P<0.001) were found. Review of the literature identified underestimation of the role of body position on aortic hemodynamics. In conclusion, increased PP in both the aorta and brachial artery were found in the supine compared to the sitting position. Reduced PP amplification and SEVR were further observed in the supine position, due to increased pressure wave reflections (AIx).