Effect of liraglutide on ambulatory blood pressure in patients with hypertension and type 2 diabetes: A randomized, double-blind, placebo-controlled trial.

AIMS: To assess the effect of liraglutide on 24-hour ambulatory blood pressure and heart rate in patients with hypertension (pre- and stage 1 hypertension) and inadequately controlled Type 2 diabetes (glycated haemoglobin 7%-10% [53-86 mmol/mol]). MATERIALS AND METHODS: Eligible patients for this investigator-initiated, parallel-group, randomized, double-blind trial were on stable background antihyperglycaemic therapy excluding insulin, glucagon-like peptide-1 receptor agonists and dipeptidyl-peptidase-4 inhibitors. Participants were centrally randomized in a 1:1 ratio to daily liraglutide 0.6 mg, titrated to 1.2 mg after the first week, or placebo for 5 weeks. The primary outcome was change in 24-hour ambulatory systolic blood pressure (SBP), and secondary outcomes included change in ambulatory diastolic blood pressure (DBP) and heart rate. We also assessed renal sodium handling. RESULTS: Of 87 patients assessed for eligibility, 62 (66.1% men) with a mean age of 60.2 years were randomized to liraglutide (n = 31) or placebo (n = 31). All participants received background therapy with metformin, whilst 35.5% were treated concomitantly with sulphonylureas and 14.5% with pioglitazone. Compared with placebo, liraglutide reduced 24-hour SBP by -5.73 mm Hg (95% confidence interval [CI] -9.81 to -1.65) and had a neutral effect on 24-hour DBP (mean difference - 1.42 mm Hg; 95% CI -4.25 to 1.40), whilst increasing 24-hour heart rate by 6.16 beats/min (95% CI 3.25 to 9.07). Findings were consistent for daytime and night-time measurements. Liraglutide did not increase urine sodium excretion. CONCLUSION: Based on 24-hour ambulatory measurements, short-term treatment with liraglutide had a favourable effect on SBP whilst increasing heart rate.

Arterial stiffness and peripheral arterial disease in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is associated with increased cardiovascular risk. We aimed to evaluate arterial stiffness and the ankle brachial index (ABI), two markers of subclinical cardiovascular disease, in SLE. We studied 55 patients with SLE (12.7% males, age 53.3 ± 15.3 years) and 61 age- and gender-matched controls. Arterial stiffness was evaluated by measuring pulse wave velocity (PWV), augmentation index (AIx) and central systolic, diastolic, pulse and mean blood pressure (BP). Peripheral arterial disease was defined as ABI ≤ 0.90. Regarding markers of arterial stiffness, patients with SLE had lower PWV and AIx than controls (p < 0.01 and p < 0.05, respectively). However, after adjusting for differences in cardiovascular risk factors between patients with SLE and controls, PWV and AIx did not differ between the two groups. Central systolic, diastolic, pulse and mean BP also did not differ between the two groups. In patients with SLE, PWV correlated independently with systolic BP (B = 0.05, p < 0.001) and waist/hip ratio (B = 6.72, p < 0.05). Regarding ABI, the lowest ABI was lower in patients with SLE than in controls (p < 0.005). However, after adjusting for differences in cardiovascular risk factors between patients with SLE and controls, the lowest ABI did not differ between the two groups. The prevalence of PAD also did not differ between patients with SLE and controls (10.0 and 5.4%, respectively; p = NS). Markers of arterial stiffness and the ABI do not appear to differ between patients with SLE and age- and gender-matched controls. However, given the small sample size, larger studies are needed to clarify whether SLE promotes arterial stiffness and PAD.

Safety profile of repeated rituximab cycles in unselected rheumatoid arthritis patients: a long-term, prospective real-life study.

OBJECTIVES: To evaluate the long-term safety of rituximab (RTX) in rheumatoid arthritis (RA) patients in daily clinical practice. METHODS: This was a multicentre (17 Greek Rheumatology sites), prospective, long-term, pharmacovigilance study of patients with moderate to severe RA and an inadequate response or intolerance to ≥1 anti-tumour necrosis factor (TNF) agents. Adverse events (AEs) were recorded and collected prospectively every 2-6 months. RESULTS: 234 patients (mean age: 59±12.5, 79.5% women, mean DAS28: 5.35±1.32) were included and followed for 27.7 months (median). The overall AEs, serious AE (SAEs) and serious infection (SIEs) rate were 48.36, 6.68 and 2.53/100 patient-years, respectively. Three cases of hepatitis B virus (HBV) reactivation were recorded (two in chronic and one in past HBV infection). Withdrawals due to AEs (5.6%) occurred more frequently during the first cycles of RTX therapy while repeated RTX cycles were not associated with an increased risk of AEs. There were 3 deaths with an incidence rate of 0.69/100 patient-years. Age ≥65 years was associated with a higher incidence rate ratio of AEs and SAEs as compared to <65 years (1.53, p=0.002 and 2.88, p=0.005, respectively). Drug retention rate during 434.28 patient-years of follow-up was 57.3%. Factors associated with drug discontinuation by multivariate analysis included age, baseline swollen joint count and no use of concomitant methotrexate therapy. CONCLUSIONS: Long-term RTX therapy in a real-life RA cohort, did not reveal any new safety issues. Advanced age was associated with increased risk of AEs and premature drug discontinuation.

T regulatory cells: a promising new target in atherosclerosis.

T regulatory cells (Tregs) comprise the cardinal mechanism of peripheral immune tolerance by modulating the function of virtually each immune cell. Given that atherosclerosis is a chronic inflammation of the arterial wall, certain components of the immune system have been proven to have a central role in its pathogenesis. Consequently, various clinical and experimental studies have been conducted to elucidate the role of Tregs in suppressing this immune-mediated inflammation. In this review, current experimental and clinical knowledge on the role of Tregs in the atherogenic process is presented after a short introduction to their generation and function. Based on these data, Treg-targeted therapeutic approaches are discussed in regard to their potential for clinical application.

Is there a role for low-dose eltrombopag as maintenance therapy in the treatment of immune thrombocytopenia?

BACKGROUND/AIM: Thrombopoietin receptor agonists (romiplostim and eltrombopag) have recently been licensed for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP) with an insufficient response to corticosteroids, immunoglobulins or splenectomy. In the present case series, we present 4 nonresponding patients with chronic ITP who achieved maintenance of complete response (CR) for a period of at least 6 months on eltrombopag treatment administered in a modified regimen of 25 mg for 2, 3 or 5 days a week. METHODS: The present study is a retrospective, nonconsecutive case series of 4 eltrombopag-treated patients with chronic ITP. Secondary ITP had been excluded in each patient, first-line therapy had failed and splenectomy had been refused. Furthermore, each patient was treated with eltrombopag, which resulted in a CR for a mean of 2 months. Consequently, decreased eltrombopag dosages have been able to maintain long-term CR. RESULTS/CONCLUSION: Despite the low quality of evidence, our study results support the use of reduced-dose eltrombopag as a maintenance therapy after achieving CR. It seems a very promising strategy for the effective maintenance of response, improving health-related quality of life, lowering costs and possibly improving the safety in the treatment of ITP.

Five Years of Deferasirox Therapy for Cardiac Iron in ß-Thalassemia Major.

Myocardial siderosis in ß-thalassemia major (ß-TM) remains the leading cause of death. Deferasirox (DFX), a new iron chelation treatment, has proved to be effective in reducing or preventing cardiac iron burden in thalassemic patients according to clinical trials with maximum duration of up to 3 years except one that was recently published and lasted 5 years. The aim of this study was to evaluate the efficacy of DFX in reducing or preventing cardiac iron burden in 23 patients with ß-TM after 5 years of therapy. All patients had a magnetic resonance imaging (MRI) T2* evaluation of their cardiac iron load before starting DFX therapy and after a period of 5 years. Ferritin levels and left ventricular ejection fraction (LVEF) were also evaluated at the same time. Deferasirox was administered in a starting dose of 30 mg/kg/day and never increased to more than 40 mg/kg/day. The MRI T2* cardiac iron load mean values before DFX was 32.82 ± 10.86 ms, and after 32.13 ± 7.74 ms, showing a stability in MRI T2* myocardial value but a significant improvement in two patients with an intermediate iron load (12 vs. 23 ms). The mean LVEF value was 68.43 ± 7.08% before treatment with DFX and 67.95 ± 5.94% after DFX therapy without significant change. Our results confirm previous studies that DFX is considered an effective chelating agent used as monotherapy for at least 5 years and is more efficacious in moderate to severe cardiac iron loaded thalassemic patients.

Evaluation of Mental Health and Physical Pain in Patients with ß-Thalassemia Major in Northern Greece.

ß-Thalassemia major (ß-TM) is a chronic, genetic blood disorder. Patients are considered to be vulnerable to emotional and behavioral problems. The aim of this study was to assess mental health and somatic pain of patients with homozygous ß-TM, who are systematically transfused in our unit. In this survey, 54 adult patients were studied. The general health questionnaire (GHQ-28) was used as mental health assessment model aimed at detecting mental disorders. The model of Binary was used as scoring method of GHQ-28. Overall ratings below 5 indicate no psychiatric problem, while a total score over or equal to 5 indicated the likelihood of a psychiatric disorder. The visual analogue scale (VAS) of pain was used as model for pain evaluation. One out of four examined patients who presented with a GHQ-28 score above or equal to 5 had an increased chance of being diagnosed with a psychiatric disorder. Concerning the pain, the majority of the studied patients scored between 1 and 3, meaning that they were feeling mild pain. There was no statistical significant correlation between age and GHQ-28 score. There was a statistical significant correlation between age and somatic symptoms (p = 0.026), anxiety and somatic symptoms (0.004) as well as anxiety and depression (p = 0.022). Thalassemic patients tend to be diagnosed with psychiatric disorders and it seems that they do not feel severe pain. More quantitative and comprehensive studies have to be conducted in order to estimate specific effective factors in psychosocial health.

CD4+CD25highFOXP3+ T regulatory cells as a biomarker of disease activity in systemic lupus erythematosus: a prospective study.

OBJECTIVES: Several studies have reported low numbers of T regulatory cells (Tregs) in active systemic lupus erythematosus (SLE). However, it is not evident if these cells may be utilised as a biomarker in assessing disease activity. METHODS: Tregs (CD4+CD25highFOXP3+) were prospectively assessed by flow cytometry in 285 separate blood samples from 100 white Caucasian SLE patients and 20 healthy controls. Patients were divided, according to disease activity (as measured by SLEDAI) into groups A (n=39, samples=94, SLEDAI=0), B (n=33, samples=92, SLEDAI=1-5), C (n=10, samples=53, SLEDAI=6-10) and D (n=18, samples=46, SLEDAI>10). Longitudinal measurements were performed in 131 cases (37 relapses, 44 remissions and 50 cases with stable disease activity) during three years. Statistics were performed by Student's t-test or one-way ANOVA; correlations with Pearson co-efficient, while p<0.05 was considered significant. RESULTS: Tregs were found significantly lower in severely active disease (group D), compared to healthy controls, inactive disease, mild and moderate disease activity (0.57±0.16% vs. 1.49±0.19%, 1.19±0.34% and 1.05±0.36%, 0.72±0.21%, p<0.05, respectively). There was a strongly inverse correlation between Tregs and SLEDAI (r=-0.644, p<0.001). Alterations in disease activity were characterised by inverse alterations in Tregs: relapse (from 1.23±0.44% to 0.64±0.19%, p<0.001, mean change 0.59±0.41%), remission (from 0.65±0.27% to 1.17±0.30%, p<0.001, mean change 0.52±0.35%). In cases with unaltered disease activity, Treg numbers remained stable (from 0.98±0.35% to 1.03±0.34%, p=0.245). Tregs were practically halved during relapse (mean reduction 42.6±22.2%), and doubled during remission (mean increment 113±120.9%). Mean change of Tregs in stable disease was significantly lower (7.3±20.6%, p<0.001). A clinically significant change in SLEDAI (sum of cases with relapse and remission, n=81) was followed by a significant (>20%) inverse change in Tregs in 71/81 cases (sensitivity 87.7%). In 50 cases of stable disease activity, Tregs were significantly changed (>20%) in 13 cases (specificity 74%). Positive predictive value (PPV) was 84.5% and negative predictive value (NPV) was 78.7%. CONCLUSIONS: CD4+CD25highFOXP3+ T regulatory cells displayed a strongly inverse correlation to disease activity in the long term. Treg alterations reflected changes in SLEDAI with high sensitivity. These cells may be a reliable biomarker for the assessment of disease activity in SLE by longitudinal measurements.

Effects of doxycycline on clinical, microbiological and immunological parameters in well-controlled diabetes type-2 patients with periodontal disease: a randomized, controlled clinical trial.

AIM: To evaluate the clinical, microbiological and immunological effects of systemic doxycycline as an adjunct to scaling and root planing (SRP) in chronic periodontitis patients with well-controlled type 2 diabetes. MATERIALS AND METHODS: Sixty-six patients compliant to oral hygiene (Hygiene Index <20%) allocated to either a test (systemic doxycycline for 21 days) or a control (placebo) group participated in the present randomized controlled trial (RCT). Clinical assessments were recorded at baseline, 3 and 6 months after therapy and included clinical attachment level (CAL), set as the primary outcome of the study, probing pocket depth (PPD), recession (RE) and bleeding on probing (BOP). At the same time points, counts of 15 subgingival species were evaluated by "checkerboard" DNA-DNA hybridization, gingival crevicular fluid samples were analysed for matrix metalloproteinase-8 (MMP-8) by ELISA and HbA1c levels were determined. Comparisons between and within groups were performed by non-parametric tests (Mann-Whitney, Wilcoxon signed-ranks and z-test for proportions with Bonferroni corrections) at the 0.05 level. RESULTS: No major differences were noticed in clinical and microbiological parameters of periodontal disease or levels of MMP-8 between the two groups. CONCLUSIONS: Adjunctive systemic doxycycline does not seem to significantly enhance the effects of SRP in well-controlled diabetes type 2 patients.

Thrombotic thrombocytopenic purpura or immune thrombocytopenia in a sickle cell/ß+-thalassemia patient: a rare and challenging condition.

The diagnosis of thrombotic thrombocytopenic purpura is one of the possible diagnosis when a patient is admitted with unexpected micro-angiopathic hemolytic anemia and thrombocytopenia. The combination of sickle cell/ß(+)-thalassemia and thrombotic thrombocytopenic purpura is rare and triggering. This article describes the poor outcome of a patient with sickle cell/ß(+)-thalassemia presenting with gingival bleeding, severe thrombocytopenia and anemia. The patient had normal renal function, no neurological deficit and he was initially treated as immune thrombocytopenic purpura. He eventually died due to multi-organ failure and brain hemorrhage even though he had started plasma exchange sessions. The co-existence of thrombotic thrombocytopenic purpura and sickle cell anemia is making the diagnosis of the former difficult. Early and rapid intervention is critical to the outcome.

Hypohidrosis induced by topiramate in an adult patient.

Hypohidrosis is an uncommon and reversible side effect of topiramate treatment, reported mainly in children. This report presents an adult patient with complex partial seizures who was treated with topiramate and developed hypohidrosis coupled with hyperthermia, related to high environmental temperature and physical exercise. Reduced sweat response was confirmed using the Neuropad test. Signs and symptoms ceased after drug discontinuation. During topiramate treatment, it is important to recognise this side effect, although the exact causal mechanism has not yet been clarified.

Influenza A/H1N1 septic shock in a patient with systemic lupus erythematosus. A case report.

BACKGROUND: Immunocompromised patients, such as systemic lupus erythematosus (SLE) sufferers have an increased risk of mortality, following influenza infection. In the recent pandemic, influenza A H1NI virus caused 18449 deaths, mainly because of adult respiratory distress syndrome or bacterial co-infections. CASE PRESENTATION: In this case report, an SLE patient with viral-induced septic shock, without overt pulmonary involvement, is discussed. The patient was administered oseltamivir and supportive treatment, including wide-spectrum antibiotics, vasopressors and steroids, according to the guidelines proposed for bacterial sepsis and septic shock. She finally survived and experienced a lupus flare soon after intensive care unit (ICU) discharge. CONCLUSIONS: To our knowledge, this is the first case to report severe septic shock from influenza A/H1N1 virus, without overt pulmonary involvement.

Chronic brucellosis patients retain low frequency of CD4+ T-lymphocytes expressing CD25 and CD28 after Escherichia coli LPS stimulation of PHA-cultured PBMCs.

Chronic brucellosis patients display a defective Th1 response to PHA. We have previously shown that heat-killed B. abortus (HKBA) can downregulate the PHA-induced increase of CD4+/CD25+ and CD14+/CD80+ cells of brucellosis patients. In the present study, we investigate the effect of E. coli LPS, as a potent stimulant of monocytes and autologous T-lymphocytes, on the PHA-cultured PBMCs of the same groups of patients. Thirteen acute brucellosis (AB) patients, 22 chronic brucellosis (CB) patients, 11 "cured" subjects, and 15 healthy volunteers were studied. The percentage of CD4+/CD25+ and CD4+/CD28+ T-lymphocytes as well as CD14+/CD80+ monocytes were analyzed by flow cytometry after PBMCs culture with PHA plus E. coli LPS. A significant decrease in the percentage of CD4+/CD25+ and CD4+/CD28+ T-lymphocytes was observed in CB compared to AB. In HKBA cultures, compared to E. coli LPS-cultures, there was a significant reduction of CD4+/CD25+ T-lymphocytes in all groups and CD14+/CD80+ in patients groups. We suggest that Brucella can modulate host immune response, leading to T-cell anergy and chronic infection.

Longterm Beneficial Effect of Canakinumab in Colchicine-resistant Familial Mediterranean Fever.

OBJECTIVE: To assess the efficacy and safety of the interleukin-1ß (IL-1ß) inhibitor canakinumab in all adolescent and adult patients with familial Mediterranean fever (FMF) identified from the Greek National Registry for off-label drug use between 2010 and 2015. METHODS: In this retrospective longitudinal outcome study, clinical and laboratory data were collected from 14 patients (7 men) aged median 38.5 years (range 13-70), with median disease duration of 14 years, and active FMF despite colchicine (n = 9) or both colchicine and anakinra (n = 5). RESULTS: All patients continued to receive canakinumab at last visit (median of 18 mos, range 13-53), which was initially given as monotherapy (n = 8) or in combination with colchicine and/or corticosteroids, every 4 (n = 7), 6 (n = 2), or 8 weeks (n = 5). Eleven patients (79%), including 6 receiving monotherapy, achieved complete clinical remission within 2 months (median), while normalization of all laboratory variables denoting inflammation occurred in 92% at 3 months (median). The remaining 3 patients achieved partial responses. Responses were sustained in all but 4 patients, who relapsed. Reducing the canakinumab administration interval from 8 or 6 weeks to 4 weeks led to suppression of disease activity in the relapsing patients. On the other hand, drug administration interval could be safely increased in 2 patients in remission. Corticosteroid doses were significantly reduced during followup. Canakinumab was well tolerated; 1 patient experienced a urinary tract infection and another one a viral gastroenteritis. CONCLUSION: Treatment with canakinumab in an individualized dosing scheme results in rapid and sustained remission in colchicine-resistant FMF.