Body

DALLAS, June 17, 2019 - Seeking new treatments to slow the progression of Alzheimer's disease, researchers found the blood pressure drug nilvadipine increased blood flow to the brain's memory and learning center among people with Alzheimer's disease without affecting other parts of the brain, according to new research in the American Heart Association's journal Hypertension.

These findings indicate that the known decrease in cerebral blood flow in patients with Alzheimer's can be reversed in some regions. However, an important question is whether this observed increase in cerebral blood flow translates to clinical benefits, the authors note.

Alzheimer's disease is the most common form of dementia. The risk for the disease increases with age and the causes are largely unknown. Previous research has shown that blood flow to the brain declines in early Alzheimer's disease.

Nilvadipine is a calcium channel blocker used to treat high blood pressure. Researchers sought to discover whether nilvadipine could help treat Alzheimer's disease by comparing the use of nilvadipine and a placebo among people with mild to moderate Alzheimer's disease. Researchers randomly assigned 44 participants to receive either nilvadipine or a placebo for six months. Neither researchers nor the participants knew who received the drug or the placebo that was evenly divided among the two groups. At the study's start and after six months, researchers measured blood flow to specific regions of the brain using a unique magnetic resonance imaging (MRI) technique.

Results showed that blood flow to the hippocampus - the brain's memory and learning center - increased by 20% among the nilvadipine group compared to the placebo group. Blood flow to other regions of the brain was unchanged in both groups.

"This high blood pressure treatment holds promise as it doesn't appear to decrease blood flow to the brain, which could cause more harm than benefit," said study lead author Jurgen Claassen, M.D., Ph.D., associate professor at Radboud University Medical Center in Nijmegen, the Netherlands. "Even though no medical treatment is without risk, getting treatment for high blood pressure could be important to maintain brain health in patients with Alzheimer's disease."

Researchers note that sample sizes were too small and follow-up time too short to reliably study the effects of this cerebral blood flow increase on structural brain measures and cognitive measures.

Study participants were screened between 2013 and 2015 as part of a larger research project comparing nilvadipine to placebo among more than 500 people with mild to moderate Alzheimer's disease (average age 73, more than half female and most were Caucasian).

In that larger project, effects on cerebral blood flow were not measured. Overall, no clinical benefit was noted with use of nilvadipine. However, a subgroup of patients with only mild symptoms of disease did show benefit, in the sense of a slower decline in memory.

Previous studies have hinted that high blood pressure treatment could reduce the risk of developing dementia. The authors think that beneficial effects on brain blood flow could explain part of this effect.

The study is one of a few to use this MRI technique to probe the effects of treatment on cerebral blood flow, making additional research critical. In addition, the small number of participants of similar race and ethnicity mean that the results may not apply to other populations.

"In the future, we need to find out whether the improvement in blood flow, especially in the hippocampus, can be used as a supportive treatment to slow down progression of Alzheimer's disease, especially in earlier stages of disease," Claassen said.

MORGANTOWN, W.Va.--If the American Cancer Society's projections prove accurate, more people will die from pancreatic cancer than from breast, brain, ovarian or prostate cancer this year.

One reason pancreatic cancer is so lethal is its resistance to traditional chemotherapy. But West Virginia University surgical oncologist Brian Boone is exploring whether FOLFIRINOX--a new combination of cancer drugs--can improve outcomes in patients whose pancreatic cancer is "borderline resectable," meaning that a tumor may be too close to a blood vessel to be removed safely.

"The way pancreatic tumors sit, they're very close to several important blood vessels that you really can't live without. That's where chemotherapy comes into play," said Boone, an assistant professor in the School of Medicine's Department of Surgery. "We try to shrink the tumor off of the vein and change it from borderline resectable to resectable, or removable by surgery."

In a recent meta-analysis of 24 studies, Boone and a team of researchers considered 313 cases of borderline resectable pancreatic cancer that physicians treated with FOLFIRINOX. They analyzed the patients' overall survival rates. They also evaluated how frequently tumors shrank enough to be surgically removed. The team found that FOLFIRINOX prolonged patients' lives, on average, and made surgery possible in more instances. Their findings appear in the Journal of the National Cancer Institute.

"There's no control group, but when you compare it to what we've historically seen in patients that are borderline resectable and that we take straight to surgery, FOLFIRINOX resulted in better survival and better rates of resection," Boone said.

More than two-thirds--or 67.8 percent--of the cancers included in the study responded well enough to FOLFIRINOX that they could be completely removed surgically. "Historically, complete removal of the tumor is accomplished in a far lower number of patients without treatment before surgery and often requires removal of a portion of the vein," he said.

On average, patients who took FOLFIRINOX survived for 22.2 months overall. Without the drug, patients with borderline resectable cancer tend to survive for about 12 months, based on Boone's clinical experience.

"There's really been a paradigm shift for pancreatic cancer, now that we have better drugs," he said.

Despite these improvements in treatment, pancreatic cancer is currently the fourth deadliest, and "it's climbing the ladder in terms of the number of people it kills," said Carl Schmidt, chief of the Surgical Oncology Division. "In my 10 years of being in practice, there's been more interest in pancreatic cancer, but moving the needle is really hard."

To that end, Boone, Schmidt and their colleagues are pursuing studies that span the laboratories where scientists conduct basic-science experiments, the infusion rooms where patients receive treatment and the operating rooms where oncologists perform surgery.

"We're developing a full spectrum of pancreatic cancer research. That's why we do the basic science: we're identifying patients at the bedside and trying to find solutions in the lab," Boone said. "And it's all driven by trying to make outcomes better for patients that we take care of every day."

Defined as serum bicarbonate less than 22 mmol/L [2], metabolic acidosis is common in people with CKD stages 4-5 (eGFR

International guidelines recommend that, when serum bicarbonate concentration falls below 22 mmol/l, CKD patients should be treated with oral sodium bicarbonate to maintain serum bicarbonate within the normal range, unless contraindicated [2]. However, until recently, very few studies have tested the effectiveness of bicarbonate therapy in improving metabolic acidosis or its potential benefits in patients with CKD.

Results of the UBI trial announced for the first time during the ERA-EDTA Congress in Budapest, now provide strong evidence for the benefits of correcting metabolic acidosis with sodium bicarbonate in people with late-stage CKD.

The prospective, open-label, randomized controlled trial assigned 740 patients with CKD-3b and CKD stage 4 to either sodium bicarbonate (376 patients) or standard care without sodium bicarbonate (364 patients). The patients had a mean age of 67.8 years, creatinine clearance 30 ml/min, and serum bicarbonate 21.5 mmol/l. At the end of three years, doubling of creatinine occurred in significantly fewer patients randomized to sodium bicarbonate: 6.6% versus 17.0% receiving standard care, p

Similarly, the likelihood of starting RRT was also significantly lower in the sodium bicarbonate group. At the end of the study, 6.9% of patients receiving sodium bicarbonate had started RRT compared to 12.3% of the standard care group--a relative risk reduction of 50% (p=0.004; HR: 0.5; 95% CI: 0.31-0.81; p=0.005). The risk of death was also significantly lower among sodium bicarbonate-treated patients at 3.1% compared to 6.8 % of the standard care group--a relative risk reduction of 57% (p=0.004; HR 0.43; 95%CI 0.22-0.87; p=0.01). Treatment with sodium bicarbonate was well tolerated, with no significant effects on blood pressure, total body weight or hospitalizations.

"There are relatively few treatments that have been shown to slow progression of CKD. As nephrologist, we have used sodium bicarbonate to correct metabolic acidosis in people with CKD for some time, but definite evidence of benefit has been lacking. Our study shows that this very cost-effective treatment is safe and improves kidney and patient survival," concluded lead investigator Dr Antonio Bellasi.

Diabetes mellitus is a significant and growing health problem which contributes significantly to the prevalence of chronic kidney disease (CKD). According to the ERA-EDTA Registry, nearly a quarter (23%) of all patients who started renal replacement therapy in 2016 were patients with diabetes. The underlying idea of the study, which has been presented as a late breaking clinical trial at the ERA-EDTA congress in Budapest today, was to assess the potential of the DPP-4 inhibitor linagliptin (LINA), an oral diabetes drug, to reduce the burden of CKD and cardiac complications as secondary diseases in people with diabetes. Only a few weeks ago it had been shown that SGLT2 inhibitors, another class of diabetes drugs, could slow CKD progression in this patient group.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are usually prescribed for patients with type 2 diabetes as second or third line drugs, when there is not sufficient treatment response to more widely used drugs like metformin. DPP-4 inhibitors block the enzyme DPP-4, which destroys incretins. Incretins stimulate the production of insulin and, thus, the blood sugar level decreases with the medication.

"But do DPP-4 inhibitors have any beneficial renal and cardiovascular effects? Can they prevent these secondary diseases of diabetes? This is what we wanted to find out in our trial," explains lead investigator Professor Dr Christoph Wanner. The multicenter, randomized, double-blind CARMELINA trial compared LINA 5 mg vs placebo, added to standard of care, in people with type 2 diabetes and CV and/or kidney disease. The study assessed the cardio-renal disease burden and effects of the medication on CV, eGFR and albuminuria outcomes in participants with or without nephrotic-range proteinuria (defined as UACR ?2200 mg/g at baseline).

It showed that 646 of the 6979 randomized participants had nephrotic-range proteinuria and, thus, suffered from renal disease. They were at high risk of CV events and had poor kidney outcomes; a 3-fold greater decline in eGFR was seen in those with nephrotic-range proteinuria at baseline

The difference in HbA1c over the full trial duration favoured LINA (-0.36%). This did not differ between patients who had nephrotic-range proteinuria at baseline and those who had not. A larger proportion of patients who had received LINA vs placebo regressed to normoalbuminuria or had a reduction of urine albumin-to-creatinine ratio of ?50% from baseline - regardless of nephrotic-range proteinuria status. However, loss in eGFR over time was not different between the groups (-6.51/year vs placebo -7.07/year), and the medication did not affect the risk for so called 3-point major adverse cardiovascular events (HR.1.02 [95% CI, 0.89, 1.17]), CV mortality (0.96 [0.81, 1.14]), or all-cause hospitalization (0.93 [0.85, 1.00]), in people with or without nephrotic-range proteinuria

"Linagliptin is effective in lowering HbA1c and albuminuria, but this did not translate into a better renal and cardiac outcome. It controlled the diabetes and it could halt albuminuria, but it had no additional clinical benefits. But the study clearly showed that there is a group of patients with diabetes who clearly are in need of outcome-enhancing therapies, because their prognosis is rather poor. Nephrotic-range proteinuria might be a good marker to stratify these patients. I would advise to treat these patients with SGLT2 inhibitors instead, or a combination of SGLT2 inhibitor and DPP-4 inhibitor. Apart from diabetes control, SGLT2 inhibitors have shown to be effective in renal and cardiovascular risk reduction [2]", concluded lead investigator Professor Wanner.

Madrid, Spain, 14 June 2019: The results of a phase 2B study presented today at the Annual European Congress of Rheumatology (EULAR 2019) demonstrate superior efficacy and comparable safety of tildrakizumab versus placebo in patients with psoriatic arthritis.1

By week 24 in the study, a significantly higher proportion of patients receiving tildrakizumab (at any dose) achieved a 90% reduction in Psoriasis Area and Severity Index (PASI 90), and a 50% reduction in American College of Rheumatology response criteria (ACR 50) versus placebo. There were four active treatment groups in which patients received 20mg, 100mg or 200mg tildrakizumab every 12 weeks, or 200mg every four weeks. The response rates improved with increasing dose however the shortening of dosing interval of 200mg from 12 to four weeks did not result in a measurable increase in skin or joint response scores. In patients receiving 200mg tildrakizumab every 12 weeks, 79.6% and 50% achieved PASI 75 and PASI 90 respectively versus 16.7% and 7.1% in the placebo group (p

"Our results demonstrate a clear separation between tildrakizumab and placebo as early as eight weeks," said Philip Mease, MD, MACR, Swedish Medical Center/Providence St. Joseph Health and the University of Washington, Seattle, Washington, USA. "A promising role is suggested for tildrakizumab in the treatment of patients suffering with psoriatic arthritis."

Psoriatic arthritis is a chronic inflammatory disease that affects the joints, causing pain and disability. Tildrakizumab is a high-affinity, humanised, monoclonal antibody targeting interleukin (IL) 23p19 and is currently approved to treat moderate-to-severe plaque psoriasis. Current recommendations state that, in psoriatic arthritis patients with peripheral arthritis (one or more tender and swollen joints), biological disease-modifying anti-rheumatic drugs (DMARDs) targeting IL 12/23 or IL-17 pathways may be considered in patients who have had an inadequate response to conventional synthetic DMARDs and for whom tumour necrosis factor inhibitors are not appropriate.3

"We welcome these promising results for tildrakizumab in patients with psoriatic arthritis," said Professor Hans Bijlsma, President, EULAR. "Extending research into different patient groups may bring benefits that address current unmet needs."

The 24-week, randomised, double-blind, placebo-controlled, multiple-dose, phase 2B study included 391 adults with psoriatic arthritis who had three or more tender and three or more swollen joints. Patients were randomised (1:1:1:1:1) to receive tildrakizumab 200mg every four weeks, 200mg, 100mg or 20mg every 12 weeks, or placebo every four weeks. Stable concomitant methotrexate or leflunomide use was permitted but not mandated.1

Serious adverse events (AEs) occurred in 2.2% of tildrakizumab-treated patents and 2.5% of placebo-treated patients. Treatment-related serious AEs occurred in 0.3% of tildrakizumab-treated patients (as judged by the investigator). The most frequent AEs included nasopharyngitis and diarrhoea with no reports of candidiasis, inflammatory bowel disease, major adverse cardiac events, or malignancy. No patients discontinued treatment due to AEs and no deaths were reported.1

Abstract number: LB0002

Annual European Congress of Rheumatology
(EULAR 2019)
Madrid, Spain, 12-15 June 2019

Madrid, Spain, 14 June 2019: The results of a study presented today at the Annual European Congress of Rheumatology (EULAR 2019) demonstrate increased rates of type I diabetes and inflammatory bowel disease (IBD) in patients that go on to develop rheumatoid arthritis (RA).1

RA is a chronic inflammatory disease that affects the joints, causing pain and disability. It can also affect internal organs. RA is more common in older people, but there is also a high prevalence in young adults, adolescents and even children, and it affects women more frequently than men. IBD is an umbrella term used to describe disorders that involve chronic inflammation of the digestive tract, such as Crohn's disease and ulcerative colitis. IBD can be debilitating and sometimes lead to life-threatening complications. Type I diabetes is a serious, lifelong condition where blood glucose levels are too high because the body can't make insulin.

Results of the study demonstrate that the RA group reported significantly more cases of inflammatory bowel disease (1.9% vs. 0.5%, p1

"While it is common for patients to have both type I diabetes and rheumatoid arthritis, our results suggest that inflammatory bowel disease and type I diabetes may predispose to rheumatoid arthritis development, which merits further study," said Vanessa Kronzer, M.D., Mayo Clinic School of Graduate Medical Education, Minnesota, USA.

Although the number of comorbidities was the same between groups in the timeframe prior to RA diagnosis, in the time period after RA diagnosis there were significantly more comorbidities reported in the RA group versus controls (median 5.0 vs. 4.0, p1

"These results are important because understanding the timeline of comorbidity development in patients with rheumatoid arthritis will inform our knowledge of the disease progression and help identify targets for improving outcomes," said Professor Hans Bijlsma, President, EULAR.

The study included 821 patients with RA from a biobank, each with a further three matched controls based on age, sex, and location of residence at the time of the biobank survey. The survey included the self-reported presence/absence and age of onset for 77 comorbidities. The mean age was 62 years, and 73% were female.1

Abstract number: OP0088

Sickle cell disease (SCD) is a form of anaemia that is inherited when both parents are carriers of a mutation in the haemoglobin gene. Currently, it can only be diagnosed in pregnancy by carrying out an invasive test that has a small risk of miscarriage and is therefore sometimes declined by parents. Now, researchers from Guy's and St Thomas' NHS Foundation Trust and Viapath Analytics, London, UK, in collaboration with non-invasive healthcare company Nonacus Ltd., Birmingham, UK, have developed a non-invasive prenatal test for the disease, the annual conference of the European Society of Human Genetics will hear tomorrow (Sunday).

Dr Julia van Campen, research scientist at Guy's and St Thomas', explains: « We have developed a method of testing for SCD using cell-free fetal DNA - DNA from the fetus that circulates in the maternal bloodstream. Although cell-free fetal DNA testing is already available for some disorders, technical difficulties have hampered the development of such a test for SCD, despite it being one of the most commonly requested prenatal tests in the UK. »

In couples who are at risk of having a baby with SCD, each partner carries a mutation in the haemoglobin gene, which means that any fetus has a one in four chance of inheriting both mutations and therefore being affected by SCD. Non-invasive prenatal diagnosis (NIPD) of conditions that are inherited in this way is difficult. "The development of a non-invasive prenatal assay for sickle cell disease has been attempted before and, until now, has not been successful,"says Dr van Campen.

The researchers analysed samples from 24 pregnant SCD carriers. Using unique molecular identifiers, a kind of molecular barcode, they were able to reduce errors, and by only analysing smaller fragments they were able to enhance the fetal contribution to the samples. This led to successful diagnosis of the sickle cell status for 21 of the 24 pregnancies, in samples from as early as eight weeks gestation, with three samples giving inconclusive results. Further development and validation of the findings is ongoing.

Worldwide, there are over 300 0001 children born with SCD each year. It is the most common genetic haematological disorder, with millions of people currently affected across the globe. There are about 14 000 people living with SCD in the UK, or one in 4600. Approximately 560 couples at risk of passing on the disease per year are detected through the national antenatal screening programme, which offers carrier testing to pregnant women and if appropriate their partners. Prenatal diagnosis is available to these couples to test whether the fetus has SCD. Previous research has shown that if the option of a non-invasive test were available, more women whose fetus is at risk of sickle cell disease would opt for prenatal testing 2.

« However, many couples are unaware that they are at risk until pregnancy occurs, even though carrier testing and follow-up genetic counselling is available through the UK National Health Service for those who are concerned that they may carry SCD, » says Dr van Campen. « It is important to raise awareness of SCD, which currently is limited. »

Research is ongoing, and before the assay can be introduced into clinical practice it needs to be tested further to be sure that it performs well enough to be used as a diagnostic test. « We also need to work to ensure that it can provide results rapidly enough to give women answers at the right time in their pregnancy, and that it can be performed at a cost that healthcare providers can afford. I am excited that this work has given better results than I had expected, and am hopeful that people will be able to build on this work to make this test available in the near future," » Dr van Campen will conclude.

Chair of the ESHG conference, Professor Joris Veltman, Director of the Institute of Genetic Medicine at Newcastle University, Newcastle upon Tyne, UK, said: "The development of non-invasive genetic tests that can be safely used during pregnancy is important to identify fetuses with severe disorders. These scientists have developed a novel state-of-the art genomics approach to do this for sickle cell disease in couples at risk. Their first results presented at the ESHG conference indicate that their test is very promising."

Madrid, Spain, 13 June 2019: The results of a phase IIa clinical trial presented today at the Annual European Congress of Rheumatology (EULAR 2019) demonstrate a rapid reduction in albuminuria and hyperuricaemia in patients with type II diabetes with combined treatment of verinurad and febuxostat.1

The primary endpoint of the study was met; results reveal a 39% reduction in urinary albumin-to-creatinine ratio (UACR) after 12 weeks with combined treatment of verinurad 9mg and febuxostat 80mg versus placebo (p=0.07). The study also shows a 57% reduction in serum urate (sUA) in the treatment group versus a 7% increase in the placebo group (p

"Although these are early clinical findings in a limited group of patients, our results show that combined treatment with verinurad and febuxostat in patients with diabetes results in a rapid reduction in hyperuricaemia and albuminuria sustained through week 24," said Robert Terkeltaub, MD, Professor of Medicine, University of California San Diego, USA. "Further studies are planned to confirm the efficacy of urate lowering strategies combining verinurad and xanthine oxidase inhibitors in slowing progression of chronic kidney disease."

Verinurad is an inhibitor of the uric acid transporter (URAT1) and is currently under investigation for the treatment of hyperuricaemia and kidney disease. Febuxostat is a potent, selective xanthine oxidase inhibitor used to lower urate levels in patients with gout and hyperuricaemia. It is recommended in patients who do not reach target on, or are intolerant to, allopurinol. It is often used in patients with renal impairment since it is primarily metabolised in the liver.2

"We welcome these positive results and look forward to the future clinical development of this novel urate-lowering treatment strategy, particularly in patients with hyperuricaemia and kidney disease," said Professor Hans Bijlsma, President, EULAR.

The trial included 60 patients with type II diabetes who had a sUA of 6.0mg/dL or above, eGFR of 30mL/min/1.73m2 or above, and UACR of 30-3500 mg/g. Patients were randomised to receive either verinurad 9mg and febuxostat 80mg (treatment group) or placebo. Patients were excluded if they had a history of gout or recent treatment with urate-lowering therapy which avoided the need to administer gout prophylaxis. Most adverse events were mild to moderate, those reported in more than one patient in the treatment group were diarrhoea, dizziness and nasopharyngitis, and only one gout flare-up was reported (in the treatment group).

Abstract number: OP0207

Madrid, Spain, 13 June 2019: The results of a study presented today at the Annual European Congress of Rheumatology (EULAR 2019) suggest that overall cancer risk is not linked to tumour necrosis factor inhibitor (TNFi) use in psoriatic arthritis.1

The study analyses the risk of primary cancer in over 8,000 TNFi-treated psoriatic arthritis patients from Sweden, Denmark, Iceland, and Finland. Results demonstrated no increase in risk of all cancer, as well as site specific cancers including colorectal, lung, malignant melanoma, pancreas, brain, female breast, endometrial, and prostate.1

"TNF inhibitors have a well-established efficacy and safety profile in patients with psoriatic arthritis and we welcome these data which contribute to our understanding in the complex area of cancer risk," said Professor Hans Bijlsma, President, EULAR.

There was a significant increase in malignant lymphomas observed within the trial (standardised incidence ratio: 1.84, 95% confidence interval: 1.20-2.82). However, it is not clear if this is due to the psoriatic arthritis disease or the TNFi treatment. There is limited data on lymphoma risk in psoriatic arthritis, however, an excess risk has been reported for several other chronic inflammatory rheumatic diseases with a well-established doubled average risk in patients with rheumatoid arthritis.2

"Our study provides convincing evidence that the use of TNF inhibitors does not increase the risk of overall cancer in patients with psoriatic arthritis," said Professor Lene Dreyer, Aalborg University Hospital, Aalborg, Denmark. "Further analysis is needed to assess whether the observed increase in malignant lymphomas is due to the psoriatic arthritis disease or the TNFi treatment."

Psoriatic arthritis is a chronic inflammatory disease that affects the joints, causing pain and disability. The disease often causes swelling of the fingers and toes, mainly because of joint inflammation. Tumour necrosis factor inhibitors have been shown to be efficacious in psoriatic arthritis.3 However, tumour necrosis factor (TNF) also plays a complex role in the development and progression of cancer and so the use of TNFi may theoretically increase the risk of tumour development.4

This population-based cohort study includes 5,218, 2,039, 270 and 526 TNFi-treated psoriatic arthritis patients from ARTIS (Sweden), DANBIO (Denmark), ICEBIO (Iceland), and ROB-FIN (Finland) respectively. Patients were followed from first registration with TNFi-treatment and linked to the national cancer registry in each country (patients with a history of cancer were excluded). The cancer rates were compared with the general population standardised to age, sex and calendar period within each country. Standardised incidence ratios were estimated for both any cancer and site-specific cancers of interest.1

Abstract number: OP0005

Previous research has suggested that some contraceptive methods may increase women's susceptibility to HIV. However, all three forms of contraception trialled were safe and highly effective, supporting their continued and increased access alongside high quality HIV prevention services.

A randomised trial of more than 7,800 African women found that a type of contraceptive injection (intramuscular depot medroxyprogesterone acetate - DMPA-IM) posed no substantially increased risk of HIV acquisition when compared with a copper intrauterine device (IUD) and a levonorgestrel (LNG) implant. The results of this first ever randomised trial in the area, published in The Lancet, counter 30 years of epidemiology research suggesting a potential association between some types of contraceptives and risk of acquiring HIV.

"Our randomised trial did not find a substantial difference in HIV risk among the contraceptive methods evaluated, and all methods were safe and highly effective at preventing pregnancy," says study co-author Professor Jared Baeten, University of Washington, USA. [1]

Co-author Professor Helen Rees, Wits Reproductive Health and HIV Institute, South Africa adds: "These results underscore the importance of continued and increased access to these three contraceptive methods, as well as expanded contraceptive choices, complemented by high-quality HIV and STI prevention services. Women's informed choice in sexual and reproductive health services is essential. This evidence will enhance women's contraceptive decision making and assist providers and policymakers in delivering high-quality, rights-based contraceptive care." [1]

More than 600,000 new HIV infections occur in African women each year, and the prevalence of HIV and STIs was high in women studied in the trial. Co-author Dr Nelly Mugo, Kenya Medical Research Institute, Kenya & University of Washington, USA, cautions: "It is important to note that none of the contraceptive methods that we evaluated was designed to be protective against HIV. Our results strongly emphasise the need for more aggressive HIV and STI prevention and management efforts for African women, including PrEP and HIV prevention integrated with contraceptive services." [1]

Although there is substantial unmet need for modern contraception for women in Africa who do not wish to become pregnant, more than 58 million African women use modern contraceptive methods. Injectable contraceptive use has increased over the past few decades in Africa, and in many settings where HIV incidence is high, DMPA-IM is the predominant contraceptive used.

Past epidemiological, clinical, and laboratory studies have suggested that DMPA-IM might increase a woman's susceptibility to HIV. However, these studies have important limitations, and results have been inconsistent, with some studies finding no increase in HIV incidence among DMPA-IM users. In March, 2017, WHO released guidance for the use of DMPA-IM by women at high risk of HIV infection, and the WHO Medical Eligibility Criteria (MEC) for the contraceptive changed from a category 1 ("a condition for which there is no restriction for the use of the contraceptive method") to a category 2 ("a condition where the advantages of using the method generally outweigh the theoretical or proven risks"). In July 2019, the results of this new trial (the ECHO trial) will be reviewed, and a guideline development group will determine whether or not DMPA-IM will remain at an MEC category 2 or may be changed.

In addition, use of other highly effective long-acting, reversible contraceptive methods, such as LNG implants and copper IUDs, is rapidly increasing in Africa, but related data on HIV risk are sparse.

The ECHO trial aimed to provide robust evidence on both of these potential risks to inform women's decision making, contraceptive counselling, and policy maker and regulatory decisions.

The trial took place across 12 sites in eSwatini, Kenya, South Africa, and Zambia, and included 7,829 women aged 16-35 years who were seeking effective contraception. The women were included if they did not have HIV, agreed to use the contraceptive method for 18 months, and had not used any of the three contraceptives included for the past 6 months. The participants were randomly divided into three groups and given DMPA-IM (2,609 women), the copper IUD (2,607), or the LNG implant (2,613). The trial was open-label meaning that the participants and their clinicians knew which contraceptive was being given. The clinicians informed women in the study that their contraceptive did not protect against HIV and advised them to also use condoms.

The researchers tracked how many women developed HIV, and any side effects of the contraception they used.

In total, 7,324 women (94% of all women included) completed their final, scheduled visit. Throughout the trial there were 397 HIV infections (3.8% per year) - 143 in the DMPA-IM group, 138 in the copper IUD group, and 116 in the LNG implant group. The differences in HIV incidence were not significant across the three groups of women.

The authors note that their study was designed to be able to detect a 50% increase in HIV risk, but that the trial was not statistically strong enough to predict increases lower than 30% - which might remain important for some women at very high HIV risk like those in the study, in terms of decision making about contraception and HIV prevention.

All three contraceptive methods were well tolerated, with less than 4% of participants in any group reporting any serious adverse event (2%, 49 women in the DMPA-IM group, 4%, 92 women in the copper IUD group, and 3%, 78 women in the LNG implant group) and less than 9% reporting adverse events resulting in method discontinuation (4%, 109 women in the DMPA-IM group, 8%, 218 women in the copper IUD group, and 9%, 226 women in the LNG implant group). Reasons for discontinuing contraceptive use were mostly due to common side effects of the contraceptive.

In addition, all three contraceptives were highly effective, with approximately 1% or less of women getting pregnant while using the contraceptive they were assigned to continuously for one year, however the injection and the implant had lower pregnancy incidence than the copper IUD. The majority of pregnancies (71%, 181 pregnancies) occurred after women discontinued their assigned contraceptive, and overall there were 255 pregnancies in the trial.

The authors note that their findings cannot be generalised to other types of contraceptives, and do not compare against if no contraceptive is used [2].

They note some limitations, including that although self-reported use of DMPA-IM during the 6 months before enrolment was an exclusion criterion, approximately 13% of women in the study were likely to have used it beforehand based on blood tests showing existing levels of the contraceptive. The authors note that this is a similar level as seen in past studies.

Writing in a linked Comment, Lisa Miyako Noguchi, Johns Hopkins University, USA, says: "Although ECHO results are largely reassuring for contraceptive methods included in the trial, a substantial unfinished agenda remains to meet the range of needs of those at risk for unplanned pregnancy and HIV infection, including stronger global and national commitments and accountability for informed choice for family planning and HIV prevention and treatment. Many factors are driving unacceptably high rates of HIV acquisition in young women, but we have good reasons to believe that contraception is not one of them."

Annual European Congress of Rheumatology
(EULAR 2019)
Madrid, Spain, 12-15 June 2019

Madrid, Spain, 13 June 2019: The results of a study presented today at the Annual European Congress of Rheumatology (EULAR 2019) identify ApoB:A1 ratio and metabolomic lipoprotein signatures as potential biomarkers for cardiovascular risk in patients with juvenile-onset systemic lupus erythematosus (JSLE).1

In depth metabolomics was used to investigate dyslipidaemia and cardiovascular risk in a cohort of patients with JSLE. Unbiased hierarchical clustering stratified patients by metabolomic profile and revealed three distinct groups. Groups One and Two were identified as high and low cardiovascular risk respectively based on their unique lipoprotein profile, immune cell phenotype and clinical presentation. Further analysis identified ApoB:A1 ratio as a highly predictive biomarker distinguishing between these high and low cardiovascular risk groups. Longitudinal analysis revealed that the ApoB:A1 ratio biomarker remained stable over time.1

"Our study identifies ApoB:A1 ratio and metabolomic lipoprotein signatures as potential new biomarkers to predict cardiovascular risk in patients with juvenile-onset SLE," said Dr George Robinson, Senior Research Associate, Centre for Adolescent Rheumatology Versus Arthritis, University College London, London, England. "Patient stratification using these biomarkers could provide an opportunity for tailored disease treatments using lipid modification therapy and lifestyle interventions."

The patients in Group One were identified as high cardiovascular risk due to their lipoprotein profile (decreased high density lipoproteins (HDL) and increased very low and low density lipoproteins (VLDL/LDL)). Group One had a significant increase in plasmablasts and activated T-cells compared to matched healthy controls and had clinical features associated with increased disease activity. These immunopathogenic properties were not seen in the low cardiovascular risk Group Two which also had the opposite lipoprotein profile (increased HDL and decreased VLDL/LDL). Group Three had an intermediate CVR but a pro-inflammatory immune cell profile.1

"Regular assessment for traditional and disease-related risk factors for cardiovascular disease is very important in patients with SLE," said Tanita Wilhelmer, Chair, Young PARE. "We welcome these data to support the identification of those at greatest risk."

This form of risk assessment is particularly important in patients with SLE as they have been found to be twice as likely to suffer from cardiovascular disease. Research shows that SLE patients are between 9- and 50-fold more likely to suffer a myocardial infarction over the general population, and 3-fold more likely to suffer a fatal myocardial infarction.

Systemic lupus erythematosus is an autoimmune disease typically affecting women between the ages of 15 and 50, and symptoms flare up unpredictably. Approximately 20% of cases begin during childhood and in these patients the disease is suggested to be more severe. The risk for certain types of deaths, primarily related to lupus activity (such as renal disease), has decreased over time, while the risk for deaths due to circulatory disease does not appear to have diminished.

The study included a discovery cohort of 35 JSLE patients and 39 age/sex matched healthy donors. Metabolic biomarker analysis and in-depth immune cell phenotyping was performed on the serum and peripheral blood mononuclear cells (PBMCs) taken from the participants. Data were analysed using cluster and correlation-correlation and receiver operating characteristic analysis. The metabolomic patient stratification was validated in a second cohort of 31 JSLE patients.1

Abstract number: OP0148

New research, published in the journal Scientific Reports, shows that women undergo a significant mental as well as physical change during the late stages of pregnancy.

The study, carried out in Cambridge by scientists from Anglia Ruskin University and the Department of Obstetrics and Gynaecology at Addenbooke's Hospital, investigated peripersonal space.

This is the area immediately surrounding the body that our brain constantly monitors, as it is where the majority of interactions with the external world occur. It is commonly described as being the area within an arm's length of another person.

Using an audio-tactile test the scientists measured, for the first time, the boundaries of the peripersonal space during pregnancy.

As well as testing women who were not pregnant, the researchers tested women at the second trimester (approximately the 20th week) when the abdomen is just beginning to enlarge, at the third trimester (approximately the 34th week) when the abdomen is clearly visible, and roughly eight weeks after giving birth.

The study found that a pregnant woman's sense of personal space expands, but only during the third trimester of pregnancy. No changes were observed at earlier stages of pregnancy or after giving birth, when the size and shape of peripersonal space were both comparable to that of non-pregnant women.

Lead author Dr Flavia Cardini, Senior Lecturer in Psychology at Anglia Ruskin University, said: "Pregnancy involves massive and rapid changes to the body both externally, as the body suddenly changes shape, and internally, while the foetus is growing.

"Our results suggest that when the body undergoes significantly large changes, at the stage when the abdomen is clearly expanded, the maternal brain also begins to make adjustments to the space immediately surrounding the body.

"Peripersonal space is considered a 'safety bubble' and it's possible that the observed expansion of this at the late stage of pregnancy might be aimed at protecting the vulnerable abdomen during the mother's daily interactions. So as the mother's bump grows, in effect the expanded peripersonal space is the brain's way of ensuring danger is kept at arm's length."

Sophia Antipolis, 13 June 2019: Overweight four-year-olds have a doubled risk of high blood pressure by age six, raising the hazard of future heart attack and stroke. That's the finding of a study published today in the European Journal of Preventive Cardiology, a journal of the European Society of Cardiology (ESC).1

"The myth that excess weight in children has no consequences hampers the prevention and control of this health problem," said study author Dr Iñaki Galán, of Carlos III Health Institute, Madrid, Spain. "Parents need to be more physically active with young children and provide a healthy diet. Women should shed extra pounds before becoming pregnant, avoid gaining excess weight during pregnancy, and quit smoking, as these are all established risk factors for childhood obesity."

According to the World Health Organization, childhood obesity is one of the most serious public health challenges of the 21st century. The problem is global and the prevalence has increased at an alarming rate. In 2016, more than 41 million children under the age of five were overweight.2

This study, based on the ELOIN cohort,3 examined the link between excess weight and high blood pressure in 1,796 four-year-olds who were followed up two years later. Blood pressure was measured at both time points, as was body mass index (BMI in kg/m2) and waist circumference.

Compared to children maintaining a healthy weight between ages four and six, those with new or persistent excess weight according to BMI had 2.49 and 2.54 higher risks of high blood pressure, respectively. In those with new or persistent abdominal obesity, the risks for high blood pressure were 2.81 and 3.42 greater, respectively. Children who lost weight did not have an increased risk of high blood pressure. The findings applied to all children regardless of sex or socioeconomic status.

"There is a chain of risk, whereby overweight and obesity lead to high blood pressure, which heightens the chance of cardiovascular disease if allowed to track into adulthood," said Dr Galán. "But the results show that children who return to a normal weight also regain a healthy blood pressure."

The best way to maintain a healthy weight and lose excess kilos is to exercise and eat a healthy diet, said Dr Galán. In addition to the central role of parents, the school curriculum needs to include three to four hours of physical activity every week. Teachers should supervise activities during breaks, while schools can offer games and sports after classes and provide nutritionally balanced meals and snacks.

Doctors should routinely assess BMI and waist circumference at early ages, added Dr Galán. "Some paediatricians think the harms of overweight and obesity begin in adolescence but our study shows they are mistaken," he said. "We need to detect excess weight as soon as possible so the damaging impact on blood pressure can be reversed."

Overweight children should have their blood pressure measured. Three consecutive elevated readings constitute high blood pressure. In young children, the most common cause is excess weight, but doctors will rule out other reasons such as heart defects, kidney disease, genetic conditions, and hormonal disorders. If the cause is overweight, more activity and dietary improvements will be advised. If lifestyle changes don't help, blood pressure lowering medication may be prescribed.

Dr Galán noted that overweight in children is most accurately assessed using both BMI and waist circumference. In the study, using either measurement alone would have missed 15% to 20% of cases.

The introduction of infliximab (Remicade), the first biologic therapy approved for the treatment of inflammatory bowel diseases (IBD), did not result in lower rates of hospitalizations or intestinal surgeries among patients living with IBD in Ontario, according to a study published by authors from several Canadian hospitals and ICES in the journal Gut.

The authors studied trends in hospitalizations, surgeries and drug costs among individuals with Crohn's disease and ulcerative colitis, collectively termed IBD, living in Ontario between 1995 and 2012. They compared trends following the introduction of infliximab in Ontario to trends that would have been expected had the drug not been introduced.

Infliximab is a type of anti-immune (anti-TNF) therapy that blocks inflammation in the gut and other organs. It is used to treat a variety of inflammatory diseases and became available in Ontario for Crohn's disease in 2001 and for ulcerative colitis in 2006.

The researchers found that even among people with Crohn's disease who received infliximab, there were no significant reductions in disease-related hospitalization or surgery rates compared to what would have been expected with conventional therapies alone. People with ulcerative colitis who received infliximab also did not experience lower surgery rates, but they did see some improvement in hospitalization rates following infliximab introduction.

"These findings are disappointing for a class of therapy that has demonstrated benefit in reducing IBD-related hospitalizations and surgeries in clinical trials," said Dr. Sanjay Murthy, lead author on the study and an IBD specialist and associate scientist at The Ottawa Hospital.

"We had expected to see larger declines in these adverse health events because they are more common in IBD patients with severe disease, and these are the same patients that we should be targeting with this therapy early in their disease to prevent hospitalizations and surgeries."

The study did not take into account the impact of this therapy on other important health outcomes, such as quality of life or workplace attendance and productivity.

"Clinicians have seen how anti-TNF therapy can dramatically improve their patients' symptoms, and in many cases even lead to complete bowel healing," said Dr. Murthy, who is also an assistant professor at the University of Ottawa. "But even though the drug clearly helps some individuals, we are not seeing some of the important benefits we would expect at a broader population level. This suggests that we may need to improve how we are using this drug in clinical practice to realize greater benefits."

About 270,000 Canadians live with IBD, and the rate of this disease is rising in Canada and around the world. The direct healthcare cost of IBD in Canada is estimated to be $1.28 billion annually. Some of the most significant health effects of IBD are hospitalizations for severe complications and intestinal resection surgery to remove diseased bowel that is resistant to treatment.

The study further showed that the average per patient drug costs for IBD have risen dramatically since the introduction of infliximab, particularly among individuals with Crohn's disease. For patients with Chron's taking infliximab, average annual publicly-funded drug costs rose from approximately $1,000 before infliximab introduction in 2001 to more than $14,000 by 2012. For ulcerative colitis patients taking infliximab, the mean drug costs rose from approximately $2,500 before infliximab introduction in 2006 to more than $10,000 by 2012.

The researchers estimate that 25 per cent of patients with Crohn's disease and eight per cent of patients with ulcerative colitis would have received infliximab by the end of their study follow-up. Anti-TNF therapies are substantially more expensive than conventional therapies for IBD - as a class, they make up the highest proportion of public drug program spending in Canada, at 8.7 per cent.

The researchers hypothesize that selecting the wrong patients, delaying the start of treatment either by not recognizing disease severity or through poor access to treatment, and incorrectly optimizing drug dosage could all be factors limiting the real-world impact of anti-TNF therapy at a population level. Criteria for reimbursement through public or private health insurance may also limit timely access to the therapy.

However, the researchers also noted persistent declines in hospitalization and intestinal surgery rates across the IBD population well before the introduction of infliximab, suggests that improvements in traditional care were already having a significant impact.

In addition, annual bowel resection rates among IBD patients were already low in Ontario at the time that infliximab was introduced - about four per cent for Crohn's disease patients and two per cent for ulcerative colitis patients - which may have left little room for further improvement.

"While it may be disappointing that this therapy did not impact IBD hospitalization or surgery rates across Ontario, this doesn't mean that it is not impacting individual patients," said Dr. Murthy. "Further research is needed to study quality of life and workplace productivity to capture the full breadth of the effects of this treatment in Ontario and in other provinces. However, our findings suggest that further education of clinicians and patients is needed before this therapy can realize its full potential."

Excess weight and body fat cause a range of heart and blood vessel diseases, according to the first study to investigate this using a method called Mendelian randomisation.

In particular, the study published in the European Heart Journal [1] today (Friday), shows that as body mass index (BMI) and fat mass increase, so does the risk of aortic valve stenosis - a condition in which the valve controlling the flow of blood from the heart to the body's largest blood vessel, the aorta, narrows and fails to open fully.

Mendelian randomisation is a way of showing whether or not individual risk factors actually cause disease, rather than just being associated with it. It uses genetic variants that are already known to be associated with potential risk factors, such as BMI and body fat, as indirect indicators or "proxies" for these risk factors. This enables researchers to discover whether the risk factor is the cause of the disease (rather than the other way around), and reduces bias in results because genetic variants are determined at conception and cannot be affected by subsequent external or environmental factors, or by the development of disease.

The researchers, led by Susanna Larsson, associate professor and senior researcher at the Karolinska Institute, Stockholm, Sweden, studied 96 genetic variants associated with BMI and body fat mass to estimate their effect on 14 cardiovascular diseases in 367,703 participants of white-British descent in UK Biobank - a UK-based national and international resource containing data on 500,000 people, aged 40-69 years.

She said: "The causal association between BMI and fat mass and several heart and blood vessel diseases, in particular aortic valve stenosis, was unknown. Using Mendelian randomisation we found that higher BMI and fat mass are associated with an increased risk of aortic valve stenosis and most other cardiovascular diseases, suggesting that excess body fat is a cause of cardiovascular disease."

People who had genetic variants that predict higher BMI were at increased risk of aortic valve stenosis, heart failure, deep vein thrombosis, high blood pressure, peripheral artery disease, coronary artery disease, atrial fibrillation and pulmonary embolism. For every genetically-predicted 1kg/m2 increase in BMI, the increased risk ranged from 6% for pulmonary embolism to 13% for aortic valve stenosis. (Above a BMI that is considered 'healthy' (20-25 kg/m2) every 1 kg/m2 increase in BMI for someone who is 1.7 metres tall (5'7") corresponds to a weight gain of nearly 3 kg.)

The researchers also found that risk of cardiovascular diseases increased with the genetic variants predicting increases in fat mass. The greatest increased risk was also for aortic valve stenosis (46% increased risk), followed by ischaemic stroke, transient ischaemic attack, atrial fibrillation, heart failure, peripheral artery disease, deep vein thrombosis, high blood pressure and coronary artery disease.

The researchers stress that although these genetic variants can predispose people to be more likely to gain excess weight, the most important factors implicated in the development of cardiovascular disease are diet and physical activity.

Professor Larsson said: "Our genes can make us somewhat more predisposed to gain body weight but lifestyle factors, such as overeating and lack of physical activity, are the major determinants of overweight. A healthy diet is the cornerstone of cardiovascular disease prevention, and how much we eat should be limited to the amount of energy required to maintain a healthy body weight, which is a BMI of between 20 to 25 kg/m2. People who are predisposed to a higher BMI may need to work a bit harder to maintain a healthy weight."

The strengths of the study include the large numbers of people involved and the fact that they were of European descent, which reduces the potential for bias from different populations. Potential limitations are that some genetic variants may be associated with more than one characteristic, that the number of cases were few for some diseases, and that there was a lack of information on the severity of aortic valve stenosis.

The damaged valve in aortic valve stenosis means that less blood leaves the heart and it has to work harder to pump enough blood out to circulate round the body. Blood can back up in other parts of the heart and sometimes the lungs. This can lead to shortness of breath, tiredness, fainting, chest pain and an irregular heart beat.