US Pharm. 2023;48(1):43-48.
Study Identifies Diabetes Dedication, Multiple Sclerosis Link
A new University of Arizona Health Sciences study found that people older than 45 years whose type 2 diabetes was treated with antihyperglycemic medications had an increased risk of multiple sclerosis (MS), particularly among women, while antihyperglycemic exposure in people younger than age 45 reduced that risk.
“Our findings reinforce the need for a precision medicine approach to preventing MS in these vulnerable populations,” said lead researcher Kathleen Rodgers, PhD, associate director of translational neuroscience at the Center for Innovation in Brain Science.
MS is an unpredictable autoimmune neurological disorder that affects the central nervous system and leads to severe physical and cognitive disability. It is estimated that nearly 1 million adults in the United States and more than 2.8 million worldwide are living with MS.
For people with type 2 diabetes, there is mounting evidence linking metabolic disorders and MS through a common driver of increased autoimmunity. This brings into question the impact of antihyperglycemic therapeutics used to treat type 2 diabetes, including insulin, on the incidence of MS.
“Previous research has shown a neuroprotective effect of antihyperglycemic medications in Alzheimer’s disease and other related dementias,” Dr. Rodgers said. “For MS, we wanted to further examine age and sex differences, particularly among men and women under 45 with type 2 diabetes.”
They found that men older than age 45 years old had a slightly significant increase of MS risk and women older than age 45 years exhibited a significant increase in MS incidence after antihyperglycemic exposure. In addition to age differences, the risk analysis by drug class showed that exposure to insulin in patients older than age 45 years old was associated with a greater increased risk compared with other therapies.
In patients younger than age 45 years, antihyperglycemic exposure was protective against the development of MS.
The study utilized a U.S.-based insurance claims database of 151 million participants to identify more than 5 million patients with a diagnosis of type 2 diabetes and either early-onset or late-onset MS. Researchers segmented the data by age—patients diagnosed with type 2 diabetes prior to or after age 45 years—and sex to decode the factors driving MS risk in both populations, especially in women over age 45 years.
The paper, “Age and sex differences on anti-hyperglycemic medication exposure and risk of newly diagnosed multiple sclerosis in propensity score matched type 2 diabetics,” was published in the journal Heliyon.
Scientists Report Encouraging HIV Vaccine Research Findings
While scientists have struggled in the past to create an effective vaccine against HIV, a novel vaccine design strategy being pursued by researchers at Scripps Research, IAVI, Fred Hutchinson Cancer Center, and the National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Research Center (VRC) shows new promise, according to data from a first-in-human clinical trial.
In a paper published in Science, the investigators reveal critical new insights into their novel vaccine strategy, which involves a stepwise approach to producing antibodies capable of targeting a wide range of HIV variants.
“The data we are publishing in Science demonstrates for the first time that one can design a vaccine that elicits made-to-order antibodies in humans. We specified in advance certain molecular properties of the antibodies that we wanted to elicit, and the results of this trial show that our vaccine antigen consistently induced precisely those types of antibodies,” says co–senior author William Schief, PhD, a professor and immunologist at Scripps Research and executive director of vaccine design at IAVI’s Neutralizing Antibody Center, whose laboratory developed the vaccine antigen. “We believe this vaccine design strategy will be essential to make an HIV vaccine and may help the field create vaccines for other difficult pathogens.”
The phase I trial tested the first stage in a multistage HIV vaccine regimen the researchers are developing. The trial results show that the vaccine had a favorable safety profile and induced the targeted response in 97% of people who were vaccinated. Importantly, the Science study also provides a detailed immunological analysis of the vaccine responses.
“HIV represents an area of dire unmet need across the world, which is what makes the findings from our phase I clinical trial so encouraging,” says Mark Feinberg, MD, PhD, president and CEO of IAVI. “Through the close-knit collaboration of many different scientists, disciplines, and institutions, we are that much closer to designing an effective vaccine that could help end the HIV pandemic.”
Broadly neutralizing antibodies (bnAbs) are a rare type of antibody that can fight and protect against many different variants of a virus, including HIV. This is why scientists have tried to develop an HIV vaccine that induces bnAbs, but thus far without success.
The researchers used a strategy known as germline targeting to eventually produce bnAbs that can protect against HIV. The first step of germline targeting involves stimulating the rare immune cells, known as bnAb-precursor B cells, that can eventually evolve into the cells that produce the bnAbs needed to block the virus. To accomplish this first step, the researchers designed a customized molecule known as an immunogen that would “prime” the immune system and elicit responses from these rare bnAb-precursor cells.
The overarching goal of the trial was to determine if the vaccine had an acceptable safety profile and could induce responses from these bnAb-precursor B cells.
“Through extensive safety and tolerability monitoring during the trial, we showed the vaccine had a favorable safety profile, while still inducing the necessary target cells,” said study author Dagna Laufer, MD, vice president and head of clinical development at IAVI. “This represents a large step forward in developing an HIV vaccine that is both safe and effective.”
To determine if the targeted bnAb-precursor B cells were induced, the researchers carried out a sophisticated analytical process.
“The workflow of multidimensional immunological analyses has taken clinical trial evaluation to the next level,” says co–senior author Adrian B. McDermott, PhD, former chief of the Vaccine Immunology Program at the NIAID VRC. “In evaluating these important immunological factors, we helped show why the vaccine antigen was able to induce the targeted response in 97% of vaccine recipients.”
Simple Tests Predict Secondary Hepatitis C Disease Risk
Even after chronic hepatitis C has been cured, portal hypertension remains the major factor driving the development of complications in advanced liver disease. In cooperation with researchers from Spain, a research team led by Georg Semmler and Mattias Mandorfer from the Division of Gastroenterology and Hepatology at MedUni Vienna’s Department of Medicine III showed that the noninvasive tests explored in their earlier studies accurately estimate the probability of sequelae.
Their findings, published in the Journal of Hepatology, refute concerns about the accuracy of these tests and recommend actions for individual disease follow-up. In their latest study, the research group analyzed all published data relating to noninvasive tests and minimally invasive hepatic venous pressure gradient measurements performed on patients before and after treatment for hepatitis C.
Working closely with colleagues from Spain, they evaluated paired measurements from 418 patients, confirming the accuracy of two noninvasive tests: U.S.-based liver stiffness measurement and platelet count, a simple blood test. Based on these findings, it was possible to develop a risk stratification system for patients post hepatitis C cure, and this has already been implemented in the Baveno VII consensus, i.e., the international recommendations for the management of portal hypertension. “The results of the study are therefore already contributing to the personalized follow-up of these patients worldwide, eliminating the need for unnecessary, sometimes burdensome examinations and enabling early initiation of preventive measures where appropriate,” emphasized first author Semmler.
Hepatitis C is a viral infection that is widespread throughout the world. For some years now, it has been successfully treated with drugs that have a direct antiviral effect and can thus be cured in over 95% of cases. However, patients with advanced scarring of the liver (advanced liver disease) remain at risk of developing secondary disease. With the exception of hepatocellular carcinoma, these complications are directly caused by the presence of portal hypertension—high blood pressure in the large vein that transports blood from the gut to the liver.
To provide follow-up care after infection with hepatitis C, it is essential that portal hypertension can be accurately identified by noninvasive testing means. “Our study has made it possible to accurately predict individual risk after hepatitis C has been cured. While it is possible to cease surveillance in a high proportion of patients, it is urgently recommended that preventive drug treatment is initiated or continued in others,” added study leader Mandorfer.
Training the Immune System in Hemophilia Patients
Hemophilia A is the most common severe form of hemophilia, almost exclusively affecting males. The disease can usually be treated well, but not for all sufferers. A study at the University of Bonn (UKB) in Germany has elucidated an important mechanism that is crucial for making the therapy effective. The results, published online in the Journal of Clinical Investigation, could help better tailor treatments.
Hemophilia A patients have a defect in a protein that is important for blood clotting: factor VIII. Most patients receive an IV injection of the functional clotting factor every few days as treatment. Frequently, however, and especially at the start of treatment, the immune system recognizes the injected agent as foreign to the body and attacks it. This is the most serious complication of hemophilia treatment because factor VIII can then no longer work.
In these cases, immune tolerance therapy, which was also developed at UKB more than 40 years ago, often helps. This involves regularly injecting the hemophiliacs with a high dose of factor VIII over several months. The immune system thereby gets used to the injected protein and tolerates it. The underlying immune mechanisms are unknown. “However, this doesn’t always work,” explains Professor Johannes Oldenburg, director of the Institute for Experimental Haematology and Transfusion Medicine at the UKB. “In about 30% of patients, tolerance induction does not lead to success. So, your body’s own defenses continue to attack and destroy the factor VIII protein, which means that factor VIII cannot be used for treatment. We wanted to know the reason for this.”
To this end, the team looked at two cell types in the immune system, B cells and regulatory T cells. B cells recognize foreign molecules in the body and produce antibodies against them, which switch off the function of the molecule. For factor VIII, this means that it is no longer effective in hemophilia treatment.
Regulatory T cells prevent an immune response from being too strong or lasting too long. The researchers have now found a new type among them that can act specifically against certain B cells rather than just nonspecifically against all immune responses. “We were able to show that immunotolerance therapy results in the generation of regulatory T cells that exclusively induce B cells against factor VIII to commit suicide,” says Janine Becker-Gotot of the Institute of Molecular Medicine and Experimental Immunology (IMMEI) at UKB. “These T cells have a sensor that allows them to recognize and attach to the corresponding B cells. In addition, they have the ability to push the self-destruct button on the surface of B cells.”
This button is a molecule called PD-1. By activating it, it starts a program in the B cell that results in its death. Every active B cell has this button. “Our experiments enabled us for the first time to detect regulatory T cells that can activate this self-destruct button only in very specific B cells, in order to specifically prevent unwanted immune responses,” said IMMEI Director Christian Kurts.
The more PD-1 buttons the B cells against factor VIII carry on their surface, the easier it is for them to be driven to suicide by immune tolerance therapy. “The amount of PD-1 varies from person to person,” Dr. Becker-Gotot explains. “If it’s very low to begin with, there’s a good chance that many inhibitor-producing B cells will survive and continue to neutralize the injected factor VIII.”
Interestingly, B cells also produce more PD-1 once they come into contact with regulatory T cells. “We can now test how strong this reaction is,” she continued. “If PD-1 levels go up shortly after starting immune tolerance therapy and then stay up, that’s a clear sign that the treatment is going to be successful.” The team is currently developing a blood test that can be used to detect whether immune tolerance therapy is working in patients during the prolonged treatment.
“Our findings have great basic scientific value,” explained Dr. Kurts.
Study: Rheumatoid Arthritis Drugs Reduce Heart Disease Risk
People with rheumatoid arthritis have a greater than average risk of cardiovascular disease, but a new study suggests that drugs commonly used to reduce joint inflammation in patients also reduce that risk.
“The reassuring message is that as your joints are improving with RA treatments, so too is your risk for cardiovascular disease,” says Joan Bathon, MD, a coleader of the study and professor of medicine and director of the division of rheumatology at Columbia University Vagelos College of Physicians and Surgeons.
Recent clinical trials have shown that immunomodulators—drugs that decrease inflammation—significantly reduce heart attacks, strokes, and other cardiovascular events in people with cardiovascular disease. But it was not clear if these drugs have a similar effect on people with rheumatoid arthritis, who have a 50% higher risk of heart disease than the average person.
More than 1.3 million adults in the United States have rheumatoid arthritis, a chronic autoimmune and inflammatory disease that causes painful joint swelling. It is known that inflammation leads to atherosclerosis and contributes to heart disease, which may explain the elevated rates of heart disease in people with rheumatoid arthritis.
Methotrexate is the first treatment choice for patients with moderate-to-severe rheumatoid arthritis, but most patients will go on a tumor necrosis factor inhibitor (TNFi) or triple therapy (methotrexate plus sulfasalazine and hydroxychloroquine) at some point.
In the new study, led by researchers at Columbia University and Brigham and Women’s Hospital, 115 adults with moderate-to-severe rheumatoid arthritis despite treatment with methotrexate were randomized to add a TNFi, either adalimumab (Humira) or etanercept (Enbrel), or to go on triple therapy.
After 6 months, both groups had similar reductions in arterial inflammation, a proxy for heart disease risk, and rheumatoid arthritis disease activity.
“We were surprised to see that both of these powerful anti-inflammatory treatment strategies reduced heart disease risk in patients with rheumatoid arthritis,” Dr. Bathon said. “Doctors still need to pay attention to the usual heart disease risk factors, such as high cholesterol, high blood pressure, and obesity. But since inflammation, a key feature of rheumatoid arthritis, elevates cardiovascular risk even further, reducing inflammation by treating the arthritis is a novel mechanism to reduce heart disease risk in these patients.”
mRNA Vaccine Meets Primary Efficacy Endpoint Against Melanoma
Moderna, Inc. and Merck announced that the phase IIb Keynote-942/mRNA-4157-P201 trial of mRNA-4157/V940, an investigational personalized mRNA cancer vaccine, in combination with Keytruda, Merck’s anti-PD-1 therapy, demonstrated a statistically significant and clinically meaningful improvement in the primary endpoint of recurrence-free survival versus Keytruda alone for the adjuvant treatment of patients with stage III/IV melanoma following complete resection. Adjuvant treatment with mRNA-4157/V940 in combination with Keytruda reduced the risk of recurrence or death by 44% (hazard ratio = 0.56 [95% CI, 0.31-1.08]; one-sided P value = .0266) compared with Keytruda alone.
“Today’s results are highly encouraging for the field of cancer treatment. mRNA has been transformative for COVID-19, and now, for the first time ever, we have demonstrated the potential for mRNA to have an impact on outcomes in a randomized clinical trial in melanoma,” said Stéphane Bancel, Moderna’s chief executive officer. “We will begin additional studies in melanoma and other forms of cancer with the goal of bringing truly individualized cancer treatments to patients. We look forward to publishing the full data set and sharing the results at an upcoming oncology medical conference, as well as with health authorities.”
“These positive findings represent an important milestone in our collaboration with Moderna,” said Dean Y. Li, president, Merck Research Laboratories. “Over the last 6 years, our teams have worked closely together combining our respective expertise in mRNA and immuno-oncology with a focus on improving outcomes for patients with cancer. We look forward to advancing this program into the next phase of development.”
The companies plan to discuss the results with regulatory authorities and initiate a phase III study in melanoma patients in 2023.
Can Gut Bacteria Cause Rheumatoid Arthritis?
Researchers at the University of Colorado (CU) School of Medicine have discovered that a unique bacteria found in the gut could be responsible for triggering rheumatoid arthritis (RA) in people already at risk for the autoimmune disease.
Kristine Kuhn, MD, PhD, associate professor of rheumatology, led a team of researchers from the Division of Rheumatology on the study, which was published in the journal Science Translational Medicine. CU School of Medicine student Meagan Chriswell was the lead author of the paper.
“Work led by coauthors Drs. Kevin Deane, Kristen Demoruelle, and Mike Holers here at CU helped establish that we can identify people who are at risk for RA based on serologic markers, and that these markers can be present in the blood for many years before diagnosis,” Dr. Kuhn said. “When they looked at those antibodies, one is the normal class of antibody we normally see in circulation, but the other is an antibody that we usually associate with our mucosa, whether it be the oral mucosa, the gut mucosa, or the lung mucosa. We started to wonder, ‘Could there be something at a mucosal barrier site that could be driving RA?’”
The CU researchers, with the help of a group led by Bill Robinson, MD, PhD, at Stanford University, took the antibodies created by immune cells from individuals whose blood markers showed they were at risk for the disease and mixed them with the feces of the at-risk individuals to find the bacteria that were tagged by the antibodies.
To further test their hypothesis, the researchers used animal models to host the newly discovered bacteria. Those experiments showed that not only did the bacteria cause the animal models to develop the blood markers found in individuals at risk for RA, but some of the models showed development of full-blown RA as well.
“Our collaborators led by Drs. Eddie James and Jane Buckner of Benaroya Research Institute confirmed that the T cells in the blood of people with RA will respond to these bacteria, but people who are otherwise healthy do not respond to these bacteria,” Dr. Kuhn said. “Through studies in humans and animal models, we were able to identify these bacteria as being associated with the risk for developing RA. They trigger an RA-like disease in the animal models, and in humans, we can show that this bacterium seems to be triggering immune responses specific to RA.”
If the unique species of bacteria is indeed driving the immune response that leads to RA in individuals already at risk for the disease, Kuhn says, it might be possible to target the bacteria with medication to prevent that response from happening.
“The next thing we want to do is identify, in larger populations of individuals at risk for RA, if these bacteria correlate with other genetic, environmental, and mucosal immune responses, and then ultimately, the development of RA,” Dr. Kuhn continued. “Then we could say, ‘This is a marker that’s useful in helping predict who will go on to develop RA,’ and apply prevention strategies. The other opportunity there is that if we can understand how it is triggering these immune responses, we might be able to block the bacteria’s ability to do that.”
The research took 5 years to conduct and analyze, Dr. Kuhn said, helped along by individuals who discovered they were at risk for RA and volunteered to support the research effort. Eventually, the researchers want to examine exactly how the bacteria triggers the immune response, as well as different methods of preventing the reaction from happening.
“There are a lot of different technologies that are just starting to come out that could selectively target a bacterium in the gut microbiome, for example, to prevent it from having immunogenic effects on the host,” she explained. “For a long time, people have thought that antibiotics could be a useful therapy for RA, but rather than the sledgehammer effect of a traditional antibiotic that’s going to wipe out a large group of bacteria, we might be able selectively target this bacterium or its effects.”
Stem Cell Transplants May Delay Disability Longer Than Some Drugs
In people with active secondary progressive multiple sclerosis (MS), hematopoietic stem cell transplants may delay disability longer than some other MS medications, according to a study published in the December 21, 2022, online issue of Neurology. The study involved autologous hematopoietic stem cell transplants, which use healthy blood stem cells from a person’s own body to replace diseased cells.
While most people with MS are first diagnosed with relapsing-remitting MS, marked by symptom flare-ups followed by periods of remission, many people with relapsing-remitting MS eventually transition to secondary progressive MS, which does not have wide swings in symptoms but instead a slow, steady worsening of the disease.
“Hematopoietic stem cell transplants have been previously found to delay disability in people with relapsing-remitting MS, but less is known about whether such transplants could help delay disability during the more advanced stage of the disease,” said study author Matilde Inglese, MD, PhD, of the University of Genoa in Italy and a member of the American Academy of Neurology. “Our results are encouraging, because while current treatments for secondary progressive MS have modest or small benefits, our study found stem cell transplants may not only delay disability longer than many other MS medications, they may also provide a slight improvement in symptoms.”
The retrospective study included 79 people with active secondary progressive MS who received stem cell transplants and 1,975 people from the Italian MS registry who were treated with MS drugs. All received treatment after being diagnosed with active secondary progressive MS. The two groups were matched for age, sex, and level of disability. Drugs included beta-interferons, azathioprine, glatiramer acetate, mitoxantrone, fingolimod, natalizumab, methotrexate, teriflunomide, cyclophosphamide, dimethyl fumarate, and alemtuzumab.
Participants’ level of disability was measured on the Expanded Disability Status Scale, a common method to quantify disability with scores ranging from 0, no symptoms, to 10 points, death due to MS. Participants were assessed at various time points over 10 years.
At the beginning of the study, participants had a median score of 6.5 for both those who received transplants and those receiving the medications. Scores of 6.0 are defined as needing to use a cane or brace intermittently or on one side to walk about 100 meters with or without resting. Scores of 6.5 are defined as needing to use a cane or brace constantly on both sides to walk about 20 meters without resting.
Five years into the study, researchers found 62% of the people who had stem cell transplants experienced no worsening of their MS disability compared to 46% of those who took medications. Also, at 5 years, researchers found people who received stem cell transplants were more likely to see sustained improvements over time, with 19% experiencing less disability than at the start of the study, compared to just 4% of people taking medications.
Over 10 years, the disability score for people who had stem cell transplants decreased by an average of 0.01 points per year, signifying less disability, while the average score for people taking medications increased by 0.16 points per year, an increase in disability.
“Our study shows that hematopoietic stem cell transplants were associated with a slowing of disability progression and a higher likelihood of disability improvement compared to other therapies,” said Dr. Inglese. “While these results are encouraging, they are not applicable to patients with secondary progressive MS who do not have signs of inflammatory disease activity; more research is needed in larger groups of people to confirm our findings.”
A limitation of the study is that it was retrospective and observational and does not prove cause and effect. It only suggests an association. The study also did not include people taking the MS drugs siponimod, cladribine, ocrelizumab, ofatumumab, or rituximab.
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