Targeting ‘broken’ metabolism in immune cells reduces inflammatory disease

The team, led by researchers at Imperial College London, Queen Mary University of London and Ergon Pharmaceuticals, believes the approach could offer new hope in the treatment of inflammatory conditions like arthritis, autoimmune diseases and sepsis.

In a study published this week in the journal Nature Communications, they explain how blocking a single enzyme enabled them to reprogram macrophages – the immune cells which are activated in inflammatory conditions – to calm their activity and reduce inflammation in rats and mice with human-like disease.

At the heart of the research is the Krebs cycle, a complex loop of reactions which cells use to feed on sugar and generate molecules of ATP, the universal energy currency for cells.

In recent years, research has shown that the usual pathway is interrupted in immune cells such as macrophages, leading to a broken Krebs cycle.

“In immune cells that have to fight invaders, the metabolism is diverted from its usual cycle to make compounds that fight microbes,” explained Dr Jacques Behmoaras, from the Department of Medicine at Imperial, who led the research.

Dr Behmoaras added: “What we have found is that there’s an enzyme involved in this diversion of the usual cycle, which make immune cells produce these bacteria-killing compounds. If you block that enzyme, you block that specific branch of their metabolism, and make the cells cause less damage during inflammation.”

Using human macrophages, the researchers found that an enzyme called BCAT1 was pivotal in reprogramming macrophages. When the cells were activated – by exposing them to molecules found on the surface of bacteria – BCAT1 interfered with their usual metabolic pathways, and regulated another enzyme, responsible for producing bacteria-killing chemicals.

They used an experimental compound called ERG240, developed by Ergon Pharmaceuticals, a small biotech company based in the US. ERG240 resembles the amino acid leucine, one of the building blocks of proteins, which is linked together by BCAT1. By flooding the cells with ERG240 they were able to jam up BCAT1 and block its action, so stopping the metabolism being diverted and ‘fixing’ the broken Krebs cycle. What’s more, the compound was shown to work in animal models of inflammation, without toxic side effects.

The team found that when ERG240 was given to mice with symptoms of rheumatoid arthritis, it reduced the inflammation in their joints by more than half while protecting the integrity of their joints. Similarly, in a rat model of severe kidney inflammation, they found that ERG240 improved kidney function by reducing the number of macrophages flooding into the affected tissue to cause inflammation.

Dr Behmoaras states that although the research is still at an early stage, there is potential for treating inflammatory conditions in patients by targeting the metabolic activity in immune cells. The team believes that BCAT1 works together with other key enzymes of the Krebs cycle, which could themselves provide targets for therapy.

However, one of the key challenges in developing a therapy would be in finding the balancing point: calming the immune cells enough such that they reduce inflammation, but enabling them to react to microbial invaders.

“I think this ability to regulate metabolism in cells could have an effect on many human diseases,” said Dr Behmoaras. “Manipulating cell activity in inflammatory diseases where macrophages have a role, could have important therapeutic benefits.

“Our next step is to understand how other enzymes in the cycle are involved, to see if there is any possibility to block them and have similar effects. Understanding the complex metabolic circuits of these immune cells is a huge task. We will need to tackle this before we can manipulate cell activity and influence disease.

“This is a growing field of research with exciting discoveries ahead.”

New Assay May Lead to a Cure for Debilitating Inflammatory Joint Disease

Current treatments for rheumatoid arthritis relieve the inflammation that leads to joint destruction, but the immunologic defect that triggers the inflammation persists to cause relapses, according to research conducted at NYU Langone Medical Center and the University of Pittsburgh.

Known as autoantibodies and produced by the immune system’s B cells, these defective molecules mistakenly attack the body’s own proteins in an example of autoimmune disease. Now the results of a study just published in Arthritis & Rheumatology suggest that clinical trials for new rheumatoid arthritis (RA) drugs should shift from their sole focus on relieving inflammation to eliminating the B cells that produce these antibodies.

“We have developed a test for measuring the underlying autoimmunity in rheumatoid arthritis patients that should be used to evaluate new treatment regimens,” says senior author Gregg Silverman, MD, professor in the Departments of Medicine and Pathology at NYU Langone and co-director of its Musculoskeletal Center of Excellence. “We believe this provides a road to a cure for rheumatoid arthritis.”

Rheumatoid arthritis is a chronic inflammatory autoimmune disease that affects 1.5 million people in the United States. The current standard of care begins with methotrexate, a drug that reduces inflammation. It is often followed by drugs that block a molecule called tumor necrosis factor (TNF), which promotes inflammation. Both of these classes of drugs can blunt the swelling and inflammation associated with rheumatoid arthritis and at times even allow patients to go into clinical remission that requires continued treatment. But when patients halt these medications, symptoms generally flare up either sooner or later. According to Silverman, the reduction of inflammation does not directly reflect the autoimmune disease that causes rheumatoid arthritis.

In the study, researchers focused on “memory” B cells, immune system cells that remember the initial errant immune encounter that recognized the body’s own proteins as foreign. In rheumatoid arthritis, memory B cells secrete molecules called anti-citrullinated protein antibodies (ACPAs). Doctors currently confirm an RA diagnosis with a blood test that looks for ACPAs, which are present in 80 percent of RA patients.

Silverman and his colleagues developed sensitive assays to detect a range of different autoantibodies present in the disease. The researchers then established a cell culture system to stimulate memory B cells, and used the assays to test what kind of antibodies the B cells produced.

The researchers tested blood samples from RA patients and from healthy donors. They found high levels of APCA-secreting memory B cells in the blood of patients with these autoantibodies, but not in patients without autoantibodies or in the healthy volunteers.

They then looked at patients who had achieved remission with either methotrexate or a TNF inhibitor. The researchers found that APCA levels were directly proportional to the recirculating memory B cells in the blood stream, confirming that current drug treatments do not affect the underlying autoimmunity in rheumatoid arthritis.

The next step, Silverman says, is to conduct long-term prospective clinical trials of new RA drugs, using the team’s new test to determine each drug’s effect on autoimmunity. The current metrics for evaluating the effectiveness of new rheumatoid arthritis drugs remain focused on reducing inflammation but not curing the disease, he says.

“We need to develop longer-term vision of how to improve the treatment of rheumatoid arthritis,” Silverman says. “This new tool may show that agents that target other molecules or cells have advantages that were previously not considered now that we can better measure those effects.”

Reports Preclinical Data Showing LEAPS Vaccine is Successful in Treating Rheumatoid Arthritis

Rheumatoid Arthritis is a chronic inflammatory disease that mainly targets the synovial membrane, cartilage and bone. It affects about 1% of the global population and is associated with significant morbidity and increased mortality. Non-steroidal, as well as steroidal anti-inflammatory medicines and now more commonly the use of anti-TNFα related therapies are the current standard treatment of patients with advanced RA, but information suggests that over half of the RA patients treated do not respond to current anti-TNFα drugs such as etanercept (Enbrel®) and infliximab (Remicade®).

New preclinical data presented by CEL-SCI demonstrated that its investigational new drug candidate CEL-4000 has the potential for use as a therapeutic vaccine to treat rheumatoid arthritis. CEL-4000 has been developed using CEL-SCI’s patented LEAPS (Ligand Epitope Antigen Presentation System) technology. Data were presented by Daniel Zimmerman, Ph.D., CEL-SCI’s Senior Vice President of Research, Cellular Immunology, at the American College of Rheumatology’s Annual Meeting in Washington DC. The poster presentation titled, “A Therapeutic Peptide Vaccine Reduces Pro-inflammatory Responses and Suppresses Arthritis in the Cartilage Proteoglycan G1 Domain-induced Mouse Model of Rheumatoid Arthritis,” was presented earlier this month.

This study was supported in part by funding of a Phase I Small Business Innovation Research (SBIR) grant in the amount of $225,000 from the National Institute of Arthritis Muscoskeletal and Skin Diseases (NIAMS), a part of the National Institutes of Health (NIH). The study was conducted in collaboration with Drs. Katalin Mikecz and Tibor Glant, and their research team at Rush University Medical Center in Chicago, IL.

“These findings, in conjunction with the results from earlier animal studies with LEAPS vaccines, support the potential that LEAPS vaccines may be useful as a therapeutic treatment for different types of rheumatoid arthritis. LEAPS vaccines may be advantageous to other therapies because they appear to act early on the immune system and inhibit the production of disease-promoting inflammatory cytokines. This is a significant step forward in the development of the LEAPS technology,” said Dr. Zimmerman.

This efficacy study evaluated the LEAPS vaccine’s effect in both the Proteoglycan (PG) induced arthritis (PGIA) and the closely related recombinant huG1 domain of PG (GIA) both in animal models of rheumatoid arthritis (RA) having a dominant T helper 1 (Th1) cytokine profile. These animal models were developed and have been studied extensively in Dr. Glant’s laboratory for over 25 years and are closely related to the human condition of many RA patients. The PGIA and GIA model also exhibits rheumatoid factor (Rf), RA-specific antibodies ACPA (anti citrulline peptide antibodies) and tend to develop spondylitis not usually seen in other RA models.

Disease severity, as determined based on the Arthritis Index and histopathology, was suppressed in mice treated with the LEAPS vaccine when compared to controls. As initially reported based on preliminary data in the PGIA model only, the reduction in disease (RA) severity following LEAPS vaccination with CEL-4000 (DerG-PG70 treatment) correlated with up-regulation of T regulatory cells (Treg) and Th2 cytokines (IL-10, IL-4 and TGF-β), reduced proliferation of PG specific T lymphocytes, and decreases in the production of Th1 and Th17 cytokines (IFN-γ and IL-17).

Stem Cells From Jaw Bone Help Repair Damaged Cartilage

Columbia College of Dental Medicine researchers have identified stem cells that can make new cartilage and repair damaged joints.

The cells reside within the temporomandibular joint (TMJ), which articulates the jaw bone to the skull. When the stem cells were manipulated in animals with TMJ degeneration, the cells repaired cartilage in the joint. A single cell transplanted in a mouse spontaneously generated cartilage and bone and even began to form a bone marrow niche.

The findings were published on October 10 in Nature Communications.

“This is very exciting for the field because patients who have problems with their jaws and TMJs are very limited in terms of clinical treatments available,” said Mildred C. Embree, DMD, PhD, assistant professor of dental medicine at Columbia University Medical Center (CUMC) and the lead author of the study. Dr. Embree’s team, the TMJ Biology and Regenerative Medicine Lab, conducted the research with colleagues including Jeremy Mao, DDS, PhD, the Edwin S. Robinson Professor of Dentistry (in Orthopedic Surgery) at CUMC.

Up to 10 million people in the United States, primarily women, have TMJ disorders, according to the National Institutes of Health. Options for treatment currently include either surgery or palliative care, which addresses symptoms but can’t regenerate the damaged tissue. Dr. Embree’s findings suggest that stem cells already present in the joint could be manipulated to repair it.

Cartilage helps to cushion the joints and allows them to move smoothly. The type of cartilage within the TMJ is fibrocartilage, which is also found in the knee meniscus and in the discs between the vertebrae. Because fibrocartilage cannot regrow or heal, injury or disease that damages this tissue can lead to permanent disability.

Medical researchers have been working to use stem cells, immature cells that can develop into various types of tissue, to regenerate cartilage. Given the challenges of transplanting donor stem cells, such as the possibility of rejection by the recipient, researchers are especially interested in finding ways to use stem cells already living in the body.

“The implications of these findings are broad,” said Dr. Mao, “including for clinical therapies. They suggest that molecular signals that govern stem cells may have therapeutic applications for cartilage and bone regeneration. Cartilage and certain bone defects are notoriously difficult to heal.” Dr. Mao is co-director of the Center for Craniofacial Regeneration at Columbia. His own research with stem cells has regenerated teeth and the meniscus, the pad of cartilage within the knee joint, and the TMJ in 2003.

In a series of experiments described in the new report, Dr. Embree, Dr. Mao, and their colleagues isolated fibrocartilage stem cells (FCSCs) from the joint and showed that the cells can form cartilage and bone, both in the laboratory and when implanted into animals. “I didn’t have to add any reagents to the cells,” Dr. Embree said. “They were programmed to do this.” And while some approaches to regenerating injured tissue require growth factors or biomaterials for the cells to grow on, she noted, the FCSCs grew and matured spontaneously.

Dr. Embree and her team also identified a molecular signal, Wnt, that depletes FCSCs and causes cartilage degeneration. Injecting a Wnt-blocking molecule called sclerostin into degenerated TMJs in animals stimulated cartilage growth and healing of the joint.

She and her colleagues are now searching for other small molecules that could be used to inhibit Wnt and promote FCSC growth. The idea, according to Dr. Embree, will be to find a drug with minimal side effects that could be injected right into the joint.

Children with juvenile idiopathic arthritis can have stunted jaw growth that can’t be treated with existing drugs, Dr. Embree noted. Since the TMJ is a growth center for the jaw, the new research may offer strategies for treating these children, and lead to a better understanding of how the jaw grows and develops. While orthodontists currently rely on clunky technologies like headgear to modify jaw growth, she added, the findings could point towards ways to modulate growth on the cellular level.

Ultimately, Dr. Embree and her team say, the findings could lead to strategies for repairing fibrocartilage in other joints, including the knees and vertebral discs. “Those types of cartilage have different cellular constituents, so we would have to really investigate the molecular underpinnings regarding how these cells are regulated,” the researcher said.

The study is titled, “Exploiting endogenous fibrocartilage stem cells to regenerate cartilage and repair joint injury.”

Promising Biomaterial To Build Better Bones With 3-D Printing

A Northwestern University research team has developed a 3-D printable ink that produces a synthetic bone implant that rapidly induces bone regeneration and growth. This hyperelastic “bone” material, whose shape can be easily customized, one day could be especially useful for the treatment of bone defects in children.

Bone implantation surgery is never an easy process, but it is particularly painful and complicated for children. With both adults and children, often times bone is harvested from elsewhere in the body to replace the missing bone, which can lead to other complications and pain. Metallic implants are sometimes used, but this is not a permanent fix for growing children.

“Adults have more options when it comes to implants,” said Ramille N. Shah, who led the research. “Pediatric patients do not. If you give them a permanent implant, you have to do more surgeries in the future as they grow. They might face years of difficulty.”

Shah and her team aim to change the nature of bone implants, and they particularly want to help pediatric patients. Shah is an assistant professor of materials science and engineering in Northwestern’s McCormick School of Engineering and of surgery in the Northwestern University Feinberg School of Medicine.

The new study, evaluating the material with human stem cells and within animal models, was published this week by the journal Science Translational Medicine. Adam E. Jakus, a postdoctoral fellow in Shah’s laboratory, is the paper’s first author.

Shah’s 3-D printed biomaterial is a mix of hydroxyapatite (a calcium mineral found naturally in human bone) and a biocompatible, biodegradable polymer that is used in many medical applications, including sutures. Shah’s hyperelastic “bone” material shows great promise in in vivo animal models; this success lies in the printed structure’s unique properties. The material is majority hydroxyapatite, yet it is hyperelastic, robust and porous at the nano, micro and macro levels.

“Porosity is huge when it comes to tissue regeneration, because you want cells and blood vessels to infiltrate the scaffold,” Shah said. “Our 3-D structure has different levels of porosity that is advantageous for its physical and biological properties.”

While hydroxyapatite has been proven to induce bone regeneration, it is also notoriously tricky to work with. Clinical products that use hydroxyapatite or other calcium phosphate ceramics are hard and brittle. To compensate for that, previous researchers created structures composed mostly of polymers, but this shields the activity of the bioceramic. Shah’s bone biomaterial, however, is 90 percent by weight hydroxyapatite and just 10 percent by weight polymer, and it still maintains its elasticity because of the way its structure is designed and printed. The high concentration of hydroxyapatite creates an environment that induces rapid bone regeneration.

“Cells can sense the hydroxyapatite and respond to its bioactivity,” Shah said. “When you put stem cells on our scaffolds, they turn into bone cells and start to up-regulate their expression of bone-specific genes. This is in the absence of any other osteo-inducing substances. It’s just the interaction between the cells and the material itself.”

That’s not to say that other substances couldn’t be combined into the ink. Because the 3-D printing process is performed at room temperature, Shah’s team was able to incorporate other elements, such as antibiotics, into the ink.

“We can incorporate antibiotics to reduce the possibility of infection after surgery,” Shah said. “We also can combine the ink with different types of growth factors, if needed, to further enhance regeneration. It’s really a multi-functional material.”

One of the biggest advantages, however, is that the end product can be customized to the patient. In traditional bone transplant surgeries, the bone — after it’s taken from another part of the body — has to be shaped and molded to exactly fit the area where it is needed. Using Shah’s synthetic material, physicians would be able to scan the patient’s body and 3-D print a personalized product. Alternatively, due to its mechanical properties, the biomaterial also can be easily trimmed and cut to size and shape during a procedure. Not only is this faster, but also less painful compared to using autograft material.

Shah imagines that hospitals may one day have 3-D printers, where customized implants can be printed while the patient waits.

“The turnaround time for an implant that’s specialized for a customer could be within 24 hours,” Shah said. “That could change the world of craniofacial and orthopaedic surgery, and, I hope, will improve patient outcomes.”

New Evidence That Testosterone May Explain Sex Difference In Knee Injury Rates

In studies on rats, Johns Hopkins Medicine scientists report new evidence that the predominance of the hormone testosterone in males may explain why women are up to 10 times more likely than men to injure the anterior cruciate ligament (ACL) in their knees.

Specifically, they found that normal male rats with natural supplies of testosterone had stronger ACLs than those that had been castrated and no longer produced the hormone. The results are described online Sept. 20 in the journal The Knee.

“The primary implication of the study is that testosterone may contribute to the ACL’s ability to withstand tensile loads and may be one of multiple factors response for the disparate ACL injury rate between men and women,” says William Romani, Ph.D., M.H.A., a physical therapist and sports medicine researcher who was a visiting faculty member in The Johns Hopkins University’s Department of Biomedical Engineering from 2009 to 2015.

Senior study author Jennifer Elisseeff, Ph.D., a biomedical engineer at The Johns Hopkins University, says the new finding could eventually lead to techniques that use circulating sex hormone levels to identify athletes at higher risk for ACL injury who may benefit from training strategies to strengthen the ligament.

The ACL is a flexible, stretchable tissue that tunnels through the knee, connecting the femur, or thigh bone, with the tibia, or shin bone. More than 200,000 people in the U.S. get ACL injuries, ranging from partial to full tears, most often while playing sports. Previous studies have found that girls and women are anywhere from two to 10 times more likely to tear an ACL than men doing similar activities. Explanations for the sex differences include differences in anatomy, strength, reflex times and hormones.

Romani, who now works with the AARP Foundation’s Experience Corps, conducted previous research on rats showing that that estrogen — a predominantly female hormone — reduces ACL strength, but he also found that knee ligaments in both sexes contain receptors for testosterone.

“Our thought was that while estrogen may make the female ACL weaker and more prone to injury, the male hormone testosterone may act to strengthen the ACL and protect it from injury,” says Romani.

In the new research, Romani and Elisseeff removed the ACL — still connected to the tibia and femur — from 16 healthy, 12-week-old male rats. Eight of the rats were normal, with testosterone levels averaging 3.54 nanograms per milliliter, and eight had been castrated, giving them nearly undetectable levels of the hormone, at 0.14 nanograms per milliliter. The researchers measured the cross-sectional area of each ACL and then connected the bones — with the ACL stretched between them — to a machine that could pull the bones apart, tugging on the ACL. Then, they tested the strength of the ligaments by measuring how much force it took to tear each ACL.

The researchers found that it took more force — 34.5 newtons, compared to 29.2 newtons — to tear the ACLs from mice with normal levels of testosterone, indicating that the ligaments were stronger. Since researchers have generally accepted that a stronger ACL is less prone to injury, the results support a link between testosterone and ACL injuries.

More work is needed to explain exactly which pathways and molecules testosterone and estrogen act through to influence ligament strength, and whether the hormones have the same impact on other ligaments in the body.

The Search for Better Bone Replacement: 3-D Printed Bone with Just the Right Mix of Ingredients

To make a good framework for filling in missing bone, mix at least 30 percent pulverized natural bone with some special man-made plastic and create the needed shape with a 3-D printer. That’s the recipe for success reported by researchers at The Johns Hopkins University in a paper published April 18 online in ACS Biomaterials Science & Engineering.

Each year, the Johns Hopkins scientists say, birth defects, trauma or surgery leave an estimated 200,000 people in need of replacement bones in the head or face. Historically, the best treatment required surgeons to remove part of a patient’s fibula (a leg bone that doesn’t bear much weight), cut it into the general shape needed and implant it in the right location. But, according to Warren Grayson, Ph.D., associate professor of biomedical engineering at the Johns Hopkins University School of Medicine and the report’s senior author, the procedure not only creates leg trauma but also falls short because the relatively straight fibula can’t be shaped to fit the subtle curves of the face very well.

That has led investigators to 3-D printing, or so-called additive manufacturing, which creates three-dimensional objects from a digital computer file by piling on successive, ultrathin layers of materials. The process excels at making extremely precise structures — including anatomically accurate ones — from plastic, but “cells placed on plastic scaffolds need some instructional cues to become bone cells,” says Grayson. “The ideal scaffold is another piece of bone, but natural bones can’t usually be reshaped very precisely.”

In their experiments, Grayson and his team set out to make a composite material that would combine the strength and printability of plastic with the biological “information” contained in natural bone.

They began with polycaprolactone, or PCL, a biodegradable polyester used in making polyurethane that has been approved by the FDA for other clinical uses. “PCL melts at 80 to 100 degrees Celsius (176 to 212 Fahrenheit) — a lot lower than most plastics — so it’s a good one to mix with biological materials that can be damaged at higher temperatures,” says Ethan Nyberg, a graduate student on Grayson’s team.

PCL is also quite strong, but the team knew from previous studies that it doesn’t support the formation of new bone well. So they mixed it with increasing amounts of “bone powder,” made by pulverizing the porous bone inside cow knees after stripping it of cells.

“Bone powder contains structural proteins native to the body plus pro-bone growth factors that help immature stem cells mature into bone cells,” says Grayson. “It also adds roughness to the PCL, which helps the cells grip and reinforces the message of the growth factors.”

The first test for the composite materials was printability, Grayson says. Five, 30 and 70 percent bone powder blends performed well, but 85 percent bone powder had too little PCL “glue” to maintain clear lattice shapes and was dropped from future experiments. “It was like a chocolate chip cookie with too many chocolate chips,” says Nyberg.

To find out whether the scaffolds encourage bone formation, the researchers added human fat-derived stem cells taken during a liposuction procedure to scaffolds immersed in a nutritional broth lacking pro-bone ingredients.

After three weeks, cells grown on 70 percent bone powder scaffolds showed gene activity hundreds of times higher in three genes indicative of bone formation, compared to cells grown on pure PCL scaffolds. Cells on 30 percent bone powder scaffolds showed large but less impressive increases in the same genes.

After the scientists added the key ingredient beta-glycerophosphate to the cells’ broth to enable their enzymes to deposit calcium, the primary mineral in bone, the cells on 30 percent scaffolds produced about 30 percent more calcium per cell, while those on 70 percent scaffolds produced more than twice as much calcium per cell, compared to those on pure PCL scaffolds.

Finally, the team tested their scaffolds in mice with relatively large holes in their skull bones made experimentally. Without intervention, the bone wounds were too large to heal. Mice that got scaffold implants laden with stem cells had new bone growth within the hole over the 12 weeks of the experiment. And CT scans showed that at least 50 percent more bone grew in scaffolds containing 30 or 70 percent bone powder, compared to those with pure PCL.

“In the broth experiments, the 70 percent scaffold encouraged bone formation much better than the 30 percent scaffold,” says Grayson, “but the 30 percent scaffold is stronger. Since there wasn’t a difference between the two scaffolds in healing the mouse skulls, we are investigating further to figure out which blend is best overall.”

Although the use of “decellularized” cow bone has been FDA-approved for clinical use, in future studies, the researchers say, they hope to test bone powder made from human bone since it is more widely used clinically. They also want to experiment with the designs of the scaffolds’ interior to make it less geometric and more natural. And they plan to test additives that encourage new blood vessels to infiltrate the scaffolds, which will be necessary for thicker bone implants to survive.

New Study Shows Common NSAIDs can cause more Harm than Good

Many patients around the world, are prescribed non-steroidal anti-inflammatory drugs (called NSAIDs) for the treatment of painful conditions, fever and inflammation. But the treatment also comes with side effects, including the risk of ulcers and increased blood pressure. A major new study from Denmark complied new research that demonstrated that a common arthritis medicine is particularly dangerous for heart patients.

The study also uncovered that older types of arthritis medicine, which have not previously been in focus, also appear to be dangerous for the heart. The study, which was carried out in collaboration between 14 European universities and hospitals, including a number of leading European heart specialists, was published in the most prestigious European journal of heart medicine, European Heart Journal.

“It’s been well-known for a number of years that newer types of NSAIDs – what are known as COX-2 inhibitors, increase the risk of heart attacks. For this reason, a number of these newer types of NSAIDs have been taken off the market again. We can now see that some of the older NSAID types, particularly Diclofenac, are also associated with an increased risk of heart attack and apparently to the same extent as several of the types that were taken off the market,” says Morten Schmidt, MD and PhD from Aarhus University, who is in charge of the research project.

Global Issue Around the World

Pain medications for osteoarthritis account for billions of dollars in annual sales globally. Most pain medications for osteoarthritis, including celecoxib which had global sales of $2.7 billion in 2014, are NSAIDs which have the side effect of elevating blood pressure, and increasing the risk of heart attacks, strokes and death. Of the 27 million Americans who live with osteoarthritis, 13.5 million also suffer from hypertension, which also increases the risk of heart attack, stroke, and death.

Late last year, a new NSAID candidate KIT-302 from Kitov Pharmaceuticals showed good promise as a combination pill that simultaneously treats joint pain and elevated levels of blood pressure. Kitov’s NSAID is a combination of celecoxib and the calcium channel blocker amlodipine.  In Kitov’s phase 3 study, this combination was documented to lower blood pressure better than amlodipine alone, thus enhancing the cardiovascular safety of the amlodipine. In contrast, and consistent with multiple prior publications, celecoxib alone raised blood pressure: An effect that correlates with an increased adverse cardiovascular event rate.

“The primary efficacy of the trial was to show that a combination of the two components of KIT-302, lowers daytime systolic blood pressure by at least 50 percent. Recognizing the cardiovascular dangers associated with NSAID use, Kitov has been working to bring a safer NSAID to market for the past three years,” explained Kitov’s Chairman and Chief Medical Officer, Dr, Paul Waymack.

“Many European countries consume more of these drugs than Denmark. But we can still do better and it’s often the case that paracetamol, physiotherapy, mild opioids or other types of NSAIDs with less risk for the heart would be better for the patients. Of course, the recommendations that have been introduced following our study and its review of the heart-related risks are a big step in the right direction in relation to patient safety,” says Morten Schmidt.