A new study published in the journal Osteoarthritis and Cartilage has found that people with newly diagnosed osteoarthritis (OA) of the knee or hip with contraindications to or precautions for NSAIDs still continue to be prescribed these drugs. Additionally they had higher use of opioids and slightly lower physical therapy (PT) use within the first year of OA diagnosis, both of which are not consistent with treatment guidelines for OA.
“We found individuals with contraindications to NSAIDs were still commonly prescribed them, placing them at risk for NSAID-related adverse events,” explains corresponding author Tuhina Neogi, MD, PhD, the Alan S. Cohen Professor of Rheumatology and professor of medicine at the school. “Additionally, they were not more likely to receive safer alternatives like PT despite its widespread recommendation as first-line intervention.”
The researchers used population-based register data to identify adults residing in Sweden (between 2004-13) without a previous knee or hip OA diagnosis. Among this group, between 2014-18, they identified people with knee or hip OA diagnosis and presence of contraindications to or precautions for oral NSAIDs at the time of OA diagnosis. They then estimated the risk of: 1) regular oral NSAID use; 2) regular opioid use; 3) PT during the first year after diagnosis among those with versus without contraindications or precautions.
Despite having contraindications to NSAIDs, 21% of those in the study were regular users of NSAIDs within the first year of their OA diagnosis. Similarly, 21% of those with precautions for using NSAIDs were also regular users. They also found a higher proportion of persons with contraindications were regular users of opioids than those without a contraindication or precaution, while a slightly lower proportion received PT.
Neogi stresses that more options for effective and safe management of OA symptoms are urgently needed, and greater work is required in narrowing and ultimately closing the evidence-knowledge-practice gap.
Nonsteroidal anti-inflammatory drugs (NSAIDs) exacerbate gastrointestinal infections by Clostridioides difficile, the leading cause of antibiotic-associated diarrhoea worldwide – but the reason why has long eluded medical science. In a new paper published in Science Advances, researchers have begun to answer that question, showing that NSAIDs disrupt the mitochondria of cells lining the colon, sensitising them to damage by pathogenic toxins.
C. difficile is a bacterium that leads to a wide range of symptoms, from mild diarrhoea to complex infection and death. The factors that influence this wide spectrum of clinical outcomes remain largely unclear, but emerging evidence suggests that factors like diet and pharmaceutical drugs influence both susceptibility to infection and disease progression. However, little is known about how these factors impact the course of C. difficile infection.
Prior studies have shown that NSAIDs like indomethacin, aspirin, and naproxen negatively affect the gut, both in patients with C. difficile infection and other conditions like inflammatory bowel disease (IBD). Long-term NSAID use can lead to stomach ulcers and intestinal injuries. One hypothesis that this is due to the effects of NSAIDs on cyclooxygenase (COX) enzymes; a process that helps reduce inflammation and pain but also impairs mucosal function in the upper gastrointestinal tract. NSAIDs also have off-target effects and have been shown to affect cellular mitochondria by uncoupling cellular mitochondrial functions, but these had not been studied in C. difficile infections.
To define these effects, Children’s Hospital of Philadelphia (CHOP) researchers, led by graduate student Joshua Soto Ocaña, used in vitro and mouse models of C. difficile infection to test how permeable colonic epithelial cells are in the presence of the NSAID indomethacin. The researchers observed that both indomethacin and C. difficile toxins increased epithelial cell barrier permeability and inflammatory cell death. They also found that the effect was additive: the combined effect on cell permeability of both toxins and indomethacin was increased compared to each independently, suggesting a synergistic effect of NSAIDs and C. difficile in increasing this pathogen’s virulence.
Surprisingly, the researchers found that NSAIDs exacerbate C. difficile infection independent of COX inhibition and instead through off-target effects on mitochondria. They did so by treating colonic epithelial cells with a precursor molecule that is similar in structure to indomethacin but lacks the ability to inhibit the COX enzyme. Not only did they find that this NSAID-like molecule induced cell death, but they also found that adding selective COX inhibitors did not increase cell death, demonstrating that COX enzyme inhibition is not required to induce epithelial cell damage during C. difficile infection and that, instead, this damage occurs through off-target effects of NSAIDs.
To test the role of off-target effects during C. difficile infection, the researchers used mice pretreated either with indomethacin or the NSAID-precursor molecule. When exposed to C. difficile, both groups of mice showed equal enhancement in disease severity and mortality compared to untreated control mice infected with C. difficile only. The researchers also observed a similar effect in mice who were pretreated with the NSAID aspirin. To further define the specific mechanisms driving these off-target effects of NSAIDs, researchers looked at mitochondrial functions in colonic epithelial cells in vitro and in mice. They observed that the combination of NSAIDs and C. difficile toxins increased damage to colonic epithelial cell mitochondria and disrupted several important mitochondrial functions.
“Our work further demonstrates the clinical importance of NSAIDs in patients with C. diff infection and sheds light on why the combination of these two may be so detrimental,” said senior author Joseph P. Zackular, PhD, Investigator and Assistant Professor of Pathology and Laboratory Medicine at CHOP. “Our mechanistic findings are a starting point for further research that aims to understand the impact of mitochondrial functions during C. diff infection. These data could also inform how NSAID-mediated mitochondrial uncoupling affects other diseases, such as small intestinal injury, IBD, and colorectal cancer.”
It may be better to let a mild fever run its course instead of automatically reaching for medication, new University of Alberta research suggests. Researchers found that, in fish models, untreated moderate fever helped them to quickly their infections, keep inflammation in check and repair damaged tissue. “We let nature do what nature does, and in this case it was very much a positive thing,” says ProfessorDaniel Barreda, immunologistand lead author on the study which is published in eLife.
Moderate fever is self-resolving, meaning that the body can both induce it and shut it down naturally without medication, Barreda explains. The health advantages of natural fever to humans still have to be confirmed through research, but the researchers say because the mechanisms driving and sustaining fever are shared among animals, it is reasonable to expect similar benefits are going to happen in humans.
That suggests the need to resist taking non-steroidal anti-inflammatory drugs at the first signs of a mild temperature, he says. “They take away the discomfort felt with fever, but you’re also likely giving away some of the benefits of this natural response.”
The study also sheds light on some benefits of moderate fever, which Barreda notes has been evolutionarily conserved across the animal kingdom for 550 million years. “Every animal examined has this biological response to infection.”
For the study, fish were given a bacterial infection and their behaviour was then tracked and evaluated using machine learning. Outward symptoms were similar to those seen in humans with fever, including immobility, fatigue and malaise. These were then matched to important immune mechanisms inside the animals.
The research showed that natural fever offers an integrative response that not only activates defences against infection, but also helps control it. The researchers found that fever helped to clear the fish of infection in about seven days – half the time it took for those animals not allowed to exert fever. Fever also helped to shut down inflammation and repair injured tissue.
“Our goal is to determine how to best take advantage of our medical advances while continuing to harness the benefits from natural mechanisms of immunity,” says Barreda.
A large randomised trial was halted after preliminary analysis found that taking aspirin after treatment for breast cancer did not reduce the risk of disease recurrence.
Laboratory studies had previously shown that aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) reduced breast cancer growth and invasion. Non-steroidal anti-inflammatory drugs (NSAIDs) display anticancer activity through the inhibition of the COX-2 enzyme, triggering processes such as apoptosis, a reduction in proliferation and inhibition of carcinogenesis. Several observational studies have shown a reduced risk of breast cancer mortality among regular aspirin users.
There was a 25% higher risk of invasive recurrence in patients who took aspirin for a median of 18 months, but not statistically different from placebo (P = 0.1258). The aspirin group had an excess of all disease-related events, including death, local and distant recurrence/progression, and new primary tumours.
The results are in line with similar trials that ended while the Aspirin after Breast Cancer (ABC) trial was ongoing, Wendy Y. Chen, MD, of Dana-Farber Cancer Institute in Boston, said during a presentation at the American Society of Clinical Oncology (ASCO) Plenary Series.
“In this double-blind, placebo-controlled randomised trial, there was no benefit of aspirin 300 milligrams daily in terms of breast cancer invasive disease-free survival,” reported Dr Chen. “Although follow-up was short, the futility bound was clearly crossed. We had reached 50% of the events, and there was a numerically higher number of events in the aspirin arm. Therefore, it was unlikely that even with further follow-up there wouldn’t be any benefit associated with aspirin.”
“Although inflammation may still play a key role in cancer, it’s important to remember that aspirin may have different effects in other cancers, such as colon, or in different settings, such as primary versus secondary prevention,” she added.
Though the trial was well designed, enrolled the right population and with adequate dosing. the trial was stopped early for futility, commented Angela DeMichele, MD, of the Abramson Cancer Center at the University of Pennsylvania.
“The direction and magnitude [of the difference in events] highly preclude the possibility that there would have been a benefit with more follow-up,” said Dr DeMichele. “Although it was not statistically significant, we cannot rule out the possibility of a potential increase in breast cancer recurrence from the use of aspirin.”
“For patients and providers at this time, aspirin should not be used simply to prevent breast cancer recurrence,” she continued. “For those situations in which there are other options, decisions about aspirin use for other indications should definitely include an individualised risk/benefit discussion between physician and patient.”
The results underscore the need for prospective, randomised clinical trials to validate the effects of interventions from observational studies, she concluded.
The ABC trial involved patients under 70 with HER2-negative, high-risk breast cancer. The study randomised 3021 participants to 300 mg of aspirin daily or matching placebo for 5 years, with the primary endpoint being invasive disease-free survival.
Dr Chen further noted that three clinical trials of aspirin or NSAID treatment ended while the ABC trial was ongoing. The Canadian-led MA.27 trial of an aromatase inhibitor plus celecoxib ended due to toxicity in the celecoxib arm. The randomised REACT trial of celecoxib in HER2-negative breast cancer showed no difference in disease-free survival after more than 6 years of follow-up.
The ASPREE trial tested low-dose aspirin on all-cause mortality in healthy older patients, and results showed a trend to increased all-cause mortality and significantly higher cancer mortality in the aspirin arm. During the post-presentation discussion, an audience member asked whether the results definitively ruled out a late benefit of aspirin, given that most patients had HR-positive disease wherein late relapse is not uncommon.
“It’s always frustrating when a study is closed early, and it was done in this case after we had reached 50% of the expected benefits,” said Chen. “There was an increase [in clinical events]. Not a statistically significant increase, but it was bordering on statistical significance. In order for aspirin to have a benefit, it would mean that in the second half, there would need to be a significantly decreased risk. It would basically need to flip and that would be biologically difficult to imagine.”
“I think it’s fair to say that this study doesn’t say definitively that there’s harm, but as for the likelihood of a benefit of aspirin, that would be extremely unlikely,” she said.
A new study has found that non-steroidal anti-inflammatory drugs (NSAIDs) suppress antibody counts as well as inflammatory levels in mice infected with the SARS-CoV-2 virus.
NSAIDs inhibit the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), which are needed for prostaglandin generation – lipid molecules involved in homeostasis and inflammation. The study used ibuprofen and meloxicam in mice infected with SARS-CoV-2. The researchers aimed to observe: viral infection through modified expression of angiotensin-converting enzyme 2 (ACE2), the cell entry receptor for SARS-CoV-2, effects on viral replication and modulated response of the immune system. However, they did not observe altered viral infection or replication.
“NSAIDs are arguably the most commonly used anti-inflammatory medications,” said principal investigator Craig B Wilen, Assistant Professor of Laboratory Medicine and Immunology, Yale University School of Medicine.
As well as taking NSAIDs for chronic conditions, eg arthritis, people take them “for shorter periods of time during infections, and [during] acute inflammation as experienced with COVID-19, and for side effects from vaccination, such as soreness, fever, and malaise,” Dr Wilen explained.
“Our work suggests that the NSAID meloxicam dampens the immune response to SARS-CoV-2 infection. Taking NSAIDs during COVID-19 could be harmful or beneficial, depending on the timing of administration,” said Dr Wilen. Dexamethasone, a potent anti-inflammatory but not an NSAID, is detrimental when administered at early stages of COVID but beneficial at later stages. NSAIDs may similarly be detrimental at the early stage because they counteract beneficial inflammation.
An antibody reduction by NSAIDs might not be harmful, but it could also reduce the immune system’s ability to mount a defence early on, or even reduce the length or magnitude of immunity or vaccination protection, Dr Wilen said. Antipyretics such as paracetamol have also been observed to blunt immune system response to vaccination.
According to Dr Wilen, the original motivation from the study “was a twitter thread, suggesting NSAIDs should not be used during COVID-19. This seemed suspicious to us, so we wanted to investigate.”
Dr Wilen and his team believed there would be no effect of NSAIDs on viral infection, which turned out to be correct. However, they also thought there would be no effect on antibody response.
“In fact, we initially didn’t even carefully look at the antibody response, because we didn’t expect it to be altered by NSAIDs. This turned out to be wrong,” commented Dr Wilen.
Journal information: Jennifer S. Chen et al. Non-steroidal anti-inflammatory drugs dampen the cytokine and antibody response to SARS-CoV-2 infection, Journal of Virology (2021). DOI: 10.1128/JVI.00014-21
