Highlights From the 2022 ACR Research Conference: Part 2

Read part two of the latest arthritis research recently presented at the 2022 American College of Rheumatology (ACR) Convergence conference, which attracted health care providers, clinicians, researchers and patients from around the world.

The 2022 American College of Rheumatology (ACR) Convergence conference recently took place in Philadelphia, Pennsylvania, attracting health care providers, clinicians, researchers and patients in person from around the world for the first time in three years.
Listen to the Live Yes! With Arthritis Podcast covering more 2022 Arthritis Research Highlights from the conference.
Here is part two of our two-part series featuring highlights of the latest in science and research presented this year (click here for part one).

Food as Medicine

Roberta Ramonda, MD, professor of rheumatology, and Francesca Oliviero, PharmD, both of the University of Padua, Italy, discussed the role of diet in inflammation, autoimmunity and rheumatoid arthritis.
Diet plays a pivotal role in arthritis, not only because of its effect on the immune system and inflammation, but also because it affects body weight, pain, other chronic health problems and overall quality of life.
At the most basic level, nutrients can be pro- or anti-inflammatory and promote or help prevent autoimmunity. Topping the pro-inflammatory list are foods that a lot of Americans eat every day: red meat, sweets, sugary drinks, salt and too many omega-6 fatty acids — mainly from corn, soy and other vegetable oils.
In comparison, what’s commonly known as the Mediterranean diet consists almost entirely of anti-inflammatory nutrients — fiber from fruits and vegetables, polyphenols and oleic acid from extra virgin olive oil and omega-3 fatty acids from fish.
The two eating plans have strikingly different effects on health:
  • Saturated fats in beef and pork raise blood levels of bacterial endotoxins, causing a surge in inflammation.
  •  Sugar and soda kill off beneficial gut bacteria and ramp up highly inflammatory Th17 cells — key factors in autoimmune disease. In several large studies, sugary drinks were also associated with seropositive rheumatoid arthritis (RA) and an increased risk of heart disease — already heightened in people with RA.
  •  A high ratio of omega-6 to omega-3 fatty acids also stokes inflammation. Americans in general get 15 times more omega-6 fatty acids than omega-3s. Most fast, processed and packaged foods contain a boatload of omega-6 vegetable oils.
The Mediterranean diet, on the other hand, lowers inflammation, reduces heart disease and RA risk and contributes to overall health.
  • Omega-3 fatty acids increase anti-inflammatory cells called regulatory T cells or Tregs and decrease Th17. Tregs stop the production of inflammatory proteins and play a critical role in preventing autoimmunity. Although some studies of omega-3 fatty acids and heart disease have had inconsistent results, few other nutrients have as much evidence to support their health benefits.'
  • Compounds called polyphenols in extra virgin olive oil decrease inflammation and increase the activity of anti-inflammatory enzymes. Polyphenols aid the growth of healthy gut bacteria and curb the growth of pathogens. Polyphenols may also help manage or prevent gout by reducing uric acid.
  • Fiber from fruits and vegetables helps increase friendly bacteria in the gut. Fiber that’s not digestible is fermented in the colon, producing short-chain fatty acids, which have a wide range of anti-inflammatory benefits and help normalize the body’s immune response.
How food is grown and when it’s eaten matter, too. Studies suggest that organic food is more nutritious than commercially farmed food, especially when eaten in season.
Genes also play a role in nutrition. Food affects genes and genes influence how food affects the body, so everyone’s nutritional journey is slightly different. Some people react to tomatoes or gluten, for example, while others don’t. A good rule of thumb is to stick to a Mediterranean eating pattern: fish a few times a week (can substitute daily fish oil capsules, which may be cheaper and easier to find), lots of vegetables and extra virgin olive oil, moderate amounts of fruit. Drs. Ramonda and Oliviero also recommend one small glass of red wine a day because it’s rich in the antioxidant resveratrol, although the benefits of red wine are still a matter of debate.

This eating plan isn’t intended to be a quick fix or a diet in any traditional sense of the word. Instead, it’s a lifelong approach to good health that can help stave off arthritis and many other chronic conditions, including heart disease, diabetes and cancer. —LINDA RATH

Cardiovascular Risk and Inflammation in Rheumatic Diseases
Elaine Husni, MD, Cleveland Clinic, Susanne Sattler, PhD, Imperial College London, and Joan Bathon, MD, Columbia University, discussed new ways of thinking about heart disease risk in people with rheumatic disease.
Dr. Husni focused on circadian rhythms — intrinsic biological rhythms that govern hormones, body temperature, the sleep-wake cycle, blood pressure and heartbeat in almost all living things on a 24-hour cycle. Circadian rhythms are maintained by molecular clocks, including a master clock in the suprachiasmatic nucleus (SCN) at the base of the brain and peripheral clocks in immune cells, blood vessels and fat cells throughout the body.
Food, sleep patterns, exercise and medications can influence circadian rhythms, but the most powerful influencer is light. Modern humans are exposed to far too much light from screens and artificial lighting, affecting sleep, the immune system and overall health. Night or shift workers, for example, have an increased risk of cancer, diabetes and heart disease; even jet lag can cause temporary stomach trouble and fatigue.
Recent findings suggest a new way of looking at the role of circadian rhythms in cardiovascular disease. Circadian rhythms control inflammatory processes. When they’re out of sync with the body’s metabolism, the result can be arteriosclerosis — the buildup of fats and cholesterol on artery walls — and eventually blood clots in veins and arteries.
Circadian rhythms also affect fat metabolism, platelet function and leukocytes — white blood cells that can contribute to the progression of cardiovascular disease. Circadian rhythms affect the activity and makeup of microbes in the gut (microbiome), too, which in turn have a strong influence on heart health.
The goal of chronotherapy — treatment based on circadian rhythms — is to find ways to bring biological clocks back into balance. This might include changing light sources, food or lifestyle patterns or manipulating the microbiome. Circadian rhythms may also serve as new targets for drugs and help determine the best time to take medications.
Is heart failure an autoimmune condition?
Dr. Sattler argued that an autoimmune response has at least a part in the development of heart failure.
Dr. Bathon suggested that in addition to antibodies to anti-citrullinated proteins (ACPAs) in the synovial fluid of patients with RA and the gum tissue of people with gingivitis (a leading contributor to RA), ACPAs also occur in vascular tissue, where they play a role in atherosclerosis and cardiovascular disease.
“It’s not just joint inflammation, but vascular inflammation as well,” she said. —LINDA RATH

The Impact of Reproductive Health Legislation on Clinical Rheumatology: Practical Guidance

Cuoghi Edens, MD, University of Chicago Medicine, Mehret Talabi, MD, University of Pittsburgh, and Meghan Clowse, MD, Duke University, discussed commonly prescribed arthritis medications that can cause birth defects and the importance of effective contraception and family planning discussions with patients. Attorney Greer Donleyof the University of Pittsburgh assessed the legal landscape for rheumatologists in the wake of the Supreme Court’s decision that overturned abortion rights.

Key takeaways include:
  • Drugs often used to treat rheumatic diseases such mycophenolate, leflunomide and cyclophosphamide can cause miscarriages and birth defects. Methotrexate, the mainstay treatment for autoimmune arthritis, has become harder to access since Roe v. Wade was overturned because in larger doses, it’s used to treat ectopic pregnancies and miscarriages.
  • Effective contraceptives such as IUDs and implants are essential in people taking arthritis medications, but many don’t use them. Rheumatologists play an important role in advising patients about the safety and effectiveness of different forms of birth control.
  • Progestin-only contraception is safe and effective for all patients with a rheumatic disease, while estrogen-based contraception such as the pill increases the risk of blood clots and may provoke flares in people with lupus.
  • Rheumatologists need to do a better job of ensuring that patients don’t have unintended pregnancies.
  • Rheumatologists don’t have much to worry about in a post-Dobbs world, even if they live in a state where abortion is limited or banned.
Learn more about contraception for people with arthritis.

Christina Chambers, PhD, University of California, San Diego, and Megan Clowse, MD, Duke University, explained why there is so little data about the safety of arthritis drugs in pregnancy and why there may be safe drugs that aren’t yet recognized.

Key takeaways include:
  • Most data on the safety of arthritis drugs in pregnancy comes from pregnancy registries, which have low enrollment, limited sample sizes, no comparison groups and misunderstood confounders — factors that might distort the true association between a cause and an outcome.
  • When the risk is extreme, such as with thalidomide or isotretinoin, limited data might not matter because the danger is obvious. But it’s not as clear-cut with many drugs, and doctors and researchers may miss a sign that a medication causes harm. It’s important to look for a pattern of birth defects and miscarriages because this provides more evidence of harm and is easier to interpret.
  • Unplanned pregnancies in people with lupus taking medications that can cause birth defects can lead to poor outcomes for about 43% of pregnant women and 70% of infants.
  • The arthritis drugs mycophenolate and cyclophosphamide may cause birth defects in 25% of fetuses and pregnancy loss in half of women taking them.
  • Prednisone, even at lower doses, increases preterm birth, unhealthy weight gain, high blood pressure and diabetes, so most doctors try not to use them in pregnancy, but they may be necessary in active lupus nephritis.
There may be out-of-the-box options, such as rituximab (Rituxan) and belimumab (Benlysta). They may not cause birth defects, but they suppress a newborn’s immune system for months, making babies more susceptible to infections and less able to respond fully to vaccines. —LINDA RATH

Mood and pain happen in the same regions of the brain; 85% of patients with chronic pain also have moderate to severe depression. Iris Navarro-Millán, MD

Inspiring Older Patients to Thrive With the 5Ms of Aging
Bjoren Buehring, MD, Chair, Department of Rheumatology, Immunology and Osteology, Bergisches Rheuma-Zentrum, Krankenhaus St. Josef, Wuppertal, Germany (on behalf of Una Makris, MD, MSc, associate professor, UT Southwestern Medical Center), Elena Myasoedova, MD, PhD, associate professor, Mayo Clinic, Jiha Lee, MD, MS, University of Michigan, and Daniel White, PT, ScD, associate professor, University of Delaware, discussed how to inspire older patients to thrive using the 5Ms of aging. 
Demographic data predicts a huge growth in the number of older patients in the coming years. As such, inspiring older patients to thrive and age well is in all our best interests.
Presenting on behalf of Dr. Makris, Dr. Buehring focused on why the aging population matters — namely a very large increase in disability caused by increases in age-related disease (such as arthritis and back pain) — and how to implement the “5Ms of aging” in rheumatology practice to improve treatment of older adults. The 5Ms are considerations that all health professionals should factor in when caring for older adults. They include:
  • Multicomplexity of an older adult living with multiple chronic conditions, advanced illness and /or with complicated biopsychosocial needs.
  • Mind, especially the possibilities of dementia, delirium and depression.
  • Mobility and level of function, whether they have impaired gait and balance, and preventing injury from a fall.
  • Medications in terms of the number of medications, whether some can be discontinued, as well as optimal prescribing, adverse medication effects and medication burden.
  • What Matters Most to the patient in terms of meaningful health outcome goals and care preferences.
The key to addressing all the patient’s issues — medical, psychosocial, financial, etc. — said Dr. Buehring, is not to be overwhelmed by taking them all on, but to focus on the one that’s most important to the patient and the provider and save the rest for another day. “Prioritize what matters most,” said Dr. Buehring. This approach is important because “multimorbidities are really common,” said Dr. Buehring. “We have good data that it is more common in inflammatory diseases, RA being one.”
Dr. Myasoedova focused on the mind aspect of the 5Ms. Key takeaways include:
  • Cognitive impairment is a spectrum and may affect memory, daily activities, language, perspective, attention and social awareness.
  • Cognition is difficult to study and measure.
  • Risk factors may be genetic, lifestyle, or unknown, for instance, the effects of inflammation, which may be more pronounced in inflammatory disease patients).
  • Cognitive impairment can be detected in about one-third of RA patients.
  • RA patients have about a 40% increase in risk of dementia compared to the general population, even accounting for age, sex and cardiovascular risk factors and cardiovascular disease. “So there’s definitely a signal that rheumatoid arthritis may contribute — somewhat independently — to this process,” said Dr. Myasoedova.
  • Controlling inflammation may help improve the outcome of dementia.
  • A multidisciplinary approach to treatment is best, incorporating general internal medicine, rheumatology, neurology, psychiatry, cardiology, geriatrics and collaboration with patient and caregiver.
Dr. Lee focused on medication. Key takeaways include:
  • Consider polypharmacy — the use of five or more medications at the same time. But more important than the number is any potential of unnecessary, ineffective or possibly harmful prescribing.
  • “Prescribing cascade” — prescribing medications to treat side effects of other prescriptions — may lead to polypharmacy.
  • “Deprescribing” — thoughtfully and systematically identify problematic medications and either taper or stop them in a manner that is safe, effective and helps older adults maximize their wellness and goals of care.
  • 40% of RA and lupus patients are using a potentially inappropriate medication.
  • Health care providers must provide ongoing and frequent assessment of risk-benefit ratio for older adults to minimize medication-related harm.
Professor White focused on mobility. Key takeaways include:
  • Falls and fear of falling are common among older adults and patients with rheumatic diseases.
  • As a result, they may decrease their activity, which can lead to a vicious cycle that increases the risk of future falls.
  • Physical therapy for older adults is designed to break this cycle, e.g., assessing and improving balance.
  • Assess their fear of falling, and their confidence of functioning in the home, for example, taking a shower, climbing stairs, etc.
  • Interventions include establishing and regularly assessing goals, encouraging daily activity, addressing strength and balance training, providing patient and family education, and providing adaptations, such as using a cane.  —BRYAN D. VARGO
Difficult-to-Treat Rheumatoid Arthritis
Iris Navarro-Millán, MD, an assistant professor at Weill Cornell Medicine and Hospital for Special Surgery, Christopher Buckley, MD, PhD, Kennedy Professor of Translational Rheumatology and director of Clinical Research at the Kennedy Institute of Rheumatology at the University of Oxford, U.K., and S. Louis Bridges, MD, PhD, physician-in-chief at Hospital for Special Surgery, presented different perspectives of treatment-resistant RA.
Despite a growing number of treatment options for RA and other rheumatic diseases, some patients just can’t find the right drug or combination of drugs to keep their disease consistently under control. In these “difficult-to-treat” cases, doctors don’t have a clear view of which patients might have resistance to treatments or why the disease doesn’t respond to treatments.
The European League Against Rheumatism (EULAR) defines difficult-to-treat RA as a case in which the disease hasn’t responded adequately to a certain number of drugs that work in different ways. In addition, the patient and/or the rheumatologist view the symptoms as problematic, and the disease is active or the patient’s quality of life is declining despite having their RA under control, explained Dr. Navarro-Millán, an osteoarthritis (OA) and RA researcher.
The consequences can be significant in many ways, including financial. In Europe, informal help from family and friends accounts for 28% of the cost, drugs for 26% and 16% is from loss of work productivity. When compared with RA patients whose disease is not difficult to treat, the primary difference is in loss of function, Dr. Navarro-Millán said. In the U.S., increased costs from disabilities in general is over $13,000 per person under 65 receiving disability compensation and about $10,000 per person over 65, according to a report by the Kaiser Family Foundation.
A number of variables are associated with onset of disability in RA patients younger than 65, and while some are disease-related, some of the main factors are not. Patients with depression had a three-fold increase in risk of becoming disabled. Those who were separated from a spouse were also at increased risk, while having a higher education level actually offset some of the risk. So it may be that the factors underlying difficult-to-treat cases may not have as much to do with the disease as with socioeconomic and other factors, she added.
People with difficult-to-treat RA also tend to be younger at disease onset — about 42 years old compared to 48 — while other factors like comorbidities are not that different, which may also point to non-disease related variables as contributing to the difficulty in controlling it. People who are disabled are at greater risk of heart attack or stroke. And RA patients younger than 65 who also have depression are at increased risk of death, according to EULAR.
It makes sense that some patients say the mental burden of disease is greater than the physical burden, Dr. Navarro-Millán said, because mood and pain happen in the same regions of the brain; 85% of patients with chronic pain also have moderate to severe depression.
Socioeconomic status and the chronic stress perpetuated by poverty and social inequities also contribute to worsening disease.
“High cost, disability, loss of independence, well-being and higher risk for cardiovascular disease are consequences of the lack of treatment options for difficult to treat RA,” she said. All this points to the need for further research in mental health and social isolation, socioeconomic status, and resilience.
Dr. Buckley discussed what is and isn’t known about difficult-to-treat RA at the cellular level. New technologies, like single-cell sequencing, which enables researchers to identify specific cells, have opened doors to better understanding the underlying causes of RA and hard-to-treat cases. Eventually it might be possible to predict which cases might be resistant to treatment, but much more research is needed.
Future research needs to look at all the factors that might contribute to RA not responding to treatment. Some are related to the disease, such as persistent inflammation, pain from structural damage and genetic factors. Others are related to physicians or insurance plans, such as misdiagnosis, step therapy requirements or failure to use a treat-to-target approach. Yet others are related to the patient, such as failure to take their meds as prescribed, socioeconomic barriers, use of alcohol or smoking, and other conditions, like depression, said Dr. Bridges.
Machine learning, big data and other approaches may help accelerate research, but there are a whole host of variables related to patients, physicians and the disease to consider in the search for treatments for these cases, he added. New insights may come from collaborations between rheumatologists and a variety of other specialists, from nurses and physical therapists to psychologists and social scientists to policy experts and patient advocates to geneticists and biostatisticians.
“What we need is collaboration across all spectrums of research with everyone putting the patient at the center,” Dr. Bridges said. “And what we really need is a truckload of innovative new projects.” —JILL TYRER
Learn about the latest Arthritis Foundation funding for research in difficult-to-treat, or “refractory,” rheumatoid arthritis. And listen to the Live Yes! With Arthritis podcast episode: 2022 Arthritis Research Highlights to hear from one of the funded researchers.