Rheumatoid arthritis

Posted on Exercise, Rheumatoid arthritis

A single session of aerobic exercise improves blood pressure in rheumatoid arthritis patients.

A study involving 20 women with rheumatoid arthritis and high blood pressure demonstrates the benefits of walking at moderate speed for 30 minutes even after tests that simulate stressful situations and tend to raise blood pressure
A study involving 20 women with rheumatoid arthritis and high blood pressure demonstrates the benefits of walking at moderate speed for 30 minutes even after tests that simulate stressful situations and tend to raise blood pressure

A 30-minute walk at moderate intensity temporarily reduced blood pressure in women with rheumatoid arthritis, not only at rest but also under stress. This was the conclusion drawn from a study involving physical and cognitive tests conducted at the University of São Paulo (USP) in Brazil.

The study was reported in an article published in the Journal of Human Hypertension and was supported by FAPESP as part of a Thematic Project on the effects of reducing sedentarism in different clinical populations. 

Rheumatoid arthritis is an autoimmune inflammatory disease affecting synovial joints and causing pain, swelling and progressive physical incapacity. People with rheumatoid arthritis also tend to have high blood pressure, and previous research has shown that the risk of death from cardiovascular disease is 50% higher for them than for the general population.

“A number of factors increase blood pressure in these patients, including chronic inflammation, lack of exercise, the adverse effect of the drugs used to treat the disease on the function and structure of blood vessels, and less elastic arteries that tend to narrow. Blood pressure can be elevated and vary more than normal during the day even when the arthritis is controlled. For these patients, we need to think about non-pharmacological strategies that enhance blood pressure control,” said Tiago Peçanha, last author of the article. Peçanha is a senior lecturer in cardiovascular physiology at Manchester Metropolitan University’s Department of Sport and Exercise Sciences in the United Kingdom and a researcher at USP’s Medical School (FM-USP) in Brazil.

Physical exercise is known to be one of the best non-pharmacological ways to control blood pressure. “However, we don’t know exactly what happens in the case of rheumatoid arthritis patients with elevated blood pressure. Mental stress and pain may well raise their blood pressure over and above the elevation due to the autoimmune disease,” said Tatiane Almeida de Luna, first author of the article. The study was part of her master’s research. “The results of our study were very positive. They reinforce the importance of exercise to cardiovascular management and as a complementary form of blood pressure control for these patients.”

According to Peçanha, the findings can apply to other autoimmune inflammatory diseases, such as lupus, psoriatic arthritis, inflammatory myopia and juvenile lupus. “Rheumatoid arthritis is an inflammatory disease model that resembles these other diseases, where inflammation and its consequences, such as elevated blood pressure, occur in a similar manner,” he said.

Systolic arterial blood pressure

High blood pressure, or hypertension, is a chronic disease defined by the World Health Organization (WHO) as systolic blood pressure equal to or above 140 mmHg and/or diastolic blood pressure equal to or above 90 mmHg. Rheumatoid arthritis patients tend to have elevated systolic arterial blood pressure – the higher of the two numbers in a reading, representing the pressure in the arteries when the heart beats and pumps blood. Prior research shows that systolic blood pressure is not ideal (under 140 mmHg) in 50% of these patients, even while they are sleeping and even with treatment for hypertension. 

According to the researchers, blood pressure rises in rheumatoid arthritis patients in response to mental stress, physical effort and pain, contributing to the high risk of cardiovascular complications of the disease. A recent study by the group found blood pressure to be elevated in post-menopausal women with rheumatoid arthritis as a response to lower limb exercise, with more severe inflammation leading to more blood pressure elevation.

Temporary reduction

In the latest study, the researchers analyzed 20 women volunteers aged between 20 and 65, and diagnosed with rheumatoid arthritis and hypertension. They were undergoing treatment for rheumatoid arthritis at Hospital das Clínicas (HC), the hospital complex run by FM-USP. 

Women of reproductive age took the tests during the first seven days of their menstrual cycle (follicular phase). All subjects underwent two sessions. The first involved pre-intervention measurement of blood pressure and heart rate, at rest and in response to different types of stress. In the second session, a randomly selected group walked at moderate speed on a treadmill for 30 minutes, while a control group stood on the treadmill for 30 minutes without performing any exercise. Both groups had their blood pressure measured before and after the session.

After exercise or rest, they took tests involving stress that could affect their blood pressure. One was a cognitive stress test (Stroop) in which they were shown a list of color words (e.g. “red”, “blue”, “green”) printed in incongruent colors (e.g. “red” printed in blue) and asked to say the color of each word rather than the word itself.

Another was a pain tolerance test (Cold Pressor) in which they were asked to place a hand in cold water at 4 °C. This was designed to produce mild to moderate pain and ended with voluntary withdrawal of the hand. Again, their blood pressure and heart rate were measured after the tests.

After the post-intervention assessments, the participants were fitted with an ambulatory blood pressure monitor for 24-hour measurement in real time. Systolic blood pressure remained stable in all 20 women before and immediately after the treadmill session, but was higher in the measurements made while they were resting. “This shows that exercise prevented a rise in blood pressure,” Peçanha said.

The 24-hour monitoring test showed that exercise lowered systolic pressure by 5 mmHg on average. “This is in line with the results of meta-analyses involving this type of exercise for the general population. This amount of reduction is significant, correlating with a 14% lower risk of death from stroke, a 9% lower risk of death from coronary arterial disease, and a 7% lower risk of all-cause death for people with hypertension,” he explained.

“The temporary effect of just one aerobic exercise session is very important since acute reductions in blood pressure on several consecutive days are expected to accumulate and lead to a sustained reduction over time, contributing to better control of hypertension in rheumatoid arthritis.”

The reduction was observed even after the stress tests. “The Stroop test is widely used in studies that analyze the cardiovascular response to mental stress, for example. In rheumatoid arthritis patients, it typically raises systolic pressure [to 16 mmHg] and diastolic pressure [to 12 mmHg] on average. In our study, however, systolic pressure fell by 6 mmHg after exercise,” he said, adding that this reduction was not observed when they performed the test after a resting period (control).

In the Cold Pressor (pain tolerance) test, systolic and diastolic pressure are expected to rise to 18 mmHg and 11 mmHg respectively on average, while heart rate typically rises by 1 bpm. In the study, systolic pressure rose even more sharply (to 25 mmHg) in six patients. 

On the day of the 30-minute walk, systolic pressure fell by 1 mmHg on average. On the day when they remained at rest, it rose by 4 mmHg.

“Stressful situations are known to increase the risk of cardiovascular events, such as stroke and heart attack. The study showed that the reduction in systolic blood pressure caused by physical exercise can potentially mitigate cardiovascular problems in rheumatoid arthritis patients,” Peçanha said.

Posted on Rheumatoid arthritis, Women's Health

Early menopause and HRT among hormonal factors linked to heightened rheumatoid arthritis risk

Having 4 or more children and fewer than 33 reproductive years also seem to be influential
Having 4 or more children and fewer than 33 reproductive years also seem to be influential

Early menopause—before the age of 45—taking hormone replacement therapy (HRT), and having 4 or more children are among several hormonal and reproductive factors linked to a heightened risk of rheumatoid arthritis in women, finds a large long term study published in the open access journal RMD Open.

Women are more susceptible to this autoimmune disease than men, note the researchers. They are 4–5 times as likely as men to develop rheumatoid arthritis under the age of 50, and twice as likely to do so between the ages of 60 and 70. And the disease seems to take a greater physical toll on women than it does on men.

While hormonal and reproductive factors are thought to contribute to women’s heightened susceptibility to the disease, it’s not entirely clear which factors might be particularly influential.

In a bid to find out, the researchers drew on 223,526 UK Biobank participants whose health was tracked for an average of 12 years.

During this time, 3313 (1.5%) women developed rheumatoid arthritis, and several hormonal and reproductive factors were associated with heightened disease risk, after accounting for potentially influential factors, such as lifestyle, level of social and economic deprivation, ethnicity and weight (BMI). 

Starting periods after the age of 14 was associated with a 17% higher risk when compared with starting them at the age of 13, while going through the menopause below the age of 45 was associated with 46% heightened risk compared with going through it at the age of 50-51. 

Fewer than 33 reproductive years—defined as the interval between starting periods and going through the menopause—was associated with a 39% heightened risk. And compared with having 2 children, 4 or more was associated with an 18% higher risk.

Hysterectomy or removal of one or both ovaries (oophorectomy) was associated with 40% and 21% higher risks, respectively, although only a few women had these procedures. 

While no clear association emerged between the use of the Pill and rheumatoid arthritis risk, HRT use and to a lesser extent, its duration, were associated with, respectively, 46% and 2% higher risks.

This is an observational study, albeit over a reasonably long period, and therefore can’t establish cause and effect, and the researchers acknowledge various limitations to their findings.

For example, the UK Biobank is made up of relatively healthy and affluent people of white ethnic background, so isn’t representative of the UK population at large.

Nevertheless, the findings prompt the researchers to suggest that hormonal and reproductive factors should be carefully evaluated in women diagnosed with rheumatoid arthritis. 

And they conclude: “The findings of this study are significant and form a basis on which novel and target-specific intervention measures to curb the risk of [rheumatoid arthritis] in women may be developed.”

Posted on Obesity, Rheumatoid arthritis

Research shows obesity is associated with worse flare symptoms and quality of life in people with early rheumatoid arthritis

Obesity
Obesity

A recent study from Hospital for Special Surgery (HSS) and others has found a correlation between obesity and more severe disease flare symptoms that negatively affect quality of life in patients with early rheumatoid arthritis (RA), a systemic, autoimmune, inflammatory disorder affecting multiple joints in the body. The study will be presented at ACR Convergence 2023, the annual meeting of the American College of Rheumatology.

RA is usually treated with a combination of medications to relieve swelling and pain while regulating the immune system. Joint surgery to relieve pain and disability, including joint replacement, may also be considered when these nonsurgical methods fail to provide lasting benefit.

“If a person with RA is experiencing frequent flares, weight could be a contributing factor,” said study principal investigator Vivian P. Bykerk, BSc, MD, FRCPC, a rheumatologist at HSS. “It may be helpful for patients to talk with their doctor about how to lose weight.”

To conduct their research, investigators used data from the prospective RA registry study called the Consortium of Early ArThritis CoHorts-USA Study (CATCH-US). This study, conducted at HSS and Johns Hopkins School of Medicine, recruited participants with at least two swollen joints and early or recent onset rheumatoid arthritis (symptoms ≤12/≤24 months) between December 2014 and May 2023. The researchers collected baseline characteristics and patient reported outcomes at each visit.

In this study, flares were determined using the OMERACT RA-Flare Questionnaire (RA-FQ), a patient-reported outcomes tool that assesses symptoms of pain, stiffness, fatigue, impacts on physical function, and impacts on social participation. Items in this tool are scored from 0 to 10, with 0 being best and 10 worst. All five scores are summed for an overall score range of 0 to 50. Investigators also collected an Evaluator Global Assessment (EGA) score, indicating rheumatoid arthritis clinical disease activity; this was scored by the enrolling rheumatologist between 0 (not active) and 10 (very active). Using a multivariable linear regression model, the investigators tested the correlation between body mass index (BMI) and RA-FQ scores, considering EGA scores and demographic factors such as age, sex, and ethnicity as covariates.

There were 134 participants in the study; 85% were female, 71% were white, and 87% were non-Hispanic. Almost half (46%) were overweight or obese. The median age was 47.3 years, and the median BMI was 24.3.

“Our key finding was that there was a linear relationship between having a higher BMI and having a higher RA-FQ score,” said lead study author Margaret Butler, a research assistant in the Department of Medicine at HSS. “As BMI got higher, RA-FQ scores increased as well, indicating that the patient would have poorer outcomes. Having a higher BMI also predicted worse scores in each of the five individual categories except physical function. The relationship was even more pronounced when you separated patients by healthy BMI, overweight BMI, and obese BMI, with patients having an obese BMI having worse RA-FQ scores compared to the other two groups.”

The researchers say that clinicians should consider patients’ BMI and RA-FQ scores when formulating treatment plans for RA flares. “Doctors should encourage patients to lose weight, if determined to be the root cause of frequent flare ups to avoid prescribing additional medications to control symptoms,” said Dr. Bykerk. “Losing weight for people with RA is a difficult problem because they have lost significant muscle mass, and that is our metabolic-driving tissue. To lose weight, patients have to build muscle and have a more nourishing, high-protein diet. We need programs to help patients do this.”

A previous study by the researchers revealed that fewer patients with RA go into remission if they are obese or overweight. Future studies will examine whether BMI influences RA flares throughout the course of the disease.

Posted on autoimmune conditions, Rheumatoid arthritis

Cause of rapid loss of vaccination protection in autoimmune diseases identified

People who are treated with TNF-α inhibitors for their autoimmune disease such as Crohn’s disease or rheumatoid arthritis lose their vaccination protection significantly earlier than average. The mechanism underlying the early decrease in antibody levels has now been eludicated by a scientific team from MedUni Vienna. In view of the results, principal investigator Ursula Wiedermann-Schmidt emphasises the importance of regular boosters for those affected. The research work has just been published in the specialist journal eBioMedicine.

The study was conducted by the Center for Pathophysiology, Infectiology and Immunology in cooperation with the Department of Gastroenterology and Hepatology of the University Department of Internal Medicine III. Patients with inflammatory bowel diseases (IBD) such as Crohn’s disease or ulcerative colitis and healthy controls were administered a SARS-CoV-2 mRNA vaccination and a booster after six months. Subsequent analyses showed that people receiving TNF-α blocker therapy had significantly lower antibody levels than healthy subjects and IBD patients receiving another form of treatment (α4β7-integrin antagonists).

TNF-α blockers are anti-inflammatory and immunosuppressive drugs from the group of biologics that are not only used for inflammatory bowel diseases, but also for other autoimmune diseases such as rheumatoid arthritis or psoriatic arthritis. According to the research team, the significantly faster loss of vaccine protection observed in the study is due to the fact that the strong inflammatory situation in these patients – despite the use of TNF-α inhibitors – inhibits the production of memory B cells in the lymph nodes. These are the cells of the immune system that are responsible for the production of long-lived plasma cells as well as antibodies and thus for long-term vaccine protection against already known pathogens – an essential prerequisite for the quality and duration of the protective effect of vaccinations.

Check of vaccination status with diagnosis of disease
“In our study we were able to elucidate the exact mechanism why only short-lived plasma cells are formed under TNF-α blocker therapy, so that antibody protection only lasts for a short time,” says corresponding author Ursula Wiedermann-Schmidt, Head of the Centre for Pathophysiology, Infectiology and Immunology and the Outpatient Clinic for Vaccinations, Travel and Tropical Medicine at MedUni Vienna. The study results apply not only to SARS-CoV-2 vaccinations, but in principle to all vaccinations. “For this group of patients, it is therefore necessary to maintain short-term protection through repeated booster vaccinations,” says Wiedermann-Schmidt. Special attention must be paid to vaccinations that are administered for the first time under TNF-α blocker therapy – here the early antibody waning and loss of protection can be most pronounced. Vaccinations performed already before the start of TNF-α blocker therapy would most likely retain their protective effect. In principle, when diagnosing an autoimmune disease (and other diseases under immunosuppressive therapy), the entire vaccination status should be ascertained as soon as possible and missing vaccinations should be supplemented before starting TNF-α blocker therapy (as well as other immunosuppressive therapies).

Posted on Rheumatoid arthritis

Novel biologic Ab-IPL-IL-17™ shows promise for rheumatoid arthritis and inflammatory bowel disease

Researchers have shown that a novel antibody generated to target an ‘essential amino acid sequence’ of both interleukin-17A and F has greater activity and potentially fewer side effects than existing biological therapies for conditions such as as rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease (IBD).

The antibody, called Ab-IPL-IL-17™, targets a specific section of signalling proteins IL-17A and IL-17F which play a central role in sustaining inflammation during onset and progression of autoimmune diseases.

Summer Outdoor Safety for Elderly Nursing Home Residents

Research published today in the Annals of Rheumatic Diseases identifies the sequence, and reports the results of animal, cell and tissue studies that demonstrate the effectiveness of Ab-IPL-IL-17™, and its potential clinical benefit for people with RA and IBD.

Authored by Dr Asif Iqbal from the University of Birmingham and Professor Francesco Maione, Head of ImmunoPharma Lab from the University of Naples Federico II, the paper reports studies which showed: 

  • Ab-IPL-IL-17™ displays potent anti-inflammatory activity in tissue and animal studies;
  • Maintains this activity without triggering unwanted ‘off target’ effects seen with some currently available, less specific, antibody therapies;
  • Reduces the pathological symptoms of arthritis and inflammatory bowel disease and is as effective as the current gold-standard treatment for RA at halting disease progression and triggering resolution.  

A patent application has been filed covering the antibody and its therapeutic use.  The researchers are seeking commercial partners who are willing to conduct a large-scale clinical evaluation of Ab-IPL-IL17™ in patients with immune-mediated inflammatory diseases (IMIDs). 

What is the essential part of IL-17?

IL-17A and IL-17F are known to stimulate a cascade of molecular signals that initiate inflammation and cause tissue damage and have been linked to numerous IMIDs. 

The researchers designed a series of peptides based on IL-17A/F and tested their ability to mimic the actions of the full proteins in cell culture.  They found a sequence that was only 20 amino acids long, and demonstrated for the first time that this sequence is responsible for IL-17’s biological activity in both mice and humans.  They called this sequence nIL-17™.

They then determined the 3D structure of this AA sequence and conducted studies that showed, at an atomic level, how the sequence ‘docks’ onto receptors that are known to trigger an inflammatory response. 

They demonstrated that this short sequence is a potent activator of the inflammatory response, stimulating the release of cyto-chemokines (inflammatory molecules which generate and amplify inflammation), to the same extent as full-length IL-17 molecules, and driving immune cell migration to an even greater extent than the parent molecules. 

The results from these cell culture experiments were confirmed in animal models, which showed the nIL-17™ truly represents the most biologically active sequence of IL-17. 

The researchers generated the novel antibody Ab-IPL-IL-17™ to target this sequence.  Further studies reported in the paper evaluated Ab-IPL-IL-17™.  

Results from antibody studies

In cell studies, Ab-IPL-IL-17™ showed potent activity, significantly decreasing the production of cyto-chemokines and reducing white blood cell migration in tissues primed for inflammation. 

Mouse studies evaluating the activity of Ab-IPL-IL-17™ against existing anti-IL-17 therapies (secukinumab, ixekizumab and bimekizumab) showed Ab-IPL-IL-17™ does not trigger unwanted immune responses, reduce the numbers of platelets, or increase the numbers of lymphocytes (white blood cells) in the blood.  Further studies in mouse models of arthritis showed that therapeutic administration of Ab-IPL-IL-17™ is as effective at halting disease progression and triggering resolution as the gold-standard current treatment for RA, infliximab.

Finally, the researchers conducted proof-of-concept studies that tested the response of tissues donated by patients with RA and IBD to Ab-IPL-IL-17™.   Here they found Ab-IPL-IL-17™ was able to reduce the pathological symptoms of disease.  In RA, where the researchers examined fibroblasts (connective tissue cells), the results strongly suggested that Ab-IPL-IL-17™ specifically inhibits the pro-inflammatory actions of chronically inflamed fibroblasts within the rheumatoid joint.