Can Rheumatoid Arthritis Be Prevented?

By Kevin Deane

More than 18 million people worldwide suffer from rheumatoid arthritis, including nearly 1.5 million Americans.

Rheumatoid arthritis is an autoimmune, inflammatory form of arthritis, meaning a person’s immune system attacks their joints, causing substantial inflammation. This inflammation can cause pain, stiffness and swelling in the joints, and in many cases, patients report fatigue and a flu-like feeling.

If left untreated, rheumatoid arthritis can lead to damage of the joints. But even when treated, this condition can lead to significant disability. In highly active disease or advanced stages, patient may have difficulty performing daily tasks, such as preparing food, caring for children and getting dressed.

Up to now, this condition has been treated once patients have already developed symptoms. But a growing body of evidence suggests this disease can be identified earlier – and maybe even ultimately prevented.

I’m a physician specializing in rheumatoid arthritis and a researcher who has conducted a clinical trial on treatments for this condition. I believe this research is moving us toward being able to identify people who are at risk for rheumatoid arthritis before the disease fully develops, and to finding treatments that will delay or prevent it altogether. 

My hope is that this could lead to changes in how we manage rheumatoid arthritis in the next several years.

Finding RA Before Symptoms Start

Currently, when someone visits their health care provider because they are experiencing joint pain or other symptoms of an immune attack, health care providers can make a diagnosis by examining the joints for swelling. The health care provider will also run tests to find blood markers called autoantibodies, which help in confirming the diagnosis. 

While not all people with rheumatoid arthritis will have abnormal blood markers, the two autoantibodies that are seen in up to 80% of people with rheumatoid arthritis are rheumatoid factor and anti-cyclic citrullinated peptide.

But multiple studies have now confirmed that rheumatoid arthritis has a preclinical stage of development. This is a time about three to five years or longer, prior to the onset of swollen joints when markers like rheumatoid factor and anti-cyclic citrullinated peptide are detectable in the blood. 

The presence of these markers indicates that autoimmunity is occurring, yet the body and organs are still functioning well, and a person who is at risk of getting rheumatoid arthritis may not feel sick yet.

Now that researchers have identified this preclinical stage, health care providers can use markers such as autoantibodies and symptoms like prolonged early morning joint stiffness to identify people who are at risk for rheumatoid arthritis but do not yet have joint inflammation.

At this point, predicting future rheumatoid arthritis is still in the research stage, although the field is working toward established ways to test for risk for rheumatoid arthritis as a routine part of health care. This is akin to how cardiovascular disease risk is assessed through measuring cholesterol levels.

Stopping or Delaying RA 

Because of advances in the ability to predict who may get rheumatoid arthritis in the future, researchers are now working on identifying treatments that can delay or prevent the full-blown condition from developing.

In particular, trials have been performed in people who tested positive for anti-cyclic citrullinated peptide, or who have other risk factors for rheumatoid arthritis. These risk factors include joint pain and subclinical joint inflammation, which is when an imaging study, like magnetic resonance imaging, sees joint inflammation that can’t be seen by a clinician examining the joints.

To date, almost all of these trials have used immune drugs that are commonly used to treat full-blown rheumatoid arthritis, such as methotrexate, hydroxychloroquine and rituximab. Researchers have been testing whether a short course of any of these drugs could lead to a lasting reset of the immune system and prevent rheumatoid arthritis from developing.

While there is not yet an approved drug for rheumatoid arthritis prevention, these studies offer hope that researchers are on track to find the right drug – as well as the right dosage and duration of that drug.

Preclinical Stage of RA

Some challenges remain to be addressed before preventive treatments become the norm in clinical care.

First, researchers need to better understand the biology of the preclinical stage of disease. Until recently, most studies have focused on patients with full-blown arthritis and generally ignored people at risk for developing the disease.

But now, researchers can use blood markers like anti-cyclic citrullinated peptide antibodies to identify those who are at risk much more easily. And a growing number of studies of people with this marker are informing how scientists understand the biology of rheumatoid arthritis development.

In particular, it is now apparent that the preclinical stage is marked by multiple circulating immune system abnormalities in cells, autoantibodies and inflammation. The hope is that researchers will find interventions that effectively target the immune system abnormalities driving the development of rheumatoid arthritis before the patient’s joints begin to swell.

Researchers are also finding that the abnormalities in the immune system during the preclinical stage may be coming from sites in the body other than the joints. An emerging idea called the mucosal origins hypothesis posits that the early autoimmunity of rheumatoid arthritis is caused by inflammation at mucosal surfaces of the body, such as the gums, the lungs and the gut. According to this theory, the joints are involved only later as the disease progresses.

More research is needed, but the mucosal origins hypothesis may help explain why periodontal disease, emphysema or other forms of lung disease and exposure to tobacco or forest fire smoke are risk factors for rheumatoid arthritis. It would also explain why certain bacteria have been associated with the disease. Future trials targeting interventions to a mucosal process could help researchers better understand the nature of this disease.

But while biomarkers like the anti-cyclic citrullinated peptide antibodies are strongly predictive for future rheumatoid arthritis, one difficulty remains: Some people who test positive for them never develop the full-blown disease.

Studies have shown that about 20% to 30% of people who are positive for anti-cyclic citrullinated peptide antibodies develop rheumatoid arthritis within two to five years, although the presence of combinations of risk factors can identify people who have a greater than 50% risk for developing the condition within one year.

This makes it difficult to find participants for clinical trials for rheumatoid arthritis prevention. If you can’t predict who will get the disease, it’s hard to know whether you’re preventing it.

So far, researchers have tried to recruit people who have already come to their health care provider with early joint symptoms of rheumatoid arthritis but still no swollen joints. That has worked well, but there are likely far more people at risk for rheumatoid arthritis who have not yet sought care.

Since health care providers are not yet testing everyone for blood markers for rheumatoid arthritis, researchers will need larger, international networks that can test for risk factors like autoantibodies to identify candidates for participation in prevention trials.

More needs to be done, but it’s exciting to see the field advancing toward the point where prevention may be part of routine clinical care for rheumatoid arthritis.

Kevin Deane, MD, is a Professor of Medicine and Rheumatology at the University of Colorado Anschutz Medical Campus.

He is the lead investigator on a U.S. trial called “StopRA” which seeks to identify people at-risk for future rheumatoid arthritis through a blood test, and then investigates whether treating them with a drug can delay or prevent future disease. You can learn more about this study by visiting their website or calling (303) 724-8330.

This article originally appeared in The Conversation and is republished with permission.

Promising Results for New Rheumatoid Arthritis Drug

By Pat Anson, Editor

A new drug being developed by Eli Lilly significantly reduces pain, inflammation and other symptoms of rheumatoid arthritis, according to the findings of an international research team published in the New England Journal of Medicine. Nearly ten percent of the patients taking the drug Baricitinib went into full remission.

Rheumatoid arthritis (RA) is a chronic autoimmune disease in which the body’s own defenses attack joint tissues, causing pain, inflammation and bone erosion. Most RA treatments focus on suppressing the immune system to reduce inflammation and slow progression of the disease.

Baricitinib inhibits two enzymes, called Janus kinase 1 and 2, which are activated in the inflammatory response to RA.

“This is the first drug to demonstrate meaningful clinical benefit in patients who’ve failed virtually every other commercial drug for rheumatoid arthritis,” said lead author Mark Genovese, MD, a professor of immunology and rheumatology at Stanford University School of Medicine.

Researchers at Stanford and Medical University of Vienna in Austria enrolled 527 RA patients from 24 countries in the Phase 3 clinical study. The patients had been living with the autoimmune disease for 14 years, on average, had moderate to severe symptoms, and had not responded well to previous treatments. Patients were divided into three groups, one with a daily dosage of 2 mg of Baricitinib, one with 4 mg, and a control group given placebos.

After 24 weeks, the patients who received Baricitinib had significant improvements in their symptoms, suffering less pain, joint swelling and other signs of disease activity. The group with the 4 mg dose showed even better results than those with the 2 mg dose, compared to the placebo group.

"With Baricitinib, we will have a drug that works even if the currently employed medications are not sufficiently effective,” said co-author Joseph Smolen, manager of the University Clinic for Internal Medicine III at Medical University of Vienna. “Almost 10 % of the patients went into full remission (a cure-like state) within six months, and almost half of the patients demonstrated significant improvement of in disease activity and physical functioning. All this may constitute a new basis for the treatment of rheumatoid arthritis that could become available in the near future."

Another advantage of Baricitinib is that it can be taken orally once a day and does not have to be administered intravenously or through injections, unlike other RA medications. Some patients in the study had side effects, such as mild upper respiratory infections and shingles.

About 1.5 million Americans and 1% of adults worldwide have rheumatoid arthritis. About three of every four people with the disease are women.

New injectable biologic drugs often work in controlling RA initially, but lose their effectiveness over time or have unacceptable side effects. They are also notoriously expensive, with some of the newer drugs costing $20,000 annually.

According to a recent study, RA patients enrolled in Medicare Part D plans paid an average out-of-pocket cost of $835 a month for a biologic in 2013. Costs varied widely depending on the drug – from $269 a month for the biologic infliximab to $2,993 a month for anakinra.

The Baricitinib trial was sponsored by Eli Lilly, which has filed for approval of the drug with the U.S. Food and Drug Administration. Three other Lilly-sponsored studies have shown  Baricitinib was effective in newly diagnosed patients, and in head-to-head competition with the RA medications adalimumab and methotrexate. Baricitinib is also being studied in trials for atopic dermatitis and systemic lupus erythematosus.

Discovery Could Lead to Earlier RA Treatment

By Pat Anson, Editor

Scientists have discovered a new protein that regulates the severity of tissue damage caused by rheumatoid arthritis, a finding that could help identify RA patients earlier for more aggressive treatment.

The protein – known as C5orf30 – was found in DNA and biopsy samples from the joints of over 1,000 RA patients in the UK and Ireland.

"Our findings provide a genetic marker that could be used to identify those RA patients who require more aggressive treatments or personalized medicine," said Professor Gerry Wilson from the School of Medicine and Medical Science, University College Dublin, who led the research.

"They also point to the possibility that increasing the levels of C5orf30 in the joints might be a novel method of reducing tissue damage caused by RA".

Rheumatoid arthritis is a chronic autoimmune disease in which the body’s own defenses attack joint tissues, causing joint pain, inflammation and bone erosion. About 1.5 million Americans and 1% of adults worldwide suffer from RA.

"These exciting findings will prompt us to further explore the role of this highly conserved protein that we know so little about, and its significance in human health and disease,” said co-author Dr. Munitta Muthana from the Medical School at the University of Sheffield.

The study, funded by Arthritis Ireland and the University of Sheffield, is published in the journal PNAS.

It is estimated that 30% of patients with rheumatoid arthritis are unable to work within 10 years of onset of the disease. It affects more women than men, and often more severely. RA is most common between the ages of 40 and 70, but it can affect people of all ages, including children.

Although there is no cure for RA, new drugs are available to treat the disease and slow joint damage. Self-management of the condition by patients, including exercise, is also known to reduce pain and disability.

One of the biggest problems in treating RA is early diagnosis and treatment, which can reduce the amount of joint damage.  

"Treatments for arthritis have improved enormously over the last number of years. Thirty years ago, rheumatologists' waiting rooms were filled with people in wheelchairs. Today, that is no longer the case. The outlook for a person diagnosed with arthritis in 2015 is much brighter than it used to be,” said John Church, CEO of Arthritis Ireland.

British researchers recently said they were close to developing a blood test that could detect both RA and osteoarthritis in its earliest stages.

Osteoarthritis (OA) is a progressive joint disorder caused by painful inflammation of soft tissue, which leads to thinning of cartilage and joint damage in the knees, hips, fingers and spine.

Researchers at the University of Warwick’s Medical School identified a biomarker linked to both forms of arthritis. Diagnostic blood tests already exist for RA, but the newly identified biomarker could lead to one which can diagnose both RA and osteoarthritis.

“This discovery raises the potential of a blood test that can help diagnose both RA and OA several years before the onset of physical symptoms," said lead researcher Naila Rabbani, PhD.

Rabbani’s research focused on citrullinated proteins (CPs), a biomarker present in the blood of people with early stage rheumatoid arthritis. Patients with RA have antibodies to CPs and the Warwick researchers established for the first time that CPs levels also increase in early-stage OA.

That research is published online in Nature Scientific Reports.