Researchers at the University of Illinois at Chicago College of Medicine have shown for the first time how the activation of a receptor provokes the inflammation and bone degradation of rheumatoid arthritis — and that activation of this one receptor, found on cells in the fluid of arthritic joints, is all that is required.
Their findings, published in the Journal of Immunology, point to a new therapeutic target to interrupt the vicious cycle of inflammation and bone erosion in rheumatoid arthritis.
Rheumatoid arthritis is a progressive autoimmune inflammatory disease of the joints. Swelling and pain, caused by certain cells flooding into the joints, is a hallmark of the disease, along with progressive bone loss. The UIC researchers have shown that the process begins with the triggering of a single receptor on a group of white blood cells.
“TLR5 does it all,” says Shiva Shahrara, UIC associate professor of rheumatology and corresponding author on the paper. TLR5, or toll-like receptor 5, is found on myeloid, or marrow-derived, cells that migrate from the blood into affected joints. Shahrara and her colleagues found that the receptor is much more abundant on myeloid cells found in the fluid of joints in patients with rheumatoid arthritis as compared to samples from healthy subjects.
In previous studies, Shahrara and her colleagues found that activation of TLR5 causes abnormal blood vessel formation in the joints of rheumatoid arthritis patients. In the new study they found that the receptor also up-regulates a potent inflammatory molecule called TNF-alpha, which recruits even more myeloid cells into the joint, where they are transformed into bone-degrading cells called osteoclasts.
In a series of experiments, the researchers uncovered multiple pathological processes driven by the activation of the receptor.
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown cause. An external trigger (eg, cigarette smoking, infection, or trauma) that triggers an autoimmune reaction, leading to synovial hypertrophy and chronic joint inflammation along with the potential for extra-articular manifestations, is theorized to occur in genetically susceptible individuals.
Essential update: Parental history of substance addiction may increase likelihood of developing arthritis
In an analysis of data on 13,036 adults from the 2005 Canadian Community Health Survey, Fuller-Thomson and colleagues found that children who grew up with a drug- or alcohol-addicted parent were at significantly increased risk for developing arthritis in adulthood. After adjustment for demographic characteristics, socioeconomic status, adult health behaviors, mental health conditions, and adverse childhood experiences, the odds ratio for developing arthritis among subjects with an addicted parent was 1.30 (95% CI: 1.12 - 1.51).
When the researchers placed TLR5-expressing myeloid cells next to joint fluid from rheumatoid arthritis patients, the cells migrated into the fluid. But if the receptor was blocked by an antibody, cell migration towards the fluid was significantly reduced.
Something in the joint fluid attracts cells with TLR5, Shahrara said – perhaps TLR5’s binding protein, which is most likely present in joints affected by rheumatoid arthritis.
The researchers also found that levels of TNF-alpha increased in joint fluid from patients with rheumatoid arthritis when myeloid cells with activated TLR5 were present. Patients with rheumatoid arthritis who take anti-TNF-alpha drugs have lower levels of TLR5 on their myeloid cells, suggesting that a positive feedback loop exists between TLR5 and TNF-alpha, so that an elevation in one causes an increase in the other.
“Not only do TLR5 and TNF-alpha regulate each other, but they work synergistically to attract more myeloid cells into the joint, where they are transformed into bone-eroding cells,” Shahrara said.
In a mouse model of rheumatoid arthritis, experimental mice given an antibody that blocked the TLR5 receptor had markedly reduced joint swelling and bone erosion compared to controls. The TLR5 antibody treatment may reduce swelling by lowering the number of myeloid cells migrating into the joints to become osteoclasts, the researchers said.
A hot topic among rheumatologists lately is whether when you treat rheumatoid arthritis (RA) matters as much as how you treat it. Some believe strongly in early arthritis treatment, prescribing an aggressive regimen of RA drugs during what is called “the window of opportunity.” Doing so, they maintain, just may stop the disease in its tracks.
“I am a strong believer in the window of opportunity, which probably spans two years after symptom onset,” says Salahuddin Kazi, MD, associate professor of internal medicine and chief of rheumatology at the Dallas VA Medical Center. “If RA goes untreated for two years, the majority of people with RA will develop joint erosion, indicating disease progression.”
“The debate over whether a window of opportunity exists is semantics to some extent,” says Arthur Kavanaugh, MD, rheumatologist and director of the Center for Innovative Therapy at the University of California, San Diego. “Some people don’t like the term because people with active disease can – and should – always be treated, even beyond the two-year mark.”
Treating RA as early as possible is not a new concept. In 1989, a study published in The Lancet emphasized the importance of starting a regimen of antirheumatic drugs early. The drugs commonly used then were hydroxychloroquine (Plaquenil) and sulfasalazine (Azulfidine); methotrexate wasn’t yet an option, and biologics were not yet developed. The main difference between discussions of early arthritis treatment 15 to 20 years ago and today are the drugs available for aggressive treatment, says Dr. Kavanaugh.
Early, aggressive treatment is particularly important for those who will develop a more serious disease. Figuring out who those patients are is quite a challenge, but guiding principles exist. “I think it’s pretty clear right now that if a patient has antibodies to rheumatoid factor (RF) or cyclic citrullinated proteins (anti-CCP) at any time during the course of disease - from day one to 12 weeks or 12 years – then he has a greater risk for persistent disease that is worse and more destructive,” says Stephen Paget, MD, rheumatologist and physician-in-chief of the Hospital for Special Surgery in New York City. “Those patients need aggressive therapy that’s constantly monitored.”
A recent study of adalimumab (Humira) plus methotrexate showed one in two people with early RA – diagnosed less than three years earlier - achieved a clinical remission at two years. More than 60 percent of the patients showed at least a 50-percent improvement in symptoms. The effect with combination therapy was observed as early as two weeks, and these differences were sustained throughout the two-year study.
Another study, the Definitive Intervention in New-Onset Rheumatoid Arthritis (DINORA) trial, is reviewing the use of infliximab (Remicade) in people with very early inflammatory RA (those who had it fewer than 14 weeks) to see if it can prevent the development of destructive disease.
While it’s ideal to initiate treatment as early as possible, aggressive treatment throughout the course of the disease is essential, say the experts.
“If you’re past that two-year mark with no treatment or treatment that wasn’t aggressive enough, all is not lost,” says Dr. Kavanaugh.
Based on her studies in mice, Shahrara thinks a drug that prevents TLR5 activation could slow or prevent the inflammation and bone erosion of later-stage rheumatoid arthritis in patients.
“When TLR5 is activated, it initiates a vicious feedback loop that results in a worsening of both the inflammatory and erosive features of rheumatoid arthritis,” Shahrara said. “The receptor is a major driver of inflammation and bone degradation. Blocking this receptor could have significant therapeutic value in interrupting joint swelling and bone loss in patients with rheumatoid arthritis.”
Seung-jae Kim, Zhenlong Chen, Nathan Chamberlain, Abdul Essani, Dr. Suncica Volkov, Dr. Shiva Arami, Dr. William Swedler, Dr. Anjali Mehta and Dr. Nadera Sweiss from the UIC College of Medicine; Michael Volin of Midwestern University Chicago College of Osteopathic Medicine in Downers Grove, Illinois; Dr. M. Asif Amin of the University of Michigan Medical School; Dr. Ellen Gravallese of the University of Massachusetts, Worcester; and Dr. Nancy Lane of the University of California, Davis Medical Center, are co-authors on the paper.
Rheumatoid arthritis most often affects the smaller joints, such as those of the hands and/or feet, wrists, elbows, knees, and/or ankles, but any joint can be affected. The symptoms often lead to significant discomfort and disability.
Many people with rheumatoid arthritis have difficulty carrying out normal activities of daily living, such as standing, walking, dressing, washing, using the toilet, preparing food, and carrying out household chores.
The symptoms of rheumatoid arthritis interfere with work for many people. As many as half of those with rheumatoid arthritis are no longer able to work 10-20 years after their condition is diagnosed.
On average, life expectancy is somewhat shorter for people with rheumatoid arthritis than for the general population. This higher mortality rate does not mean that everyone with rheumatoid arthritis has a shortened life span. Rheumatoid arthritis itself is not a fatal disease. However, it can be associated with many complications and treatment-related side effects that can contribute to premature death.
Although rheumatoid arthritis most often affects the joints, it is a disease of the entire body. It can affect many organs and body systems besides the joints. Therefore, rheumatoid arthritis is referred to as a systemic disease.
This research was supported by grants AR056099 and AR065778 from the National Institutes of Health, grant PR093477 from the Department of Defense, a grant from Within Our Reach from The American College of Rheumatology and an Arthritis Foundation Innovative Research Grant.