Many of the widespread conditions affecting people all over the world are increasingly being linked to chronic inflammation. However, the underlying mechanisms causing and sustaining this inflammation are not always clear.
Taking a closer look at arthritis, ongoing research is focusing on the role of inflammation in the development and maintenance of many forms of the disease, including recently osteoarthritis, which was not traditionally believed to be linked to inflammation.
Forms of arthritis, from the most common, include osteoarthritis, rheumatoid arthritis, juvenile arthritis, spondyloarthritis, and lupus.
Rheumatoid arthritis (RA) is an inflammatory disorder affecting synovial joints between bones, accordingly, patients are usually given drugs to suppress the inflammation. Research has shown that RA is strongly linked to a number of immune cells - mainly B-cells, T-cells and macrophages - with each type contributing differently to the condition. These various immune cells produce several 'immunomodulatory' molecules, either in the synovium within joints or in circulating blood.
Many studies aim to understand the inflammatory role of these immune cells and molecules, particularly because RA raises the risk of other inflammatory disorders including Sjögren’s syndrome and pericarditis.
One of the standard approved treatments for RA is anti-tumor necrosis factor (TNF) therapy, in which TNF is targeted and blocked by the inhibitors to cease the inflammation signaling that causes RA. Other treatments target T-cells, to minimize the T-cell-mediated killing of healthy cells which is the main root cause of all autoimmune disorders.
Less common 'biological' therapies use B-cell and T-cell depletion as a treatment, blocking the activation of Janus kinases which are involved in cell signalling. In doing so, they can block the intracellular inflammatory process.
Recent advances in research are also uncovering more about the role of inflammation in osteoarthritis (OA) - both directly, and as a factor in other disease-causing pathways.
OA has long been viewed as a mechanical rather than inflammatory condition, with the inflammatory pathways in OA being activated in response to joint injury. Many still consider that inflammation is a secondary feature of OA, occurring as a result of tissue injury and the reparative process which follows. In contrast, the inflammation in RA is characterized as an autoimmune response, in which the body attacks its own tissues.
But in recent years, animal and human studies have highlighted an increasingly important role for inflammation in the synovium within joints, while inflammation also influences the regulation of various steps in the inflammatory response. Low grade inflammation is known to play a role in cartilage degeneration and repair.
Many of the top risk factors for knee OA are themselves linked to inflammation. These include obesity, which increases the levels of pro-inflammatory immune substances released from adipose tissue. Previous joint injury can trigger inflammation via the production of tumor necrosis factor, as also seen in RA, and interleukin-1 - a major regulator of inflammation.
The National Institute of Arthritis and Musculoskeletal and Skin Diseases held a roundtable meeting of experts to discuss the issue. They state, "A better understanding of the interactions between the inflammatory process and pathophysiology of OA may provide possible treatment options that could improve the outcomes for patients at various progressive stages - including pre-symptomatic."
Synovitis, an inflammation of the synovial membrane, occurs after joint injury, and may be the initiating event that leads to OA. New data suggest that all components of the joint, including the cartilage, synovium, menisci, and subchondral bone, are affected by the inflammatory process, setting the stage for the initiation of cartilage breakdown and the beginnings of OA.
The transition from acute, injury-related pain to chronic, persistent pain is not well understood. If inflammation could be targeted to prevent the transition to chronic, persistent pain, this would have a tremendous impact. But translating basic knowledge of immunological mechanisms underlying inflammation into clinical practice is still challenging.
A further type of arthritis is juvenile idiopathic arthritis (JIA), the most common chronic rheumatic disease in childhood. It is considered a complex inflammatory disease with many links to the immune system.
The chronic inflammatory response in JIA involves uncontrolled activation of both the innate and adaptive immune systems, affecting synovial tissue and leading to chronic disease. Adding to the complexity, JIA is not a single disorder but a group of different autoimmune inflammatory diseases.
One subtype is similar in many ways to RA in adults, others such as JIA are more similar to spondyloarthritis.
Spondyloarthritis, or SpA, is a group of inflammatory diseases that cause arthritis of a kind which involves inflammation in entheses - where ligaments and tendons attach to bones - in many areas of the body.
It can affect the back, pelvis, neck and some larger joints, as well as internal organs, such as the intestines and eyes. The most common subtype is ankylosing spondylitis, followed by psoriatic arthritis. The subtype enteropathic arthritis is linked to inflammatory bowel disease.
In fact, gut inflammation is present in many patients with SpA, not only those showing clear intestinal inflammation. Recent evidence suggests that this inflammation may be driven by intestinal dysbiosis, and furthermore, that it is not a consequence of inflammation but involved in the development of the SpA.
A research team led by Dr Angelo Ferrante of the University of Palermo, Italy, recently stated that subclinical gut inflammation is "an important pathophysiological event actively participating in the pathogenesis of the disease".
They explain, "The dysregulation of intestinal epithelial barrier possibly modulated by intestinal dysbiosis modulates local and systemic inflammation possibly representing the occult mechanism of the disease."
On a similar theme, researchers from Keele University, UK, believe they have found evidence of a link between antibiotic use and arthritis. They carried out a study showing that taking antibiotics can lead to a raised risk of rheumatoid arthritis.
As well as killing bacteria, antibiotics can also affect the gut microbiota which is integral to health, particularly the immune system, they report. Antibiotics are thought to reduce microbial abundance and species diversity, and their use in childhood has been linked to several autoimmune conditions. Rheumatoid arthritis is one such condition.
Team member Dr Lindsay Hall said, “The more we learn about the complexity of the microbiome, and how factors including antibiotics impact these diverse microbial ecosystems, the more insights we have into how this may alter key health outcomes. The challenge now is to unpick the mechanisms that link the microbes to different conditions, including rheumatoid arthritis, so that we can develop new therapeutics.”
Another relatively common arthritis-related condition is lupus. It is a systemic autoimmune disease with uncontrolled inflammation during intermittent flare-ups, which may be triggered by environmental factors.
A study in 2000, based at Michigan State University, found hopeful evidence that consumption of the omega 3 fatty acids EPA and DHA from marine sources may reduce lupus symptoms, due to their anti-inflammatory and pro-resolving properties.
Related work on RA has found similar outcomes. In a paper, experts on inflammation from Queen Mary University of London, UK, explain that "RA may arise from a decreased ability of the host immune response to engage resolution programmes that prevent the precipitation of acute inflammation into chronicity".
"Central to the termination of ongoing inflammation is a newly uncovered genus of mediators," they write, which they term specialized pro-resolving mediators. These mediators are made by immune cells using essential fatty acids, including omega 3 fatty acids.
The authors add that during pain from non-resolving joint inflammation there is a downregulation of these mediators and lower levels of omega 3 fatty acids. "Strategies to increase the production of these molecules through essential fatty acid supplementation are linked with decreased joint inflammation and promotion of joint protection," they write.
Mounting evidence suggests that inefficient inflammation resolution is behind the chronic nature of most, if not all, forms of arthritis. Increased knowledge of these resolution mechanisms and their biomarkers will be very useful for clinicians.
Therapies to help minimize inflammation and prevent further damage, disease progression, and disability, would significantly improve arthritis patients' quality of life.
Kaylee Carter is a Registered Nurse in the Burn Center at Wake Forest Baptist Health in North Carolina. Her medical career began as a phlebotomist in 2012. Since then she has climbed the degree ladder from CNA, LPN, ADN, and she is two semesters away from her BSN. She maintains ACLS, PALS, BLS, ABLS, and ABLS instructor certification. Kaylee has spent several years as a staff nurse on the Burn Center and recently stepped into the Clinical Nurse Educator role. She is very passionate about nursing retention and is the principal investigator for a research study related to burn nurse retention at her facility. 
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