Introduction:
Bone erosion is a term used in radiology to describe a break in the cortical bone that results in the destruction of the natural barrier separating the bone marrow compartments from the extraskeletal tissue, most commonly in joints, on mineralized cartilage, or close to the sites where periarticular ligaments insert and where tenosynovitis (inflammation of protective layer around tendons) is present. In cases of rheumatoid arthritis (RA), bone erosions in the joints are typically regarded as permanent end-state alterations.
In RA, the synovial membrane (synovium) experiences chronic inflammation, which leads to hyperplasia and the development of pannus (extra growth in the bone), a thicker, hypertrophic synovial membrane that invades the nearby cartilage and bone and causes erosions of the bone and destruction of the cartilage. Disease-modifying antirheumatic medications (DMARDs), which reduce inflammation and retard disease development, were previously the cornerstones of RA treatment. However, thanks to advances, the biological agents of today are made precisely to stop the main mediators of the RA inflammatory process.
What Are Bone Erosions in Rheumatoid Arthritis?
The most prevalent kind of chronic inflammatory arthritis, rheumatoid arthritis (RA), is characterized by continuous synovial membrane (a layer lining joint cavities) inflammation, which may lead to gradual joint bone and cartilage loss. RA is a multicompartmental disease that affects the bone marrow, synovium, cartilage, tendons, and cortical bone. Early in the course of RA, sometimes just weeks after diagnosis, bone erosions start to occur. Within 8 weeks of the start of the disease, more than 10 % of patients experience bone erosions; by 1 year, erosions can affect up to 60 % of patients.
In RA patients, bone erosions worsen over time and contribute to joint deterioration, impairing functional capacity. As a result, the existence of bone erosions indicates a more severe clinical history, making them a crucial indicator of the outcome of RA. However, erosions are not just present in RA patients; they can also be seen in healthy individuals and can be a symptom of other joint diseases such as psoriatic arthritis, osteoarthritis, and crystal arthropathies like gout. In routine clinical practice, the presence, number, and size of bone erosions, as well as the number of joints with erosions on conventional radiographs in RA patients, serve as diagnostic, staging, and damage progression prediction landmarks.
How Do Bone Erosions Occur in Rheumatoid Arthritis?
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Bone-Degrading Cells
Bone-degrading cells called osteoclasts are responsible for causing bone erosions to form. These cells have been found to generate resorption pits at the pannus-bone interface, which eventually result in erosions of the bone. According to imaging studies, bone erosions in RA frequently develop before bone marrow edema. According to histologic studies, bone erosions in RA are caused by a localized collapse of cortical bone close to the replacement of bone marrow fat by inflammatory cells. Additionally, osteoclasts, macrophages, plasma cells, CD8+ T lymphocytes, and B cells have been found to infiltrate the bone marrow. As a result, accelerated bone resorption (destruction of bone) and finally the emergence of bone erosions are caused by inflammatory cells and osteoclasts infiltrating bone close to inflamed synovium.
2. Impaired Bone-Forming Cells
Inflammation impairs bone-forming cells called osteoblasts, leading to failure of bone erosions to repair in RA. Moreover, tumor necrosis factor (TNF), a key factor in RA pathogenesis, is a potent inhibitor of osteoblast differentiation. Type I collagen and osteocalcin production by osteoblasts is inhibited by TNF, as is the formation of alkaline phosphatase, which plays a role in the mineralization of the bone matrix and also triggers the apoptosis of osteoblasts.
3. Cytokines
Cytokines are proteins that control inflammation in the body. It is well-recognized that increased cytokine production is a key factor in the development of osteoclastogenesis and bone degradation in RA.
(i) Interleukins
A cytokine involved in the pathogenesis of RA is interleukin-1 (IL-1), which is generated in the RA synovium by synovial macrophages and peripheral blood monocytes. Osteoclast activation is induced by IL-1. Th17 cells, which are T helper cell types that produce IL-17, and other cytokines such as IL-6, IL-15, IL-33, and IL-34, are crucial to the pathophysiology of RA and elevated differentiation of osteoclasts i.e., bone-degrading cells.
(ii) Tumor Necrosis Factor
Tumor necrosis factor (TNF), which is primarily involved in the pathophysiology of RA, is strongly expressed by synovial macrophages and peripheral blood monocytes in RA patients. Both directly acting on osteoclast precursors and indirectly by increasing the RANK signaling pathway (a pathway that regulates osteoclast differentiation), TNF increases osteoclast differentiation.
4. Innate Immunity
The initial line of defense against invasive infections is referred to as innate immunity. The immunoreceptor tyrosine-based activation motif (ITAM) signaling pathway is one mechanism that signals the control of the function of myeloid cells like macrophages, neutrophils, and innate immune cells like natural killer cells and affects the development and function of B and T cells in adaptive immunity. Additionally, increased osteoclastogenesis results from the ITAM signaling pathway being activated in RA. Toll-like receptors are another mechanism. TLRs, or toll-like receptors, serve as crucial for innate immunity. TLR activation suppresses osteoclastogenesis in osteoclast precursors during the early stages of differentiation, but it promotes osteoclastogenesis in cells that have already begun osteoclast differentiation. TLRs also aid mature osteoclasts in surviving.
5. Autoantibodies
Antibodies against citrullinated proteins (ACPAs) are found in RA patients and are helpful in the identification of the disease because of their high specificity. Since bone erosions can be seen in RA patients as soon as a few weeks after diagnosis and ACPA positivity precedes the onset of the disease by years, it is possible to hypothesize that osteoclast activation and bone resorption begin prior to the onset of RA and are triggered not only by synovitis and cytokines but also by autoantibodies like ACPA.
What Are the Therapeutic Implications for Bone Erosions in Rheumatoid Arthritis?
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Biological DMARDs
Conventional synthetic disease-modifying antirheumatic medications (DMARDs), such as Methotrexate, Sulfasalazine, and Chloroquine, have only mildly improved the condition of people with rheumatoid arthritis (RA), and only in a small percentage of these patients do they fully cure bone erosions. But, recently developed biological DMARDs are a distinct kind. They block molecules like cytokines that indicate or support inflammation and target certain immune system cells that cause it. It has been researched in recent years as to whether biological medicines used to treat RA inflammation can also mend bone erosions. Achieving clinical remission or low disease activity, biological and synthetic DMARDs reduce RA inflammation, stop bone erosions from progressing further, and lead to partial bone regeneration. These medications, however, are unable to fully cure and reverse the erosions due to the presence of joint inflammation.
2. Gene Therapy
For RA gene therapy, a number of gene targets have been investigated. Gene therapy is a promising method for treating RA as it has demonstrated success in a number of preclinical and clinical studies. However, before RA gene therapy is used in clinical settings, however, more research is required to learn more about pharmacokinetics and safety concerns.
Conclusion:
It is important to remember that keeping bones strong can also stop or slow down bone deterioration. Taking it gradually at first and proceeding with some cardio and strength-training workouts, starting with low-impact activities like swimming are some smart preventive measures. Additionally, Prednisone and Methotrexate are two examples of anti-inflammatory drugs whose prolonged usage can harm bones. Regular medical visits are therefore important to avoid or minimize complications of rheumatoid arthritis such as bone erosions.
