Question

what is the pathophysiology of Anaemia of inflammation (Rheumatoid Arthritis patient)?

Answer 1

  

                          Pathophysiology of Anaemia of inflammation (Rheumatoid Arthritis patient)

Rheumatoid arthritis (RA) is a disease that leads to inflammation of the joints and surrounding tissues. It is a long-term disease. It can also affect other organs. The cause of RA is not known. It is an autoimmune disease. This means the immune system of the body mistakenly attacks healthy tissue. RA can occur at any age, but is more common in middle age. Women get RA more often than men. Infection, genes, and hormone changes may be linked to the disease. Smoking may also be linked to RA.It is less common than osteoarthritis (OA). OA which is a condition that occurs in many people due to wear and tear on the joints as they age.

               Although the pathophysiology of RA is not completely understood, the process generally involves dysregulated inflammation, with antigen presentation, T-cell activation, and autoantibody production all serving as mediators in the inflammatory process

   Rheumatoid arthritis (RA) is a disease that leads to inflammation of the joints and surrounding tissues. It is a long-term disease. It can also affect other organs.

Treatments: Disease-modifying antirheumatic drug

Symptoms: Inflammation

Rheumatoid arthritis (RA) is a disease that leads to inflammation of the joints and surrounding tissues. It is a long-term disease. It can also affect other organs.

pathophysiology

                 Rheumatoid Arthritis (RA) is a chronic autoimmune disease. When the immune system is functioning normally, it recognises things like harmful bacteria and viruses, and responds by creating an “army” of antibodies that seek out and fight them off. In an autoimmune disease, the body mistakenly thinks that normal tissues or organs of the body are harmful, leading to inflammation and damage.

The Merriam-Webster dictionary definition of pathophysiology is: the physiology of abnormal states; specifically, the functional changes that accompany a particular syndrome or disease.

In RA, this effectively results in the body’s immune system attacking the tissues of the joints, causing pain and inflammation. RA can cause permanent damage to joints, especially in the early years of the disease. Let’s learn a little more of the science behind the development of RA.

The pathway to development of rheumatoid arthritis

Whilst the cause of RA is not fully understood, a number of risk factors such as smoking, obesity, and family history have been implicated in the development of RA.

Trigger
Broadly speaking, the combination of these factors can send a trigger to the body to create antibodies – known as autoantibodies – that seek out joint linings. These autoantibodies include rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (anti-CCP).

Inflammation
This results in the production of chemicals being released including tumour necrosis factor alpha (TNF-α), Interleukin (IL)-1, IL-6, IL-8, transforming growth factor beta (TGF-β), fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF).

Joint and tissue destruction
These chemicals inflame and damage the body’s cartilage, bone, tendons, and ligaments, resulting in the symptoms seen in Rheumatoid Arthritis.

     

                The synovitis, swelling, and joint damage that characterize active RA are the end results of complex autoimmune and inflammatory processes that involve components of both the innate and adaptive immune systems. In a susceptible individual, the interaction of environment and genes results in a loss of tolerance of self-proteins that contain a citrulline residue. These proteins are generated via post translational modification of arginine residues to citrulline residues by the enzyme peptidyl arginine deiminase. Patients with shared epitopes generate citrullinated peptides that are no longer recognized as “self” by the immune system, which consequently develops ACPAs against them. Comparison of magnetic resonance imaging (MRI) and synovial biopsy data from healthy individuals with MRI and biopsy data from patients positive for RF and/or ACPA demonstrate that systemic autoantibody production precedes inflammation and adhesion molecule formation in the synovium, indicating that perhaps some secondary event is required to initiate involvement of the synovium in RA. In a study of 79 patients with RA, the initial appearance of RF and ACPA preceded the development of clinical RA involving the synovium by a median of 4.5 years.

               

                 Synovitis occurs as a consequence of leukocyte infiltration into the synovium. The accumulation of leukocytes in the synovium does not result from local cellular proliferation but rather from migration of leukocytes from distant sites of formation in response to expression of adhesion molecules and chemokines by activated endothelial cells of synovial micro vessels. The interior of the inflamed synovium is hypoxic, presumably as a result of the proliferation of synovial cells and reduction in synovial capillary flow as a consequence of increased fluid volume in the synovium. Hypoxia, in turn, stimulates angiogenesis in the synovium, perhaps by inducing the formation of factors that stimulate vessel formation such as vascular endothelial growth factor.

                  Immune activation and RA disease progression is a complex process that involves interactions between components of both the adaptive and innate immune pathways. The nature of these interactions is greatly affected by the local cytokine and chemokine environment of the synovium in which they take place. In established RA, the synovial membrane is populated by a variety of inflammatory cell types that work together to cause joint destruction.

                      

                    The importance of the adaptive immune pathway in RA is suggested by the presence of dendritic cells, a major class of antigen-presenting cells that expresses a variety of cytokines, HLA class II molecules, and costimulatory molecules in close proximity to clusters of T cells in the synovium. Dendritic cells present antigens to T cells that are present in the synovium and also serve as one component of the T-cell activation process.Activation of T cells requires 2 signals. The first signal is antigen presentation to the T-cell receptor. The second signal, the costimulatory signal, requires interaction of the cell surface protein CD80/86 on the antigen-presenting (dendritic) cell with the CD28 protein on the T cell. Blockade of the costimulatory signal through competitive inhibition of CD80/86 interferes with T-cell activation and downstream events. The effectiveness of CD80/86 blockade as a treatment for RA validates the concept that T cells play an active role in the pathophysiology of RA.

                 When T-cell activation does occur, naïve T helper (Th) cells differentiate into 3 major subpopulations (Th1, Th2, and Th17) with distinct cytokine production profiles and functions. Although RA has long been considered to be a disease that is mediated by Th1 cells, recent interest has been focused on the Th17 subpopulation. Dendritic cells and macrophages both secrete transforming growth factor β, interleukin (IL)-1β, IL-6, IL-21, and IL-23, cytokines that support Th17 differentiation and suppress production of regulatory T cells, thus shifting the homeostatic balance in the synovium toward inflammation. In turn, Th17 cells produce IL-17A, IL-17F, IL-22, IL-26, interferon-g, the chemokine CCL20, and the transcription factor ROR-g. Production of IL-17A stimulates fibroblast-like synoviocytes (FLSs) and macrophage-like synoviocytes to upregulate production of IL-26, which induces production of the inflammatory cytokines IL-1β, IL-6, and TNF-α by monocytes; these cytokines stimulate further differentiation of Th17 cells. In addition to antigen-driven inflammatory pathways, inflammation can be mediated through antigen-nonspecific pathways initiated by cell-to-cell contact between activated T cells and macrophages and fibroblasts.

                          Humoral adaptive immunity also plays an integral role in the pathogenesis of RA. The contribution of B cells to autoimmune disease can be mediated through several potential mechanisms. Defects in B-cell tolerance checkpoints can result in autoreactive B cells that act as antigen-presenting cells that are capable of activating T cells. B cells can also produce both pro- and anti-inflammatory cytokines. Finally, B cells can function as antibody-producing cells. Separately or in combination, these mechanisms can contribute to RA pathogenesis.30 Additional support for the involvement of B cells in RA is provided by the successful use of agents that deplete specific B-cell populations for the management of RA. Rituximab, a monoclonal antibody directed against CD20-positive B cells, has demonstrated success in RA clinical trials and is currently approved for use in patients with RA who are refractory to TNF inhibitors.

                Cells of the innate immune system, including macrophages, mast cells, and natural killer cells, are located in the synovial membrane, whereas neutrophils are typically found in the synovial fluid. Macrophages, in particular, are important effectors of synovitis that act through phagocytosis; antigen presentation; and the release of pro-inflammatory cytokines, reactive oxygen intermediates, prostanoids, and matrix-degrading enzymes.

                   Intracellular signalling pathways are also involved in the pathogenesis of RA. All of the various cytokines, chemokines, antibodies, and antigens that contribute to inflammation bind to receptors on the cell surface of specific target cells. Receptor binding typically results in a cascade of intracellular signalling events that ultimately converges upon the nucleus of the cell and alters gene expression in ways that can affect cell function. In particular, changes in gene expression in immune cells are frequently associated with production and secretion of inflammatory mediators in response to a particular stimulus. Secretion of these mediators into the extracellular milieu results in further amplification and/or modification of the original signal. Examples of intracellular signalling pathways include the mitogen-activated protein kinase (MAPK) pathway, the Janus kinases (JAK) pathway, the signal transducers and activators of transcription (STAT) pathway, spleen tyrosine kinase (Syk) signalling, and the nuclear factor κ-light-chain enhancer of activated B cells (NF-κB) pathway. Cross communication between pathways has been reported.

                          Intracellular signalling pathways are essential for a normal immune response, and aberrations in these pathways may contribute to autoimmune disease. The first generation of small molecules directed against intracellular targets is now being used for the treatment of RA. Further understanding of these pathways will likely lead to the identification of additional therapeutic targets. The inflammation of RA is also associated with characteristic changes in mesenchymal tissue. FLSs, which are normally resident in the synovium, proliferate and change their phenotype in the setting of RA.9 In the inflamed synovium, cell contact between FLSs and T cells results in the induction of a variety of inflammatory mediators and adhesion molecules, including IL-6, TNF, interferon-g, intracellular adhesion molecule-1, and vascular cell adhesion molecule-1. Altered FLSs invade the cartilage of the joint and produce a variety of proteases that contribute to joint destruction.

Histopathology

Synovium

The synovium, in normal joints, is a thin delicate lining that serves several important functions. The synovium serves as an important source of nutrients for cartilage since cartilage itself is avascular. In addition, synovial cells synthesize joint lubricants such as hyaluronic acid, as well as collagens and fibronectin that constitute the structural framework of the synovial interstitium.

1. Synovial lining or intimal layer: Normally, this layer is only 1-3 cells thick. In RA, this lining is greatly hypertrophied (8-10 cells thick). Primary cell populations in this layer are fibroblasts and macrophages.

2. Subintimal area of synovium: This is where the synovial blood vessels are located; this area normally has very few cells. In RA, however, the subintimal area is heavily infiltrated with inflammatory cells, including T and B lymphocytes, macrophages, mast cells, and mononuclear cells that differentiate into multinucleated osteoclasts. The intense cellular infiltrate is accompanied by new blood vessel growth (angiogenesis). In RA, the hypertrophied synovium (also called pannus) invades and erodes contiguous cartilage and bone. As such, it can be thought of as a tumor-like tissue, although mitotic figures are rare and, of course, metastasis does not occur.

Cartilage

Composed primarily of type II collagen and proteoglycans, this is normally a very resilient tissue that absorbs considerable impact and stress. In RA, its integrity, resilience and water content are all impaired. This appears to be due to elaboration of proteolytic enzymes (collagenase, stromelysin) both by synovial lining cells and by chondrocytes themselves. Cytokines including IL1 and TNF drive the generation of reactive oxygen and nitrogen species and while increasing chondrocyte catabolic pathways and matrix destruction, also inhibit new cartilage formation. Polymorphonuclear leukocytes in the synovial fluid may also contribute to this degradative process.

Bone

Composed primarily of type I collagen, bony destruction is a characteristic of RA. This process is primarily driven by the activation of osteoclasts. Osteoclasts differentiate under the influence of cytokines especially the interaction of RANK with its ligand. The expression of these are driven by cytokines including TNF and IL1, as well as other cytokines including IL-17. There may also be a contribution to bony destruction from mediators derived from activated synovial cells.

Synovial Cavity

The synovial cavity is normally only a “potential” space with 1-2ml of highly viscous (due to hyaluronic acid) fluid with few cells. In RA, large collections of fluid (“effusions”) occur which are, in effect, filtrates of plasma (and, therefore, exudative – i.e., high protein content). The synovial fluid is highly inflammatory. However, unlike the rheumatoid synovial tissue in which the infiltrating cells are lymphocytes and macrophages but not neutrophils, in synovial fluid the predominant cell is the neutrophil.

      Conclusions

           RA, a common autoimmune disease, is associated with inflammation and swelling of the synovium of the joint and, if left untreated, often results in destruction of both the bony and cartilaginous elements of the joint and resultant disability. A variety of comorbidities associated with systemic inflammation contribute to the increased mortality seen in patients with RA compared with the general population. Although the pathophysiology of RA is not completely understood, the process generally involves dysregulated inflammation, with antigen presentation, T-cell activation, and autoantibody production all serving as mediators in the inflammatory process. Diagnosis of RA is based on the patient history and physical examination demonstrating synovitis in multiple joints. Indices of disease activity have been developed to guide treat-to-target approaches to pharmacological intervention.