Transcription
Hello. In this video, we're going to look at rheumatoid arthritis, which is a systemic rheumatological disorder affecting multiple joints. The clinical presentation of rheumatoid arthritis is arthritis, which is symmetrical. We have pain, swelling, as well as nodules around the area. Hand involvement is early in the disease and affects the metacarpal phalangeal and proximal interphalangeal joints.
In rheumatoid arthritis, there's also extra-articular involvement, which we'll look at later on. But first, let us look at the hand involvement in rheumatoid arthritis and see how it differs to osteoarthritis. So here is rheumatoid arthritis and osteoarthritis. So in osteoarthritis, the joints affected are the distal interphalangeal joints as well as the proximal interphalangeal joints; whereas in rheumatoid arthritis, it is the proximal interphalangeal joints and the metacarpal phalangeal joints as well. You can have other joint involvement, such as the wrist. So these joints are affected early in the disease in rheumatoid arthritis, but as the disease progresses, you can have other features occurring in the hands. These are swan neck, boutonniere deformity of the thumb.
So in swan neck, what you have is you have the distal interphalangeal joints flexed, but the proximal interphalangeal joints hyper-extended. In boutonniere, it's the opposite: you have the distal interphalangeal joints hyperextended and the proximal interphalangeal joints flexed. The Z deformity of the thumb is essentially the thumb looking like a Zed; it's sort of bent, hyper-extended. In the hands, the hands can also deviate medially. This is referred to as ulnar deviation. So those were the features of the hands in rheumatoid arthritis. Let us actually look at what happens inside the joints.
So let us zoom into this finger here. And just to recap the anatomy here, we have the bone, the joint capsule, the synovial membrane, also known as a synovium. The synovial membrane, also known as a synovium, which produces the synovial fluid, which helps in lubrication as well as supplying nutrients to the area. Then we have the cartilage here in blue. In rheumatoid arthritis, you essentially have inflammation of the synovium, of the synovial membrane. You have synovitis, and this causes pain and swelling, which occurs in rheumatoid arthritis. This also leads to bone and cartilage erosion/breakdown. Another feature we can see in the joints of rheumatoid arthritic patients is angiogenesis.
So that was the macroscopic view of the joint, just an overview. Let's look at it in a more deep, in a lot more detail, at a cellular level. Let us zoom into this area and see what cells are involved. So just to, just to show where we are here, we have the bone, the synovium. Here's the fluid; here in yellow and blue is the cartilage. And again, I'm drawing the synovium really big because it is inflamed. Right, the synovial membrane. Now, the synovial membrane is made up of these cells known as fibroblast-like synoviocytes, and these guys are very important in the pathogenesis of rheumatoid arthritis. So again, rheumatoid arthritis is where we have inflammation of the synovial membrane, of the synovium. Now, the exact trigger of the inflammation of the disease is really not quite, not quite known. However, we are now looking at what cells we can find here and what cells are involved.
So we have macrophages here, and they're, they're normally around here as well, but they essentially begin secreting cytokines such as TNF alpha, interleukin-1, and interleukin-6, which of course leads to inflammation. The cytokines also stimulate the fibroblast-like synoviocytes. When the fibroblast-like synoviocytes are stimulated, they essentially become activated, and then they begin to proliferate. At the same time, they also begin assisting in RANKL expression, stimulating the RANKL expression, which, together with the cytokines here, will stimulate osteoclast activity, which will lead to bone erosion. What we find in rheumatoid arthritis, when the fibroblast-like synoviocytes are stimulated and proliferate, they also begin secreting proteases. These proteases essentially cause the cartilage to break down, so we get cartilage degradation. And the cartilage also secretes proteases, and it's sort of like a feedback loop. Another interesting feature of the fibroblast-like synoviocytes is that when it's stimulated, when it's activated, these guys can actually migrate from joint to joint. So they can migrate from the hand joint on one side to the hand joint on the other, and this is why we get symmetrical arthritis in rheumatoid arthritis. We also can find T cells in the area, in the synovium. T cells make up about fifty percent of the immune cells in this area, so they're very important in the pathophysiology. T cells promote inflammation essentially, and they secrete, they can secrete interleukin-17, which will promote macrophage activity as well as stimulate the fibroblast-like synoviocytes. The T cells also help in the expression of RANKL, which will stimulate osteoclast for bone erosion. We also find plasma cells in the area, and plasma cells only make up a small majority, about five percent of the immune cells, and they essentially assist in inflammation through cytokines as well as through antibodies.
Now, in the fluid, in the synovial fluid—not in the synovial membrane—in the synovial fluid, we can find neutrophils. And neutrophils, they, they essentially produce proteases and reactive oxygen species, which will essentially cause bone and cartilage degradation/erosion, so they contribute to inflammation. In the synovial fluid, we also find the immune complexes, which is a feature of rheumatoid arthritis. These immune complexes are essentially antibodies that bind to one another, and they essentially promote inflammation. So those are the cells that we can find in an inflamed joint in rheumatoid arthritis. Again, another feature around this area is that we see angiogenesis. Also, the cytokines that are produced by all these cells, they help increase vascular permeability and expression of adhesion molecules on the vascular vasculature, allowing for these immune cells to migrate into the joints.
But where do all these cells come from? Why do they migrate into these joints and cause rheumatoid arthritis? Well, as I mentioned, we don't actually know, but there are a few theories out there. So let's go to the pre-rheumatoid arthritis phase, before a person has rheumatoid arthritis, and there are many possible things that could contribute to the development of rheumatoid arthritis. These include genetics, epigenetic modifications, smoking, a bacteria called Porphyromonas gingivalis, which can lead to gingivitis. Essentially, these things, they can cause modification of autoantigens. What do I mean by modifications of autoantigens? It essentially, what I essentially mean is modification of your own antigens to make it seem foreign to the immune cells. So you're modifying your, so these things can lead to modifications of your own antigens, leading to an immune response. And the modifications of autoantigens include what's known as citrullination. Not only this, things can occur in the joints, such as you can have a synovial injury or hyperplasia, or you can have infection within the joint, and this will trigger, you know, cytokine release, and it will cause inflammation. This inflammation that occurs in the joints can also lead to modification of autoantigens, so modification of your own antigens, making it seem foreign, and this also includes citrullination. So because you have modifications of your own antigens, this will be recognized by antigen-presenting cells, and it will essentially activate the antigen-presenting cells to initiate an immune response. The antigen-presenting cell will migrate to the lymph nodes, where here I'm drawing the lymph node—remember the lymph node here is green—and within the lymph node, we have the germinal center, where we have B cells. Anyway, the antigen-presenting cell will activate T cells here in the area, so we can have a CD4 T cell activation. And when the CD4, when the T cell is activated, the CD4 T cell, it can activate then B cells in the germinal center, and this can be through co-stimulation. When the B cells are activated, they will begin to, you know, proliferate; they will begin to class switch, and they will become plasma cells. Then plasma cells will then produce autoantibodies; they will produce the antibodies against your own antigen essentially. So then what? Well, you have now CD4 T helper cells, and then you have the antibodies and the plasma cells, and they will also have homing receptors and stuff like that, which will allow them to migrate to joint tissue. So that is how they move into the joints in rheumatoid arthritis. So I hope that made sense.
Now, it's important to talk about the antibodies because they're an important feature in rheumatoid arthritis. We have two main antibodies found, and these are—we look at one, one of them at a time. So the first one is the rheumatoid factor, which is an IgM antibody, and it's present in 75 percent of people with rheumatoid arthritis. What these guys do is that they target the Fc portion of IgG antibodies, so the constant region, and they essentially are the ones that are, that, that in that form the immune complex and can deposit in the synovial fluid. The rheumatoid factor not only, you know, forms immune complexes with, but with itself, but with the IgG as well as complement proteins, so it will promote inflammation. The second antibody is the anti-citrullinated protein antibody. Now, these guys, as the name suggests, they target citrullinated proteins. These are things such as fibrin and filogrin. Now they target citrullinated proteins. What are they? Well, citrullinated proteins are essentially proteins who have arginine residues that have been converted to citrullinate, and this sort of change deems, makes it seem foreign to the body, and that is why when we have modifications of our autoantigens, such as citrullination, our body thinks it's foreign. And unfortunately, in our joints, um, we have these sort of tissues, so therefore, um, that's how it can, so that's how this antibody contributes to the pathophysiology. Um, but essentially, there's these rheumatoid factor and anti-citrullinated protein antibodies; they're important for in helping diagnose rheumatoid arthritis. Not everyone has rheumatoid factor, but the anti-citrullinated protein antibody, it is a lot more specific for rheumatoid arthritis. So I hope that all made sense.
Now it's important that we talk about the extra-articular involvement within rheumatoid arthritis. So what I'm talking about is involvement of other organs around the body and how rheumatoid arthritis causes problems there too. So these extra-articular involvement is a result of the cytokines produced within the joints and stuff, and these are mainly TNF alpha, interleukin-1, and interleukin-6. So within the blood, we have increasing inflammatory cytokines, and they essentially contribute to many things around the body. For example, in the skin, they contribute to the nodule formation. In the liver, because of the cytokines, the liver will begin producing more CRP or ECR proteins, which are inflammatory markers, as well as the liver will produce a lot more hepcidin, which will contribute to anemia in rheumatoid arthritis. Cardiovascular involvement: well, these cytokines and this inflammation that's occurring will actually promote atherogenesis, so plaque formation, and it can also lead to promote, you know, myocardial infarction as well as stroke. Neurological involvement includes fatigue and depression, and these can be attributed to anemia. Bone involvement is very serious in rheumatoid arthritis—sorry, musculoskeletal involvement. So these, these include osteopenia, which can lead to osteoporosis. In the muscles, the inflammation causes can lead to insulin resistance, which, which can result in muscle weakness. And also bone marrow involvement: we can have thrombocytosis, which is a lot of platelets, which can contribute to, you know, to the plaque from a, the thrombus formation, as well as we have anemia. So I hope that made sense, and I hope you enjoyed this video. We looked—so those are the extra-articular involvement of rheumatoid arthritis. You also have lung involvement, such as pleural effusion and lung infection, but this can be attributed to the treatment used for rheumatoid arthritis, which involves glucocorticoids, and as we know, glucocorticoids suppress the immune system. Um, I hope you enjoyed this video. We looked at the clinical manifestations, the hand involvement, the pathophysiology, the causes, potential causes, as well as the articular manifestations of rheumatoid arthritis. Thank you for watching. Bye.