Rheumatoid Arthritis

The bones in our bodies provide support for their movement. The place where 2 or more bones meet is called a joint, joints may be immovable, slightly movable, or freely movable. A Synovial Membrane surrounds movable joints inside the membrane Synovial fluids lubricates and nourishes the joint tissue such as the cartilage. Articular cartilage is a tough slippery covering on the ends of the bones which allows smooth joint movements. Joints give the body 

1. Flexibility

2. Precision of movement 

3. Help in supporting the bodyweight  

Arthritis is a type of disorder that affects joints which can lead to pain and inflammation.

Rheumatoid Arthritis is the second most common type of arthritis, the joints most commonly affected are the wrists, hands, knees, ankles, and feet. It typically occurs on the same joint on both sides of the body. It can also affect other organs in the body such as the eyes, skin, heart, lungs, kidney, nervous system, and digestive tract.

Rheumatoid Arthritis is said to be an autoimmune disorder, which means the body will attack itself by mistake. In Rheumatoid Arthritis the immune system attacks joints and tissues. Here is how it happens: the white blood cells of the immune system move into the joint; they release chemicals called the cytokines which attack the cells of the synovial membrane. These cells cause synovial cells to release other destructive substances. They also cause the synovial membrane to grow new blood vessels and form a thickened area called a Pannus.

Over time as the Pannus grows it invades and destroys the areas of cartilage and bone inside the joint. Inflammation causes fluid to build up in the joint making the joint swell. Eventually, without treatment, the joint space narrows, and Ankylosis can occur. Ankylosis is a fusion or growing together of bones in the joint, this results in the loss of the ability to move the joint. There is no cure for Rheumatoid Arthritis however doctors commonly prescribe various combinations of the following medications that when taken together can reduce inflammation and pain thereby slowing down the joint damage. These include Nonsteroidal Anti-inflammatory Drugs or NSAIDs, steroids, and Standard Disease-Modifying Antirheumatic Drugs or DMARDs. IF standard DMARDS aren’t working doctors may prescribe newer drugs called Biologics, also known as Biologic DMARDs.

Physical and occupational therapy along with low impact exercise can increase muscle strength and help keep joints limber. For severe Rheumatoid Arthritis that has not been helped by other treatments, a doctor may recommend a surgical procedure. An example of a joint replacement procedure also known as arthroplasty may be recommended. For the case where the joints are difficult to replace joint fusion also known as Arthrodesis may be recommended, during this procedure the joint is removed the bones are fused together with Bone Graft. Another surgical procedure for severe Rheumatoid Arthritis Synovectomy. During this procedure, the Synovial membrane surrounding the joint is removed. In some cases, an Arthritic joint may need to be replaced with an artificial joint.

In Rheumatoid Arthritis, the term “arthr” refers to joints and “itis” refers to inflammation, and Rheumatoid comes from rheumatism which is more broadly referred to as a musculoskeletal illness. So Rheumatoid Arthritis is a chronic inflammatory disorder that mostly affects the joints, but can also involve other organ systems like the skin, the lungs as well. A healthy joint typically has 2 bones covered with articular cartilage at the ends. Articular cartilage is a type of connective tissue that acts like a protective cushion is a lubricated surface for bones to smoothly glide. One type of joint like the knee joint is called a Synovial Joint.

A Synovial Joint connects 2 bones with a fibrous joint capsule that is continuous with the periosteum or the outer layer of both bones. The fibrous capsule is lined with a synovial membrane that has cells that produce Synovial fluid and remove debris. The Synovial fluid is normally a viscous fluid like a jelly-like part of a chicken egg and it helps to lubricate the joint. In order to help serve these Synovial cells, the Synovial membrane also has blood vessels and lymphatics which is running through it. Together with the Synovial membrane and the articular cartilage will form the inner lining of the joint space. 

(Image to be added soon)

Causes 

Rheumatoid Arthritis is said to be an autoimmune process that is typically triggered by an interaction between a genetic factor and the environment. For example for a person with a certain gene for an immune protein like human leukocyte antigen, or HLA-DR1 and HLA-DR4, might develop Rheumatoid Arthritis after getting exposed to something in the environment like cigarette smoke, or specific pathogen like a bacteria that lives in intestines. These environmental factors can cause modification of our own antigens, such as an iGg antibody or other proteins like Type 2 collagen or vimentin. Type 2 collagen and vimentin can get modified through a process called Citrullination. That is when the amino acid arginine found in these proteins is converted into another amino acid citrulline. Due to the susceptible genes HLA-DR1 and HLA-DR4, immune cells are not that clever enough, so they usually get confused by these changes and they are unable to recognize these proteins as self-antigens. The antigens get picked up by antigen-presenting cells and get carried to the lymph nodes to activate CD4+ T-helper cells. T-helper cells stimulate the nearby B cells to start proliferating and differentiating into plasma cells which produce specific antibodies against these self-antigens. In Rheumatoid Arthritis, T-helper cells and antibodies enter the circulation and reach the joints.

Once there the T cells secrete cytokinesis like interferon-y and interferon-17 to recruit more inflammatory cells like macrophages into the joint space. The macrophages will also produce inflationary cytokinesis, which is like a tumor necrosis factor or TNF-a, interleukin-1, interleukin-6 which together along with the T cells cytokinesis, stimulate synovial cells in order to proliferate. The increase in synovial cells, as well as the immune cells, creates a pannus, which is a thick swollen synovial membrane with granulation or scar tissue that is made up of fibroblasts, myofibroblasts, and inflammatory cells. Over time, the pannus can damage the cartilage and other soft tissues and also erode bone.

Activated synovial cells also secrete proteases that break down the proteins in the articular cartilage. Without the protective cartilage, the underlying bones are exposed and can directly rub against each other. In addition, the inflammatory cytokines increase the protein on the surface of the T-cells known as RANKL or receptor activator of the nuclear factor kappa-B ligand. RANKL allows the T-cells to bind RANK,  a protein on the surface of the osteoclasts to get them to stop breaking down the bone. Meanwhile, antibodies also enter the joint space, one of the antibodies is called Rheumatoid factor or RF, which is an IgM antibody that targets the constant Fc domain of altered IgG antibodies.

Another antibody is an anti-cyclic citrullinated peptide antibody or CCP which targets citrullinated proteins. When these antibodies bind to their targets they form immune complexes that accumulate in the synovial fluid. We can say there they activate a complement system of a family of 9 small proteins that work in an enzymatic cascade to promote joint inflammation and injury. Finally, the chronic inflammation causes angiogenesis or the formation of the new blood vessels which are seen around the joint that allows even more inflammatory cells to arrive. As the disease progressed, multiple joints on both sides of the body got inflamed and gradually destroyed. But the fact is these inflammatory cytokines don’t just stay within the tight joint space, instead, they tend to escape through the bloodstream thereby reaching multiple organ systems causing extra-articular problems, meaning problems beyond the joint space. For example, interleukin-1 or 6 will travel to the brain where they will act as pyrogens causing fever. In skeletal muscle, they promote protein breakdown, and in the skin as well as many visceral organs they lead to the formation of the rheumatoid nodules, which are round like shaped collections of macrophages and lymphocytes which has a central area of necrosis or tissue death.

The blood vessels can also get infected, their walls get inflamed which would result in various forms of vasculitis and this will make them prone to developing atheromatous or fibrofatty plaques. In response to inflammatory cytokines, the liver also starts producing a high amount of hepcidin, a protein that decreases the serum iron levels by inhibiting its absorption by the gut and trapping it into macrophages or liver cells. Meanwhile, within the lung interstitium, fibroblasts get activated and proliferate causing fibrotic or scar tissue that makes it harder for the alveolar gas exchange, whale also the pleural cavities surrounding the lungs can get inflamed and they fill up with fluids known as Pleural Effusion and this can sometimes mess with lung expansion. 

Symptoms 

Rheumatoid Arthritis will involve multiple joints, which usually are 5 or more, symmetrically, which means the same joint groups on both sides of the body, like both hands for instance. Commonly affected joints are the small joints like metacarpophalangeal joint and proximal interphalangeal joint of the hands and the metatarsophalangeal joint of the feet. As the disease worsens, it can start to affect the larger joints like the shoulders, elbow, knees, and ankles. During flares or the sudden worsening of the disease, the affected joints get extremely swollen, warm, red, and painful. Over time they become stiff especially in the morning or after being inactive for a prolonged period of time.

People with  Rheumatoid Arthritis may develop specific deformities usually of the metacarpophalangeal joint of the hand such as ulnar deviation of the fingers. Deformities are also common in the interphalangeal joints such as the so-called boutonniere or the buttonhole deformity. This occurs when the extensor tendon in the back of the finger splits and the head of the proximal phalanges pokes through like a button through a buttonhole causing flexion of the proximal interphalangeal joint and the hyperextension of the distal interphalangeal joint. Another finder deformity is the swan neck deformity which is the opposite so there’s hyperextension of the proximal interphalangeal joint and flexion of the distal interphalangeal joint. Now in the knee joint, a one-way valve can form with fluid from the swollen knee filling the semimembranosus bursa. When that happens, the synovial sac can get so swollen that it bulges posteriorly into the popliteal fossa, creating a synovial fluid-filled cyst called a Baker or popliteal cyst. Now extra-articular manifestation includes non-specific symptoms of inflammation such as fever, low appetite, malaise, or muscle weakness. Organ-specific manifestations include rheumatoid nodules or firm bumps of tissue and these are most commonly found in the skin around pressure points such as the elbows, more rarely in the lungs, the heart, or the sclera of the eye. There’s also an increased risk of atherosclerosis and therefore heart attack or stroke. There is also anemia, interictal lung fibrosis, and pleural effusion, which can present as progressive shortness of breath. If we see one particularly serious condition that is associated with Rheumatoid Arthritis the Felty Syndrome which is a triad of Rheumatoid Arthritis splenomegaly and granulocytopenia, which can lead to life-threatening infections. 

Diagnosis

Diagnosis of Rheumatoid Arthritis usually involves

1. Confirmatory blood tests, like looking for the presence of the Rheumatoid factor and anti-citrullinated peptide antibody. 

2. Additional imaging studies such as X-ray usually reveal decreased bone density around the affected joints, soft tissue swelling, narrowing of the joint space, and bony erosions. 

Treatment 

Long term management of Rheumatoid Arthritis is the use of disease-modifying antirheumatic medications like methotrexate, hydroxychloroquine, sulfasalazine, and which can help to suppress the inflammation. In addition, there are a variety of medications called biologic response modifiers or biologics. Some biologics such as abatacept work by suppressing the activity of the T-cells or others such as rituximab suppresses B cells. There are also biologics such as adalimumab, etanercept, and infliximab that block various chemokines like tumor necrosis factor. Anakinra blocks interleukin 1 and tocilizumab blocks interleukin 6. Treatment of acute flares can be done with anti-inflammatory medicines like NSAIDS, as well as short time use of glucocorticoids.