Advanced Pathophysiology

Rheumatoid Arthritis

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Speaker 2: In rheumatoid arthritis, arthr refers to joints, itis means inflammation and rheumatoid comes from rheumatism, which more broadly refers to 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 and the lungs as well.

All right, so a healthy joint typically has two bones covered with articular cartilage at the ends. Articular cartilage is a type of connective tissue that acts like a protective cushion. It's a lubricated surface for bones to smoothly glide against.

One type of joint, like the knee joint, is called a synovial joint. A synovial joint connects two bones with a fibrous joint capsule that's 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 fluids and remove debris. The synovial fluid is normally a viscous fluid like a jelly part of a chicken egg, and it helps to lubricate the joint.

To help serve these synovial cells, the synovial membrane also has blood vessels and lymphatics running through it. Together, the synovial membrane and the articular cartilage form the inner lining of the joint space.

Rheumatoid arthritis is an autoimmune process that's typically triggered by an interaction between a genetic factor and the environment.

For example, 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 a specific pathogen like a bacteria that lives in the intestines.

These environmental factors can cause modification of our own antigens, such as IgG antibodies or other proteins like type 2 collagen or vimentin.

Type 2 collagen and vimentin can get modified through a process called citrullination. That's when the amino acid arginine found in these proteins is converted into another amino acid citrulline.

Meanwhile, due to the susceptibility genes HLA-DR1 and HLA-DR4, immune cells are sometimes not clever enough, so they get confused by these changes and they no longer 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 differentiate into plasma cells, which produce specific autoantibodies against these self antigens.

In rheumatoid arthritis, T-helper cells and antibodies enter the circulation and reach the joints. Once there, T-cells secrete cytokines like interferon gamma and interleukin-17 to recruit more inflammatory cells like macrophages into the joint space.

Macrophages will also produce inflammatory cytokines like tumor necrosis factor or TNF alpha interleukin-1 and interleukin-6, which together with the T-cell cytokines stimulate synovial cells to proliferate.

The increase in synovial cells and immune cells creates a pannus, which is a thick, swollen synovial membrane with granulation or scar tissue 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, which break down the proteins in the articular cartilage. And without the protective cartilage, the underlying bones are exposed and can directly rub against each other.

In addition, inflammatory cytokines increase the protein on the surface of T-cells known as RANKL or receptor activator of nuclear factor kappa-B ligand. RANKL allows T-cells to bind RANK, a protein on the surface of osteoclasts, to get them to start breaking down bone.

Meanwhile, antibodies also enter the joint space. One antibody is called rheumatoid factor or RF, which is an IgM antibody that targets the constant FC domain of altered IgG antibodies.

Another antibody is anti-cyclic citrullinated peptide antibody or CCP, which targets citrullinated proteins.

When these antibodies bind to their targets, they form immune complexes, which accumulate in the synovial fluids.

There, they activate the complement system, a family of nine small proteins that work in an enzymatic cascade to promote joint inflammation and injury.

Finally, the chronic inflammation causes angiogenesis or the formation of new blood vessels around the joint, which allows even more inflammatory cells to arrive.

As the disease progresses, multiple joints on both side of the body get inflamed and gradually destroyed. But these inflammatory cytokines don't just stay within the tight joint space. Instead, they escaped through the bloodstream and reach multiple organ systems causing extra articular problems, meaning problems beyond the joint space.

For example, interleukin-1 or 6 travel to the brain where they act as pyrogens inducing fever. In skeletal muscle, they promote protein breakdown. And in the skin as well as many visceral organs, they lead to the formation of rheumatoid nodules, which are round shaped collections of macrophages and lymphocytes with a central area of necrosis or tissue death.

Blood vessels can also be affected. Their walls get inflamed resulting in various forms of vasculitis and make them prone to developing atheromatous or fibro-fatty plaques.

In response to inflammatory cytokines, the liver also starts producing high amounts of hepcidin, a protein that decreases serum iron levels by inhibiting its absorption by the gut and trapping it into macrophages or liver cells.

Meanwhile, within the lung interstition, fibroblasts get activated and proliferate causing fibrotic or scar tissue that makes it harder for the alveoli gas exchange. Also, the pleural cavity surrounding the lungs can get inflamed and they fill up with fluids known as pleural effusion. And this can sometimes mess with lung expansion.

Rheumatoid arthritis typically involves multiple joints, usually five or more symmetrically, meaning the same joint groups on both sides of the body like both hands, for instance.

Commonly affected joints are the small joints like the metacarpal phalangeal joints and proximal interphalangeal joints of the hand and the metatarsal phalangeal joints of the feet.

As the disease worsens, it can start to affect large joints like the shoulders, elbows, knees, and ankles.

During flares or 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 metacarpal phalangeal joints 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 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 hyperextension of the distal interphalangeal joint.

Another finger deformity is the swan neck deformity, which is the opposite. So there is 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 posterially into the popliteal fossa, creating a synovial fluid-filled cyst called a Baker or popliteal cyst.

Extra-articular manifestations include nonspecific 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, they can be found in the lungs, the heart or the sclera of the eye.

There is also an increased risk of atherosclerosis and therefore heart attack or stroke. There is also anemia, interstitial lung fibrosis, and pleural effusions, which can present as progressive shortness of breath.

One particularly serious condition that's associated with rheumatoid arthritis is Felty syndrome, which is a triad of rheumatoid arthritis, splenomegaly and granulocytopenia. And it can lead to life threatening infections.

Diagnosis of rheumatoid arthritis usually involves confirmatory blood tests, like looking for the presence of rheumatoid factor and anti-citrullinated peptide antibody.

Additionally, 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.

The long term management of rheumatoid arthritis is the use of disease modifying antirheumatic medications like methotrexate, hydroxychloroquine and sulfasalazine, 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 T-cells, or others such as rituximab suppress 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 medications like NSAIDs, as well as short term use of glucocorticoids.

All right, so as a quick recap, rheumatoid arthritis is a systemic inflammatory disorder of autoimmune origin that's primarily characterized by progressive symmetric joint destruction, especially in the wrist and fingers, but may also affect other joints and many organs such as the skin, heart, blood vessels and lungs. It's marked by elevated rheumatoid factor and anti-cyclic citrullinated peptide antibodies.