Rheumatoid arthritis

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 lungs as well.

Alright, 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 - 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 is continuous with the periosteum or 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 the jelly-like part of a chicken egg and it helps 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 is 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 II collagen or vimentin.

Τype II 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 sometimes are 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- γ 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- α, interleukin- 1 and interleukin- 6, which together with the T-cell’s 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 cartilage and other soft tissues and also erode bone.

Activated synovial cells also secrete proteases which break down the proteins in the articular cartilage.

Without the protective cartilage, the underlying bones are exposed and can directly rub against one another.

In addition, inflammatory cytokines increase a protein on the surface of T- cells, known as RANKL or receptor activator of nuclear factor kappa-B ligand.

RANKL allows the 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 fluid.

There, they activate the complement system, 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 new blood vessels around the joint, which allows even more inflammatory cells to arrive.

As the disease progresses, multiple joints on both sides of the body get inflamed and gradually destroyed.