Rheumatoid Arthritis Pathophysiology (signs and symptoms)

Summary

This educational video delves into rheumatoid arthritis, a systemic disorder affecting multiple joints with symmetrical arthritis as a hallmark. It differentiates hand involvement in rheumatoid arthritis from osteoarthritis, highlighting characteristic deformities like boutonniere and swan neck. The script explores the cellular and molecular underpinnings, including synovitis, angiogenesis, and the role of cytokines and immune cells. It also discusses rheumatoid factor and anti-citrullinated protein antibodies, crucial for diagnosis, and the extra-articular impacts on organs, emphasizing the disease's systemic nature.

Takeaways

• 🤕 Rheumatoid arthritis is a systemic rheumatological disorder affecting multiple joints, characterized by symmetrical arthritis with pain, swelling, and nodules.
• 👐 Early hand involvement in rheumatoid arthritis typically affects the metacarpal phalangeal and proximal interphalangeal joints, differing from osteoarthritis which affects the distal interphalangeal joints.
• 🔍 As rheumatoid arthritis progresses, it can lead to deformities such as swan neck, boutonniere, and Z-thumb, and may also cause ulnar deviation of the hands.
• 🧬 The pathophysiology of rheumatoid arthritis involves inflammation of the synovial membrane (synovitis), leading to bone and cartilage erosion, and is associated with angiogenesis.
• 🔬 At the cellular level, rheumatoid arthritis involves various immune cells, including macrophages, fibroblast-like synoviocytes, T cells, plasma cells, and neutrophils, which contribute to inflammation and tissue damage.
• 💉 The activation of fibroblast-like synoviocytes and the secretion of proteases lead to cartilage degradation, and these cells can migrate to cause symmetrical arthritis.
• 🏠 T cells play a significant role by promoting inflammation, secreting interleukin-17, and contributing to the expression of RANKL, which stimulates osteoclast activity for bone erosion.
• 🌐 The exact trigger of rheumatoid arthritis is unknown, but theories include genetic factors, epigenetic modifications, smoking, and bacterial infections that may lead to modification of autoantigens.
• 🏥 Antibodies such as rheumatoid factor and anti-citrullinated protein antibodies are important for diagnosing rheumatoid arthritis and contribute to the disease's pathophysiology.
• 🌐 Extra-articular involvement in rheumatoid arthritis can affect various organs due to increased inflammatory cytokines, leading to issues like skin nodules, liver inflammation, cardiovascular problems, neurological issues, and bone marrow involvement.
• 👋 The video concludes by highlighting the complexity of rheumatoid arthritis, covering clinical manifestations, hand involvement, pathophysiology, potential causes, and extra-articular manifestations.

Q & A

What is rheumatoid arthritis?

Rheumatoid arthritis is a systemic rheumatological disorder that affects multiple joints, characterized by symmetrical arthritis with pain, swelling, and nodules around the affected areas.

How does rheumatoid arthritis affect the hands?

Rheumatoid arthritis affects the hands by causing involvement of the metacarpal phalangeal and proximal interphalangeal joints early in the disease, leading to deformities such as swan neck, boutonniere, and Z deformity of the thumb.

What is the difference between the joint involvement in rheumatoid arthritis and osteoarthritis?

In rheumatoid arthritis, the proximal interphalangeal and metacarpal phalangeal joints are primarily affected, while in osteoarthritis, the distal interphalangeal joints are commonly affected along with the proximal interphalangeal joints.

What is synovitis and why is it significant in rheumatoid arthritis?

Synovitis is the inflammation of the synovial membrane, which is significant in rheumatoid arthritis as it leads to pain, swelling, and eventually bone and cartilage erosion.

What role do fibroblast-like synoviocytes play in the pathogenesis of rheumatoid arthritis?

Fibroblast-like synoviocytes, when stimulated, become activated, proliferate, and secrete proteases that cause cartilage breakdown. They also contribute to bone erosion by stimulating osteoclast activity through RANKL expression.

How do T cells contribute to the inflammation in rheumatoid arthritis?

T cells promote inflammation by secreting cytokines such as interleukin-17, which stimulates macrophage activity and fibroblast-like synoviocyte proliferation, as well as contributing to RANKL expression for bone erosion.

What is the significance of angiogenesis in rheumatoid arthritis?

Angiogenesis, the formation of new blood vessels, occurs in the joints of rheumatoid arthritis patients and contributes to inflammation by increasing vascular permeability and allowing immune cells to migrate into the joints.

What are the two main antibodies found in rheumatoid arthritis and their roles?

The two main antibodies are rheumatoid factor, an IgM antibody that targets the Fc portion of IgG antibodies forming immune complexes, and anti-citrullinated protein antibody, which targets citrullinated proteins, both contributing to the inflammation and pathophysiology of rheumatoid arthritis.

What is citrullination and how does it relate to rheumatoid arthritis?

Citrullination is the conversion of arginine residues to citrulline in proteins, making them seem foreign to the immune system. This modification of autoantigens can trigger an immune response, contributing to the development of rheumatoid arthritis.

What are some of the extra-articular manifestations of rheumatoid arthritis?

Extra-articular manifestations of rheumatoid arthritis include skin nodules, increased CRP and hepatin production leading to anemia, cardiovascular issues such as atherosclerosis, neurological issues like fatigue and depression, and musculoskeletal problems including osteopenia and muscle weakness.

How do the cytokines produced in rheumatoid arthritis joints affect other organs in the body?

Cytokines like TNF alpha, interleukin-1, and interleukin-6 produced in the joints can enter the bloodstream, contributing to inflammation and various issues in organs such as the skin, liver, cardiovascular system, and nervous system.

Outlines

00:00

🤕 Rheumatoid Arthritis: Clinical Presentation and Hand Involvement

This paragraph introduces rheumatoid arthritis as a systemic rheumatological disorder affecting multiple joints symmetrically, with early hand involvement. It distinguishes rheumatoid arthritis from osteoarthritis by the specific joints affected, such as the metacarpal phalangeal and proximal interphalangeal joints, versus the distal interphalangeal joints in osteoarthritis. The paragraph also covers deformities like boutonniere and swan neck, and the Z deformity of the thumb, which are characteristic of rheumatoid arthritis. It concludes with a brief mention of extra-articular involvement and a microscopic look at the joint anatomy, inflammation, and the role of the synovial membrane in the disease process.

05:02

🔬 Cellular Pathogenesis of Rheumatoid Arthritis

The second paragraph delves into the cellular level of rheumatoid arthritis, focusing on the synovial membrane and the cells involved in its pathogenesis. It describes the activation and proliferation of fibroblast-like synoviocytes, which contribute to inflammation and bone erosion through the secretion of cytokines and proteases. The paragraph also discusses the role of macrophages, T cells, plasma cells, and neutrophils in the inflammatory process, including the production of cytokines and immune complexes that promote inflammation and joint damage. Additionally, it touches on the phenomenon of angiogenesis and the migration of immune cells into the joints, ending with a note on the unknown triggers of the disease and potential contributing factors.

10:02

🧬 Autoantibodies and Pre-Rheumatoid Arthritis Phase

This paragraph discusses the role of autoantibodies in rheumatoid arthritis, specifically rheumatoid factor and anti-citrullinated protein antibodies, which are key for diagnosis and contribute to the disease's pathophysiology. It explains the process of autoantigen modification, such as citrullination, which can trigger an immune response. The paragraph outlines the pre-rheumatoid arthritis phase, considering factors like genetics, epigenetics, smoking, and bacterial infections that may lead to autoantigen modification. It describes the activation of antigen-presenting cells, T cells, and B cells, leading to the production of autoantibodies that target the body's own antigens, and how these cells migrate to the joint tissue, resulting in rheumatoid arthritis.

15:04

🏥 Extra-Articular Manifestations and Treatment Considerations

The final paragraph addresses the extra-articular manifestations of rheumatoid arthritis, which affect organs beyond the joints due to systemic inflammation caused by cytokines. It covers skin nodules, liver inflammation leading to increased CRP and acute-phase proteins, anemia, cardiovascular issues like atherosclerosis, myocardial infarction, and stroke, neurological impacts like fatigue and depression, and musculoskeletal complications including osteopenia, insulin resistance, and bone marrow involvement. The paragraph also mentions lung involvement as a potential side effect of treatment with glucocorticoids, which suppress the immune system. The summary concludes with a brief overview of the video's content, thanking the viewer for watching.

Keywords

💡Rheumatoid Arthritis

Rheumatoid Arthritis (RA) is a chronic inflammatory disorder that affects the joints, causing pain, swelling, and potentially joint damage. In the video, it is the central theme, with a focus on its systemic nature and the specific impact on multiple joints, particularly the hands. The script describes the symmetrical arthritis, which is a hallmark of RA, and distinguishes it from osteoarthritis.

💡Symmetric Arthritis

Symmetric arthritis refers to the inflammation that occurs in matching joints on both sides of the body, such as both hands or both knees. It is a key clinical presentation of RA, as mentioned in the script, and helps differentiate it from other types of arthritis that may affect joints asymmetrically.

💡Metacarpal Phalangeal Joints

The metacarpal phalangeal joints are the knuckle joints that connect the fingers to the hand. The script highlights their early involvement in RA, indicating that they are among the first joints affected by the disease, which leads to characteristic symptoms like pain and swelling.

💡Synovial Membrane

Also known as the synovium, the synovial membrane lines the inside of the joint capsule and produces synovial fluid, which lubricates the joint. The script explains that in RA, this membrane becomes inflamed (synovitis), leading to pain, swelling, and eventually bone and cartilage erosion.

💡Bone Erosion

Bone erosion is the process where bone tissue is progressively destroyed, leading to joint deformity and loss of function. The script describes how synovitis in RA leads to bone erosion, which is a significant aspect of the disease's progression and impact on joint health.

💡Angiogenesis

Angiogenesis is the formation of new blood vessels. The script mentions angiogenesis as a feature seen in the joints of RA patients, which contributes to the inflammatory process by increasing vascular permeability and allowing immune cells to migrate into the joints.

💡Fibroblast-like Synoviocytes

Fibroblast-like synoviocytes are cells found in the synovial membrane. The script explains that in RA, these cells become activated and proliferate, contributing to the inflammation and destruction of cartilage and bone through the secretion of proteases and involvement in osteoclast activation.

💡T Cells

T cells are a type of white blood cell that play a significant role in the immune response. In the context of RA, as described in the script, T cells are found in the synovium and contribute to inflammation by secreting cytokines and promoting the activity of other immune cells like macrophages and fibroblast-like synoviocytes.

💡Plasma Cells

Plasma cells are antibody-producing cells derived from B cells. The script notes that in RA, plasma cells contribute to inflammation by producing rheumatoid factor and anti-citrullinated protein antibodies, which target the body's own antigens and promote further immune response.

💡Rheumatoid Factor

Rheumatoid factor is an autoantibody that targets the Fc portion of IgG antibodies. The script explains that it is present in about 75% of people with RA and contributes to inflammation by forming immune complexes that can deposit in the synovial fluid.

💡Extra Articular Involvement

Extra articular involvement refers to the effects of RA beyond the joints, affecting other organs and systems in the body. The script discusses various manifestations of this, including skin nodules, liver inflammation, cardiovascular issues, neurological symptoms, and musculoskeletal problems, all linked to the systemic inflammation caused by RA.

Highlights

Rheumatoid arthritis is a systemic rheumatological disorder affecting multiple joints.

Clinical presentation includes symmetrical arthritis with pain, swelling, and nodules.

Hand involvement in rheumatoid arthritis typically affects the metacarpal phalangeal and proximal interphalangeal joints early in the disease.

Extra articular involvement in rheumatoid arthritis can affect organs outside the joints.

Rheumatoid arthritis differs from osteoarthritis in the joints affected and the pattern of joint involvement.

Swan neck and boutonniere deformities are specific hand deformities seen in rheumatoid arthritis.

Ulnar deviation is a characteristic hand deviation in rheumatoid arthritis.

Inflammation in rheumatoid arthritis involves the synovial membrane, leading to synovitis and subsequent bone and cartilage erosion.

Angiogenesis is a feature of rheumatoid arthritis, contributing to the disease's progression.

Fibroblast-like synoviocytes play a crucial role in the pathogenesis of rheumatoid arthritis by producing proteases and stimulating osteoclast activity.

T cells are significant in the synovium, promoting inflammation and contributing to bone erosion through RANKL expression.

Plasma cells contribute to inflammation through cytokines and antibodies in rheumatoid arthritis.

Neutrophils in the synovial fluid produce proteases and reactive oxygen species, causing bone and cartilage degradation.

Immune complexes in the synovial fluid are a feature of rheumatoid arthritis, promoting inflammation.

The etiology of rheumatoid arthritis is not fully understood but involves genetic and environmental factors.

Citrullination is a post-translational modification implicated in the autoimmune response in rheumatoid arthritis.

Rheumatoid factor and anti-citrullinated protein antibodies are significant for diagnosing rheumatoid arthritis.

Extra articular manifestations of rheumatoid arthritis include skin nodules, liver inflammation, cardiovascular issues, neurological symptoms, and musculoskeletal problems.

Lung involvement in rheumatoid arthritis can be a side effect of treatment with immunosuppressive drugs.

Transcripts

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 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 a 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 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 swatness 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

the air 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 they were the they were the uh the

hand

what will the features of the hands in

rheumatoid arthritis let us actually

look at what happens inside the joints

so let us zoom into the this a 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 uh

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 fibro fibroblasts like synoviocites

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

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 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

fibroblasts like synoviocytes

when the fibroblasts like stand over

your sites are stimulated

they essentially become activated and

then they begin to proliferate

at the same time they also begin

assisting in rank l expression

stimulating the rank l 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 fibroblasts like synovial sites

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 secrete proteases and it's sort of

like a feedback loop

another interesting feature of where of

the fibroblasts like synovial sites is

that when it's stimulated when it's

activated

these guys can actually migrate from

joint to join

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 uh immune cells in this

area so they're very important in the

pathophysiology

t cells uh promote inflammation

essentially and they secrete they can

secrete interleukin-17 which will

promote macrophage activity as well as

stimulate

the fibroblasts like synoviocites

the t cells also help

in the expression of rank l 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 a 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 porphyramonas

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

so 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 oto

antibodies 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 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

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 fact that 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 citrulline 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-citrullated 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 hepatin

which will contribute to anemia

in rheumatoid arthritis cardiovascular

involvement well these cytokines and

this inflammation that's occurring will

actually promote

arthrogenesis so plaque formation and it

can also lead to promote you know

myocardial infarction as well as stroke

neurological involvement include

fatigue

and depression and these can be

attributed to anemia

um 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 platelet which can

contribute to you know to the

plaque from a uh the thrombus formation

as well as we have anemia

so i hope that made sense and i hope you

enjoyed this video we look

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

glucocorticoid suppresses 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