Feb 27 - Rheumatoid Arthritis

Question 1

What is Rheumatoid Arthritis (RA)?

Answer 1

A chronic inflammatory disease with possible periods of remission
It symmetrically affects peripheral joints
It is immune system-mediated
It is a systemic disease, potentially affecting the eyes, lungs, heart, nervous system, spleen and lymph system and blood cells

Question 2

When is RA onset?

Answer 2

Because it’s an immune response, it typically starts earlier in life (between the ages 25 and 50)

Question 3

Is RA hereditary?

Answer 3

There is likely a genetic component for the development of RA, but it is not hereditary

Question 4

Does RA affect mortality?

Answer 4

Mortality is 30% higher due to the systemic effects (heart, lungs and eyes) than in the general population with the same age and sex

Question 5

The exact cause(s) of RA is unknown but it is known to involve what?

Answer 5

Genetics (non-modifiable)
Smoking (modifiable)
Infection (inconclusive)
Autoimmunity

Question 6

How is genetics involved with RA?

Answer 6

It may predispose an individual as a result of environmental triggers. Twin concordance is 15-35%, therefore external factors are also likely involved

Question 7

How is infection involved with RA?

Answer 7

An infection may activate inflammatory pathways that “prime” the development of RA

Question 8

How is autoimmunity involved with RA?

Answer 8

Antigen-driven auto-antibodies - rheumatoid factor (RF) is an antibody detected in the blood of 80% of adults with RA. Anti-cyclic citrullinated peptide (anti-CCP) is an important surrogate marker for the diagnosis and prognosis of RA. It is as sensitive but more specific than RF. Anti-CCP is important in early detection even prior to RA

Question 9

Besides RF and anti-CCP, what are other tests that can be used to diagnose RA?

Answer 9

Antinuclear antibody (ANA) is a general test used to evaluate a person for autoimmune disorders such as lupus, MS, Sjorgren’s syndrome (affects mucous membranes to cause dry eyes and dry mouth) and RA. Erythrocyte sedimentation rate (ESR) reflects the degree of inflammation in the body. C Reactive Protein (CRP) also denotes inflammation but it is a better indication of the amount of inflammation in the body compared to ESR levels

Question 10

What is the synovial membrane?

Answer 10

A thin layer of connective tissue (1-3 cell layers thick) between the joint capsule and the synovial cavity

Question 11

What is synovial fluid?

Answer 11

An ultra-filtrate of blood that diffuses across the synovial membrane and into the joint cavity

Question 12

What composes the synovial fluid?

Answer 12

It is composed of hyaluronan (regulates cartilage viscosity) and lubrican (lubricates surface of cartilage)

Question 13

What are cells responsible for the production of synovial fluid?

Answer 13

Fibroblast-like synoviocytes

Question 14

Describe the normal synovial membrane

Answer 14

Normal synovial membrane is composed of a thin cellular lining (one to three cell layers thick) and an underlying interstitium, which contains blood vessels but few cells

Question 15

What is fibronectin?

Answer 15

General cell adhesion molecule; it acts like “glue” to hold collagen cells together that make up the cartilage

Question 16

What are hallmark characteristics of RA?

Answer 16

Pannus formation (growth of fibrous tissue in the joint) causes loss of bone and erodes cartilage
Synovial fluid houses activated inflammatory immune system activated cells (there are all the mediators of infection but there is no infection)

Question 17

What are the immune system activated cells present in RA?

Answer 17

Fibroblast-like synoviocytes
Macrophage-like synoviocytes
Macrophages (phagocytic cells)
T cells (part of cellular immunity; drive cytokines, interleukins, interferons, etc.)
B cells (part of humoral immunity; B cells differentiate into plasma cells, which produce antibodies)

Question 18

How do the mediators of inflammation enter the joint?

Answer 18

Via the ultra-filtrate of the blood that diffuses from the synovial membrane and into the joint cavity (blood vessels supply the synovial membrane)

Question 19

Describe the pathogenesis of the inflammatory immune system response that leads to RA

Answer 19

A foreign antigen (a protein, which resembles proteins that make up the collagen in the bone) is picked up by an antigen-presenting cell (APC). The APC presents the antigen to the T cells. This activates the T cells, which activate mediators of inflammation (cytokines, interleukins, etc.; cellular immunity). These mediators of inflammation activate B cells to differentiate into plasma cells, which production of antibodies against tissue in joints (RF, anti-CCP, ANA, ESR, CRP)

Question 20

What do the antibodies of RA do?

Answer 20

They eat away the collagen

Question 21

What are osteoclasts? How do they become involved in RA?

Answer 21

Osteoclasts are responsible for bone resorption - breaking down of bone. Osteoclast formation is stimulated by the immune response (the mediators of inflammation)

Question 22

How are fibroblasts involved in RA?

Answer 22

Fibroblast formation is stimulated by the immune system. This causes pannus formation leading to the loss of cartilage and bone, activation for matrix metalloproteinases (degrade bone matrix) and the production of pro-inflammatory cytokines (tumor necrosis factor alpha, interferon gamma and IL-6)

Question 23

How many T cells are found in the RA synovium?

Answer 23

T cells make up 30-50% of lymphocytes in the RA synovium

Question 24

The activation of T cells by some unknown auto-antigen leads specifically to what?

Answer 24

Production of cytokines, prostaglandins, cytotoxines
The release of inflammatory cytokines, matrix metalloproteinases (degrade bone), osteoclasts (break down bone), and B cells lead to antibodies that are involved in the phagocytosis of bone cartilage

Question 25

What are some examples of pro-inflammatory cytokines? Anti-inflammatory cytokines? How are these cytokines involved in RA?

Answer 25

Pro-inflammatory: TNF-alpha, IL-1, IL-6, IL-7 Anti-inflammatory: Il-4, IL-10 In RA, IL-6 is the most abundant cytokine in the synovium. It stimulates the synthesis of acute-phase reactants from the liver osteoclasts, T-lymphocytes and B lymphocytes. Serum IL-6 positively correlates with increased disease activity and it is also involved in causing anemia of chronic disease

Question 26

How do B cells affect RA?

Answer 26

B cells are thought to affect RA in 3 ways: 1. Production of auto-antibodies (RF, anti-CCP, ANA) 2. Stimulation of cytotoxins and free radical release 3. Activation of T cells

Question 27

Explain how B cells affect RA via the production of auto-antibodies, and the stimulation of cytotoxins and free radical release

Answer 27

Antibodies are involved in the phagocytosis of the cartilage and bone creating more inflammation of the joints. Cytotoxins and free radical release damage synovium and bone.

Question 28

Explain how B cells affect RA via the activation of T cells

Answer 28

There is a positive feedback loop between the humoral and cellular immune response. Activation of T cells by B cells in turn promotes the release of pro-inflammatory cytokines (IL-1, IL-6, TNF-alpha)

Question 29

Describe the clinical presentation of patients with RA

Answer 29

Symptoms usually develop and progress over months. RA usually begins early Often pain or stiffness begins in 1 or 2 joints; usually progresses to poly-articular presentation (5+ joints) Hot, swollen joints Pain persists for over an hour upon waking; often lasts all day May have systemic complaints: fatigue, weakness, low-grade fever, loss of appetite, and depression (can precede articular symptoms) Symptoms can vary day-to-day

Question 30

What are the criteria for the diagnosis of RA?

Answer 30

Must present with 4 or more of the following for over 6 weeks (time is critical): - morning stiffness in and around the joints lasting over an hour - soft tissue swelling of 3 or more joints observed by an MD - symmetric presentation - subcutaneous nodules - positive for RF and/or anti-CCP - radiologic evidence

Question 31

What are the areas (joints) affected in RA?

Answer 31

``` Proximal interphalangeal joints (very common) Metacarpophalangeal joints (very common) Wrists (common) Elbows (common) Knees (common) Ankle (very common) Metatarsophalangeal joints (very common) ```

Question 32

What are some of the clinical characteristics of RA?

Answer 32

The joints affected most frequently by RA are the small joints of the hands, wrists and feet Elbows, shoulders, hips, knees, and ankles may be involved Joint stiffness is typically worse in the morning Duration of stiffness tends to be correlated directly with disease activity, usually exceeds 30 minutes, and may persist all day Chronic inflammation with lack of an adequate exercise program results in loss of range of motion, atrophy of muscles, weakness, and deformity

Question 33

What are some of the laboratory tests used for the diagnosis of RA?

Answer 33

Rheumatoid factor Antic-cyclic citrullinated peptide (anti-CCP) Elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) Antinuclear activity (ANA) Iron (Fe): absorption correlated inversely with ESR and CRP resulting in normocytic normochromic anemia Blood platelets: thrombocytosis common in RA resulting in too many platelets, resulting in an elevated risk of blood clots and CV events

Question 34

What is CCP? Why is anti-CCP important?

Answer 34

Citrullination (i.e., deamination) of arginine residues Normal process for skin formation and other physiological functions During inflammation results in the production of antigenic epitope Antibodies to citrullinated proteins (anti-CCP) become elevated, and can be used as the most sensitive and specific test for RA May be detected up to 15 years before onset of clincial symptoms of RA

Question 35

Besides laboratory tests (anti-CCP, RF, ESR, ANA, etc.), what are other tests used for the diagnosis of RA?

Answer 35

Joint fluid aspiration may show increased white blood cell counts without infection crystals Joint radiographs may show peri-articular osteoporosis, joint space narrowing, or erosions

Question 36

What are the systemic effects of RA?

Answer 36

``` Rheumatoid nodules Cardiopulmonary disease Eye diseases Sjogren's syndrome (dry eyes and dry mouth) Rheumatoid vasculitis ```

Question 37

RA can cause rheumatoid nodules. Elaborate.

Answer 37

20% of cases Extensor surface of the arm Can also affect the lungs, heart or sclera of the eyes Fibrous cells surround necrotic tissue centre Often painless

Question 38

RA can cause cardiopulmonary disease. Elaborate.

Answer 38

Can cause pericarditis (inflammation of the lining of the heart) Can cause atherosclerosis (leading cause of death in RA) - may be causes by chronic inflammation

Question 39

RA can cause eye diseases. Elaborate.

Answer 39

Reduced tear production can result in chronic eye irritation (episcleritis) In severe cases, can lead to corneal ulceration (which can lead to blindness)

Question 40

RA can cause Sojgren's syndrome. Elaborate.

Answer 40

10-15% of all RA patients will develop Sjogren's syndrome Affects exocrine gland function (chronic xerostomia (bad breath due to dry mouth), keratoconjunctivitis sicca (dry eyes)) Plus dental complications and eye damage

Question 41

RA can cause rheumatoid vasculitis. Elaborate.

Answer 41

Commonly seen as digital nail bed infarcts | Usually after long-standing disease

Question 42

Describe the clinical course of RA

Answer 42

The majority of patients (75-80%) have cyclic-type of disease course (flares followed by periods of remission/control) 10% have mild disease which is stable and easily controlled 15% have severe/aggressive disease which responds poorly to treatments and leads to significant morbidity/premature mortality

Question 43

What are some non-pharmacological treatment options for RA?

Answer 43

Rest -important component of treatment plan -fatigue is a major factor in RA -also reduces pain (but must avoid excessive rest as it makes RA worse) Occupation/physical therapy Assistive devices (canes, walkers, splints, etc.) Weight loss (reduce joint stress) Surgery (for severe diseases; tendon repair, joint replacements)

Question 44

What are the major pharmacological treatment classes

Answer 44

NSAIDs Corticosteroids (i.e. prednisone) Disease-modifying anti-rheumatic drugs (DMARDs)

Question 45

What is the role of NSAIDs in RA?

Answer 45

For analgesia and inflammation (decrease prostaglandin synthesis); rarely used as monotherapy - no effect on disease progression

Question 46

What is the role of corticosteroids in RA?

Answer 46

They decrease inflammation and immunosuppression

Question 47

What can the overuse of corticosteroids cause?

Answer 47

The overuse cause the depletion of calcium in the bones (calcium resporption) - the bones become very brittle

Question 48

What can the overuse of NSAIDs cause?

Answer 48

NSAIDs can aggrevate the stomach and can aggrevate asthma symptoms

Question 49

What is the role of DMARDs in RA?

Answer 49

These agents modify the course of disease and improve prognosis They include non-biologic and biologic agents They suppress cellular and humoral immune system responses

Question 50

Describe the DMARD treatment guidelines

Answer 50

All individuals with early RA (<6 months) should start DMARD Early treatment reduces mortality and long-term complications of RA Should start with non-biologic agents (e.g., NSAIDs, steroids, methotrexate, leflunomide, sulfasalazine, hydroxychloroquine) Biologics indicated when poor disease response to non-biological DMARDs or advanced progression of RA

Question 51

How do biologics work?

Answer 51

All biologics work by one of 3 mechanisms: 1. Interfere with cytokine function 2. Inhibit the "second signal" or "co-stimulation" required for T cell activation 3. Depleted B cells (reduce self-antibodies) They are relatively well-tolerated - caution with immunosuppression and opportunistic infections Increased risk of infection and tuberculosis (TB skin test for all)