Pathology & Pathogenesis Of Rheumatoid Arthritis Flashcards by frankiespeck@hotmail.co.uk Speck

What are the different sources of musculoskeletal pain?

Soft tissue
Bone
Joint
Referred/central

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What are the 2 different types of joint disorder?

Degenerative: OA

2. Inflammatory: infection (e.g. septic arthritis), crystal arthropathy (e.g. gout/pseudogout) or autoimmune disorder

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What are the 3 different types of autoimmune inflammatory joint disorder?

RA
Connective tissue disorder e.g. SLE or Sjogren’s syndrome
Spondylo-arthritis inv. spine as well as joints

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What are the causes of inflammatory polyarthritis?

Infection e.g. streptococcal septic arthritis
Post infectious
Reactive arthritis
Crystal arthritis e.g. gout
RA
SLE
Sarcoidosis

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What are the causes of virus arthralgia?

Hep B and C
Rubella
Parvovirus infection (erythrovirus)

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What are the key features of a joint?

Hyaline cartilage smooth joint is in synovial cavity surrounded by synovial fluid which lubricates joint
Synovium (serous membrane) is a sheet of fibrous connective tissue that secretes synovial fluid surrounding this
Joint capsule spans the 2 bones and surrounds all of this protecting and supporting the joint

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What are synovocytes?

Specialised cell present in layers no more than 4 cells thick but commonly just 1, that produce synovial fluid

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What is the function of synovial fluid?

Metabolite exchange medium

Lubricant for synovial joints

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Serum autoantibody detection DOES NOT equal ____ ___. Why?

Autoimmune disease

Because we are all constantly developing autoimmunity that our body detects and controls and also, the presence of autoAbs increases in frequency the older we get

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Why does the prevalence of autoantibodies (autoAbs) increase with advancing age?

Repeated exposure to infection

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How are T cells regulated?

In the thymic cortex, millions of T cells are made every day with different fates:

Many recognise self-peptides strongly so undergo clonal deletion
Many do not recognise anything and die through neglect
A few recognise self-peptides weakly so are allowed to mature and leave the thymus

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How are B cells regulated?

B cells which meet and therefore recognise self-Ag in the bone marrow are anergised (clonal anergy) which means they are alive but unresponsive and suppressed

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Give some examples of autoimmunity theories.

Defects in T reg cells
Molecular mimicry between pathogens and self-peptides when a foreign Ag looks similar to a self Ag
Polyclonal activation of anergised B cells during immune responses or infection e.g. EBV causing recognition of self Ags
Sequestered Ag not seen by developing T and B cells so when exposed for e.g. in trauma, it is seen as foreign (e.g. sperm or eyes)

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Why do some people get autoimmune disease and others don’t?

Genetic susceptibility -> autoimmune diseases are clustered in families AND in individuals

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What are some theories of autoimmunity triggers causing genetically susceptible people to get autoimmune diseases?

Female hormones (and also pregnancy)

2. Trigger such as infection

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What genes are many autoimmune diseases associated with? What does this suggest?

HLA/MHC gene involved with antigen presentation by T cells which suggests that presentation of self-peptides to autoreactive T cells is significant

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What gene is rheumatoid arthritis (RA) associated with?

HLA-DR4 (and HLA-DR1)

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What is rheumatoid factor (RhF)?

A IgM autoAb against the Fc fragment of IgG - present in RA (~70%), other rheumatic disorders, sarcoidosis, infections and advancing age so DO NOT CHECK IT IN A PATIENT WITH JOINT PAIN

How does rheumatoid arthritis (RA) cases often present clinically when taking a patient history?

Often young-middle age females (20-50yrs)
Pain/stiffness in joints
Gradual/sudden onset
Symmetrical usually in hands, feet and other joints
Extra-articular features in 20% of patients such as fatigue, anorexia, weight loss, low grade fever and anaemia
Usually RA is present in a family member
Smoking increases risk of RA development

What are the 3 key signs to look out for to catch it early so it can be treated early with a better outcome?

S: early morning joint STIFFNESS lasting > 30 mins
S: persistent SWELLING of 1 joint or > esp. hand joints
S: SQUEEZING the joints is painful

What joints can rheumatoid arthritis (RA) affect?

Hands/feet most commonly
Elbows/knees
Hip
Shoulder
Neck
TMJ

How does the rheumatoid arthritis (RA) hand deformity advance if not treated early?

Early fusiform swelling
Ulnar deviation/MCP subluxation
Swan neck deformities
Boutonniere deformities: PIP joint bent towards palm whilst DIP joint is bent back away

What are rheumatoid nodules?

Firm lumps that appear subcutaneously on hands, heels and elbows and also at pressure points that are not usually painful e.g. present commonly on knuckles (MCP joint) of hand

What extra-articular features can be caused by rheumatoid arthritis (RA)?

Cardiac: pericarditis, valve problems + atherosclerosis -> IHD + CVA
Pulmonary: pleural effusions, rheumatoid nodules + pulmonary fibrosis
Blood: anaemia (chronic/haemolytic) + splenomegaly (Felty’s syndrome)
Bones: localised osteoporosis
Skin: rheumatoid nodules, vasculitis + leg ulcers
Neurological: C1/C2 atlanto-axial subluxation + nerve compression
Eyes: scleritis + xerophthalmia (2ndary Sjogrens syndrome)

What is a classical give-away sign of pericarditis?

Chest pain that is worst when lying down so patients have to lean forward to make it better

How can you reduce a patients rheumatoid arthritis (RA) related increased risk of atherosclerosis and ischaemic heart disease (IHD)?

Address risk factors such as: Smoking Raised cholesterol Obesity

What is the pathogenesis of rheumatoid arthritis (RA)?

1. Genetically predisposed individual (HLA-DR4/DR1) + immunological trigger causes a T-cell mediated immune response causing cytokine production (TNF + IL-1) 2. RhF forms an immune complex with IgG so complement fixates upon it 3. Inflammatory response of synovium due to Wayward immune response 4. Inflammatory cells recruited (e.g. PMNs, macrophages, lymphocytes) that phagocytose immune complexes and there is release of lysosomal enzymes + PGs 5. Angiogenesis in synovium causes synovial proliferation/hyperplasia + Pannus invasion 6. Destruction of articular cartilage and underlying bone (enhanced by cytokines) which recruits further inflammatory cells in a cycle 7. Destruction causes ankylosis

Why is there redness and swelling in rheumatoid arthritis (RA)?

Vasodilation

What are the key early and late changes in the pathogenesis of rheumatoid arthritis (RA)?

Early: inflammation of synovium Late: secondary changes in the cartilage such as loss of cartilage and pannus-filled erosion

What is pannus?

An abnormal layer of vascular granulation tissue

How would you investigate rheumatoid arthritis (RA) using pathology?

- Haematological: FBC would show anaemia of chronic disease and thrombocytosis - Acute phase response: ESR/CRP moderately raised - Hepatic: increased ALP + decreased albumin - Immunology: RhF + anti-cyclic citrillunated peptides Abs (anti-CCP)

What are the causes of anaemia in rheumatoid arthritis (RA)?

Active disease Blood loss Marrow suppression by drugs Felty's syndrome (encompasses RA, splenomegaly + leucopenia)

What would you detect radiologically in early disease?

X-rays usually normal although synovitis can be detected on a US or MRI

What would you detect radiologically in established disease?

X-rays of hands and feet would show: - Soft tissue swelling - Juxta-/-periarticular osteopenia - Joint space narrowing due to loss of cartilage - Erosion of bone - Subluxation (also of atlanto-axial C1-2) due to joint capsule damage - Deformity

How would you treat rheumatoid arthritis (RA) will analgesia?

1. Paracetamol 2. NSAIDs +/- paracetamol 3. Weak opioid e.g. codeine 4. Moderate opioid e.g. tramadol 5. Strong opioid e.g. morphine

What combination of drugs are used to treat rheumatoid arthritis (RA)?

1. Combination therapy with MTX/SSZ w/ analgesia 2. Corticosteroids e.g. Prednisolone can be used short-term whilst waiting for combination therapy to work 3. Biological therapies if this does not work 4. Adjunctive therapies e.g. Bisphosphonates for osteoporosis

How do corticosteroids work?

1. Usually given orally e.g. Prednisolone or intra-articular e.g. Cortisone 2. Inhibit TFs reducing transcription of many cytokines genes e.g. IL-1, IL-2 and TNF 3. Reduced clonal proliferation of Th cells 4. Reduced inflammation

What are the 2 types of disease-modifying-anti-rheumatic drugs (DMARDs)?

1. Antiproliferative: Methotrexate (MTX) (against folate activity) or Azathioprine (against purine synthesis) that both inhibit DNA synthesis 2. Immunomodulators: Sulfasalazine (SSZ)

What are the side effects of the anti-proliferative disease-modifying-anti-rheumatic drugs (DMARDs)?

- Increased infection risk and more severe/prolonged infections - Teratogenic so avoid in women of child-bearing age - GI: mouth ulcers, nausea, diarrhoea - Hair loss

What biological agents are available for rheumatoid arthritis (RA)?

Monoclonal Ab (MAb) therapy via IV or self-injection by patients: - Infliximab: anti-TNFα - Rituximab: anti-CD20 on B cells - Inhibitor of T cell activation - Anti-IL6

What is the problem with biological agents?

They are expensive and NICE approval is needed HOWEVER if patents have expired, biosimilar drugs are now available that are cheaper although these may not exactly the same or work in the same way so they may not be as effective and have more side effects

Why are biosimilar monoclonal antibodies (MAbs) not identical to original agent?

Each MAb is a unique protein in how it folds and its structure so no 2 will ever be exactly the same

What is the prognosis of rheumatoid arthritis (RA)?

Good with early diagnosis, treatment and disease control with < 10% becoming severely disabled - each patient will be different with variable symptoms often with flare-ups requiring drug therapy so treatments are individualized to the patient

What complications may need to be managed with rheumatoid arthritis (RA)?

Reduced immunity from immunosuppression Complications of drug treatment