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MPH322 Musculoskeletal - RA > 3. Rheumatoid Arthritis > Flashcards

3. Rheumatoid Arthritis Flashcards

1
Q

Main aim of treatment of rheumatoid arthritis

A
  • Relieve pain and inflammation

- Prevent joint destruction

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2
Q

What is rheumatoid arthritis?

A

An inflammatory autoimmune disease of cellular and humeral components of immunity

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3
Q

5 step potential progression of rheumatoid arthritis

A

Induction - Caused by genes, host factors and environment
Chronicity - Chronic phase - APC (antigen presenting cells) activate T-cells that activate B cells. Which produce cytokines, chemokines and growth factors.
Effector cells - Macrophages, synoviocyte and osteoclasts
Pathology - Cause inflammation and tissue damage
Outcome - Pain, stiffness, swelling, tenderness
- Deformities and disability

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4
Q

When treating, should we target to treat inflammation and tissue damage

A

Inflammation - we should never try to target osteoclasts as treatment

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5
Q

Risk factors for Rheumatoid Arthritis

A

Female - inc by post-partum and breast feeding

Cigarette smoke

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6
Q

What is a pannus?

A

An abnormal layer of fibrous material

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7
Q

What are the 3 main cytokines involved in the cytokines

A

TNF alpha
IL-17
TH-17 and TH-1

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8
Q

Role of COX enzyme.

What does each isoform do?

A

Produce PG from arachidonic acid

COX 1 - Constitutive enzyme found in constant levels and various tissues
COX 2 - inducible enzyme - levels are low in most tissues

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9
Q

What does COX 1 do?

What does aspirin do?

A

Participates in the synthesis of PG

  • Catalyses the formation of TXA2 in the platelets leading to aggregation
  • Irreversibly inhibit COX1 by acetylation of the SER529
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10
Q

Role of PG

A

Cytoprotective effect on the GI tract

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11
Q

What does COX 2 do?

A

More selective active site there for it has selective binding
- Inhibit the production of prostaglandins

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12
Q

Difference between COX 1 and 2?

A

COX2 has a larger active site due to a different amino acid sequence. Therefore it is selective to larger inhibitors

Gives anti-inflammatory side effects with less side-effects
- Lower tendency to produce GI bleeding/ peptic ulcers

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13
Q

What is the function of PG and Thromboxane?

A

PG - E2 and I2 - Pain and inflammation

Thromboxane - TxA2 - Vasoconstriction and inc platelet aggregation - Thrombosis

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14
Q

NSAID side effects and symptoms

A 
GI tract 
- Heartburn 
- Dyspepsia 
- Abdominal pain 
Serious - Ulceration and bleeding
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15
Q

List NSAIDs by most COX-2 selective to least selective

A
  • Celecoxib
  • Meloxicam, Diclofenac etc
  • Ibuprofen and Naproxen
  • Aspirin
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16
Q

What are the different risks associated with selectivity of COX-2 and COX-1 enzymes

A

COX-2 - Cardiovascular risk

COX-1 - Gastrointestinal Risk

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17
Q

What MHRA advice has been given for Diclofenac?

A

Patients with serious underlying heart conditions e.g heart failure, heart disease, circulatory problems or previous MI or stroke should no longer use diclofenac.

Patients that smoke, have high blood pressure , raised cholesterol, diabetes or history of smoking should only use after careful consideration with their GP.

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18
Q

Name 3 never COX-2 Inhibitors

A
  • Etoricoxib
  • Parecoxib
  • Lumiracoxib
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19
Q

Increased conc of what are found in synovial fluid of patients with RA

A

IL-1 and TNFa

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20
Q

Roles of IL-1 and TNFa

A

Act synergistically to increase production of enzymes that degrade components of cartilage matrix

  • increase expression of adhesion molecules on endothelium, contributing to the migration of neutrophils and lymphocytes from the circulation
  • Stimulate pro-inflammatory mediators e.g IL-8, PGE2 and IL-6§
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21
Q

Pro inflammatory effects of IL-1

A

increase in:

  • ^ TNFa
  • ^ Osteoclast activation
  • ^ Angiogenic factors
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22
Q

Proinflammatory effects of TNFa

A

increase in:

  • ^ IL-1
  • ^ Cell Death
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23
Q

Proinflammatory effects of both IL-1 and TNFa

A

Increase in:

  • ^ COX-2
  • ^ PGE2
  • ^ NO
  • ^ Adhesion Molecules
  • ^ Chemokines
  • ^ Collagenases
  • ^ IL-6
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24
Q

How does RA first present itself?

A

Stiffness in one or more joints,

- Usually accompanied by pain on movement and by tenderness

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25
Q

List 7 types of criteria for RA

A
  • Morning stiffness
  • Arthritis of 3 or more joints
  • Arthritis of hand joints
  • Symmetric arthritis
  • Rheumatoid nodules
  • Serum rheumatoid factor
  • Radiographic changes to RA
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26
Q

What are rheumatoid nodules, how do we treat?

A
  • Occurs in almost seropositive patients
  • Central area of fibrinoid material surrounded by proliferating mononuclear cells
  • We do not treat
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27
Q

3 investigatory tests

A
  • FBC - Normochromic/normocytic anaemia and thrombocytosis
    - ESR and CRP are raised in proportion to inflammation activity
  • Radiology - Xray shows joint narrowing or erosion
  • Synovial fluid - sterile with high neutrophil count
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28
Q

What 4 blood markers do we look for?

A
  • ESR - The more rapidly the cells settle the more inflammation in the joints - inc in fibrinogen, inc in clotting speed
  • CRP - protein produced in the liver when there us inflammation anywhere - more sensitive measure than ESR
  • RF - non specific auto antibody found in blood of patients with RA - does not specifically mean that they will have RA
  • Anti-CCP antibodies - these are antibodies to proteins altered by inflammation - these are rarely found in patients without rheumatoid arthritis but not always in patients with RA
29
Q

What is DAS28?

Is it reliable?

A
  • Disease activity score in 28 joints
  • provides number on scales 0-10
  • High - >5.1
  • Medium - 3.2-5.1
  • Low 2.6-3.2
  • Not always - If only the feet are affected this could be misleadingly low
30
Q

How do we treat symptoms and flares? Dose?

A

NSAID or COX-2 inhibitor - Co-prescribe with PPI
- give lowest effective dose

Glucocorticoid therapy - only in flares - not for long term due to SE

31
Q

Initial treatment

A

Monotherapy - Conventional DMARDs

  • Methotrexate, leflunomide, sulfasalazine
  • Can also have hydroxychloroquine, escalate as tolerated
32
Q

4 suggested MOA for Methotrexate?

A

Suggested MOA -

  • inhibition of purine and pyrimidine synthesis
  • supression of transmethylation reactions with accumulation of polyamines
  • Reduction of antigen-dependant T-cell proliferation
  • Promotion of adenosine release with adenosine-mediated to suppress of inflammation
33
Q

Why is methotrexate favourable?

A

Rapid onset (6-8), good efficacy, favourable toxicity profiles, administration and low cost

34
Q

What is the starting dose for methotrexate? do we monitor?

A
  • 5-10mg orally then inc according to max weekly dose 20mg
  • Also take folic acid 5mg to reduce side effects - not on the same day
  • Hepatotoxicity and bone marrow
35
Q

How does methotrexate block purine and pyridine synthesis?

A
  • Inhibition of Dihydrofolate reductase(DHFR) decreases tetrahydrofolte (THF) levels
  • Results in attenuated DNA/protein/ lipid methylation
  • inhibition of thamidylate synthase (TS) interference with DNA synthesis
  • Inhibition of 5-aminoimidazole-4-carboxamide ribonucleotide(AICAR) transformylase blocs de novo purine synthesis
36
Q

How do we prevent methotrexate toxicities?

A

Folic acid supplements 1-5mg per day - this gives no impact on the therapeutic effects

37
Q

What is the typical dose of sulphasalazine? when do we use it?

A

500mg/day increasing by 500mg weekly to 2-3g a day

added to methotrexate or alone if the patient has methotrexate intolerance

38
Q

What do we monitor for sulphasalazine?

A

FBC, urinalysis every 4 weeks - ask patient about skin rash or ulceration within each visit

39
Q

Side effects for sulphasalazine?

A

Cough, diarrhoea, nausea, dizziness, fever

40
Q

What is the mechanism of action for leflunomide?

A

Inhibition of dihydroorate dehydrogenase(DHODH) leads to decrease rUMP(uridine monophosphate), decreased DNA and RNA synthesis
Inhibition of T-cell proliferation and G1 cell cycle arrest

41
Q

What is the typical dose for leflunomide?

A

100mg daily for 3 days then 10-20mg once daily

42
Q

What are the side effects of leflunomide?

A

Life threatening liver toxicity in first 6 months

43
Q

How do we monitor leflunomide?

A

FBC & FLTs every 2 weeks for the first 6 months

then every 6 weeks

44
Q

What is hydroxychloroquine?

A

used to treat palindromic rheumatism

45
Q

What do we monitor with hyroxychloraquine?

A

Monitor any visual impairments

46
Q

What is the typical dose for hydroxychloroquine?

A

200-400mg daily
max. 6.5mg/kg daily

should only be given on expert advice

47
Q

Summary of CDMARDs

  • Mechanism of action?
  • What do they do?
  • Side effects?
  • Monitoring?
  • Time of response?
A
  • Unclear
  • inhibit release of inflammatory cytokines
  • Majority cause bone marrow and hepatic toxicity
  • Full blood count, liver function tests, electrolytes are routinely monitored
  • typically 6 weeks to 3 months
48
Q

What do bDMARDs target?

A
  • TNFa
  • IL-6
  • T-Cells
  • B-Cells
49
Q

When do we use bDMARDs?

A

If cDMARDs monotherapy does not work

50
Q

Name different types of biological agents:

A
  • Monoclonal antibodies -
    - Infliximab - Murine
    - Adalimumab - Human
  • Recombinant p75 TNF receptor - Etanercept
  • PEGylated Fab’ fragment - Certolizumab pegol
51
Q

What is sarilumab?

A

human monoclonal antibody against the IL-6 receptor

52
Q

What is etanercept?
What is the dose?
what is the SE?

A

Anti-TNFa agent

  • 25mg twice weekly or 50mg once weekly
  • injection site reactions, infections and allergic reaction
53
Q

What is the typical dose for infliximab?
Common adverse effects?
When is it contraindicated?

A

3mg/kg at weeks 0,2,6 then every 8 weeks

  • acute infusion-related reactions, infections, delayed hypersensitivity
  • People with moderate or severe heart failure, those withy TB
54
Q

What is the typical dose for adalimumab?

What does it target?

A

40mg once every 2 weeks

- TNFa

55
Q

What does Golimumab target?

A

TNFa

56
Q

What is Tolicizumab?

A

Anti IL-6

57
Q

What does IL-6 do?

A
  • Cause chronic inflammation - Neutrophils, Macrophage, T-cells
  • joint destruction - RANKL
  • increased platelets - Bone marrow
  • Decreased RBC - Bone Marrow
  • antibody production - B-cells
58
Q

When do we use abatacept?

A

in combination with methotrexate

  • patients with moderate to severe active RA
  • patients with insufficient response or intolerance
    - including at least 1 TNFa
59
Q

How do we administer abatacept?

A

30 minute intravenous infusion
after this it is repeated at week 2, 4 and then every 4 weeks after that
14 infusions in first year - 13 the year after

60
Q

What is JAK? Give an example

A

Janus kinase inhibitors

  • Tofacitinib - JAK1/JAK3
  • Baraicitinib - JAK1/JAK2
61
Q

What is Rituximab? What does it do?

A

Genetically engineered chimeric monoclonal antibody

- decreases b-cell targeting cells bearing the CD20 surface marker

62
Q

When do we use rituximab?

A

Combination with methotrexate for treatment of adults with severe rheumatoid arthritis with inadequate response or intolerance to other DMARDs including one or more TNF inhibitor

63
Q

How is Rituximab administered?

A

Given as two 1000mg IV infusions

- 2 weeks apart

64
Q

What is the side effects of Rituxumab?

A

Infections

65
Q

How does Rituximab work?

A

TNFa blockade and IL-1 receptor antagonism significantly reduce disease activity

66
Q

What are the advantages(1) and disadvantages(3) for biological DMARDs?

A

+ They slow more joint damage than traditional DMARDs

  • Expensive - parental route
  • Not all patients respond to biological therapy
  • More evidence is needed to know true therapeutic value and economic evaluation
67
Q

Mechanism of action for Tofacitinib - 4 stages

A
  • different cytokines, lymphokines and growth factors signal through cell surface receptor tyrosine kinase
  • Activated JAKs phosphorylate STAT
  • Tofacitinib as JAK inhibitor prevents phosphorylation of STAT
  • Therefore, Prevention of translocation of STAT dimer into nucleus and activation of gene transcription
68
Q

Biological indicators summary

- Name 8 targets and the drug used to treat

A
  • IL-6 - Tocilimumab
  • TNF - Infliximab, Etanercept, adalimumab
  • IL-1 - Anakinra
  • JAK - Tofacitinib
  • RANKL - Denosumab
  • CD80 - Abatacept
  • CD20 - Rituximab
  • SYK - Fostamatinib

MPH322 Musculoskeletal - RA (5 decks)

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