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Health 31 > Rheumatoid Arthritis > Flashcards

Rheumatoid Arthritis Flashcards

1
Q

LO
Focus on rheumatoid arthritis (RA) and how it affects patients
Understand its:
Epidemiology
Manifestations
Co-morbidities
Classification criteria
Early treatment requirements

Pt 2
- Risk factors
- shared epitope hypothesis
- role of autoantibodies

Pt3
- understand major cellualr + soluble factors involved in RA pathogenesis

Pt4
- understand current treatment strategies for RA+ consider future drug targets

A
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2
Q

What is rheumatoid arthritis?

A

autoimmune disease w chronic synovial inflammation that -> destruction of articular cartilage + bone

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3
Q

what does the chronic and persistent synovial inflammation lead to?

A

destruction of articular cartilage and bone

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4
Q

this causes a decline in joint function and progressive disability, what is the typical age range of onset?

A

40-70

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5
Q

what is the condition called if diagnosed below the age of 18

A

juvenile ideopathic arthritis

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6
Q

which gender is this more common in?

A

women

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7
Q

difference between amount of treatment options available for OA and RA?

A

OA: no treatment
RA: lots. can be treated better if diagnosed EARLIER

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8
Q

which two areas on the body are common sites for symmetrical polyarthritis and associated with pain and swelling?

A

small joints of hands and feet

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9
Q

do patients often experience pain in the morning or at night time which resolves throughout the day as the patient moves around?

A

morning

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10
Q

what lab features would you expect to see in a patient with RA?

A

↑ CRP and ESR,
presence of autoantibodies RF and ACPA
ultrasound showing erosive joint

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11
Q

why does RA improve with movement throughout day while OA gets worse?

A

RA: caused by swelling and oedema in joints. gets better w movement

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12
Q

how does level of acute phase reactants change in RA and give an example of type

A

increased
CRP

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13
Q

What joint does RA not typically involve?

A

axial skeleton - spine

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14
Q

AS (anylosing spondylitis) mainly affects which joint in which gender

A

mainly axial joints in men

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15
Q

RA is charactetrised by what pattern of joint involvement?

A

symmetrical.
predom hands and feet

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16
Q

synovium: thin memb few cells thick. what does it produce and why?

A

synovial fluid to allow joint to move

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17
Q

how can RA -> bone erosion and thinning of the cartilage

A

swollen inflamed synovial memb

becomes thicker + expands + influx of immune cells into it
makes whole thing get in way of normal joint funcn as its so swollen

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18
Q

how do OA and RA differ in terms of synovium?

A

OA: little/ no swelling
+ disease manifests initially as bone and cartilage surfaces

RA: swollen inflamed synovial memb

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19
Q

invasive synovium is called…

A

panus

starting to eat away at cartilage and bone

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20
Q

what systemic co morbidities are associated with this disease?

A

athersclerosis + heart disease,
vasculitis
lung inflammation + resistant scarring

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21
Q

why do patients being treated for RA have an infection risk?

A

immunosuppressed due to treatment with anti TNF + corticosteroids

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22
Q

comorbidities decrease life expectancy by average of 10 yrs. what can this be improved by?

A

earlier + better treatment

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23
Q

do patients with RA have a higher or lower risk of lung cancer and lymphoma?

A

higher

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24
Q

what changes can a patient make to reduce their RA symptoms and thus systemic inflammation?

A

stop smoking, control weight, bp and cholesterol and early and effective treatment

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25
Q

under the RA 1987 classification (american rheumatism association criteria) the patient must satisfy 4 out of 7 criteria at least. How long do criteria 1-4 need to be present for?

A

at least 6 weeks

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26
Q

why is the 2010 classfication superior to the 1987 one?

A

involves serology and acute phase reactants

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27
Q

what are the 4 criteria in the 2010 ACR/EULAR criteria for classification of RA?

A

joint involvement
serology
acute phase reactants
duration of symptoms

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28
Q

what results in delays in px attending GP about RA? to do w symptoms

A

initial symptoms may come on gradually and often vague (tiredness, aches, pains)
sometimes assumed to be due to old age/ overuse

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29
Q

what is RA often confused w, esp in early stages?

A

arthritides

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30
Q

list some of the risk factors of RA?

A
  • Age
  • female gender (3:1)
  • genetic predispositions
  • environmental risk factors
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31
Q

What are examples of genetic predispositions to RA?

A
  • HLA-DBR1 gene variants (shared-epitope)
  • single nucleotide polymorphisms (SNP) in PTPN22, CTLA4, STAT4, IL-6, NF-Kb, PAD enzymes

…. no 1 gene identified as cause BUT know some combinations likely to increase chance of RA

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32
Q

What are the environmental risk factors for RA?

A
  • Smoking
  • dust/silica exposure
  • microbes: P. gingivalis
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33
Q

the shared epitope is an HLA DRB1 encoded 5 amino acid sequence motif carried by majority of RA patients and is a risk factor for severe disease.
What is the possible mechanism that drives disease?

A

acts as signal transduction ligand, activates nitric oxide and reactive oxygen species production,
enhances polarization of Th17 cells: key mechanism in autoimmunity

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34
Q

for patients with no ACPA but still have RA, is the presence of PTPN and smoking still relevant in increasing the risk of developing the disease?

A

no, link is only strong in ACPA positive patients

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35
Q

together w ACPA- positive RA, what factor increases risk of RA?

A

smoking

but just bc higehr risk doesnt mean youll get the disease

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36
Q

what do rheumatoid factor (RFs) recognise

A

= autoantibodies, recognise Fc portion of IgG

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37
Q

why can RF not be used alone to diagnose RA?

A

not specific and RF antibodies present in many diseases.

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38
Q

what peptide assay broadly detects antibodies against ACPAs and has high specificity + excellent sensitivity in RA?

A

anti-CCP assay

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39
Q

why are polymorphisms in PAD enzymes associated with severe disease?

A

citrullination of arginine -> citrulline which then generates autoantibodies

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40
Q

name some risk factors associated with RA that induce/increase ACPA formation?

A

periodontal disease,
air polutants and smoke
dysbiotic microbiota

…. as ↑ cittrulination of proteins thus ↑ chances of getting autoantibodies to citrullinate proteins

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41
Q

peptidylarginine deiminases: family of enzymes that mediate post-translational modifications of protein arginine residues to produce…

A

citrulline.

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42
Q

why is early treatment key?

A

prevents irreversible bone damage

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43
Q

list the cells that migrate into the joints from the blood?

A

neutrophils,
dendritic cells,
effector and regulatory T cells
B cells

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44
Q

role of neutrophils in ra

A

arrive early in inflammn
make chemokines to recruit other cells (IL)17

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45
Q

role of dendritic cells in ra

A

activate T cells w antigen, costimulatory mols + cytokines
- IL12 and 23 turn T cells on
- IL10 turn T cells off (Possible future cell therapy)

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46
Q

role of effector t cells in ra

A

mount immune response against self antigens + help B cells make antibodies

47
Q

role of b cells in ra

A

make antibodies against self proteins (RF and ACPA)

48
Q

role of regulatory t cells in ra

A

make IL10 to turn immune resposne off (possible furture cell therapy)

49
Q

what does possible future cell therapy involves (regarding cells migrating to joints form blood)?

A

IL10 (dendritic and regulatory Tcells), turning T cells off

50
Q

list the cells that are resident in the joint?

A

chrondocytes,
fibroblast like synovial cells,
macrophage,
osteoclast,
mast cell
adipocytes

51
Q

role of chrondocytes in the joint

A

make MMPs to degrade cartilage
enz

52
Q

role of fibbroblast like synovial cells in the joint. 2

A

make MMPs and invade + degrade cartilage and bone
secrete cytokines eg IL6 to attract + retain leukocytes in joint

53
Q

role of macrophage in the joint

A

make lots of cytokines to activate OC and immune cells

54
Q

role of osteoclasts in the joint

A

make enz and degrade/ consume bone

55
Q

role of mast cells in the joint

A

make vasoactive factors that attract immune cells to joint

56
Q

role of adipocytes in the joint

A

make anti-inflammatory adipokines (eg leptin)

57
Q

pathoegnesis of RA? p420

A
58
Q

around a third of patients do not respond to any drug, why might this be the case?

A

there is no normal disease progression or pathology and cellular basis of disease differs between patients

59
Q

What are the 2 aims of RA drug therapies?

A
  • slow disease progression
  • control symptoms

+ treat to target strategy

60
Q

what is meant by the treat to target strategy?

A

treat active RA with the aim of remission or low disease activity if remission not possible

(get disease under control aggressively + quickly + maintain it there)

61
Q

What score is used to monitor disease activity in rheumatoid arthritis?

A

Disease Activity Score (DAS) 28

62
Q

the DAS 28 is the main scoring tool and counts how many of the 28 joints are swollen or tender. What 2 blood measurements would be taken?

A

CRP and ESR

63
Q

What composes the DAS 28 score?

A
  • no. swollen joints/28
  • no. tender joints/28
  • take blood to measure ESR or CRP
  • ask px to make global assessment of health (10cm line between v good/bad)
  • results fed into mathematical formula to produce score
64
Q

what does DAS 28 above 5.1 mean?

A

active disease

65
Q

what does a DAS 28 of below 3.2 mean?

A

low disease activity

66
Q

what is a DAS 28 below 2.6 mean?

A

remission

67
Q

What are the 4 treatment options for RA?

A
  • conventional disease modifying anti-rheumatic drugs (cDMARDs)
  • biological originator (bo) DMARDs
  • glucocortiocoids (short-term)
  • NSAIDs
68
Q

What are disease modifying anti-rheumatic drugs DMARDs?

A

compounds which reverse symptoms/disease/disability and disease progression by interfering w pathogenesis

69
Q

What else should be given when initiating cDMARDs?

A

glucocorticoid bridging treatment

70
Q

What are examples of cDMARDs?

A
  • methotrexate
  • sulfasalazine
  • hydroxychloroquine
  • leflunomide (2nd line)
71
Q

What are examples of boDMARDs? 4

A
  • B cell inhibitors
  • interleukin inhibitors:
  • T-cell co-stimulation inhibitors
  • TNF inhibitor
72
Q

give example of boDMARD: B cell inhibitor

A

rituximab

73
Q

give example of boDMARD: interleukin inhibitor

A

tocilizumab

74
Q

give example of boDMARD: T-cell co-stimulation inhibitor

A

abatacept

75
Q

give 5 examples of boDMARD: TNF inhibitors

A

adalimumab, certolizumab pegol, etanercept, golimumab, infliximab

76
Q

abatacept: T-cell co-stimulation inhibitor. what type of drug is it?

A

receptor

77
Q

what is the MoA of methotrexate in RA?

A

inhibits activation of b and t cells

78
Q

methotrexate: developed as a chemo drug. whats its MoA in cancer?

A

inhibits synthesis of DNA, RNA, thymidylates + proteins to prevent cell proliferation

79
Q

What is the half-life and metabolism of methotrexate?

A

hepatic + cellular metabolism,
half-life of 3-15 hrs (relatively short)

80
Q

side effects of methotrexate?

A

sickness, loss of appetite, sore mouth, diarrhoea, hair loss, (blood count, liver and lungs)

81
Q

What monitoring is required for methotrexate due to its side effects?

A
  • reporting all signs and symptoms of infection
  • FBC + LFT every 1-2 weeks to avoid blood dyscrasias and liver cirrhosis until stabilised
82
Q

etancercept is a decoy receptor. human recombinant receptor Fc fusion protein. what does it do?

A

bind to TNF so cant bind ot own receptor

83
Q

rituximab, an anti-B cell drug opsonises and kills B cells in 3 ways:

A
  • complement-mediated cytotoxicity
  • phagocytosis by macrophages
  • direct lysis by NK cells
84
Q

What is phase 1 of pharmacological management of RA?

A

Try up to 2 conventional DMARDs + glucocorticoid for 6 months

85
Q

What is phase 2 of pharmacological management of RA?

A

Try a second conventional DMARD/ add a biologic if disease is severe for another 6 months

86
Q

What is phase 3 of pharmacological management of RA?

A

Try a DMARD from a different class for another 6 months

87
Q

What drug (class) is MabThera?

A

rituximab - B cell inhibitor

88
Q

What drug is Humira?

A

adalimumab

89
Q

What drug class is infliximab and what kind of biologic is it?

A

TNF inhibitor, chimeric monoclonal antibody

90
Q

What drug class is adalimumab and what kind of biologic is it?

A

TNF inhibitor, human recombinant antibody

91
Q

What drug class is golimumab and what kind of biologic is it?

A

TNF inhibitor, human monoclonal antibody

92
Q

What drug class is certolizumab pegol, and what kind of biologic is it?

A

TNF inhibitor, humanised Fab fragment

93
Q

What are the key side effects of TNF-inhibitors?

A
  • skin reactions at injection site
  • infections
  • sick
  • fever
  • headaches
  • reactivation of TB
94
Q

What are the 3 phases of pharmacological management of RA?

A

phase I, II, and III where each is 6 months

95
Q

What general monitoring is required for patients on cDMARDs?

A
  • 6 months: DAS28
  • full blood count and biochemical screen
  • liver function
96
Q

RA SGT—————————–
examples of clinical manifestations associated with RA?

A
  • Pain (including night pain) and swelling at small joints of hands and feet
  • Morning stiffness in and around affected joints
  • Reduced mobility
  • Positive RF/ ACPA in serology
  • Fatigue very common
97
Q

what to monitor in RA px as part of Treat to target strategy?

A

Monitor px to see how responding to drugs.
Monitor DAS28 score

Reason for so many types of drugs as don’t work in all px. Diff underlying causes in diff px but manifest with different phenotype

98
Q

whats a huge risk factor (environmental) for RA?

A

smoking

99
Q

first line therapy for RA?

A

Conventional synthetic DMARDs
* Methotrexate
* Sulfasalazine
* Leflunomide
* Hydroxychloroquine

100
Q

contraindications to use of cDMARDs?

A

liver and renal? Disease
Pregnancy or breastfeeding
If none, start of methotrexate + short term glucocorticoids/ corticosteroids/ steroid same thing
Get inflammation under control ASAP. Gluc to reduce that
DMARDs more for long term maintenance of treating disease
Goes back to 2 aims of therapy

101
Q

What are the implications related to the use of DMARDs and the potential side effects of these drugs?

A

suppress immune system to control inflammation  increase risk of infection. Symptoms:
o chills, fever, sore throat, painful urination: report to doctor immediately.
o Also make receiving live vaccines dangerous

102
Q

Methotrexate Inhibits activation of B and T cells
list some SEs

A

Teratogenic (more for Leflunomide)
Can travel through breast milk

  • Stomach upset!!!
  • nausea
  • Increased risk of infection
103
Q

monitoring req for px on cDMARDs?

A
  • Pre treatment: renal, liver, FBC
  • CRP in case of inflammation
  • DAS28 to detect and monitor disease state/ activity
  • liver function for any abnormalities as potential for DMARDs to cause liver damage. Need blood analysis to monitor liver function
  • WBC counts
104
Q

px on cDMARDs, what else could you suggest they take?

A
  • Other conventional synthetic DMARD: leflunomide
  • Or introduce bo DMARDs i.e Infliximab, etanercept, adalimumab
  • Add a glucocorticoid to treatment
  • NSAIDs
  • JAK inhibitors
105
Q

what additional monitoring is required for hydroxychloroquine

A

Eye test
annually
monitor eye health and hydroxychloroquine retinopathy
Very rare. Ocular toxicity

106
Q

HTN associated with which RA drugs?

A

Leflunomide
Glucocorticoids
NSAIDs (diclofenac)

107
Q

what form of NSAIDs better for RA px?

A

Topical rather than oral for small joints / knees

108
Q

Diclofenac and many NSAIDs also associated with an increased risk of what?

A

CV events

109
Q

How does tramadol differ from other opioid drugs

A

Synthetic opioid, is less strong and addictive compared to other opioids

110
Q

What concerns would you have about PRN use of tramadol?

A

may be risk of dependency/ addiction- avoid high doses
* Risk of respiratory depression
* Interacts with lots of other meds
* Potential SE: seizures. Especially if PRN: could be exceeding recommended dose

111
Q

How does leflunomide work

A
  • conventional synthetic DMARD
  • Acts as an immunomodulatory and immunosuppressive agent
  • Inhibits pyridine synthesis
  • Stops proliferation of lymphocytes
  • Inhibits enzyme: DHODH
  • … need to synthesise DNA to proliferate as going through mitosis.
  • Can’t do that
112
Q

leflunomide
major adverse effects

A

SE:
* Nausea, GI upset
* Minor hair loss
* Agranulocytosis, lack of blood cells—> increased infection risk.
* Weight loss
* Teratogenic:

113
Q

what to monitor with leflunomide ?

A

liver!

Health 31 (16 decks)

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