Rheumatoid Arthritis Flashcards
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
What is rheumatoid arthritis?
autoimmune disease w chronic synovial inflammation that -> destruction of articular cartilage + bone
what does the chronic and persistent synovial inflammation lead to?
destruction of articular cartilage and bone
this causes a decline in joint function and progressive disability, what is the typical age range of onset?
40-70
what is the condition called if diagnosed below the age of 18
juvenile ideopathic arthritis
which gender is this more common in?
women
difference between amount of treatment options available for OA and RA?
OA: no treatment
RA: lots. can be treated better if diagnosed EARLIER
which two areas on the body are common sites for symmetrical polyarthritis and associated with pain and swelling?
small joints of hands and feet
do patients often experience pain in the morning or at night time which resolves throughout the day as the patient moves around?
morning
what lab features would you expect to see in a patient with RA?
↑ CRP and ESR,
presence of autoantibodies RF and ACPA
ultrasound showing erosive joint
why does RA improve with movement throughout day while OA gets worse?
RA: caused by swelling and oedema in joints. gets better w movement
how does level of acute phase reactants change in RA and give an example of type
increased
CRP
What joint does RA not typically involve?
axial skeleton - spine
AS (anylosing spondylitis) mainly affects which joint in which gender
mainly axial joints in men
RA is charactetrised by what pattern of joint involvement?
symmetrical.
predom hands and feet
synovium: thin memb few cells thick. what does it produce and why?
synovial fluid to allow joint to move
how can RA -> bone erosion and thinning of the cartilage
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
how do OA and RA differ in terms of synovium?
OA: little/ no swelling
+ disease manifests initially as bone and cartilage surfaces
RA: swollen inflamed synovial memb
invasive synovium is called…
panus
starting to eat away at cartilage and bone
what systemic co morbidities are associated with this disease?
athersclerosis + heart disease,
vasculitis
lung inflammation + resistant scarring
why do patients being treated for RA have an infection risk?
immunosuppressed due to treatment with anti TNF + corticosteroids
comorbidities decrease life expectancy by average of 10 yrs. what can this be improved by?
earlier + better treatment
do patients with RA have a higher or lower risk of lung cancer and lymphoma?
higher
what changes can a patient make to reduce their RA symptoms and thus systemic inflammation?
stop smoking, control weight, bp and cholesterol and early and effective treatment
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?
at least 6 weeks
why is the 2010 classfication superior to the 1987 one?
involves serology and acute phase reactants
what are the 4 criteria in the 2010 ACR/EULAR criteria for classification of RA?
joint involvement
serology
acute phase reactants
duration of symptoms
what results in delays in px attending GP about RA? to do w symptoms
initial symptoms may come on gradually and often vague (tiredness, aches, pains)
sometimes assumed to be due to old age/ overuse
what is RA often confused w, esp in early stages?
arthritides
list some of the risk factors of RA?
- Age
- female gender (3:1)
- genetic predispositions
- environmental risk factors
What are examples of genetic predispositions to RA?
- 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
What are the environmental risk factors for RA?
- Smoking
- dust/silica exposure
- microbes: P. gingivalis
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?
acts as signal transduction ligand, activates nitric oxide and reactive oxygen species production,
enhances polarization of Th17 cells: key mechanism in autoimmunity
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?
no, link is only strong in ACPA positive patients
together w ACPA- positive RA, what factor increases risk of RA?
smoking
but just bc higehr risk doesnt mean youll get the disease
what do rheumatoid factor (RFs) recognise
= autoantibodies, recognise Fc portion of IgG
why can RF not be used alone to diagnose RA?
not specific and RF antibodies present in many diseases.
what peptide assay broadly detects antibodies against ACPAs and has high specificity + excellent sensitivity in RA?
anti-CCP assay
why are polymorphisms in PAD enzymes associated with severe disease?
citrullination of arginine -> citrulline which then generates autoantibodies
name some risk factors associated with RA that induce/increase ACPA formation?
periodontal disease,
air polutants and smoke
dysbiotic microbiota
…. as ↑ cittrulination of proteins thus ↑ chances of getting autoantibodies to citrullinate proteins
peptidylarginine deiminases: family of enzymes that mediate post-translational modifications of protein arginine residues to produce…
citrulline.
why is early treatment key?
prevents irreversible bone damage
list the cells that migrate into the joints from the blood?
neutrophils,
dendritic cells,
effector and regulatory T cells
B cells
role of neutrophils in ra
arrive early in inflammn
make chemokines to recruit other cells (IL)17
role of dendritic cells in ra
activate T cells w antigen, costimulatory mols + cytokines
- IL12 and 23 turn T cells on
- IL10 turn T cells off (Possible future cell therapy)
role of effector t cells in ra
mount immune response against self antigens + help B cells make antibodies
role of b cells in ra
make antibodies against self proteins (RF and ACPA)
role of regulatory t cells in ra
make IL10 to turn immune resposne off (possible furture cell therapy)
what does possible future cell therapy involves (regarding cells migrating to joints form blood)?
IL10 (dendritic and regulatory Tcells), turning T cells off
list the cells that are resident in the joint?
chrondocytes,
fibroblast like synovial cells,
macrophage,
osteoclast,
mast cell
adipocytes
role of chrondocytes in the joint
make MMPs to degrade cartilage
enz
role of fibbroblast like synovial cells in the joint. 2
make MMPs and invade + degrade cartilage and bone
secrete cytokines eg IL6 to attract + retain leukocytes in joint
role of macrophage in the joint
make lots of cytokines to activate OC and immune cells
role of osteoclasts in the joint
make enz and degrade/ consume bone
role of mast cells in the joint
make vasoactive factors that attract immune cells to joint
role of adipocytes in the joint
make anti-inflammatory adipokines (eg leptin)
pathoegnesis of RA? p420
around a third of patients do not respond to any drug, why might this be the case?
there is no normal disease progression or pathology and cellular basis of disease differs between patients
What are the 2 aims of RA drug therapies?
- slow disease progression
- control symptoms
+ treat to target strategy
what is meant by the treat to target strategy?
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)
What score is used to monitor disease activity in rheumatoid arthritis?
Disease Activity Score (DAS) 28
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?
CRP and ESR
What composes the DAS 28 score?
- 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
what does DAS 28 above 5.1 mean?
active disease
what does a DAS 28 of below 3.2 mean?
low disease activity
what is a DAS 28 below 2.6 mean?
remission
What are the 4 treatment options for RA?
- conventional disease modifying anti-rheumatic drugs (cDMARDs)
- biological originator (bo) DMARDs
- glucocortiocoids (short-term)
- NSAIDs
What are disease modifying anti-rheumatic drugs DMARDs?
compounds which reverse symptoms/disease/disability and disease progression by interfering w pathogenesis
What else should be given when initiating cDMARDs?
glucocorticoid bridging treatment
What are examples of cDMARDs?
- methotrexate
- sulfasalazine
- hydroxychloroquine
- leflunomide (2nd line)
What are examples of boDMARDs? 4
- B cell inhibitors
- interleukin inhibitors:
- T-cell co-stimulation inhibitors
- TNF inhibitor
give example of boDMARD: B cell inhibitor
rituximab
give example of boDMARD: interleukin inhibitor
tocilizumab
give example of boDMARD: T-cell co-stimulation inhibitor
abatacept
give 5 examples of boDMARD: TNF inhibitors
adalimumab, certolizumab pegol, etanercept, golimumab, infliximab
abatacept: T-cell co-stimulation inhibitor. what type of drug is it?
receptor
what is the MoA of methotrexate in RA?
inhibits activation of b and t cells
methotrexate: developed as a chemo drug. whats its MoA in cancer?
inhibits synthesis of DNA, RNA, thymidylates + proteins to prevent cell proliferation
What is the half-life and metabolism of methotrexate?
hepatic + cellular metabolism,
half-life of 3-15 hrs (relatively short)
side effects of methotrexate?
sickness, loss of appetite, sore mouth, diarrhoea, hair loss, (blood count, liver and lungs)
What monitoring is required for methotrexate due to its side effects?
- reporting all signs and symptoms of infection
- FBC + LFT every 1-2 weeks to avoid blood dyscrasias and liver cirrhosis until stabilised
etancercept is a decoy receptor. human recombinant receptor Fc fusion protein. what does it do?
bind to TNF so cant bind ot own receptor
rituximab, an anti-B cell drug opsonises and kills B cells in 3 ways:
- complement-mediated cytotoxicity
- phagocytosis by macrophages
- direct lysis by NK cells
What is phase 1 of pharmacological management of RA?
Try up to 2 conventional DMARDs + glucocorticoid for 6 months
What is phase 2 of pharmacological management of RA?
Try a second conventional DMARD/ add a biologic if disease is severe for another 6 months
What is phase 3 of pharmacological management of RA?
Try a DMARD from a different class for another 6 months
What drug (class) is MabThera?
rituximab - B cell inhibitor
What drug is Humira?
adalimumab
What drug class is infliximab and what kind of biologic is it?
TNF inhibitor, chimeric monoclonal antibody
What drug class is adalimumab and what kind of biologic is it?
TNF inhibitor, human recombinant antibody
What drug class is golimumab and what kind of biologic is it?
TNF inhibitor, human monoclonal antibody
What drug class is certolizumab pegol, and what kind of biologic is it?
TNF inhibitor, humanised Fab fragment
What are the key side effects of TNF-inhibitors?
- skin reactions at injection site
- infections
- sick
- fever
- headaches
- reactivation of TB
What are the 3 phases of pharmacological management of RA?
phase I, II, and III where each is 6 months
What general monitoring is required for patients on cDMARDs?
- 6 months: DAS28
- full blood count and biochemical screen
- liver function
RA SGT—————————–
examples of clinical manifestations associated with RA?
- 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
what to monitor in RA px as part of Treat to target strategy?
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
whats a huge risk factor (environmental) for RA?
smoking
first line therapy for RA?
Conventional synthetic DMARDs
* Methotrexate
* Sulfasalazine
* Leflunomide
* Hydroxychloroquine
contraindications to use of cDMARDs?
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
What are the implications related to the use of DMARDs and the potential side effects of these drugs?
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
Methotrexate Inhibits activation of B and T cells
list some SEs
Teratogenic (more for Leflunomide)
Can travel through breast milk
- Stomach upset!!!
- nausea
- Increased risk of infection
monitoring req for px on cDMARDs?
- 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
px on cDMARDs, what else could you suggest they take?
- Other conventional synthetic DMARD: leflunomide
- Or introduce bo DMARDs i.e Infliximab, etanercept, adalimumab
- Add a glucocorticoid to treatment
- NSAIDs
- JAK inhibitors
what additional monitoring is required for hydroxychloroquine
Eye test
annually
monitor eye health and hydroxychloroquine retinopathy
Very rare. Ocular toxicity
HTN associated with which RA drugs?
Leflunomide
Glucocorticoids
NSAIDs (diclofenac)
what form of NSAIDs better for RA px?
Topical rather than oral for small joints / knees
Diclofenac and many NSAIDs also associated with an increased risk of what?
CV events
How does tramadol differ from other opioid drugs
Synthetic opioid, is less strong and addictive compared to other opioids
What concerns would you have about PRN use of tramadol?
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
How does leflunomide work
- 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
leflunomide
major adverse effects
SE:
* Nausea, GI upset
* Minor hair loss
* Agranulocytosis, lack of blood cells—> increased infection risk.
* Weight loss
* Teratogenic:
what to monitor with leflunomide ?
liver!
