Rheumatoid Arthritis Flashcards
RA risk factors:
Age.
Incidence greater in over –
Sex.
Double the incidence in –
Genetics/inherited traits.
Smoking.
History of live –
Early Life Exposure as — during pregnancy or low – family
Obesity.
over 60s
some
live births
smoking
low income
Mortality is increased – folds
Resulting in a decreased lifespan of 7 to 10 years
Death comes early
Main cause - — and –
60% higher
Treatment reduces this risk
2 folds
heart attacks n strokes
( check slide 5)
stages of RA:
Stage 1:This is early stage RA. This stage involves the initial inflammation in the – and swelling of — tissue. The swelling causes the symptoms of joint pain, swelling, and stiffness.
Stage 2:In the moderate stage of RA, the inflammation of the synovial tissue becomes – enough that it creates – damage. In this stage, symptoms of loss of – and decreased joint — become more frequent.
Stage 3:Once the disease has progressed to stage three, it is considered – RA. Inflammation in the synovium is now destroying not only the – of the joint but the – as well. Potential symptoms of this stage include increased pain and swelling and a further decrease in mobility and even muscle— . Physical— of the joint may start to develop as well.
Stage 4:In the end stage of RA, the inflammatory process — and joints stop functioning altogether. Pain, swelling, stiffness and loss of mobility are still the primary symptoms in this stage.
joint capsule
synovial tissue
severe
cartelige dmaange
mobility
range of motion
severe
caartlige
bone
strength
deformaties
ceases
Post-translational modifications and autoantibodies in RA:
1-Citrullination
-Conversion of – to– by —
-PAD can be released by – or originate from – .
2- Carbamylation
- Conversion of – to – by a – reaction with –
- – cyanate level inrenal disease, inflammation and smoking.
3-These post-translational modifications can be recognized by – .
The best-known antibodies in rheumatoid arthritis : — , — , —
arginine to citrullin
by peptidylarginine deiminase
neutrophils
bacteria
lysine to homocitrulin
chemical
cyanate
elevated
autoantibodies
best known antibodies as:
rheumatoid factor (RF),
anti-citrullinated protein antibody (ACPA)
anti-carbamylated protein antibody (anti-CarP)
- inflammation is not a – process as its Complex, highly – set of interactions between cells, soluble mediators and the tissues
Essential – mechanism—- response of the tissues to – or — (e.g. infection)
Problem arises when inflammation is – and leads to— - Resolution of inflammation is important to limit – done by inflammatory process
This involves:
1- Removal of —
2- — apoptosis
3- Release of —
4- Transformation of — (inflammatory) macrophages to — (phenotype) - Failure of resolution leads to —
single
regal;ated
defense and protective response
irritation or injury
unchecked
tissue damage
limit damage
pro inflammatory mediators
neutrophils
pro resolving mediators
M1 to M2
chronic inflamamation
NSAID’s are used to treat –
Act to inhibit – and – production
Are — , — and —
as:
aspirin ( — )
ibuprofen
indomethacin
meclofenamate
diclofenac
inflammation
cooxygenase n prostaglandin
anti inflammatory anglestic and anti pyretic
irreversible
– inhibitors: celecoxib,rofecoxib
developed to protect against –
Have similar efficacies to that of the — inhibitors, but the – side effects are decreased by ~50%.-
- Selective COX-II inhibition is associated with reduced — (PGI2 / prostacyclin) production by —
- Little or no inhibition of potentially —- production
-Therefore an exaggerated — effect will be observed in patients treated chronically with Coxibs!
-All NSAIDS except – appear to increase– risk
-The increased risk is – dependent
-Avoid NSAID use in patients at high risk of – event
When using – use – dose for – period
COX II
gastric ulceration
non selective
GIT
reduced prostaglandin I2 (PGI2 / prostacyclin)
vascular endothelium
prothrombotic platelet thromboxane A2 production
prothrombtic effect
naproxen
cardivsasuclar risk
dose dependent
cardiovascular event
lowest dose n shortest period
glucotocidoes:
-These increase — (lipocortin) production which inhibits — reduce the production of – and – ,— ,— and—
-decreases — , — and – but increase in —
- lymphocytes are also — (T>B; CD4+>CD8+)
adverse effects on — metabolism
annexin
phospholipase A2
reduce IL-1 . IL-2 interferone prostaglandin and lecukotrines
decreases basophils estinophils and monocytes
increases neutrophils
reduced
carbohydrate
sulasalazine:
-Developed in the late 1930s by Dr. Nana Svartz (Swedish Rheumatologist) for the treatment of —
- Anti-inflammatory: —
- Antibiotic: —
- Sulfasalazine consists of – and – joined by an – bond.
Reduced by the — to — and — (5-ASA) in bowel
infective polyarthritis
salicylic acid
sulfapyrdine
salsilic acid + sulfapyridine
azo bond
bacterial enzyme azoreductase to sulfapyridine abd 5-aminosalyslic acid
sulfasalzine MOA:
-Active moiety is — not –
-Mode of action –
effects — activity,
reduced production of — – from monocytes/macrophages,
inhibits – proliferation etc.
sulfasalzine adverse effects:
Side effects primarily due to –
skin reactions,
hepatitis,
pneumonitis,
agranulocytosis,
aplastic anemia
Males - oligospermia and infertility
gastrointestinal upset less severe hematologic toxicities
5-aminosalicylic acid not sulfapyridine
unclear
neutrophil
IL-1 , TNF
T cell proliferation
sulfaprydine
act by interfering with dihydrofolate reductase necessary for DNA synthesis
inhibits replication of B and T-cells
used in rheumatoid arthritis and psoriasis and in combination with cyclosporine to prevent GvHD
this is known as —
methotrexate - anti folate
in methotrexate :
Dose used in RA is much – than dose used for cancer
- Minimum of 15 mg once per week in RA
- 30 mg/m2 (~ 45 mg ) twice weekly during cancer remission
- Anti-inflammatory effect is not inhibited by —
MOA is unclear but in RA:
1- MTX is— (long half-life)
2- Inhibits Aminoimidazole carboxamidoribonucleotide ( — ) transformylase
3-Leads to increased — production
4-Anti-inflammatory via —
lower
folic acid supplementation
poly-gluatamated
AICAR
adenosine
adenosine receptors
adenosine :
-Acts on — :
- — coupled receptors
-A1, A2A, A2B, and A3
-Found on – immune cells
-Acts to increase —
adenosine receptors
g protein
multiple
pro resolution
methotrexate toxicity:
Folic acid supplementation to prevent —
Hepatotoxicity
Pulmonary damage – pulmonary fibrosis/pneumonitis
Myelosuppression/blood dyscrasias
Gastrointestinal problems such as nausea, stomach upset, and loose stools
Stomatitis or soreness of the mouth
Infection
Alopecia
side effects
lefluomide:
-Leflunomide inhibits – - and — replication
-inhibition of — (DHODH)
DHODH is essential for de novo – synthesis
- Used for –
-side effects are increased — enzymes and – disturbance
- – metabolite teriflunomide also approved for MS
b n T cell replication
dihydroorotate dehydrogenase
pyrimidine
RA
liver
mild gi
active
