Rheumatoid Arthritis Flashcards
what is an autoimmune disease
disregulation of the immune system with loss of self-tolerance
what is myalgia
muscular pain
what are some common features of autoimmune diseases
malaise, fatigue, weight loss, myalgia, arthritis, anaemia
how is RA diagnosed
presence of synovitis in at least one joint, absence of alternative diagnosis and achievement of 6/10 on RA scale
what are the points on the RA scale
2 to 10 large joints = 1pt 1 to 3 small joints = 2pts 4 to 10 small joints = 3pts >10 joints = 5pts upper limit of ULN = 2pts greater than 3x ULN = 3pts elevated acute phase response = 1pt symptoms lasting >6wks = 1pt
what is the synovial layer
between ligaments
can become inflamed
what does a high ESR indicate
more inflammation
stands for erythrocyte sedimentation rate
who is more likely to get RA
women
increases with age then decreases after age 75
what is the cell level response to RA
macrophage forms major histocompatibility complex which attaches to a T-cell receptor and activates the T-cell
this releases activated B=cells that can activate macrohages
this causes inflammation
what antibodies are specific to rheumatoid arthritis
ACPA
anti-citrullinated protein antibodies
Anti-BiP, anti-SA
what antibodies are associated with RA
Anti-RA33, anti-calpastatin, ANCA and ANA, anti-collagen type II, anti-fibronectin, anti-GPI
what occurs during synovial inflammation and joint erosion
the synovial membrane becomes inflamed and cartilage begins to swell, synovial fluid is released and the joint capsule swells
eventually the bone erodes and the tendons become inflamed
what are the symptoms of arthritis
pain, stiffness in joints, symmetrical swelling in joints, fatigue, flu-like symptoms, morning stiffness
what affect does RA have on the skin
rheumatoid nodules, ulcers, vasculitis
what effect does RA have on the CNS and PNS
cerebrovascular disease, mononeuritis multiplex (vasculitis), carpal tunnel syndrome
what effect does RA have on the eyes
scleritis, episcleritis, sicca syndrome
what effect does RA have on the smaller arteries and veins
leucocytoclastic vasculitis
what effect does RA have on the heart
pericardial effusion, ischaemic heart disease, pericarditis
what effect does RA have on the blood
anaemia f chronic disease, neutropenia, haemolytic anaemia
what effect does RA have on the kidneys
amyloid disease
what effect does RA have on the lungs
pleural disease, pulmonary nodules, diffuse intersistal fibrosis, obliterative bronchitis
what are the radiology assessment tools for RA
sharp score, LArsen index
what are the disease activity indicators for RA
ACR response criteria
EULAR response criteria
disease activity score
what is the radiological evidence of early RA
soft tissue swelling, periarticular osteopenia, narrowing of joint space, loss of cartilage, cystic erosions
what lab tests are used to evaluate RA
ESR, CRP, RF (rheumatoid fctor), full blood count, electrolyte levels, creatinine levels, hepatic enzyme levels, urinalysis, synovial fluid analysis, ACPA
what is a DAS score
a rating of how painful, swollen or tender joints in the body are
joints included are DAS28
what DAS score gives high disease activity
5.1+
what DAS score indicates remission
2.6 to 3.2
what is the HAQDI scoring system
patients rate task difficulty: 0 = no difficulty 1 = some difficulty 2 = much difficulty 3 = unable to do so
what are the comorbidity risks with RA
circulatory system, infections, respiratory system, digestive system, malignant neoplasm, genito-urinary system
what genotype is associated with severe RA
HLA-DRB1
what are the main categories of drug used to treat RA
analgesics, NSAIDS, glutocorticoids, csDMARDS (methotrexate), bMARDS
what are some examples of csDMARDS
methotrexate, sulfasalazine, hydroxychloroquine, leflunomide, gold
what is an example of triple therapy
methotrexate, hydroxychloroquine, sulfasalazine
what are some examples of double therapy
methotrexate and leflunomide/sulfasalazine/hydroxychloroquine/gold
uulfasalazine and plaquenil (hydroxychloroquine)
how does methotrexate work
substitutes as folic acid, interferes with the denovo synthesis of purines, affects rapid cell turnover
what is the dose of methotrexate given
7.5 to 25mg weekly
takes 6-8wks for action
what are the common side effects of methotrexate
malaise, nausea, rise in liver enzymes
oral ulcers, alopecia, lover and bone marrow toxicity can all be dose sensitive
how does hydroxychloroquine work
anti-malarial medication used in inflammation, highly concentrated in cells and increases cellular pH - it interferes with the cell’s ability to degrade and process proteins
what is the recommended dose of hydroxychloroquine
200-400mg od
take 6-12wks for action
what are the common side effects for hydroxychloroquine
rash, nausea, diarrhoea, difficulty reading
how does sulfasalazine work
salicylic acid anti-inflammatory combined with sulfapyridine abx
what is the recommended dose of sulfasalazine
bd dose
dose starts od and increases slowly to qds
takes 6-8wks to work
what are some common side effects of sulphasalazine
malaise, nausea, rash, headaches, dizziness, abdominal pain
how does leflunomide work
coverted to A177-1726 in the GI tract and liver which inhibits dihydro-orotate dehydrogenase in the synthesis of pyrimidines
what is the recommended dose for leflunomide
10-20mg od
takes 6-8wks to work
what are some common side effects of leflunomide
diarrhoea, nausea, malaise, hypertension, alopecia, rash
how do TNF inhibitors work
inhibit TNF released by macrophages
what are some risks of using TNF inhibitors
infusion reactions with infliximab, injection site reactions with adalimumab and enanercept
risk of infection, malignancy, neurological complications, autoimmune disease and worsening of congestive heart failure
what is rituximab
b-cell depleting monoclonal anti-CD20 anti-body
Fc receptor gamma-mediated antibody-dependent cytotoxicity
causes b-cell apoptosis
how does abatacept work
t-cell co-stimulation
soluble receptor composed of CTLA-4 and Fc fragment of IgG
blocks reactions with CD28 on t-cells
cause t-cell death
what are some RA surgeries
arthroplasty
tendon repair
what are steroids derived from
hormones derived from mevalonic acid
what enzyme produces mevalonic acid (used for steroids)
HMG-CoA reductase
the target for statins
what steroid is converted to cholesterol
lanosterol
what is the role of glutocortecoids
to promote glucogenesis and glycogen formation and reduce inflammation
what are the three steps of cholesterol synthesis
cholesterol -> pregnenolone -> progestagens -> glucocorticosteroids/androgens/mineralcorticoids
what structure gives anti-inflammatory action
hydroxy or ketone group at carbon 11 on steroids
what basic structure do all steroids share
four ring structure (6,6,6,5)
what do cortisol and cortisone do
stress hormones that promote gluconeogenesis
how is prednisolone produced
from prednisone (keto derivative) by drug metabolism
what disease results with excessive steroid use
Cushing’s syndrome
sudden withdrawal can result in adrenal insufficiency
what is Cushing’s syndrome
the body reduces the amount of hormones it produces
tapering of steroids reduces this risk
how do NSAIDS work
reduce the production of leukotrienes and thromboxanes (lipids)
they inhibit cyclooxygenase 1 and 2 (COX1 and 2)
what is the function of cyclooxygenase
control synthesis of leukotrienes and thromboxanes
COX1 is constituative (produced in low levels in all tissues)
COX2 is inducible (in response to injury)
what is aspirin
irriversible, selective COX1 inhibitor
effect is potenated by caffeine
what is Reye’s syndrome
inflammation of the brain
risk of aspirin in <16s
what is ibuprofen
reversible COX 1 and 2 inhibitor
analgesic, anti-inflammatory and antipyretic activity largely due to COX2 inhibition
only S-enantiomer is active (naproxen is S-enantiomer but rest are racemic)
risk of ulcers due to COX1 inhibition
what is diclofenac
strong COX2 inhibitor, weak COX1 inhibitor
increases risk of cardiovascular complications but reduced risk of ulcers
duration of action is 6-8hours due to accumulation is synovial fluid
what are selective COX2 inhibitors
selectively inhibit COX2
increased risk of cardiovascular complications, efficacy is similar to other NSAIDS
naproxen has lower cardiovascular risk but not widely used
what does DMARD stand for
disease modifying anti-rheumatic drugs
how does sulfasalazine work
scavenges toxic reactive oxygen species produced by neutrophils (white blood cells) by inhibiting NFK-beta
in the gut, the azo group is reduced to aminosalicylic acid which is the radical scavenger
how does methotrexate work
slow-binding inhibitor of mammlian and bacterial dihydrofolaye reductase (DHFR)
DHFR uses NADPH to perform the reaction
slow-binding changes the enzyme and increases binding affinity
methotrexate binds to bacterial enzyme and to NADPH complex
what does methotrexate effectiveness rely on
substrate concentration and incubation time
build up of NADPH levels increases drug potency
aim is to reduce dose do not all WBCs are affected
how does leflunomide work
inhibits dihydroorodate reductase, an FMN-dependent (FMN= flaromononucleotide) oxidoreductase involved in uracil and thymine biosynthesis
pro-drug hydrolysed to form terifunomide in plasma and intestinal mucosa
how does terifunomide work
undergoes E/Z interconversion
inactivates dihydroororate dehydrogenase results on decreased availability of SNA precursors and hence proliferation of WBCs
how does paracetamol work
inhibitos cycloocygenase enzymes by quenching the oxidising species produced by the enzyme
more potent inhibitor of COX2 than COX1 so may have cardivascular side effects
does not increase inflammatory mediators
used in treatment for osteoarthritis
what is tofacitinib
non-tyrosine kinase (janus kinase-JAK) invilved in cytokine signalling
highly expressed in RA patients
tofacitinib inhibits JAKs and if a reversible ATP inhibitor
long lasting treatment
what are chloroquine and hydroxychloroquine
sulfate salts that promote oral bioavailability of treatments
chloroquine can cause renal toxicity
what is azathiprine
purine analogue that inhibits proliferation of white blood cells
side effects include bone marrow suppression
what is cyclophosphamide
‘mustard gas’
alkylates guanine residues in DNA
used in RA and vascilitis
what is vascilitis
inflammation and destruction of blood vessels
