DMARDs and Rheumatoid Arthritis Flashcards
1.overview of RA 2.criteria for dignaosis of RA 3.basic management 4. NICE guidelines 5.Convential DMARDS 6.Biologicals
prevelance
total NUMBER of cases of a disease in a population at a certain moment in time.
incidence
number of new cases occurring in a population over a defined time interval
UK prevelance of RA
400,000
UK incidence of RA
12,000
what areas of body are affected in RA? (reason it is more serious than OA)
- small joints of hands + feet = carpals + MCP + MTP
- tendon sheaths
- systemic inflammation - heart, lungs, kidneys, skin
which joint in the hand is usually spared in RA?
DIP (distal interphalangial) joint
Does RA present symmetrically or asymmetrically + why ?
RA- symmetrical - autoimuune disease - inflammation - occurs on BOTH sides of the body
why is treatment for RA agressive?
severity of symptoms if left untreated:
- hands + feet severly deformed
- systemic effect - IHD, CKD
- larger joints affected - shoulder, hips, knees
- premature mortality
4 diagnositic features for RA?
- affects small joints
- pain >6wks
- symmetrical
- seropostive for RF
What score for 2010 ACR/EULAR criteria qualifies RA diagnosis?
score ≥ 6/10
What is the aim of RA treatment?
- prevent sever joint deformity (slow progression of disease)
- prevent flare ups
What are the 2 types of drugs invovled in management of RA?
- DMARDs - disease modifying anti rheumatics
- Pain relief
- analgesics= NSAIDs, corticosteroids
Management of newly diagnosised RA
NICE guidelines - high dosage DMARD combination therapy (symptoms >3mths)
What is the significance of having aggreesvie high dosage DMARD intially?
- controls RA + prevent progression
- 5yr- no DMARD = 60% patients = severe joint deformity
- DMARD =<10% patients = severe joint deformity
(observable on X-ray - bone erosion + joint instability)
What is the management of RA if DMARDs combmination theraphy is not tolerated?
DMARD monotheraphy
cases - comorbidities + pregnancy (avoid MTX)
What are the 2 groups of DMARDs
- conventential
2. biologicals
List the 6 convential DMARDs
- methotrexate (MTX)
- leflunomide
- hydrochoroquine
- sulfasalazine
- azathioprine
- gold salts
Gold standard for RA from conventential DMARDs
methotroxate
METHOTREXATE (MTX)
- MOA
- dosage
- administration
- Side effects
- Time before benefits seen
- folic acid antagonist in ALL ACTIVELY DIVIDING cells
- 2.5mg tablets (intially 5-10mg) 1.pw
- oral /SC or IM injection
- affects haemtopoesis + liver function - affects all actively dividng cells - bone marrow + liver
- 3-12 wks
Describe MOA of methotrexate
hint-slide 8
- enters cell via A.T through folic acid transporter
- glutamination of MTX
- directly inhibits DIHYDROFOLATE REDUCTASE- prevents formation: dihydrofolic acid - tetrahydrofolic acid - block purine biodynthesis - blocks RNA synthesis
- indirectly inhibits THYMIDYLATE SYNTHESASE -blocks DNA synthesis
What treatment is methotrexate also involved in?
- chemotherapy
2. abortions
SULFASALAZINE
- special use*
1. MOA
2. dosage
3. administration
4. Side effects
5. Time before benefits seen
- special use* - treat systemic effects of RA
1. remains in L.I - metabolism to 5ASA -treats ULCERATIVE COLITIS
2. 500mg daily
3. oral- tablet
4. haemolytic anaemia
5. 12 wks
Why does sulfasalazine remain in the large intestine?
metabolite 5ASA (5-aminosalicylic acid) =poorly absorbed into bloodstream
Activation of which Th cell causes the release of pro-inflammatory cytokines?
Th17 in lamina propria
What condition does the release of the pro-inflammatory cytokines IL1,6,23 cause?
ankylosing spondylitis- chronic inflammatory disease of axial skeleton
What conditions does the release of pro-inflammatory cytokines IL17,22 cause?
IBD (ulcerative colitis)
What are the 2 systemic effects in RA caused by the activation of Th17 activation in the lamina propria of the gut?
- IBD
2. ankylosing spondylitis
Other than to treat RA what can sulfasalazine be used for?
antibioitic
what is sulfasalzine comprised of?
sulfapyridine + salicylate with azo bond
HYDROCHLOROQUINE
- MOA
- dosage
- administration
- Side effects
- Time before benefits seen
1.
- acc in lysosomes - acidic- prevents protein modifications- decreases proteolyitc enzymes- in synovcytes type B
- blocks Toll like receptor 9
2. 400mg daily
3. ORAL
4. psoriatic rash + skin plaques
5. 12wks for benefit
What is the function of Toll 9 an which drug is thought to block its action?
Hydrochloroquine
-toll like receptor 9 - recg DNA containing immune complexes- decreases act. of dendritic cells - present antigens to B cells - make autoantibody
What can hydrochloroquine be used to treat other than RA?
anti-malarial
LEFLUNOMIDE
- MOA
- dosage
- administration
- Side effects
- Time before benefits seenWhat can hydrochloroquine be used to treat other than RA?
- inhibits DIHYDROOROTATE DEHYDROGENASE - inhibits PRYADMIDINE BIOSYNTHESIS - blocks DNA + RNA synthesis
- 10-20mg daily
- oral
- liver damage, lung disease, immunosuppression, diarrhoea, hair loss
- 12wks
Under what circumstances would Leflunomide be used?
if methotrexate can not be tolerated -pregnancy + comorbitidies
AZATHIOPRINE
- use
- MOA
- in combination with
- immunosuppression (see transplantation - to prevent rejection)
- interferes with purine synthesis - DNA synthesis
- prednisolone - can use smaller dose (if used with AZT)
GOLD SALTS
- MOA
- dosage
- administration
- Side effects
- Time before benefits seenWhat can hydrochloroquine be used to treat other than RA?
- prevents inflammation at MCP
- 50mg
- injection 1 weekly (NOT ORAL)
- painful + granulation/cysts surrounding injection
- 4-6mnths
What are the 2 main disadvantages with using traditional DMARDs?
- slow acting - 1 weekly
2. target immune cells - immunosuppresion- monitor for infection (TB) + malignancy (skin cancer)
What is the effect of using traditional DMARDs on the production of pro-infl cytokines?
- target immune cells: APC, T cell, B cell
- prevent active division
- decrease production of pro-infl cytokines
- decrease synovial inflammation, systemic inflammation, destructive changes
Which DMARDs target both T+ B cells?
MTX + LEF
Which DMARDs target both APC + T cells?
SSZ + Gold
Which DMARDs only targets APC?
Anti-malarials
What are the 5 possible targets for biological DMARDs?
- TNFα
- IL6
- IL1
- T cell
- B cell
What are the most popular biological DMARDs?
TNFα blockers
ETANERECEPT + INFLIXAMAB + ADALIMUMAB
ETANERCEPT
- define
- components
- dosage
- administration
- time for effect
- FUSION PROTEIN
- TNF receptor 2 + Fc human IgI
- 50mg weekly
- SC
- 1-4wks
OLDEST
INFLIXIMAB
- define
- components
- dosage
- time for effect
- monoclonal antibody against TNFα
- IgI + mouse Fv
- 3mg/kg 2-3hrs in 2-6hr duration
- INFUSION
- days
tolerance- create antibody’s to foreign mouse part of drug
MOA for Infliximab
- decoy for TNFα receptor
- binds to TNFα - unable to bind to receptor on synoviocyte - unable to act on joint- no inflammation
What can Infliximab treat other than RA?
pustular psoriasis
ADALIMUMAB
- define
- components
- dosage
- administration
- time for effect
- monoclonal antibody
- both Fc + Fv porion = HUMAN
- 40mg
- SC
- 1-4wks
unlike inflixmab - no tolerance develops- all HUMAN
Name the 3 anti-TNFα biological DMARDs
- etanercept
- infliximab
- adalimumab
Which group of drugs are rarely used to treat RA and why?
- IL-1 blockers = ANAKINRA + RILONACEPT
- daily injection - patient compliance
- used to treat GOUT
RITUXIMAB
- cell target?
- what is it
- dosage
- administration
- time for effect
- B cell
- monoclonal antibody against CD20 receptor on B cell
- X2 1000mg 2 wks apart
- infusion
- 3 months post infusion
What is the problem with use of Rituximab?
- depletes B cell population for 1 year (both normal + malignant)
ABATACEPT
- cell target
- what is it
- dosage
- administration
- time for effect
- T cell
- FUSION PROTEIN -
MOA for Abatacept
CTLA-4 on Abatacept binds to CD28 on Tcell- prevents binding to APC - prevents activation of T cell - prevents release of inflam cytokines
TOCILIZUMAB
- target
- define
- dosage
- administration
- use with
- IL6 receptor
- HUMANISED monocloncal antibody
- 8mg/kg MONTHLY
- IV
- MTX
Which 3 biological DMARDs are fusion proteins?
- etanercept
- rilonacept
- abatacept
ending in CEPT = fusion protein
Which 4 biological DMARDs are monoclonal antibodies?
- rituximab
- tocilizumab
- adalimumab
- inflixmab
MOA for Tocilizumab
binds to IL6 receptor - blocks IL6 binding to its receptor - block signalling from IL-6
What are the 2 advantages of using biological DMARDs over conventional DMARDs?
- faster effect
- do not damage body’s immune cells - no immunosuppression
Gold standard for RA from biological DMARDs
TNFα blockers -less depression like symptoms