1
Q
pathophysiology of RA
genetics + environmental trigger
A
1) Citrullinated antigens picked up by APC
2) T cell mediated immune resp (T, B, macro, fibroblasts-like synoviocytes)
a. Inflamm cytokines IL17, TNF, IL1, IL6
b. Signal via JAKs
3) Inflamm respon + Recruit inflamm cells
a. Angiogenesis in synovium
b. Synovial proliferation
4) Release proteases & Prostaglandins
5) Destruction of articular cartilage & underlying bone
2
Q
3 causes of articular destruction
A
- Pannus invasion (thick, swollen synovial mem + granulation tissue)
* Fibroblasts, inflamm cells, myofibroblasts - Incr RANKL on T cells (cytokines incr protein on T cell surface)
* Binds to osteoclasts (Breakdown of bone) - Antibodies immune complex
* Ab bind to target and form complexes
* Activate complement system —– Rheumatoid factor (RF)
* Target altered IgG Ab
* Anti-cyclic citrullinated peptide Ab —– target citrullinated proteins
3
Q
cause of RA
A
Chronic systemic inflammatory autoimmune disease
Targets: synovial tissues, bone erosion, joint deformity
- Immune complexes activated
- Incr proliferation
- Cytokine production (IL1, IL6, TNF, IFN-y, JAK-STAT pathway)
- Adhesion and trafficking
- B cells and T cells
- Some phagocytes (neutrophils, macrophages)
- Production or metalloproteinases and other effector molecules
- Migration of polymorphonuclear cells
- Erosion of bone and cartilage
4
Q
presentation of RA
A
- inflammation
* worse than OA (pain, swell, erythematous, warm)
* morning stiff > 30mins, symmetrical polyarthritis - systemic sx
* general ache/ stiff, fatigue, weight loss, fever, depression - extra-articular complications
- chronic = deformities (swan-neck, boutonniere, nodules, cyst)
- loss of physical function
5
Q
extra-articular complication of RA
A
eye, heart, hematology, lung, renal, skin, vascular
6
Q
lab findings of RA
A
- autoAb (may be -ve at early state)
○ RF
○ Anti-CCP assays - Acute phase response (active disease/ inflamm)
○ ESR incr
○ CRP inr - FBC
○ Hematocrit decr
○ PLT incr
○ WBC incr - Radiologic x-rays/ MRI
○ Narrow of joint space
○ Erosion (around margin of joint)
○ Hypertrophic synovial tissue
7
Q
diagnosis of RA
A
- Hx, PE, labs, radiographs
- ≥4 of following
- Early morning stiffness ≥1hr x ≥6wks
- Swelling of ≥3joints for ≥6wks
○ Polyjoints (large & small joints) - Swelling of wrist/ MCP/ PIP joints ≥ 6wks
- Rheumatoid nodules
- +ve RF/ anti-CCP tests
- Radiographic changes
(may not be avail at early stage): RF, anti-CCP, radiographic
8
Q
tx goals
A
- remission/ low disease activity (6mnths)
- Boolean 2.0 criteria
- Tender joint count ≤1
- Swollen joint count ≤1
- CRP ≤ 1mg/dL
- Pt global assessment (10cm VAS ≤2cm)
- SDAI, CDAI, DAS28
9
Q
RA tx plan
A
- Anti-inflammatory agents
- NSAID: short term relief of pain and stiffness (need PPI for GI SE)
- CS: bridge anti-inflammatory therapy (DMARD slow onset) ≤3MNTHS
○ Slow withdrawal over wks - mnths to reduce ADR
- csDMARD (Methotrexate, sulfasalazine, leflunomide, hydroxychloroquine)
- bDMARD (TNF, ILRA, anti CTLA4, anti-CD20, anti-IL6 receptor)
- tsDMARD (jak-stat pathway)
10
Q
approach
A
1) csDMARD + NSAID (bridge 3mnths)
2) bDMARD added when pt on MTX but not at target
* TNFa tried first ○ Not rely on IA glucocorticoid for sx relief ○ Add bDMARD/ tsDMARD ○ Triple therapy (+hydroxy & sulfasalazine) - Less risk of ADR & lower costs * Try other class of bDMARD before ts DMARD
3) tsDMARD
* Gradual discontinuation of MTX or DMARD
* Dose reduction/ incr interval
11
Q
monitor tx
A
- Monitor freq in active disease (1-3mnths)
- Adj tx if no improvement/target not reached by 6mnth
- CBC, WBC, PLT (myelosupp)
- LFT (hepatotoxicity)
- Scr (MTX)
- Lipid panel (part of bDMARD and tsDMARD - metabolic derangement)
12
Q
selection of bDMARD/ tsDMARD
A
- pre-DMARD (screen/ tx infection)
- Do not use >1 bDMARD/ tsDMARD at the same time
- CI during selection
○ Hypersensitivity to components, form
○ Severe infections (sepsis, TB, opportunistic infections)
○ HF (TNFa i) - Anti-drug Ab may occur with TNF a inhibitor
○ Loss of efficacy
○ Switch to another class bDMARD (diff MOA) when fails / lack efficacy 3mnths
○ tsDMARD as last line (greater risk of MACE, malignancy)
13
Q
tsDMARD as last line (greater risk of major adverse CVS events, malignancy)
risk factors
A
- CVS risk factors
* > 65yo
* hx for past/ current smoking
* obesity
* PMH of DM, HTN - malignancy risk factors (hx/ current)
- thromboembolic risk
* PMH of MI, HF, inherited blood clotting disorders, blood clot
* use of CHC, HRT
* undergoing major surgery
* immobility
14
Q
bDMARD & tsDMARD safety concerns
A
- inj site/ infusion rxn (acute vs delayed)
- myelosupp (CBC, WBC, PLT)
- infection (URTI, TB, hepatitis, opportunistic infection)
- malignancy risk
- autoimmune disease (SLE, lupus, demyelinating peripheral neuropathies)
- CVS (HF =TNFa) (HTN = IL6, JAKi, TNFa)
- pul disease/ toxicity (interstitial disease)
- thrombosis (JAKi, IL6i)
- hep (LFT)
- metabolic (hyperlipidemia)
- GI perforation (IL6, JAKi)
15
Q
GI perforation risk
CVS risk
A
GI: IL6i, JAKi, CD20 rituximab (onset 6day)
* diverticulitis
* > 65yo
* GC use
* NSAID use
CVS:
* HF: TNFa inhibitors
* HTN: IL6, JAKi
16
Q
initiating bDMARD/ tsDMARD
A
- Pre-tx screening (TB, Hep B & C)
- vacc required before initiation (pneumococcal, influenza, hep B, varicella zoster)
- lab screen (CBC, WBC, PLT, LFT, Lipid, Scr, preg)
17
Q
low disease activity/ remission
A
- =/> 6mnths at target
- Continuation of all DMARDs > reduction of dose/ gradual discontinuation but
- Triple therapy: discontinue sulfasalazine > hydroxy
○ Lower ADR, better tx persistence - MTX + bDMARD/ tsDMARD
○ Gradual discontinuation of MTX or DMARD
○ Dose reduction/ incr interval
18
Q
analgesics short term
A
3mnths
NSAID: inhibit PG synthesis
CS: anti-inflam, immunosuppressive
* PO < 7.5 mg prednisolone
* IA Q3 mnthly (< 2-3x/yr)
* discont if bMDARD/ tsDMARD started
19
Q
Methotrexate indication
A
- 1st line choice DMARD therapy
- Long term efficacy, acceptable toxicity, low cost
- Assoc w/ sig. lower mortality
- mod-high disease activity + ST analgesics
- Combined with other sDMARDs for optimal effects
20
Q
MOA of methotrexate
A
- Incr adenosine lvl, activate adenosine A2a receptor
a. Inhibit 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/ IMP cyclohydrolase (ATIC)
b. Anti-proliferative effects on T cells
c. Inhibit macrophage functions
d. Decr in pro-inflamm cytokines, adhesion molecules, chemotaxis, phagocytosis - [minor action] Inhibit dihydrofolate reductase and thymidylate synthetase (decr folic acid, decr cell proliferation)
21
Q
SE of methotrexate
A
- ND, anorexia, stomatitis, LIVER, lung fibrosis, myelosupp, TENS/SJS
- Reduction in folic acid, decr cell proliferation
- NV, mouth & GI ulcer, hair thinning
- Leukopenia, hepatic fibrosis, pneumonitis
- Concomitant folic acid or folinic acid 12-24hr after methotrexate (decr toxicity)
22
Q
MTX dose
A
initiate 7.5mg once weeklu
titrate: 2.5-5mg/wkly (every 4-12wks based on resp)
TARGET: 15mg/day (within 4-6wks of initiate)
max: 25mg/wk
23
Q
folic acid dose
A
5mg/ wk
24
Q
CI of methotrexate
A
pre-exist liver disease/ AST/ALT > 3X ULN (75% dose)
immunodeficient
blood dyscrasias
teratogenic
crcl < 30ml/min (<50ml = 50% dose)
25
DDI of methotrexate
NSAID/ COX2i (incr conc of MTX)
PPI (incr conc of MTX)
probenecid (incr conc of mTX)
vaccines (decr effect of vaccine)
alcohol (hepatotoxic)
26
methotrexate monitor
sx: SOB, cough, NV, mouth sores, D, jaundice, skin , infection
FBC, LFT, SCr
(AST, ALT, albumin, bilirubin)
27
sulfasalzine MOA
Metabolised to sulfapyridine (active) + 5ASA
MOA: unknown, maybe mediated by effect on gut microflora
* Decr IgA and IgM rheumatoid factors
* Suppress T and B cells, macrophages
* Decr inflamm cytokines (IL1 b, TNF, IL6)
28
sulfasalzine ADR
NV, headache, rash, infertility (reversible in M)
genitourinary, urine discolouration, headache, dizzy
hemolytic anemia, neutropenia (HLAB*0801, HLA-A*3101)
29
CI for sulfasalazine
* sulfonamide allergies
* G6PD def
eGFR < 60ml/min: initiate at lower dose
dialysis: initiate 250mg OD ~ 1g/day
30
monitor sulfasalazine
sx: NV, rash, infection
FBC
31
leflunomide MOA
* Converted to teriflunomide (active)
* MOA: decr lymphocyte action
- Inhibits dihydroorotate dehydrogenase
- Decr pyrimidine synthesis and growth arrest at G1 phase
- Inhibit T cell proliferation and B cell autoAB prodcution
- Inhbit NF-kB activation pro-inflamm pathway
32
leflunomide SE
D, elevation of liver enzymes, alopecia, weight gain, teratogenic, skin rash, headache, myelosupp
long t1/2 (even yrs detectable)
Wash out : Cholestyramine (bile salt binding resin) -- before preg
33
CI for leflunomide
ALT > 2X ULN
Teratogenic
34
monitor in leflunomide
sx: D, hair loss, jaundice, infection
FBC, LFT (ast, alt, albumin, bilirubin)
35
Hydroxychloroquine (best tolerated) MOA
inhibit chemotaxis of eosinophils, neutrophils, complement-dependent antigen-Ab reaction
Anti-malarial agent. Effective anti-inflamm agent in RA (but least potent DMARD)
MOA:
* Reduce MHC class II expression and APC
* Reduce TNF-a, IL1 and cartilage resorption
* Antioxidant activity
36
SE of hydroxychloroquine
tolerable
SE: NV, stomach pain, hair loss, ocular toxicity (retinopathy)
photosensitive, hyperpig
hypogly, headache, dizzy, QT prolong
37
dose adj in hydroxychloroquine
no specific dosage adj in renal/ hep
* metabolites excreted in urine (t1/2 40d)
C: preg
38
monitor in hydroxychloroquine
eye exam- retinopathy (ophthalmoscopy)
G6PD def
39
preg use what
Can use:
* Sulfasalazine (B), Hydroxychloroquine (C)
- both have risk of G6PD def
Cannot use: Teratogenic
* Methotrexate
* Leflunomide *req wash-out with cholestyramine, (long t½)
BMARD: TNFa inhibitors
40
bDMARD eg
Better tolerated, add as adjunct so that csDMARD dose can be lowered
* anti-TNF (infliximab, adalimumab, etanercept)
* IL1R antagonist: Anakinra
* Anti CTLA4 IG: Abatacept
* Anti-CD20: rituximab
* Anti-IL6 receptor mAb: tocilizumab
41
Anti-TNF
1) Infliximab (chimeric 25%)
* Chimeric IgG1: binds TNFa
* IV infusion (hosp)
2) Adalimumab (human 100%)
* Fully human IgG1: Binds TNF-a
* SQ self admin
3) Etanercept (decoy TNFR2 receptor - IgG1 fusion protein intercepts TNF)
* Recombinant fusion protein
* Binds TNF-a and TNF-b
* SQ self admin
42
TNF blockers indication
RA pt who do not respond well with sDMARD therapies
Combi with MTX for optimal effects
43
TNF blockers ADR
resp infection and skin infection, incr risk of lymphoma, optic neuritis, exacerbation of multiple sclerosis, leukopenia, aplastic anemia
44
TNF blocker CI + monitor
CI: live vaccination, Hep B
Monitor: screen for latent or active TB
hf iii,iv
45
IL1R antagonist: Anakinra
○ Humanised. Recombinant IL1 receptor antagonist
* SQ (self admin)
○ Differ from endogenous prot by 1 methionine added to N-terminus. Not glycosylated
○ Competitive inhibitor of IL1, binds to IL1 receptor , block signalling
* Less effective than anti-TNF bDMARDs
46
anakinra ADR
infections, INJ site rxn
47
Anti CTLA4 IG: Abatacept MOA + SE
MOA: recombinant fusion protein w/ CTLA4-Fc IgG1.
* binds to CD80& CD86
* Prevents CD28 activation
* T cell therapy (IV or sc)
SE: resp infection in COPD, incr lymphoma incidence
48
Anti-CD20: rituximab MOA + SE
MOA: chimeric mAb IgG1 directed at CD20 on pre- and mature B cells
* Depletes CD20+ B cells, block APC, autoAb and cytokine lvl
* B cell therapy (IV)
SE: rash (1st dose), resp infection in COPD
caution: GI perforation
49
Anti-IL6 receptor mAb: tocilizumab MOA + SE
MOA: Humanised IgG1, binds to IL-6 receptor
* Prevent homodimerisation of IL6R b signalling
SE: infection, skin eruptions, stomatitis, fever, neutropenia, incr ALT/AST, hyperlipidemia
50
tocilizumab DDI
Int. with CYP450, 3A4, 1A2, 2C9 substrates
Metabolised by proteolytic enzymes
by inhibiting IL6 = incr expression of CYP450 enzymes
51
4. tsDMARD (cytokine JAK-STAT pathway) indication
Tofacitinib
* Better response in combi with methotrexate in mod-severe RA
□ Tofa + MTX ~ bDMARD + MTX
* Mono if intolerance to methotrexate
* In methotrexate and multiple bDMARD-refractory active RA
* Approved for psoriatic arthritis (PsA)
* DO NOT COMBINE WITH bDMARDs (only csDMARDs)
□ Immunosupp risk
LAST LINE
52
JAKi MOA (small molecule JKi)
Block cytokine production (stop JAK/ STAT activation of gene transcription)
□ Tyrosine kinase
□ Signal transducer and activator of transcription
Binds to JAK proteins inside cells to prevent JAKs from transphosphorylating associated cytokines & growth factor receptor
53
JAKi ADR
* Cytopenia (neut, lymphocytes, PLT, NK cells)
* Immunosuppression (opportunistic infection -- herpes zoster infection)
* Anemia (JAK2 activation by erythropoietin)
* Hyperlipidemia (incr total LDL, HDL, choelsterol, TG)
* higher risk of major adverse cardiovascular events (MACEs) and malignancy
* CVS, malignancy, thromboembolic events
54
ROA of bDMARD & tsDMARD
TNFa: sc inj (except infliximab = IV)
IL1, CTLA4: sc inj
IL6, CD20: IV infusion
tofacitinib: PO
55
non pharm
* VACCINATION (TB, hep -- pre-DMARD)
* Pt education regarding RA & management
* Psychosocial int
* CBT (enhance self efficacy/ QOL)
* Rest inflamed joint/ use splints to support joints & reduce pain
* Caution -- not to promote sedentary lifestyle
* Physical activity & exercise (swim, no weight bearing exercises)
* Maintain range of joint motion
* Incr muscle strength
○ Avoid contractures & muscle atrophy
○ Maintain/ incr joint stability
○ Reduce fatigue & pain
* Improve sleep
* PT/OT (supervised exercise)
* Nutritional & dietary counselling
* Weight management if obese
* Reduce inflamm (fish oil EPA/DHA 5.5mg OD)
* Reduce ASCVD risk
3154 MSK
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