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PR3154 MSK IC1,10-18 > IC16 OA & RA > Flashcards

IC16 OA & RA Flashcards

1
Q

What are the red flags for OA?

A

Red Flags:

  1. Infection
  2. Trauma / Fracture
  3. Malignancy
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2
Q

What is OA in general?
What are the RF of OA?

A

OA:

  • Degenerative disease with inflammation of bone and joint cartilages, ↑with age
  • Progressive and irreversible loss of cartilage

RF:

  1. Genetics
  2. Anatomic factors → bow legged/knocked knee
  3. Joint injury from sports / surgery / overuse
  4. Obesity → ↑load on your weight bearing joints.
  5. Age → ↑thinning, ↓hydration, ↑brittleness of ECM
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3
Q

What is the patho of OA?
What are the compensatory actions in OA?

A

Patho:
Articular cartilage damage
→ ↑chondrocyte activity to remove/repair damages
→ aberrant chondrocyte function → ↑breakdown
+ subchondral, meniscus, ligament, synovium release vasoactive peptides, cytokines & matrix metalloproteinases (MMPs) → ↑breakdown of collagen
→ cartilage loss & apoptosis of chondrocytes
→ formation of fibrillations (splitting of tissues) in cartilages & cartilage shards
Shards cause inflammation → effusion (collection of fluid) & synovial thickening
→ subchondral bones rub against each other
→ becomes dense, more brittle & stiffer, ↓weight bearing ability
→ development of sclerosis (hardening), microfractures, osteophytes (compensation to stabilise)
→ pain due to 1)activation of nociceptive nerve endings in joints by mechanical & chemical irritants + 2)distension of synovial capsule

Compensatory response:

  1. Cartilage degradation – cartilage damage → chondrocytes undergo phenotypic switch as they proliferate → produce improper mineralised collagen → weakening & degradation of collagen matrix in synovium
  2. Bone remodelling & osteophyte formation – weakened collagen matrix causes thickening of subchondral bones → sclerosis & formation of bone spurs (osteophytes) → latter causes “widening” joints to stabilize joints
  3. Synovial inflammation – weakened collagen matrix → cartilage shards → lymphocytes & macrophages recruited by synovial membrane to remove debris → proinflammatory cytokines produced → synovitis (inflammation) → contribute to disease progression
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4
Q

What are the S&S of OA?
What are the pain characteristics?

A

S&S & Diagnosis of OA

  1. Inflammation
    a. Pain
    b. Swelling
    c. Red and warm
  2. Morning stiffness <30mins → stiffness reduce when moving but recurs when resting
  3. Limited joint movement
  4. Functional limitation/ instability  ↑risk of falls
  5. Asymmetrical polyarthritis → injure one side first
  6. Possible location (weight-bearing joints) → fingers, knee, hip, spine
  7. Crepitus on motion (noisy)
  8. Bone enlargement
  9. Associated with anxiety, depression, sleep disturbances

Pain characteristics:

  1. slow progression over years
  2. Worse with joint use, pain relieved by rest
  3. Usually worse in late afternoon / early evening (night pain possible in severe disease)
  4. Knees → worse going down the stairs / slope compared to going up
  5. Most severe over joint line
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5
Q

What are the diff stages of OA?

A

Progressive stages:

Stage 1: sharp pain when use joints + cannot do high impact activities e.g. running, modest effect on function
Stage 2: pain more constant with unpredictable episodes of stiffness + daily activities start to be affected
Stage 3: Constant dull aching pain punctuated by episodes of often unpredictable intense exhausting pain + severe limitations in functions (cannot walk) + nocturnal pain

look at pg 38

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6
Q

What are the radiographic findings of OA?

A

Radiographic Findings (advanced years):

  1. Joint space narrowing
  2. Marginal osteophytes
  3. Subchondral sclerosis
  4. Abnormal joint alignment
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7
Q

How to diagnose OA?

A

Diagnosis:

  • History taking, Physical symptoms, >45 y/o
    o no need imaging/labs to confirm diagnosis, unless younger pts, unusual sx/red flags
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8
Q

What are the goals of treatment for OA?

A

Goals of Treatment

  1. relieve pain
  2. improve range of motion & joint function
  3. improve QOL
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9
Q

What is 1st line for OA?

A

Non-pharm:)

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10
Q

What are the non-pharm for OA? Including surgery

A

Non-Pharmacological Treatment (1st line) + Surgical Interventions

  1. Exercise
    a. ↓pain &improve physical function
    b. Muscle strengthening
    c. Neuromuscular training
    d. Low-impact aerobic e.g. walking, swimming, aquatic aerobics
    e. Mind-body e.g. Tai chi
    f. 30mins (3x/week)
    g. Refer PT
  2. Lose weight
  3. Information & support e.g. Knee Brace

Total joint arthroplasty → postoperative rehab is very impt (PT)

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11
Q

What are the possible pharm management for OA?

A

Appropriate Selection of Pharmacotherapy + Counselling Points
Drug treatment for OA (primarily symptomatic)

  1. Pain relief and/or anti-inflammatory
    a. TOP NSAIDs
    i. e.g. diclofenac patch (accumulate in the synovial fluids); kefentech
    b. PO NSAIDs / Coxibs e.g. Celecoxib 100mg BD
    i. (Often give long acting NSAIDs since used long term e.g. celecoxib, but if mild & not continuous pain then can give shorter acting & older NSAIDs e.g. ibuprofen 400mg q4-6hr)
    ii. + PPI prophylaxis
    iii. Look out for ADRs + CI + DDI (IC13)
    c. Paracetamol / tramadol / duloxetin
    d. Intra-articular Corticosteroids → short term relief (max 3 inj/yr)
  2. Symptomatic slow acting drugs for OA
    a. Intra-articular hyaluronic acid (HA)
    i. Large glycosaminoglycan (naturally in synovial fluids)
    ii. Shock absorption, traumatic energy dissipation, protective coating of cartilage, lubrication, ↓pain & stiffness
    iii. Induce biosynthesis of HA and extracellular matrix
  3. (NOT GOOD, NOT recommended, just supplements)
    a. Chondroitin sulphate
    b. Glucosamine
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12
Q

What are the compartments of immune system involved in RA?

A

Compartments of immune system involved:
1. Innate immunity
a. Phagocytes e.g. neutrophils, macrophages
b. Cytokines & chemokines
2. Adaptive immunity
a. B cells
b. T cells
c. Cytokines & chemokines
- Immune cells will
o Proliferate
o Cytokine production
o Adhesion & trafficking

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13
Q

What is RA Epidemiology, Etiology, Pathophysiology?

A

RA Epidemiology, Etiology, Pathophysiology

  • Chronic autoimmune inflammatory systemic disease
  • Occur at any age
  • More common in women
  • Genetic predisposition

Patho:
Genetic predisposition + immunologic trigger
→ citrullinated antigens are phagocytose by APC
→ T cell mediated immune response
→ T cells, B cells, macrophages, synoviocytes produce TNF, IL-1, IL-6  signal via JAK pathway
→ inflammatory response
→ angiogenesis in synovium → synovial cell proliferation → pannus invasion
→ recruit inflammatory cells e.g. macrophages
→ release proteases & PGE2
→ destruction of articular cartilage & underlying bones (e.g. ↑RANKL on T cells → break down of bone by osteoclast)

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14
Q

What are the S&S of RA?

A

S&S:

  1. Inflammation → Pain, swelling, red, warm
  2. Early morning Joint stiffness >30mins
  3. Pain worse in the morning
  4. Symmetrical (may start with one side first but eventually affect both)
  5. Polyarthritis
  6. Location:
    a. Small joints: lower joints of fingers, wrist
    b. Large joints: elbows, shoulders, hips, knees, ankles
  7. Systemic Symptoms (esp. >60y/o): generalised aching, stiffness, fatigue, fever, weight loss, depression
  8. Deformities e.g. swan neck → ↓physical function & ↓ADL
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15
Q

What are the lab findings of RA?

A

Lab Findings:

  1. Autoantibodies
    a. Rheumatoid Factor (RF) – +ve
    b. Anti-citrullinated peptides antibodies (Anti-CCP) – +ve
  2. Inflammation
    a. ↑ Erythrocytes sedimentation rate (ESR)
    b. ↑CRP
  3. FBC
    a. ↑platelets
    b. ↑WBC
    c. ↓hematocrit
  4. Radiologic:
    a. Narrowing of joint space
    b. Erosion of joint
    c. Hypertrophic synovial tissue
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16
Q

How to diagnose RA?

A

Diagnosis:

  • Do all the above
  • At least 4 sx/lab findings for >6wks
    o Early morning stiffness >1hr, swelling of >3joints, swelling of wrist/MCP/PIP joints, rheumatoid nodules, RF, anti-CCP, radiographic changes
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17
Q

What are the goals of treatment for RA?

A

Goals of treatment

  1. Remission & ↓disease activity at least 6 months
  2. Return to full function
  3. Maintain remission
  4. Boolean 2.0 criteria
  5. SDAI/CDAI/DAS 28
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18
Q

List the pharm for RA. (generally)

A

Pharmacotherapy + Counselling points

  1. Corticosteroids (short term)
  2. DMARDS
    a. csDMARDs
    b. bDMARDS
    c. tsDMARDS
    Extra: NSAIDs NOT really useful since not immunosuppressive, but still can give mainly as symptomatic
19
Q

How to start meds for mod-sev RA? What is the dose? What is the TCU?

A

Algorithm:
Starting (Mod-Sev disease activity):

  1. (1st line) MTX 7.5mg once weekly
    → increase by 2.5-5mg q4-12wks
    → target: 15mg/wk by 6 weeks
    → max: 25mg/day
  2. + folic acid 5mg once weekly
  3. + short term PO Prednisolone 5-7.5mg QD (3 months)
    a. When starting/changing DMARDs
    b. Tapered and stopped within 3 months
    c. Stopped if bDMARDs/tsDMARDs are started
  4. (2nd line) Sulfasalazine /leflunomide if MTX is CI
  5. Monitor every 3 months
20
Q

What meds for low disease activity for RA?

A

Starting (low disease activity), consider this order:

  1. Hydroxychloroquine (better tolerated than MTX)
  2. Sulfasalazine
  3. MTX
  4. Leflunomide
21
Q

If not improvement after 3 months/never reach target in 6 months, what to do next?
What needs to be done before starting bDMARDs/tsDMARDs?

A

If not improvement after 3 months/never reach target in 6 months :

  • Add bDMARDs/tsDMARDs
    o Do NOT use them together
    o Consider CI (under IC13)
    o Anti-drug antibodies may occur with anti-TNF inhibitors
    o bDMARDs preferred since tofacitinib have ↑risk of MACEs, malignancy, thromboembolic events
    o switch to a diff bDMARD of another MOA if the 1st one failed
  • OR add hydroxychloroquine & sulfasalazine (triple therapy, cheap, less ADR)
  • If already on bDMARDs/tsDMARDs, change to a different class

**When starting bDMARDs/tsDMARDs, you need to do:

  1. Pre-treatment screening
    a. TB latent/active
    b. Hepatitis B & C
  2. Vaccination
    a. Pneumococcal, influenza, hepatitis B, varicella zoster
  3. Lab screening/monitoring
    a. FBC, LFTs, lipid panel, SCr
22
Q

If at target at 6 months, what to do next?

A

If at target at 6 months:

  1. Do NOT stop DMARD abruptly, taper to low dose / stop
    a. If triple therapy: taper and stop sulfasalazine, while keeping Hydroxychloroquine
    b. If bDMARDs/tsDMARDs: taper and stop MTX
23
Q

What are the non-pharm for RA?

A

Non-pharmacological

  1. Exercise
    a. Swimming
    b. AVOID high intensity weight bearing exercises / activities
  2. Splint/braces for support
  3. Nutritional diet / weight management
  4. CBT
24
Q

What is the place in therapy of NSAIDs in RA?

A

NSAIDs + PPI (to ↓GIT ADRs)
e.g. celecoxib

  • short term relief of pain & stiffness

Place in therapy:

  • symptomatic relief of inflamm. & pain
25
Q

What is the MOA and place in therapy of corticosteroids in RA?

A

Corticosteroids

  • anti-inflammatory & immunosuppressive

Place in therapy:

  • low dose bridging anti-inflammatory therapy (PO Prednisolone 7.5mg OD 3 months)
  • do NOT continue long term
26
Q

What are the ADRs of corticosteroids?

A

1) Osteonecrosis/ osteoporosis
2) insulin resistance/ diabetes
3) GI ulcer if use with NSAIDs
4) cataract / glaucoma
5) ↑CVD risk
6) infections
7) myopathy
8) psychiatric sx
9) hirsutism / skin thinning

27
Q

What is the MOA and place in therapy of MTX in RA?

A
  • folic acid analogue
    1) (major) ATIC & AICAR enzyme inhibition → ↑adenosine levels
    2) (minor) dihydrofolate reductase & thymidylate synthase inhibition → ↓nucleic acid production impt in cell division → ADRs e.g. Nausea, hair loss

Overall effects:
1) ↑adenosine & activates adenosine A2a receptor → anti-inflammatory
2) anti-proliferative effects on T cells
3) Inhibit macrophage functions
4) ↓pro-inflammatory cytokines

Place in therapy:

  • 1st line (slow onset of weeks-months, does NOT help with pain)
  • Long term efficacy, acceptable toxicity, cheaper
  • assoc. w significant ↓mortality
28
Q

What are the ADRs of MTX? How can you reduce the ADRs?

A

1) N&V
2) mouth & GI ulcers
3) hair thinning
4) myelosuppression
- ↓ADRs:
Give concomitant high dose folic acid/folinic acid/ folinate 12-24hrs after methotrexate

5) leukopenia
6) hepatic fibrosis
7) pneumonitis
8) ↑transaminases
9) TENS/SJS

29
Q

Why is folinate or folinic acid better than folic acid as rescue therapy for MTX?

A

(Rescue therapy: folinic acid/folinate is rapidly converted into N5,N10-methylene-FH4. This bypasses dihydrofolate reductase route → more efficient at rescuing MTX tox
VS
Folate is NOT efficient due to depletion of N5,N10-methylene-FH4 as dihydrofolate reductase is inhibited → give high dose folate since cheaper)

30
Q

What are the CI of MTX?
What needs to be monitored when taking MTX?

A

1) Sev renal impairment: avoid
CrCL <30mL/min
2) Pregnancy

Monitor: FBC (RA anaemia), LFTs (since can ↑transaminases), SCr(renal impairment)

31
Q

What is 1 ADR of sulfasalazine?

A

1) Sulfonamide allergies

32
Q

What is the MOA and place in therapy of hydroxychloroquine?

A

Hydroxychloroquine

  • ↓MHC II expression & antigen presentation
  • ↓TNF-alpha, IL-1 & cartilage resorption
  • antioxidant

Place in therapy:
Best tolerated, but least effective

33
Q

What are the ADRs of hydroxychloroquine?
What are the CI?

A

ADRs:
1) N&V
2) stomach pain
3) dizziness
4) hair loss
5) ocular toxicity

CI:
1) preexisting retinopathy
2) caution in G5PD deficiency

34
Q

What are the ADRs and CI of leflunomide?

A

ADRs:
1) alopecia
2) ↑transaminases
3) myelosuppression

CI:
1) ALT >2x ULN
2) cholestyramine
3) Pregnancy

35
Q

What is an example of a tsDMARD?

A

Targeted synthetic DMARDS (tsDMARDs)
- Cytokine JAK-STAT pathway drugs

PO Tofacitinib

36
Q

What is the MOA and place in therapy of tofacitinib?

A

PO Tofacitinib

MOA:

  • non-selective JAK (Janus Kinase) pathway inhibitor (JAK1,2,3)
  • blocks cytokine production by blocking JAK/STAT activation of gene transcription

Place in therapy:

  • adjunct to MTX for mod-sev RA
  • monotherapy if intolerant of MTX
  • effective in MTX/bMDARD refractory RA (technically last line due to lots of ADRs since non-selective)
37
Q

What are the ADRs and CI of tofacitinib?

A

ADRs:
1) cytopenia
2) Immunosuppression (results in opportunistic infection)
3) Anaemia
4) Hyperlipidemia
5) ↑risk of MACEs & malignancy, thromboembolic events

Do NOT combine with biological DMARDs (severe immunosuppression, thus ↑risk of opportunistic infection)

38
Q

What are some examples of bDMARDs?

A

Biologics DMARDs (bDMARDs)

  • May not necessarily be more potent than csDMARDs but useful when patient can’t tolerate csDMARDs
  • More specific thus given if can’t tolerate MTX
  1. anti-TNF agents
  2. IL-1R antagonist
  3. IL-6R mab
39
Q

What is the MOA of anti-TNF agents andplace in therapy?

A

Anti-TNF mabs
e.g. infliximab IV

greater range of TNF targeting options, thus anti-TNF biologics are usually 1st choice among the bDMARDs when needed

MOA:

  • all binds to TNF
  • block TNF signaling
  • reduce T cell activation
  • Etanercept → decoy TNFR2 receptor-IgG1 fusion protein intercepts TNF

Infliximab – chimeric mab, most immnunogenic
Adalimumab – recombinant human mab
Golimumab – recombinant human mab
Etanercept – recombinant fusion protein, longest t1/2, least immunogenicity

Place in therapy:

  • 1st adjunct with MTX when do NOT respond well to MTX/csDMARDs
40
Q

What are the ADRs and CI of anti-TNF agents?
What needs to be screened before taking anti-TNF agents?

A

ADRs:
1) Respiratory/skin infection
2) risk of lymphoma
3) optic neuritis
4) exacerbation of multiple sclerosis
5) leukopenia
6) aplastic anaemia

CI:
1) live vaccine
2) Hepatitis B
3) HF

Monitoring:

  • Screen for latent or active TB (since immunosuppressant can cause worsening/ reactivation of this)
41
Q

What is the MOA and place in therapy of anakinra for RA?

A

IL1R antagonist
e.g. anakinra SQ

MOA:

  • binds to IL-1R
  • recombinant IL-1R antagonist (differs by 1 methionine, not being glycosylated)
  • block IL-1 signaling

Place in therapy:

  • less effective than anti-TNF bDMARDs
42
Q

What is the MOA of tocilizumab?

A

IL6R mabs
e.g. tocilizumab IV

MOA

  • binds to IL-6R alpha
  • blocks IL-6 signaling
  • prevents binding of IL-6 to IL-6alpha & homodimerization of IL-6R beta signaling

Tocilizumab – humanized mab

43
Q

What are the ADRs of tocilizumab?
What are the DDI?

A

ADRs:
1) infections
2) skin eruptions
3) stomatitis
4) fever
5) neutropenia
6) ↑ALT/AST
7) hyperlipidemia

DDI:
interacts with CYP450 3A4, 1A2, 2C9 substrates
→ becos even though Tocilizumab is metabolized by proteolytic enzymes, IL-6 ↓ expression of these CYP450 enzymes, so Tocilizumab (blocking effect of IL-6) will ↑ expression of CYP450

44
Q

What are the safety concerns with bDMARDs/tsDMARDs? (11)

A

Safety concerns with bDMARDs/tsDMARDs:

  1. Injection site reactions
  2. Myelosuppression
  3. Infections → pre-DMARDs screening + vaccinations
  4. Malignancies
  5. Autoimmune
  6. CVD e.g. HF (avoid anti-TNF inhibitors)
  7. Hepatic effects
  8. Metabolic effects
  9. Pulmonary disease
  10. GI perforation (esp. w JAK inhibitors, IL-6 inhibitor)
  11. Thrombosis (esp. w JAK inhibitors, IL-6 inhibitor)

PR3154 MSK IC1,10-18 (8 decks)

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