IC16 OA & RA

Question 1

What are the red flags for OA?

Answer 1

Red Flags:

1. Infection
2. Trauma / Fracture
3. Malignancy

Question 2

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

Answer 2

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

Question 3

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

Answer 3

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

Question 4

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

Answer 4

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

Question 5

What are the diff stages of OA?

Answer 5

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

Question 6

What are the radiographic findings of OA?

Answer 6

Radiographic Findings (advanced years):

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

Question 7

How to diagnose OA?

Answer 7

Diagnosis:

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

Question 8

What are the goals of treatment for OA?

Answer 8

Goals of Treatment

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

Question 9

What is 1st line for OA?

Answer 9

Non-pharm:)

Question 10

What are the non-pharm for OA? Including surgery

Answer 10

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)

Question 11

What are the possible pharm management for OA?

Answer 11

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

Question 12

What are the compartments of immune system involved in RA?

Answer 12

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

Question 13

What is RA Epidemiology, Etiology, Pathophysiology?

Answer 13

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)

Question 14

What are the S&S of RA?

Answer 14

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

Question 15

What are the lab findings of RA?

Answer 15

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

Question 16

How to diagnose RA?

Answer 16

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

Question 17

What are the goals of treatment for RA?

Answer 17

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

Question 18

List the pharm for RA. (generally)

Answer 18

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

Question 19

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

Answer 19

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

Question 20

What meds for low disease activity for RA?

Answer 20

Starting (low disease activity), consider this order:

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

Question 21

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?

Answer 21

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

Question 22

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

Answer 22

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

Question 23

What are the non-pharm for RA?

Answer 23

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

Question 24

What is the place in therapy of NSAIDs in RA?

Answer 24

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

• short term relief of pain & stiffness

Place in therapy:

• symptomatic relief of inflamm. & pain

Question 25

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

Answer 25

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

Question 26

What are the ADRs of corticosteroids?

Answer 26

**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

Question 27

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

Answer 27

- 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

Question 28

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

Answer 28

**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**

Question 29

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

Answer 29

(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)

Question 30

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

Answer 30

1) Sev renal impairment: avoid CrCL <30mL/min 2) Pregnancy Monitor: FBC (RA anaemia), LFTs (since can ↑transaminases), SCr(renal impairment)

Question 31

What is 1 ADR of sulfasalazine?

Answer 31

1) Sulfonamide allergies

Question 32

What is the MOA and place in therapy of hydroxychloroquine?

Answer 32

Hydroxychloroquine - ↓MHC II expression & antigen presentation - ↓TNF-alpha, IL-1 & cartilage resorption - antioxidant Place in therapy: Best tolerated, but least effective

Question 33

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

Answer 33

ADRs: 1) N&V 2) stomach pain 3) dizziness 4) hair loss 5) **ocular toxicity** CI: **1) preexisting retinopathy 2) caution in G5PD deficiency**

Question 34

What are the ADRs and CI of leflunomide?

Answer 34

ADRs: 1) alopecia 2) ↑transaminases 3) myelosuppression CI: 1) ALT >2x ULN 2) cholestyramine 3) Pregnancy

Question 35

What is an example of a tsDMARD?

Answer 35

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

Question 36

What is the MOA and place in therapy of tofacitinib?

Answer 36

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)

Question 37

What are the ADRs and CI of tofacitinib?

Answer 37

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)**

Question 38

What are some examples of bDMARDs?

Answer 38

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

Question 39

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

Answer 39

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

Question 40

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

Answer 40

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)

Question 41

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

Answer 41

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

Question 42

What is the MOA of tocilizumab?

Answer 42

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

Question 43

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

Answer 43

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

Question 44

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

Answer 44

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)