IC16 OA & RA Flashcards
What are the red flags for OA?
Red Flags:
- Infection
- Trauma / Fracture
- Malignancy
What is OA in general?
What are the RF of OA?
OA:
- Degenerative disease with inflammation of bone and joint cartilages, ↑with age
- Progressive and irreversible loss of cartilage
RF:
- Genetics
- Anatomic factors → bow legged/knocked knee
- Joint injury from sports / surgery / overuse
- Obesity → ↑load on your weight bearing joints.
- Age → ↑thinning, ↓hydration, ↑brittleness of ECM
What is the patho of OA?
What are the compensatory actions in OA?
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:
- Cartilage degradation – cartilage damage → chondrocytes undergo phenotypic switch as they proliferate → produce improper mineralised collagen → weakening & degradation of collagen matrix in synovium
- 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
- 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
What are the S&S of OA?
What are the pain characteristics?
S&S & Diagnosis of OA
- Inflammation
a. Pain
b. Swelling
c. Red and warm - Morning stiffness <30mins → stiffness reduce when moving but recurs when resting
- Limited joint movement
- Functional limitation/ instability ↑risk of falls
- Asymmetrical polyarthritis → injure one side first
- Possible location (weight-bearing joints) → fingers, knee, hip, spine
- Crepitus on motion (noisy)
- Bone enlargement
- Associated with anxiety, depression, sleep disturbances
Pain characteristics:
- slow progression over years
- Worse with joint use, pain relieved by rest
- Usually worse in late afternoon / early evening (night pain possible in severe disease)
- Knees → worse going down the stairs / slope compared to going up
- Most severe over joint line
What are the diff stages of OA?
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
What are the radiographic findings of OA?
Radiographic Findings (advanced years):
- Joint space narrowing
- Marginal osteophytes
- Subchondral sclerosis
- Abnormal joint alignment
How to diagnose OA?
Diagnosis:
-
History taking, Physical symptoms, >45 y/o
o no need imaging/labs to confirm diagnosis, unless younger pts, unusual sx/red flags
What are the goals of treatment for OA?
Goals of Treatment
- relieve pain
- improve range of motion & joint function
- improve QOL
What is 1st line for OA?
Non-pharm:)
What are the non-pharm for OA? Including surgery
Non-Pharmacological Treatment (1st line) + Surgical Interventions
- 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 - Lose weight
- Information & support e.g. Knee Brace
Total joint arthroplasty → postoperative rehab is very impt (PT)
What are the possible pharm management for OA?
Appropriate Selection of Pharmacotherapy + Counselling Points
Drug treatment for OA (primarily symptomatic)
- 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) - 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 - (NOT GOOD, NOT recommended, just supplements)
a. Chondroitin sulphate
b. Glucosamine
What are the compartments of immune system involved in RA?
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
What is RA Epidemiology, Etiology, Pathophysiology?
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)
What are the S&S of RA?
S&S:
- Inflammation → Pain, swelling, red, warm
- Early morning Joint stiffness >30mins
- Pain worse in the morning
- Symmetrical (may start with one side first but eventually affect both)
- Polyarthritis
- Location:
a. Small joints: lower joints of fingers, wrist
b. Large joints: elbows, shoulders, hips, knees, ankles - Systemic Symptoms (esp. >60y/o): generalised aching, stiffness, fatigue, fever, weight loss, depression
- Deformities e.g. swan neck → ↓physical function & ↓ADL
What are the lab findings of RA?
Lab Findings:
- Autoantibodies
a. Rheumatoid Factor (RF) – +ve
b. Anti-citrullinated peptides antibodies (Anti-CCP) – +ve - Inflammation
a. ↑ Erythrocytes sedimentation rate (ESR)
b. ↑CRP - FBC
a. ↑platelets
b. ↑WBC
c. ↓hematocrit - Radiologic:
a. Narrowing of joint space
b. Erosion of joint
c. Hypertrophic synovial tissue
How to diagnose RA?
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
What are the goals of treatment for RA?
Goals of treatment
- Remission & ↓disease activity at least 6 months
- Return to full function
- Maintain remission
- Boolean 2.0 criteria
- SDAI/CDAI/DAS 28
List the pharm for RA. (generally)
Pharmacotherapy + Counselling points
- Corticosteroids (short term)
- DMARDS
a. csDMARDs
b. bDMARDS
c. tsDMARDS
Extra: NSAIDs NOT really useful since not immunosuppressive, but still can give mainly as symptomatic
How to start meds for mod-sev RA? What is the dose? What is the TCU?
Algorithm:
Starting (Mod-Sev disease activity):
-
(1st line) MTX 7.5mg once weekly
→ increase by 2.5-5mg q4-12wks
→ target: 15mg/wk by 6 weeks
→ max: 25mg/day - + folic acid 5mg once weekly
-
+ 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 - (2nd line) Sulfasalazine /leflunomide if MTX is CI
- Monitor every 3 months
What meds for low disease activity for RA?
Starting (low disease activity), consider this order:
- Hydroxychloroquine (better tolerated than MTX)
- Sulfasalazine
- MTX
- Leflunomide
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?
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:
-
Pre-treatment screening
a. TB latent/active
b. Hepatitis B & C -
Vaccination
a. Pneumococcal, influenza, hepatitis B, varicella zoster -
Lab screening/monitoring
a. FBC, LFTs, lipid panel, SCr
If at target at 6 months, what to do next?
If at target at 6 months:
- 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
What are the non-pharm for RA?
Non-pharmacological
- Exercise
a. Swimming
b. AVOID high intensity weight bearing exercises / activities - Splint/braces for support
- Nutritional diet / weight management
- CBT
What is the place in therapy of NSAIDs in RA?
NSAIDs + PPI (to ↓GIT ADRs)
e.g. celecoxib
- short term relief of pain & stiffness
Place in therapy:
- symptomatic relief of inflamm. & pain
What is the MOA and place in therapy of corticosteroids in RA?
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
What are the ADRs of corticosteroids?
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
What is the MOA and place in therapy of MTX in RA?
- 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
What are the ADRs of MTX? How can you reduce the ADRs?
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
Why is folinate or folinic acid better than folic acid as rescue therapy for MTX?
(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)
What are the CI of MTX?
What needs to be monitored when taking MTX?
1) Sev renal impairment: avoid
CrCL <30mL/min
2) Pregnancy
Monitor: FBC (RA anaemia), LFTs (since can ↑transaminases), SCr(renal impairment)
What is 1 ADR of sulfasalazine?
1) Sulfonamide allergies
What is the MOA and place in therapy of hydroxychloroquine?
Hydroxychloroquine
- ↓MHC II expression & antigen presentation
- ↓TNF-alpha, IL-1 & cartilage resorption
- antioxidant
Place in therapy:
Best tolerated, but least effective
What are the ADRs of hydroxychloroquine?
What are the CI?
ADRs:
1) N&V
2) stomach pain
3) dizziness
4) hair loss
5) ocular toxicity
CI:
1) preexisting retinopathy
2) caution in G5PD deficiency
What are the ADRs and CI of leflunomide?
ADRs:
1) alopecia
2) ↑transaminases
3) myelosuppression
CI:
1) ALT >2x ULN
2) cholestyramine
3) Pregnancy
What is an example of a tsDMARD?
Targeted synthetic DMARDS (tsDMARDs)
- Cytokine JAK-STAT pathway drugs
PO Tofacitinib
What is the MOA and place in therapy of tofacitinib?
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)
What are the ADRs and CI of tofacitinib?
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)
What are some examples of bDMARDs?
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
- anti-TNF agents
- IL-1R antagonist
- IL-6R mab
What is the MOA of anti-TNF agents andplace in therapy?
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
What are the ADRs and CI of anti-TNF agents?
What needs to be screened before taking anti-TNF agents?
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)
What is the MOA and place in therapy of anakinra for RA?
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
What is the MOA of tocilizumab?
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
What are the ADRs of tocilizumab?
What are the DDI?
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
What are the safety concerns with bDMARDs/tsDMARDs? (11)
Safety concerns with bDMARDs/tsDMARDs:
- Injection site reactions
- Myelosuppression
- Infections → pre-DMARDs screening + vaccinations
- Malignancies
- Autoimmune
- CVD e.g. HF (avoid anti-TNF inhibitors)
- Hepatic effects
- Metabolic effects
- Pulmonary disease
- GI perforation (esp. w JAK inhibitors, IL-6 inhibitor)
- Thrombosis (esp. w JAK inhibitors, IL-6 inhibitor)
