Osteoarthritis and Rheumatoid Arthritis

Question 1

Name the csDMARDs

Answer 1

MTX, sulfasalazine, leflunomide, hydroxychloroquine, ciclosporine

Question 2

Name the tsDMARD

Answer 2

Tofacitinib

Question 3

Name the 5 classes of bDMARDs and their drugs

Answer 3

anti-TNF: infliximab, adalimumab, golimumab, etanecept
IL-1R antag: anakinra
Anti-IL-6:L tocilizumab
Anti-CTLA4: abatacept
Anti CD20: rituximab

Question 4

What type of drug is MTX (csDMARD) and how can it be administered?

Answer 4

Folic acid analogue
PO (variable absorption), SQ or IM

Question 5

Describe MTX’s MOA

Answer 5

• inhibits ATIC and AICAR = increasing adenosine levels,
• inhibits dDHFR = decreasing purine synthesis
• results in anti-proliferative effects on T cells + inhibition of macrophage functions + decrease in in pro-inflammatory cytokines, adhesion molecules, chemotaxis and phagocytosis

Question 6

What are SE (and rare and serious ones) of MTX? (4+3)

Answer 6

SE: n&v, mouth and GI ulcers, hair thinning
Rare and serious: leukopenia, hepatic fibrosis and pneumonitis

Question 7

How can MTX side effects be kept to a minimum

Answer 7

administration of concomitant folic acid or folinic acid given 12-24h after MTX to decrease its toxicity levels

Question 8

Why is folinic acid more effective than folic acid

Answer 8

It is rapidly converted to N5 and N10-methylene-FH4, bypassing DHFR activity, making it more efficient at rescuing methotrexate toxicity

Question 9

What are 3 positive effects of sulfasalazine (csDMARD)

Answer 9

1. decreased IgA and IgM rheumatoid factors
2. suppression of macrophages, T and B cells
3. decrease in inflammatory cytokines (eg. IL-1β, TNF, IL-6)

Question 10

What are SE of sulfasalazine (csDMARD)

Answer 10

n&v, HA, rash, hemolytic anemia, neutropenia, reversible infertility in men

Question 11

What are 4 positive effects of leflunomide (csDMARD)

Answer 11

1. inhibits dihydroorotate dehydrogenase
2. decreases pyrimidine synthesis and growth arrest at G1 phase
3. inhibits T cell proliferation and B cell autoantibody production
4. inhibits NF-κB activation pro-inflammation pathway

Question 12

What is the consideration for past leflunomide use in pregnant patients?

Answer 12

Very long half life (years after dosing) so cholestyramine wash-out may be administered for example before pregnancy

Question 13

What are SE of leflunomide?

Answer 13

diarrhea, liver enzyme elevation, alopecia, weight gain, teratogenic

Question 14

What are 3 positive effects of hydroxychloroquine (csDMARD)?

Answer 14

1. reduces MHC class II expression and antigen-presentation
2. reduces TNF-α and IL-1 and cartilage resorption
3. antioxidant activity

Question 15

What are SE of hydroxychloroquine?

Answer 15

n&v, stomach pain, dizziness, hair loss, ocular toxicity

Question 16

How should JAK inhibitors like tofacitinib be used?

Answer 16

may not be the most useful alone, but have shown great efficacy when used in combination eg. combining tofacitinib with MTX or another csDMARD

monotherapy in patients with intolerance to MTX and is effective in MTX- or multiple bDMARD-refractory RA

tsDMARDs should NOT be combined with bDMARDs

Question 17

What is the MOA for tofacitinib (tsDMARD)?

Answer 17

Janus kinase (JAK) pathway inhibitor, therefore blocking cytokine production

Question 18

What are SE of tofacinib

Answer 18

cytopenia, immunosuppression (resulting in opportunistic infections), anemia, hyperlipidemia

Question 19

Arrange anti-TNF bDMARDs according to immunogenecity

Answer 19

The more humanised the biologic, the less immunogenic it is (infliximab > adalimumab > golimumab > etanercept)

Question 20

What are anti-TNF bDMARD half lives like?

Answer 20

Monoclonal antibodies have half-lives of 1-2 weeks while etanercept has a half-life of about 70 hours

Question 21

How does anakinra (IL-1R antag) compare to anti-TNF bDMARDs?

Answer 21

less effective than anti-TNF bDMARDs

Question 22

What are SE of anakinra (IL-1R antagnoist)

Answer 22

infections, injection site reactions

Question 23

What are SE of tocilizumab (IL-6R antagonist)

Answer 23

Infections, skin eruptions, stomatitis, fever, neutropenia, increase in ALT/AST, hyperlipidemia, interacts with CYP450 3A4, 1A2 or 2C9 substrates

Question 24

What are SE of abatacept (anti-CTLA4Ig)

Answer 24

respiratory infection in COPD, increased incidence of lymphoma

Question 25

What are SE of rituximab (anti-CD20)

Answer 25

rash in first dose, respiratory infection in COPD

Question 26

What are contraindications to bDMARD therapy

Answer 26

Live vaccination Hepatitis B and C

Question 27

What are the risk factors for OA?

Answer 27

Genetic predisposition Anatomic factors (bow-legged, or knocked-knee) Joint injury (from sports or surgery) Obesity (greater weight on load-bearing joints, metabolic OA) Aging (changes in ECM) Gender Occupation

Question 28

Explain the pathophysiology of OA

Answer 28

articular cartilage damage → chondrocyte activity increases Abberant chondrocytes → more breakdown subchondral bone releases vasoactive peptides and MMP → increases collagen breakdown Both of these factors lead to cartilage loss and chondrocyte apoptosis → forms fibrillations in cartilage and cartillage “shards” Cartillage shards cause inflammatory and pathologic changes in joint capsule and the synovium, mediated by TNF-α, IL-1, PGE2 and NO → effusion and synovial thickening Subchondral bones rub against each other → more brittle and decreased weight bearing ability → development of sclerosis, microfractures and osteophytes

Question 29

What are osteophytes

Answer 29

sideway extention from bones as the joint is not there for protection compensatory structures to stabilise osteoarthritic joints

Question 30

What are the 3 main occurrences in OA pathophysiology

Answer 30

1. Cartilage degradation 2. Bone remodelling and osteophyte formation 3. Synovial inflammation

Question 31

Describe the clinical presentation of OA

Answer 31

pain, swelling, erythema and warmth (from inflammation), morning stiffness < 30 mins limited joint movement (loss or RoM) functional limitation instability asymmetrical polyarthritis (typically on weight bearing joints)

Question 32

Describe pain onset and when the pain worsens in OA

Answer 32

onset is insidious (slow progression over the years) and is worse with joint use and relieved by rest

Question 33

How is OA diagnosed?

Answer 33

- Clinical diagnosis can be made without imaging in: - ≥ 45 years old, activity-related joint pain (in one or a few joints), morning stiffness ≤ 30 mins

Question 34

When should additional testing be done for OA?

Answer 34

younger patients presence of atypical signs and symptoms that suggest other diagnoses: hx of recent trauma, rapidly worsening sx or deformity or concerns for infection or malignancy

Question 35

What are goals of treatment in OA

Answer 35

pain relief (and of inflammation if any) improving or preserving RoM ,joint fx and QoL

Question 36

What are NPM for OA? (3)

Answer 36

1. Exercise (mainstay) 2. Weight management 3. Information and support (empower)

Question 37

What are pharmacological treatments for OA?

Answer 37

1. TOP NSAIDs 2. PO NSAIDs or coxibs 3. PO paracetamol/tramadol 4. IA glucocorticoid

Question 38

What are risk factors for GI bleeds or ulcers? (4) HANG (if 3 or 4 RFs present, use coxib instead)

Answer 38

1. history of ulcers 2. >65 yo 3. NSAIDs (high dose or chronic) 4. glucocorticoids, antiplatelet or anticoagulant use

Question 39

What are risk factors for NSAID-induced AKI

Answer 39

CKD, volume depletion (due to HF, nephrotic syndrome, cirrhosis), severe hypercalcemia, drugs like aminoglycosides, amphotericin B, radiocontrast material, diuretics, ACEi, ARBs, and age > 65 yo

Question 40

What eGFR value should NSAIDs be avoided in

Answer 40

eGFR < 15

Question 41

Describe the pathophysiology of RA

Answer 41

Genetic predisposition and immunologic triggers cause citrullinated antigens to be picked up by APCs → trigger T-cell mediated immune response (inflammatory response) Inflammation → angiogenesis in the synovium and synovial cell proliferation → recruit inflammatory cells → production of inflammatory cytokines (IL-17, TNF, IL-1 and IL-6) → signal via JAK pathway → destruction of articular cartilage and underlying bone Synovial cell proliferation → pannus invasion → destruction of articular cartilage and underlying bone

Question 42

Describe the clinical presentation of RA

Answer 42

pain, swelling, erythema and warmth (inflammation MUCH worse than OA) morning stiffness > 30 mins (pts usually take a long time to get out of bed) symmetrical polyarthritis (usually starts w small joints of hands and legs)

Question 43

How should an RA diagnosis be made (based on sx) (4/6)

Answer 43

- Diagnosis should come with 4 of the following 6: - Early morning stiffness ≥ 1h x ≥ 6 weeks - Swelling of ≥ 3 joints x ≥ 6 weeks - Swelling of wrist/MCP/PIP joints x ≥ 6 weeks - Rheumatoid nodules - RF +ve and/or anti-CCP tests - Radiographic changes

Question 44

What are relevant lab findings for RA diagnosis?

Answer 44

- Autoantibodies → RF +ve, anti-CCP assays +ve (both of these tests being negative does NOT exclude an RA diagnosis as they may show up as negative in early disease stages) - Acute phase response → ESR increase, CRP increase - FBC → decreased hematocrit, increased platelets, increased WBC - Radiologic X-ray or MRI → narrowing of joint space, erosion (around joint margin), hypertrophic synovial tissue

Question 45

What are goals of treatment for RA?

Answer 45

remission or low disease activity for at least 6 months (achieve maximal function improvement, stop disease progression, prevent joint damage, control pain)

Question 46

What is considered remission according to the Boolean 2.0 criteria? (4)

Answer 46

- Tender joint count (TJC) ≤ 1 - Swollen joint count (SJC) ≤ 1 - CRP ≤ 1mg/dL - Patient global assessment (PGA) using 10ccm VAS ≤ 2cm

Question 47

DMARDs are first line therapy for RA, explain how they help with the disease.

Answer 47

DMARDs alter disease progression and help to slow/prevent radiographic joint damage, improve physical function and lower ESR/CRP

Question 48

How and when should first line treatment for RA (csDMARDs) be started?

Answer 48

- DMARDs should be started as soon as the diagnosis is made (MTX should be part of first treatment strategy) (slow onset of action between weeks and months) - Sulfasalazine, leflunomide or hydroxychloroquine should be considered if MTX is contraindicated or not tolerated

Question 49

Which drugs are preferred for low and mod-high disease activity in RA patients

Answer 49

low: hydroxychloroquine (better tolerated) mod-high: MTX

Question 50

How should MTX be dosed?

Answer 50

MTX should be started 7.5mg OW increased by 2.5 to 5mg per week, up to a target dose of 15mg a week within 4-6 weeks of initiation (fast to control disease as soon as possible)

Question 51

What dose of folic acid should MTX be given with?

Answer 51

5mg OW

Question 52

How should other csDMARDs be initiated?

Answer 52

- Sulfasalazine: initiate w 500 mg OD or BD, increase by 500 mg/week to 1g BD (maintenance), max 3000 mg/day - Hydroxychloroquine: 200 – 400 mg in one or two divided doses (max 5 mg/kg/day) - Leflunomide: 100 mg/day x 3 days (optional loading dose), 20 mg/day (maintenance dose)

Question 52

How should glucocorticoids be used in RA?

Answer 52

Short-term low-dose glucocorticoids can be dded when starting or changing DMARDs for moderate to high RA disease activity (≤ 7.5mg/day prednisolone up to 3 months) Discontinue if bDMARDs or tsDMARDs are started

Question 53

What is triple therapy in csDMARDs?

Answer 53

MTX hydroxychloroquine sulfasalazine

Question 54

If csDMARDs do not work, which of the other DMARDs are preferred?

Answer 54

bDMARDs are preferred (tsDMARD carries a higher risk for major adverse cardiovascular events (MACEs) and malignancy, compared to TNFα inhibitors for patients with risk factors)

Question 55

What 3 things should be screened for and checked before initiating bDMARDs or tsDMARDs

Answer 55

1. **Pre-treatment screening** → for TB (start after completing anti-TB treatment), and for hepatitis B and C (avoid if untreated disease is detected) 2. **Vaccination required before initiation** → pneumococcal, influenza, hepatitis B, varicella zoster 3. **Laboratory screening and monitoring** → CBC with differential white count and platelet count, LFT (ALT, AST, bilirubin, ALP), lipid panel and SCr