15.2 - Rheumatoid Arthritis & Drugs

Front 1

R.A.
What non-drug treatments?

Back 1

1. Education about disease has been shown to improve outcomes: a 6 week course called the "arthritis self management course" has been well evaluated (TG)
2. Exercise improves outcomes and doesnt sig worsen RA: mod intensity 30min 2-3 times per week
3. Mediterranean diet has been shown effective: may be merely a healthy lifestyle
4. Physical and occupational therapy review

Front 2

R.A.
Complications to manage?

Back 2

Increased osteoporosis

Sjorgan's syndrome: dry eyes, dry mouth, purple spots on face, bilateral parotid gland enlargement in menopausal women, often with R.A.

Increased risk of death due to Cardiovascular disease
1. discourage smoking
2. Manage other risk factors

Front 3

R.A.
It is important that the disease is diagnosed and managed ASAP to improve prognosis (much joint damage occurs early in the disease)
- S&S
- Diagnosis

Back 3

Joint tenderness WITH SWELLING occuring:
1. greater than 6 weeks
2. morning stiffness ?1/2hr
3. at least 3 joints
4. bilateral
5. rheumatoid factor positive
6. anti-CCP antibody positive (cyclic citrulinated peptide)
7. bony erosions evident on radiographs of hands or feet; but rarely evident in early disease

Front 4

What is the significance of RF and anti-CCP?

Back 4

Autoantibody. High levels are found in 80% RA patients, and almost 100% of patients with Sjorgan's syndrome. May also be elevated in other autoimmune diseases or in patients without disease. High levels of RhF is a poor prognostic indicator.

Anti-CCP antibodies have a similar selectivity but a higher sensitivity (90-95%) cf RhF test. May be a more accurate prognostic tool.

Front 5

What drugs should be given in the early stages (i.e. undifferentiated inflammatory condition) & to help symptoms

Back 5

1. NSAID
2. If contraindicated or severe disease, prednisolone 5-10mg d. This may delay diagnosis, however. These relatively low doses can be used to control disease also - use of >15mg/d should be avoided
3. FISH OIL: 3-4g of omega-3 FA per day or ~).2g/kg; easiest and cheapest if use ~15mL liquid fish oil on juice, follow with another shot of juice & food & lie on left side for 15min to prevent reflux; 6-8 weeks for response; also reduces CV risk and hypertension and renal risk with cyclosporin

Front 6

DMARDs
What is out there? - Name the immunosupressants

Back 6

Immunosuppressants
1. Azathioprine
2. Cyclosporine
3. Leflunomide
4. Methotrexate
5. RITUXIMAB

Front 7

DMARDS
Name the antirheumatics

Back 7

1. Gold Salts (auranofin, aurothiomalate)
2. Hydroxychloroquine
3. Penicillamine
4. Sulfasalazine

Front 8

DMARDs
Name the cytokine blockers

Back 8

1. Anakinra
2. Adalimumab
3. Etanercept
4. Infliximab

Front 9

RA.
Which DMARD is chosen for
mild disease?
mild-moderate disease?
The next step?
In the mean time?

Back 9

Mild: MTX, hydroxychloroquine, sulfasalazine
Mod: MTx
Next: combination MTX with sulfasalazine and hydroxychloroquine
Meanwhile: give pulse or intra-articular steroids while waiting for DMARD to kick in

Front 10

Fish oils
- cautions
- which oil to avoid?

Back 10

- Bleeding risk; monitor for signs of bleeding esp if anticoagulated
- Avoid cod liver oil: contains cholesterol and too much vitamin A and D

Front 11

Before starting a DMARD, do what? (3)

Back 11

Assess for potential
- active or latent infection, such as hepatitis or TB
- immunisation needs (esp for live vaccines)
- history or cancer

Front 12

Less than 20% will achieve remission with Methotrexate although most will find some symptom improvement. What doses are usually used? How long wait before increasing dose?

Back 12

Methotrexate:
*5-10mg WEEKLY, up to 25mg weekly (oral=IM=SC)
* Takes 1-2 months to see a result; wait about 2 months for improvement, inclusive of dosing adjustments

Front 13

What is something weird to consider if MTX is not working?

Back 13

If it has been well tolerated, consider trying IM or SC route, as there is some evidence that BA is reduced in some patients.

Front 14

How does MTX work?

Back 14

It is an antimetabolite, which inhibits DHFR (dihydrofolate reductase), which is responsible for the production of tetrahydrofolate, needed for DNA production. A "folate antagonist" as DHF is made from folate

Front 15

MTX dose forms, brands

Back 15

2.5mg.30, 10mg.50 tabs (Methoblastin)
2.5mg/ml.2mL x5 inj
25mg/ml.2mL x5 inj

Front 16

MTX
- Adverse effects

Back 16

1. GI adverse effects: n/v, diarrhoea, stomatitis
2. Myelosuppression
3. Rash, itch, hives, photosensitivity
4. Pulmonary toxicity
5. Hepatotoxicity

Front 17

MTX
- Management of
1. GI A/Es
2. Bone marrow toxicity

Back 17

1. Divide the dose into 3, and take at 0, 12 and 24hrs
AND
folic acid: e.g. 5mg once or twice weekly, or 1mg daily, not on same day as MTX
2. extra caution in the aged and in renal impairment

Front 18

MTX
- Pulmonary toxicity?

Back 18

Can develop rapidly and may be fatal. Often occurs as fever, dyspnoea, chest pain and dry, non-productive cough. Lesions such as pneumonitis and pulmonary fibrosis can occur at all doses at any time during treatment. Pulmonary toxicity may not be fully reversible; corticosteroids may relieve symptoms. Also consider the possibility of infection, eg P. jirovecii pneumonia.

Front 19

MTX
- hepatotoxicity?

Back 19

Increased transaminases are common and usually transient and asymptomatic. Chronic hepatotoxicity (including necrosis, fatty change, periportal fibrosis or cirrhosis) generally occurs with long term therapy and cumulative doses >1.5 g.

Front 20

MTX
- counselling

Back 20

1. once weekly with food, on the same day each week
2. Report signs of pulmonary toxicity
3. Phototoxicity: avoid excess sun exposure
4. LABEL 5: DIs
5. increased risk of infection, and importance of SOME vaccines (not live ones)

Front 21

MTX
- Contraindications (6)
(n.b. these are not CI in neoplastic disease)

Back 21

1. preg (cat D), bf
2. severe renal impairment or chronic liver disease
3. alcohol dependence
4. poor nutritional status
5. bone marrow suppression or immunosuppression
6. peptic ulcers or ulcerative colitis

Front 22

MTX
- Drug interactions to do with activity, adverse effects, absorption, clearance

Back 22

1. folate antagonists: trimethoprim (increase BM suppression), sulfamethoxazole (also decreases MTX clearance)
2. drugs affecting platelet funciton: SSRIs, valproate, NSAIDs
3. Hepatotoxic: leflunomide, acitretin
4. Calcium folinate: antidote,; folic acid
5. cholestyramine: reduces enterohepatic recycling
6. drugs increasing conc: doxycycline, tetracycline, cyclosporin, NSAIDs (unlikely if MTX <20mg/week; aspirin can be used), omeprazole and pantoprazole (use ranitidine), probenecid (esp if >20mg/week, avoid or reduce dose)
7. BM suppression

Front 23

MTX
- Monitoring required

Back 23

Baseline: CBC, RF, LF, hepatitis B and C serology (high risk patients), pulmonary function test and chest X-ray (annual)
Monthly for 6/12, then every 1-2/12 (or monthly with leflunomide): CBC, LFTs, RF

Front 24

As stated, <20% achieve remission with MTX alone. What combinations with MTX are used?

Back 24

1. MTX + hydroxychloroquine (HCQ) + sulfasalazine
2. MTX + leflunomide
3. MTX + cyclosporin
4. MTX + biological DMARDs

Front 25

Sulfasalazine
- MOA
- Indications
- CI / cautions
- RF / LF
- Preg / BF

Back 25

- MOA unknown; anti-inflammatory, immunosuppressant
- R.A., UC, Crohn's disease
- CI: sulphonamide allergy
- Caution: may exacerbate immunosuppression, BM suppression, blood dyscrasisa, asthma, severe allergy
- RF: may worsen, LF: caution, hepatically cleared
- BF: safe, Preg: safe, cat A, but give 5mg folic acid d

Front 26

Sulfasalazine
- dose forms, brands
- dosing
- dosing advice

Back 26

500mg.100 tab Salazopyrin
500mg.100 EC tab: Salazopyrin EN, Pyralin EN

2-3g d, starting at 500mg d and increasing weekly by 500mg

Take with food to reduce stomach upset

Front 27

Sulfasalazine (Salazopyrin)
- A/Es

Back 27

Common
- vomiting, diarrhoea
- fever
- rash
- reversible male infertility!
- haemolysis (not usually severe)
Infrequent
- photosensitivity
- yellow-orange skin/urine
- blood dyscrasias!

Front 28

Sulfasalazine
- Monitoring required

Back 28

CBC, LFTs, RF
- baseline
- 2-4/52 for 3/12
- then every 3/12

Front 29

Sulfasalazine
- how long does it take to work?

Back 29

1-3/12; trial for 4/12

Front 30

Hydroxychloroquine
- MOA
- Indications (3)

Back 30

- Anti-inflammatory, possibly immunosuppressive
- RA (mild)
- SLE
- Prophylaxis and treatment of malaria when chloroquine is not available

Front 31

Hydroxychloroquine
- dose forms, brands

Back 31

- 200mg.100 PLAQUENIL

Front 32

Plaquenil
- dosing

Back 32

* give >200mg as divided doses
R.A.: 400-600mg d for 1-3/12, maintain on 200-400mg d (Max 6mg/kg/d based on ideal body weight)

SLE: 400-800mg, maintain on 20-400mg d

Front 33

Plaquenil
- Contraindications
- Considerations
- RI / LI

Back 33

1. retinopathy, allergy to chloroquine or HCQ, pregnancy (cat D: neurological changes in fetus), children <6
2. may worsen blood disorders;
increased suseptability to severe skin reactions with psoriasis

- OK
- contact info centre re BF, in case you were wondering

Front 34

Plaquenil
- adverse effects

Back 34

common
- nausea, diarrhoea
- rash
- alopecia
infrequent
- tinnitus, vertigo, deafness
rare
- retinal toxicity
- SJS

Front 35

Plaquenil
- monitoring

Back 35

1. Monitor just visual: if over 40 or hx of eye disease, an opthalmic exam is recommended; reassess annually. If taking >6mg/kg/d, RI, LI, over 70, >800g cumulative, monitor every 3-6 months
*stop drug if any problems occur

Front 36

Plaquenil
- counselling
- time to benefit

Back 36

1. Tell your doctor promptly if you have any difficulty with your sight, particularly seeing entire words or faces, intolerance of bright light, reduced night vision.
2. Sunglasses: may reduce chance of eye problems
3. Take with food

Benefit: 2-6 months!!

Front 37

Place of HCQ in treatment of R.A.?

Back 37

Less effective but better tolerated than other agents. Reasonable first choice for mild R.A.

Front 38

Penicillamine
- I never see this drug, so just tell me briefly:
1. brand, dose form, dose
2. time to work
3. toxicities
4. admin advice

Back 38

1. D-Penamine (125mg, 250mg.100 tabs)
2. 3-6 months
3. Blood dyscrasias, renal failure, neurological disturbances (Stop use of drug if these occur)

Front 39

Leflunomide can also be used in combination with MTX
- dose forms, brands
- dosing

Back 39

- Arava, Arabloc: 20mg.30, 10mg.30 tabs
- Starter pack: 100mg.3, 20mg.30 (Arava)

100mg d for 3 days. Then 20mg d. 10mg d if 20mg is poorly tolerated

Front 40

Leflunomide (Arabloc)
- MOA

Back 40

- Inhibits pyrimidine synthesis in rapidly dividing cells; Uricosuric, immunosuppressive, antiproliferative

Front 41

Arava
- Indications

Back 41

R.A.
Psoriatic arthritis

Front 42

Arabloc
- CI (6)
- Cautions (2, from CI)
- RI?

Back 42

1. allergy
2. Pregnancy, Cat X, teratogenic in animals; Also do not breastfeed
3. Severe infection
4. Hepatic impairment
5. Hx of SJS, TEN
6. Severe immunosuppression or BM depression

Other hepatotoxic drugs
Women should use contraception for 2 YEARS after stopping (half life of 2-4 weeks)

Fine

Front 43

Arava
- A/Es

Back 43

Common
- GI pain, n/v, diarrhoea
- Kidney stones
- Hypertension
- Pneumonia - rarely interstitial lung disease
- Raised LFTs: usually resolves at beginning or treatment; rare cases of fatal liver injury within first 6months
- Hair loss, mild allergies, irch , eczema,
- Dizziness, headache

Front 44

Arabloc
- Counselling (3)

Back 44

Immediately report
- blood dyscrasias: mouth ulcers, sore throat, fever, tierdness, paleness, bleeding
- lung problems: cough, dyspnoea
- liver problems: abdominal pain, jaundice

DO NOT DRINK ALCOHOL - increases risk of liver damage

AVOID live vaccines; check with doctor

Front 45

Arava
- Monitoring
- Time to onset of effect

Back 45

- Start after about 4 weeks, stabilise after 4-6 months
- Baseline: BP, CBC, RF, LF, hep B and C serology if high risk
- CBC 2/52 for 6/12, then every 2/12
- LFTs, RF 1/12 for 6/12, then every 2/12 (monthly with MTX combo)

Front 46

Arabloc
- what happens if LFTs do raise, given leflunomides long half life of 2-4 weeks?

Back 46

if LFTs >3x normal:
(A) give 8g Questran tds for 11 days; or
(B) give 50g activated charcoal qid for 11 days
** duration varies

Front 47

What sort of evidence is there for the leflunomide/MTX combo?

Back 47

Evidence of greater efficacy from one study.
There is an increased risk of blood dyscrasias (leucopenia), pneumonitis, and hepatic toxicity

Front 48

MTX is also combined with cyclosporin
- dosing, dose forms, brands?
- PBS

Back 48

10mg.60, 25mg.30, 50mg.30, 100mg.30 (Neoral, Cicloral)
100mg/mL.50mL (Neoral)

PBS-A for severe R.A
PBS-S100 for transplant, etc

1.5mg/kg bd for 6-12/52
Increase by 0.25-0.5mg/dose increments to a max of 2mg/kg bd
Adjust every 1-2 months

Front 49

Neoral
- CIs (4)
- Cautions (2 drugs)

Back 49

- Renal impairment (any)
- Uncontrolled HTN
- Malignancy
- Significant infection

1. Nephrotoxic drugs
2. Hyperkalaemic drugs

Front 50

Neoral
- BF / Preg
- RI / LF

Back 50

- Preg Cat.C (ltd data)
- BF: excreted in milk (ltd data)
- RI: CI
LF: ok

Front 51

Cicloral
- A/Es

Back 51

Common:
gingival hyperplasia, hirsutism, hypertension, increased BGLs, hypercholesterol, nephrotoxicity (dose related), neurotoxicity (seizures)

Front 52

Cicloral
- Monitoring required

Back 52

- Baseline: CBC, BP, RF, LFTs
- RF, BP every 2/12 until stable dose, then every 3/12
- Periodic LFTs, CBC, K

Front 53

Neoral
- time to benefit

Back 53

- 2-4 months; trial for 6 months

Front 54

Neoral
- what do you do if CrCl raises?

Back 54

If >30% rise in SeCr on >1 occassion, reduce dose
If >50%, halve dose
Stop treatment if Cr does not return to baseline in 1/12

Front 55

Neoral
- DIs (just in general terms)

Back 55

1. BGLs
2. Nephrotoxic
3. Potassium retention
4. Neurotoxic (seizures)
5. CYP3A4 metabolites, p-gp substrates

Front 56

Azathioprine has also been used for R.A.
- dose forms, dose
- time to effect
- monitoring

Back 56

- 25mg.100, 50mg.100 tablets (Azapin, Azahexal, Imuran, Thioprine, Azamun)
- 1mg-2.5mg/kg/d; maintainence 50-150mg d in d.d.
- RF, LFTs, CBC every 1-2/52 and then every 1-3/12
- Stop if neutropenia or thrombocytopenia occurs
- may take 2-3 months; trial for 6 months max

Front 57

In general, all patients given DMARDs should be asked to what?

Back 57

Report unusual symptoms related to infection: fever, cough

Front 58

Gold salts
- name them and their dose forms
- indications
- CIs

Back 58

Auranofin: 3mg.60 tablets
Aurothiomalate: Myocristine 10mg, 20mg and 30mg injections by deep IM injection
- Hx of BM suppression or blood disorders, severe or chronic skin conditions (hives, eczema), SLE, RI, HI

Front 59

Gold salts
- Comparative onset of effect and efficacy
- Toxicities

Back 59

- About 3-6 months for both
- Auranofin is less effective and less toxic
- Diarrhoea with auranofin, vasomotor reactions with IM form
- Common: blood dyscrasias, nephrotoxicity, elevated LFTs, dyspepsia, stomatitis, n/v, taste disturbance

Front 60

Cytokine blockers in R.A.
- which ones?
- MOA?

Back 60

Adalimumab (Humira) - monoclonal AB binds TNFa
Anakinra (Kineret) - human IL-1 receptor antagonist
Etanercept (Enbrel) - bind TNFa
Infliximab (Remicade) - chimeric monoclonal AB to TNFa

Front 61

What are the major A/Es of the cytokine blockers

Back 61

All: increased risk of infection
Adalimumab: worsening HF
Anakinra: neutropenia
Etanercept: allergy, worsening HF
Infliximab: allergy, infusion reactions, worsening HF

Front 62

What is the onset of effect of cytokine blockers

Back 62

Adalimumab and anakinra in 2 weeks, with max in 3-4 months
Etanercept, infliximab: start within 12 weeks

Front 63

What monitoring is required for cytokine blockers?

Back 63

FBE at baseline.
LFT at baseline for infliximab

Front 64

How are the cytokine blockers administered?

Back 64

all SC except for infliximab (IV infusion every 8 weeks)
Etanercept is 1-2x weekly
Adalimumab is weekly
Anakinra is daily

Front 65

Refer to table 15.2 on p594 of AMH

Back 65

OK