Rheumatoid arthritis

Question 1

Rheumatoid Arthritis is a common systemic autoimmune disorder affecting 1% of UK population. who is most likely to be affected by this disease?

Answer 1

1) Pre-menopause, women 3 times more like to be affected than men (1:1 after menopause)
2) Can present at any age but peak prevalence between 30-50 years
3) Gradual onset of symptoms most common

Question 2

the cause of Rheumatoid Arthritis is unknown but what is the proposed mechanism?

Answer 2

1) Non-specific inflammation
2) Synovial T cell activation
3) B cell activation, auto-antigen antibodies and rheumatoid factors
4) Production of pro-inflammatory cytokines (IL-1 and TNF-alpha) & chemokines
- Chronic inflammation is maintained by rheumatoid factors and continuous stimulation of macrophages by pro-inflammatory cytokines and chemokines

Question 3

explain the Pathology of RA

Answer 3

1) Characterised by chronic synovitis (inflammation of synovial lining of joints, tendons sheaths or bursae)
2) New synovial blood vessels, induced by angiogenic cytokines, and endothelial cell activation accelerates leucocyte extravasion into the synovium
3) Synovium proliferates, growing out over cartilage surface, and forms a pannus.
4) Pannus destroys articular cartilage and subchondral bone, producing bony erosions
5) Subcutaneous rheumatoid nodules form

Question 4

summarise the symptoms and clinical features of RA

Answer 4

1) Insidious onset of pain
2) Early-morning stiffness (lasting more than 30 minutes)
3) Swelling in small joints of hands and feet
4) Joint capsules are weakened leading to instability, subluxation (partial dislocation) and deformity
5) Multiple joints may become involved: Wrists, elbows, shoulders, cervical spine, knees, ankles, feet
6) Joint effusions and muscle wasting
7) Periarticular features- Bursitis

Question 5

How is RA diagnosed?

Answer 5

1) Blood count: Anaemia (normochromic and normocytic)
- Thrombocytosis (over-production of platelets)
- Raised ESR and CRP
2) Serum autoantibodies: Rheumatoid factor present in 70-80% RA cases (but not only in RA)
- Antinuclear factor present in 30% RA cases
- Anti-citrulline-containing peptide (CCP) in 50-60% early RA cases and in erosive disease
3) Radiology (erosion at joint margins)
4) Sterile synovial fluid with high neutrophil count

Question 6

There is no cure available for RA so therapeutic goals are remission of symptoms, return to full function and maintenance of remission. explain how RA is managed pharmacologically.

Answer 6

There are three general classes of drugs commonly used in the treatment of rheumatoid arthritis:

1) NSAIDS to relieve pain and stiffness
2) Disease-modifying anti-rheumatic drugs (DMARDs)
3) Corticosteroids
- Methotrexate is normally the first medicine given for rheumatoid arthritis, often alongside another DMARD and a short-course of corticosteroids to relieve any pain

Question 7

List some DMARDs used in RA

Answer 7

1) Penicillamine
2) Gold salts
3) Antimalarials (chloroquine, hydrochloroquine)
4) Sulfasalazine
5) Methotrexate
6) Cytokine inhibitors (adalimumab, anakinra, etanercept, infliximab)

Question 8

Explain why NSAIDs/COX 2 inhibitors are used in the treatment of RA and what is the typical dose prescribed

Answer 8

1) Relieve pain and stiffness but do not slow disease progression of RA
2) Pain relief is rapid (full effect within 1 week) but anti-inflammatory effect of NSAID may take up to 3 weeks
3) Start with low dose of least gastric toxic NSAID (i.e. ibuprofen 200-400mg tbs) then change if necessary
4) Slow-release preparation at night (i.e. slow release) can help early morning symptoms
5) Gastric protection is recommended (PPIs etc)

Question 9

Explain why Corticosteroids are used in the treatment of RA and what is the typical prescribed dose

Answer 9

1) RA requires long-term treatment therefore benefit-to-risk ratio for use of corticosteroids for RA is low!
2) Might be used for specific indications:
- Disease flares, pulse with high dose corticosteroids until other drugs take effect
- If patient shows no response to other drug therapies
- Intra-articular injections to relieve symptoms in 1-2 joints

Question 10

DMARDs are used in the treatment of RA. when is therapy normally initiated and what should be given in combination with?

Answer 10

1) Recommended for use in combination (with methotrexate) but also used individually if combination cannot be tolerated
2) Started early in disease (3-6 months). Can take several months to show therapeutic effects
- Require clinical monitoring to ensure that serious adverse effects do not occur

Question 11

Sulfasalazine is the first choice DMARD monotherapy for RA in the UK. what is its MOA and how effective is it?

Answer 11

1) Exact mechanism of action in treatment of RA is not known . immunosuppressant actions possibly by scavenging toxic oxygen metabolites produced by neutrophils
2) Effective in 70% of patients after 1 year

Question 12

what dose of Sulfasalazine should be given in RA and what are the common side effects?

Answer 12

1) Initially 500mg daily by mouth, increased by 500mg at intervals of 1 week to max of 2-3g daily in divided doses
2) Common side effects are GI disturbances, malaise and headache, rashes, blood disorders (in first 3-6 months)

Question 13

1) what needs to be monitored in patients who have started taking sulfasalazine?
2) what supplement is normally given alongside sulfasalazine?

Answer 13

1) Blood counts and liver function tests required initially and then monthly for first 3-6 months
2) Folic acid supplements may be required to counteract impaired folic acid absorption

Question 14

Antimalarials are used in RA. outline the MOA of antimalarials and explain the disadvantages of taking this drug

Answer 14

1) antimalarials in arthritis is poorly understood: Direct anti-inflammatory effect by stabilising lysosomes, inhibiting the release of lysosomal enzymes and, hence, inhibiting their inflammatory effects
2) Antimalarials are better tolerated than gold or penicillamine but may cause ocular toxicity/progressive loss of vision on long term treatment
3) Hydroxychloroquine is used to treat moderate active RA
- Chloroquine should only be used if all other drugs have failed and is less commonly used

Question 15

summarise the recommendations for monitoring for hydroxychloroquine use

Answer 15

1) Pre-treatment assess renal and liver function, get optometrist assessment if present, record visual acuity.
- If no abnormality, initiate treatment
2) During treatment, assess visual symptoms and acuity annually, refer to ophalmologist if changes/blurring of vision (discontinue treatment)

Question 16

Hydroxychloroquine is an antimalarial used in RA. what dose of this drug is taken and how long will it take for it to work?

Answer 16

1) Well tolerated with effect observed within 1-3 months

2) 400mg daily in divided doses, then 200-400mg daily for maintenance

Question 17

What are the side effects of hydroxychloroquine?

Answer 17

1) Common side effects: GI disturbance, headache, skin reactions. less common ocular toxicity
2) VERY TOXIC in over-dosage: maximum dose of 6.5mg/kg daily
- Risk of ocular toxicity increases with abnormal liver or kidney function, after cumulative dose of 800g, or in patients >70 years

Question 18

what is the MOA of Methotrexate?

Answer 18

1) A “folic acid antagonist”, inhibits dihydrofolate reductase, reducing availability of tetrahydrofolic acid, which suppresses cell division in immune cells, suppressing cell-mediated immunity. (Inhibits DNA synthesis)

Question 19

why do RA patients stop treatment with methotrexate after a while, even though it has a quick response rate?

Answer 19

1) Higher response rate to methotrexate than to other DMARDs but high risk of adverse effects!
2) 50% RA patients stop treatment within 2 years because of adverse effects or lack of efficacy.
3) Response often seen in 4-6 weeks

Question 20

explain why Careful monitoring is required for those taking methotrexate and state what is monitored

Answer 20

1) Careful monitoring is required to detect/prevent occurrence of serious adverse effects such as blood disorders (some fatal), renal impairment, liver cirrhosis, pulmonary fibrosis
2) FBC, renal and liver function tests prior to, repeated weekly until therapy is stabilised and then every 2-3 months thereafter

Question 21

what dose of methotrexate is given to those suffering with RA ?

Answer 21

1) Moderate to severe RA, by mouth, 7.5mg once weekly, adjusted according to response to max. weekly dose of 20mg)
2) SC, IM or IV injection in severe active RA: maximum weekly dose of 25mg

Question 22

what is the counselling advice for methotrexate?

Answer 22

1) Advise patient carefully of dose, frequency and reason for taking MTX and other prescribed medicines (i.e. folic acid)
2) Patients must report side effects indicating onset of blood disorders, liver toxicity or respiratory effects.
3) avoid self medication with OTC aspirin or ibuprofen

Question 23

what are the adverse side effects of methotrexate and how can the risk of some adverse effects be reduced?

Answer 23

1) Common side effects include stomatitis, GI disturbance, alopecia, mild drug-induced hepatitis, pneumonitis, blood disorders, rash
2) To reduce risk of some adverse effects, a weekly folic acid supplement the following day is given

Question 24

aurothiomalate is a gold salt that can be used in RA. explain the MOA of this drug and its tolerability.

Answer 24

1) Gold salts are believed to suppress cell-mediated immune reactions
2) Adverse effects are common and can be serious/fatal so careful monitoring is necessary

Question 25

Penicillamine can be used in the treatment of RA. what is the MOA of this drug and how effective is it?

Answer 25

1) Mechanism of penicillamine is not fully known for RA treatment.
- chelation of metals?
- Altering synthesis and/or maturation and cross-linking of collagen
- Anti-inflammatory effects
2) Effective in 60% of patients within 8-12 weeks and 70% of patients within 6 months.
- Reduction in joint swelling and nodules, ESR rate and RhF titre decrease

Question 26

what dose of Penicillamine is given for the treatment of RA?

Answer 26

1) Start with 125-250mg daily orally with food, increasing after 4-6 weeks to 500-750mg daily
2) Give lowest effective dose to minimise risk of adverse effects (some are dose-dept e.g. rashes and stomatisis), may decrease dose once in remission
3) If no response/improvement in I year, discontinue use

Question 27

the high incidence of serious side effects limits the use of Penicillamine. list the side effects commonly associated with this drug

(40-60% patients will have adverse effects and 30% will need to discontinue treatment)

Answer 27

1) Common side effects include nausea (initally), loss of taste, rashes (very common), blood disorders, proteinuria (20%), hair loss
- hypersensitivity may occur (rarely) in patients with penicillin allergy

Question 28

Patients require monitoring when taking penicillamine. outline what is monitored and when treatment should be discontinued

Answer 28

1) monthly blood counts, urine tests, renal function
2) Discontinue in case of blood disorders (fall in platelet or WBC count)
3) report any symptoms that might indicate side effect (bruising/bleeding, rashes, sore throat, mouth ulcers etc)

Question 29

outline the use of Cytokine modulators (Biologics) in the treatment of RA. what drug is usually given in combination?

Answer 29

1) Used for highly active rheumatoid arthritis if patient has failed to respond to at least 2 standard DMARDs, including methotrexate (unless it is contraindicated)
- Only used under specialist supervision
2) Cytokine modulators are often given in combination with methotrexate (unless it is contraindicated)

Question 30

what are the common side effects of Cytokine modulators and when should treatment be discontinued?

Answer 30

1) infections (TB,septicaemia), nausea, vomiting, abdominal pain,hypersensitivity reactions, fever, headache…
2) Recommended that “biologics” are discontinued after 12 weeks if no response seen

Question 31

1) Etanercept, infliximab and adalimumab are first line biologics. outline how these drugs work.
2) Rituximab, abatacept and tocilizumab are some other biologics that can be used for RA. when should treatment with these drugs be initiated?

Answer 31

1) Etanercept, infliximab and adalimumab are tumour necrosis factor (TNF) inhibitors
2) Rituximab, abatacept or tocilizumab might be used if 2 standard DMARDs and one or more TNF inhibitor have failed

Question 32

Biologics work by blocking the activity of TNF, a chemical messenger. how does blocking TNF action reduce or stop different aspects of inflammation in RA?

Answer 32

1) Anti-TNFs may also ‘switch off’ the production of other inflammatory molecules, including cytokines that are regulated by TNF
2) They also reduce the flow of WBC’s into the rheumatoid joint from blood vessels around the joint. By preventing this movement of inflammatory cells, anti-TNFs help to reduce the swelling in joints and also reduce the damage to the joints that can be caused by
those cells

Question 33

Leflunomide is a DMARD that can be used in RA. outline the MOA of Leflunomide and state how long it will take to experience the therapeutic effects of this treatment?

Answer 33

1) Potent inhibitor of pyrimidine synthesis that affects T cell proliferation and, thus, is immunomodulatory
2) Therapeutic effect starts after 4-6 weeks

Question 34

what are the side effects of Leflunomide?

Answer 34

1) Severe adverse effects include bone marrow toxicity, hepatotoxicity, infection and malignancy.
2) Other side effects: GI disturbance, hypertension, headache, dizziness, hair loss
- Active metabolite of leflunomide persists for a long time which can be a concern if serious adverse effects are experienced

Question 35

what needs to be monitored in patients taking Leflunomide?

Answer 35

Blood counts and liver function

Question 36

Being a disease-modifying antirheumatic drug (DMARD), azathioprine is used for the management rheumatoid arthritis. what is the MOA of this drug?

Answer 36

1) Interfers with purine synthesis and is cytotoxic
2) Active metabolite (mercaptopurine) inhibits DNA synthesis
3) Represses both cell-mediated and antibody immune reactions by preventing the clonal expansion of T and B cells

Question 37

what are the side effects of azathioprine and what should be monitored?

Answer 37

1) Severe adverse effects include bone marrow toxicity, mild hepatotoxicity, infections (herpes zoster), GI disturbances and skin rashes
2) Patients must be monitored; Blood counts

Question 38

Ciclosporin is a DMARD that is licensed for severe active RA when conventional second-line therapy is ineffective. what is the MOA of this drug and what are the side effects?

Answer 38

1) Immunosuppressive action through inhibition of the T cell-mediated immune responses.
- Can slow rate of joint erosion and improve symptom control in partial-responders to methotrexate
2) Side effects include nephrotoxicity, hepatotoxicity, hypertension…