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What is the key aspect of slowing progression and managing symptoms of theumatic diseases?`
For rheumatoid arthiris, what are:
- the systemic sysmptoms?
-The duration of morning stifness?
-Worst time of the day?
-Efect of activity on symptoms?
Prominent, including fatigue
Insidious, affects multiple joints
more than 1h
- Lessens with activity
- Worse after periods of rest
- May hurt with use
For Osteoarthrisis what are:
- the systemic sysmptoms?
-The duration of morning stifness?
-Worst time of the day?
-Efect of activity on symptoms?
- 1 joint or a few weight bearing joints
as day progresses
- worsen with activity
- lessen with rest
Define rheumatiod arthritis
- A chronic, systemic inflammatory disirder characterised by inflammation and deformity of the synovial joints and inflammation o the surrounding tissues such as tendons, ligaments and muscles
- It is a lymphocyte mediated autoimmune disease
what age is rheumatoid arthritis common in?
Which genger is rheumatoid arthritis more common in?
Which joints does rheumatoid arthritis usually involve?
Explain the pathophysiology of rheumatoid arthritis
- what does synovial fluid contain?
-what is the surfaces of bone joints covered with? Whats it composed of?
- what is synovitis and how does it occur?
- synovial fluid contains phagocytic cells which remove debris and microbes.
- Joint bones are covered with hyaline cartliage. Composed of: collagen, water, proteoglycans and chrondocytes (synthesise and enzymatically digest the matrix)
- Synovitis is an abnormal inflammatory response of the synovial membrane. It occurs when the synovium become hyperplastic, increases vascularity and becomes infiltrated with inflammatory cells (predominantly CD4+ T cells).
- Antigen activated CD4+ T cells stimulate monocytes, macrophages and synovial fibroblasts to produce IL-1, IL-6 and TNF-alpha to secrete matrix metalloproteinases. Activated CD4+ T cells also stimulate B cells. These changes cause formation of pannus which is rich in inflammatory cytokines that causes destruction of bone and cartliage.
What is the early presentation of rheumatoid arthritis?
- -Soft tissue swelling or effusion of the affected part
- -morning stiffness in the affected part
- -local soft tissue swelling with warmth and redness
- -weakness, fatige, anorexia, weight loss
- -low grade fever
What is the late presentation of rheumatoid arthritis?
- Joint and tendon destruction
- -deformity and loss of function (ulnar deviation, swan-neck, hammer toes)
- -functional limitations
- -pain, reduced mobility, fatigue and depression (disrupts family life, makes social interactions difficult, reduced learning capacity)
What radiographic investigations would you expect to see in rheumatoid arthritis?
- Juxta-articular osteoporosis
- Joint erosion
- Joint space narrowing
What haematological investigations would you expect to see in rheumatoid arthritis?
- Rheumatiod factor (RhF)
- Antibodies to anti-citrullinated peptide antibodies (anti CCP or ACPA)
- Elevations in CRP and ESR - non specific can be used to monitor treatment response
- Mild anaemia
What are the cardiovascular extra-articular manifestations? (4)
- Pericardial and myocardial inflammation which can progress to heart failure and increased risk of MI
- Severe rheumatiod vasculitis may occur
- Mild anaemia due to excess cytokines that inhibit EPO production
- High risk of cardiovascular disease due to drug induced hypertension and reduced ability to exercise
What are the respiratory extra-articular manifestations?
Shortness of breath due to inflammation of the lung pleura, pulmonary fibrosis or pulmonary nodules
What are the integument (outer covering of body) extra-articular manifestations?
Subcutaneous rheumatoid nodules, usually on hands or arms. Painless
What are the eyes and mouth extra-articular manifestations?
- Saliva and tear production can be reduced -- associated to sjogrens syndrome
- Eyes in 1% of people, can cause episcleritis
What are the nervous extra-articular manifestations?
Areas less commonly affected?
- Peripheral sensory neuropathy due to compression of nerves near inflammed joints and tendons
- Presents as muscle weakness and/or pins and needles. Affects hands, wrists and ankles
- Soles of feet, spinal cord and fingers = less common.
What are the musculosketal system extra-articular manifestations?
Muscle weakness and atrophy
What is the diagnosis of rheumatiod athritis?
Why is early diagnosis essential?
- No one test for diagnosis
- Clinical observations and lab tests
- Untreated RA results in joint damage, deformities and some degree of diasbility
- Aggressive and early therapy critical to improving long term outcomes
Prognosis of rheumatiod athritis
What are the three courses?
- Monocyclic - complete sustained remission within two years ~33%
- Polycyclic - most common course, acute flares and remissions ~40%
- Progressive - constant and destructive, responsible for deformity, disfigurement and premature death ~20%
Rheumatiod athritis management, what are the three aspects?
- Pain management with analgesics
- Disease modification with DMARDs or bDMARDs
- Agressive management of co-morbidities such as cardiovascular risk factors
Why do rheumatiod athritis patients need to be regularly monitored?
For drug toxicity and to minimise rheumatiod athritis co-morbidities such as osteoporosis and atherosclerosis
What is the effect of NSAIDs in rheumatiod arthritis?
How should they be used?
as symptom relief. They do not modify disease progress
- Used at the lowest dose possible and for the shortest period of time
- Should be used in conjunction with a DMARD
- No NSAID is better than any other
What does of omega-3-polyunsaturated fatty acids is required in rheumatiod arthritis patients to have beneficial effects?
15mL fish oil daily or ~12 fish oil capsules
May have anti-platelet activity -- careful in anticoagulants and antiplatelet agents
When are corticosteroids used in rheumatiod arthritis?
What three ways is prednisolone used?
To control severe inflammation in early disease or active flares
They provite symptomatic disease and slow disease progression
- as initial bridging therapy until DMARDs take effect (corticosteriods take hours-days to work, DMARDs take 6weeks-6 months). If used more than 2-3 weeks, generally taper to reduce risk of rebound flare
- In the management of acute flares (dose variable. Short-term pulse therapy can supress an active flare).
- In combination with DMARDs when DMARD therapy is suboptimal
What are the actions of DMARDs in rheumatiod arthritis?
- Limit disease progression
- Good toxicity profile
- Preserve joint function
- Reduce symptoms
- Induce clinical remission
Name 5 DMARDs
- Gold salts
Name 5 bDMARDs
- TNF-a inhibitors: Adalimumab
- Cytokine modulators: Abatacept
What are the benefits of early DMARD treatment in rheumatiod arthritis?
- 75% of joint erosions occur within the first two years and 25% of patients already have erosions at diagnosis
- Early DMARD use decreases the rate of joint damage
- Early DMARD use makes the disease easier to control int he long term
- Delayed DMARD therapy decreases the ability of single drug therapy to induce remission
When is combination DMARD therapy superior to monotherapy in rheumatiod arthritis patients? (2)
What is the most common combination?
When is corticosteroids co-prescribed?
- With recent onset of RA
- Those not adequately controlled on monotherapy
Methotrexate + sulfasalazine or hydroxychloroquinone. Or both.
For short term flares or as briding therapy
What type of drug is methotrexate?
What is the usual dose and how long does it take to work for rheumatiod arthritis?
- Folic acid analogue - binds to dihydrofolate reductase to antagonise folic acid. Impairs cell division.
- Can also increase intracellular adenosine which inhibits inflammatory cell activation.
- Usual dose is 2.5-10mg ONCE A WEEK, dose depending on disease severity.
- Allow 4-6 weeks at each dose level to assess response, response usually seen after 1-2 months
- Max dose 25mg weekly
What are the adverse effects of methotrexate?
How can they be limited?
Nausea and mouth ulcers
- Limit by dose reduction, co-administration of folic acid +/or parenteral delivery of methotrexate.
- Folic acid is usually co-administered with methotrexate, usually 10mg weekly not on the day that methotrexate is adminstered
How is Sulfasalazine used in rheumatiod arthritis?
What are the side effects that commonly make patients cease the drug?
How long can it take to work?
Whats the usual dose?
Used as a monotherapy in mild-moderate RA, or in combination for more severe disease
- Nausea and GI problems -- minimise by starting low dose and titrating slowly
- Rash or more severe allergic reaction -- do not use in patient with an allergy to sulphonamides
- Headache, reversible male infertility and macrocytosis
May take 1-3 months of treatment before benefit is seen. Stop if nothing happens after 4 months.
Usual dose = 2-3g/day in 2-3 doses (start from 500mg daily and increase)
How does leflunomide work in rheumatiod arthritis?
Onset of effect?
Why can the metabolite be prolonged in the body?
What occurs in 2-5% of patients?
Blocks dihydroorotate dehydrogenase to inhibit de novo synthesis of pyramidines -- inhibits activated lymphocytes
4-12 weeks is the onset of action
the active metabolite has a long half life due to is being enterohepatically recycled. Can be washed out with cholestyramine or charcoal
Usual dose: 10-20mg daily
Diarrohea is common
2-5% of patients develop abnormal LFT's -- raised transaminases. Increased risk of liver disease in combination with methotrexate: monitor liver
Advantage of hydroxychloroquinone in rheumatiod arthritis?
Common adverse effects?
Generally better tolerated than other agents
Less active than other agents
400mg daily for 3 months then reduced to 200mg (some patients relapse on 200mg/day though)
- nausea+dizziness -- dose reduction may help
- rash -- need cessation
- ocular toxicity -- rare but requires monitoring by regular eye checkups
How does cyclosporin work in rheumatiod arthritis?
When's it used?
What are the adverse effects?
It's an immunosupressant that inhibits cytokine release from activated T-cells
Used in moderate to severe RA unresponsive to other DMARDs
- Reversible renal impairment and hypertension common
- Hirsutism, gingival hyperplasia, GI disturbances, weight gain, odema, hepatic dysfunction, hyperlipidaemia, anaemia
How do gold salts work for rheumatiod arthritis?
What are the two types?
Onset of action?
Inhibit maturation and function of phagocytes and T-cells
Oral - auranofin, and injectable - aurothiomalate
- Adverse effects: diarrhoea, dyspepsia, stomatitis, nausea, vomiting, taste disturbances, rash, itching, alopecia, conjunctivitis, blood dyscrasias, nephrotoxicity, elevated liver enzymes.
- More: see lecture notes page 55.
How does penicillamine work in rheumatiod arthritis?
What form is it used for?
Onset of action?
Common and rare side effects?
Inhibits collagen formation, reduced RhF and circulating immune complex concentrations in blood and synovial fluid
Used for moderate-severe RA due to poor tolerability and delayed effects
May take 3-6 months before benefit is seen, stop if theres no response after 6 months
- Common A/E: rash, stomatisis, dysgeusia
- Rare: myelosupression, proteinuria, renal toxicity & autoimmune syndromes
Azathioprine MOA in rheumatiod arthritis?
When's it used?
Prodrug for mercaptopurine. Inhibtis purine synthesis, gene replication and T-cell activation by acting against rapidly dividing cells
Used in moderate to severe RA unresponsive to other DMARDs. Onset of action: 2-3 months, cease after 6 months if no response.
GI intolerance. Rare: myelosupression and hepatotoxicity
When is anti-TNF-a used in Rheumatoid arthritis?
Whats the advantage over tratidional DMARDs?
How are they all given?
For people who fail on DMARDs
Rapid onset of action compared with traditional DMARDs
- Increased risk of infection
- Reactivation of latent TB and inactive hepatitis B
All given parentally
How do infliximab and adalimumab work in Rheumatoid arthritis?
They are anti-TNF-a monoclonal antibodies which inhibit binding to cell surface TNF receptors
Infliximab - What kind of monoclonal antibody is it and hows it work?
What's it co-prescribed with?
What reactions are more severe with infliximab?
Adalimumab - what kind of monoclonal antibody is it?
- It is a chimetic monoclonal antibody.
- Composed of both human and mouse proteins
- Antiboies against infliximab are produced by the body
- Co-prescribed with methotrexate to minimise the formation of antichimera antibodies
- Infusion-related reactions are more severe
- Fully humanised monoclonal antibody
- Retatins antigenic potential so methotrexate is still used commonly
Etanercept - what type of protein is it?
Hows it work?
New drug, don't know much
- It's a fusion protein
- Acts as a dummie receptor for TNF-a and TNF-b. Binds to the TNF factor which biologically inactivates it.
Name cytokine modulators (5)
Why must disease activity in Rheumatiod Arthritis be measured?
Define Rheumatiod Arthritis remission
What can montor therapy response?
To adjust therapy
- Symptomatic relief
- Normal inflammatory markers
- Absence of joint swelling
- # of swollen/tender joints
- ADL function
- ESR and CRP measures
What are the causes of Cardiovascular disease co-morbidities in Rheumatiod Arthritis?
How do you treat them? (5)
- Drugs used to treat RA such as corticosteriods
- Extra-articular manifestations of RA
- Manage: cholesterol,
- anti-platelet therapy
- tight HTN and diabetic control
- diet & exercise
- smoking cessation
What are the causes of increased susceptablility to infection co-morbidities in Rheumatiod Arthritis?
- Consider vaccinations
- Montior signs of sepsis
- Serious infections may require witholding DMARDs for 1-2 weeks
- Increase steroid to cover the stress response
What are the causes of GI disease co-morbidities in Rheumatiod Arthritis?
Medications such as MTX, NSAIDs and corticosteroids
- Minimise dose and duration of NSAIDs and corticosteriods
- Consider co-prescription if proton pump inhibitors if clinicall warranted
- Ensure adequate co-prescription of folate supplements
What are the causes of Osteoporosis co-morbidities in Rheumatiod Arthritis?
Resoption of bone due to disease and drugs such as corticosteroids which decrease bone density
- Supplement with vitamin D and calcium
- Bisphosphonates for corticosteriod induced osteoporosis
What are the causes of anaemia co-morbidities in Rheumatiod Arthritis?
Blood loss from nsaids - iron deficiency
- Iron, B12 and folate tests to determine the cause
- Treat anaemia
- Adequate co-prescription of folate with MTX
What are four types of spondyloarthropathies?
- Ankylosing Spondylitis
- Psoriatic Arthritis
- Colitic Arthritis
- Reactive Arthritis
What is the typical presentation of spondyloarthropathies?
- Sacroilic joints and spine
- associated with HLA-B27
Inflammation in the attachment sites of tendons and ligaments to bone