Rheumatoid Arthritis Flashcards
What is the epidemiology of rheumatoid arthritis ?
In NZ: affects 1-2% of none population
Predominantly female (3:1)
Occurs in all ethnic groups, climates and altitudes
Can develop at any age but most likely between 35-45 years
What is rheumatoid arthritis?
Chronic progressive systemic autoimmune disease characterised by inflammation of the synovial tissue in joints causing swelling, pain, stiffness be joint destruction.
It has symmetrical joint involvement.
Can result in deformity and disability if untreated.
Associated with increased risk of CBD and MI
What is juvenile rheumatoid arthritis?
Rheumatoid arthritis occurring at <16 years
What are the risk factors of rheumatoid arthritis?
Sex - women more likely to develop
Age- RA can occur at any age, but most commonly begins between 40-60 years of age
Genetics- presence of HLA-DR4 more common in patients with RA. PTPN22 and other genes also identified as risk factors
Smoking- quitting can reduce risk
Infections- by bacteria or virus
Hormones- explains why disease is more common in women than in men
What is the Pathogenesis of rheumatoid arthritis?
Environmental triggers such as smoking, microorganisms and stress, and/of genetic pre-dispositions such as HLA-DR4, PTPN22 can result in dysregulation of the humoural cell mediated components of the immune system which can cause autoimmunity.
B cells can produce RF and anti-CCP antibodies, directed at common antigens expressed widely outside of the joint. the presence of these antibodies can precede the synovial inflammation of RA by decades.
From whichever reason, an antigen is able to activate CD4+ T cells which in turn activate B plasma cells, macrophages and leukocytes.
B cells produce autoantibodies which activate and combine with complement activates neutrophils and stimulates an immune response. They also bind to and activate macrophages in the synovium. Neutrophils release cytotoxins, oxygen free radicals and OH radicals promoting cellular damage to synovial and bone.
Macrophages release cytokines causing fibroblasts, chrondrocytes and synovial cells to proliferate. They also increase collagenase, elastase, resulting in pannus formation and destruction of bone.
T cells also activate macrophages and fibroblasts resulting in tissue destruction.
What are the main clinical presentations of rheumatoid arthritis?
Pain in the joints Swelling at joints (warmth and redness) Stiffness in the mornings Fatigue Muscle pain Loss of appetite Anemia
What are the extra articular sites of rheumatoid arthritis?
Haematological Pulmonary Cardiac Neurological Vasculitis (inflammation of bloodvessels) Rheumatoid nodules (asymptomatic) Ocular
What are the implications of haematological RA?
Anemia
Leukopenia –> susceptibility to infection
What are the implications of pulmonary RA?
Pleuritis
Pneumonitis (pulmonary fibrosis)
What are the implications of cardiac RA?
Pericarditis/myocarditis
This is higher in those with a more active inflammation
What are the implications of neurological RA?
Carpal tunnel and nerve compression
What are the implications of ocular RA?
Scleritis
Uveitis
Sjögren’s syndrome (atrophy of the lacrimal duct causing decreased tear formation, dry and itchy eyes) artificial tears can be used to relieve symptoms
How is rheumatoid arthritis diagnosed?
Early morning stiffness >1 hours Arthritis of 3 or more joint areas Asymmetrical arthritis (70% of patients) Involvement of hand joints Rheumatoid nodules X-ray changes Positive RF
Patient is said to have RA if the exhibit 4/7 criteria for at least 6 weeks
What is seen in the lab tests in rheumatoid arthritis?
RF detectable in 60-70% of patients
Elevated ESR and CrP (markers for inflammation)
Anti CCP antibodies (present in 50-85% of patients)
Increased WBC
Anemia common
Thrombocytopenia (result of toxicity of MTX etc)
Synovial fluid usually turbid and less viscous
What is the DAS?
Disease activity score.
This is the measure of activity in RA
Used to ascertain whether treatment is effective based on the number of swollen and tender joints at specific locations.
What is the DAS based on?
The assessment of 28 joints routinely used in Clinical practice, to assess potential treatment with biologicals and to evaluate their effectiveness and whether they should be continued.
What parameters does the disease activity sore use?
Number of joints tender to touch
Number of swollen joints
Erythrocyte sedimentation rate
Patient assessment of disease activity
What are the diseases related to the differential diagnosis of RA?
Osteoarthritis Gout Systemic lupus erythematous Psoriatic arthritis Lyme disease
What are the desired outcomes / treatment goals of RA?
Reduce pain and inflammation Minimise and prevent joint damage Maximise joint movement Control of systemic involvment Remission Improvise quality of life
What are the drugs used for acute- mild to moderate RA disease for a patient NOTT pregnant and not planning to be?
Methotrexate
Sulphasalazine
Leflunomide
Hydroxychloroquine
Sodium arothiomalate injection gold
Azathioprine
+Corticosteroids like prednisolone, methyl prednisolone acetate, dexamethasone sodium phosphate
+NSAIDs
What is methotrexate?
Anticancer agent but also first line (gold standard) for RA with onset starting within 3-4 weeks and full effect achieved by 12 weeks
How does methotrexate work?
It is a dihydrofolate reductase inhibitor preventing tetrahydofolate synthesis.
Inhibits cytokine production and purine biosynthesis
May stimulate adenosine secretion which may be responsible for anti inflammatory properties.
What are the precautions with methotrexate ?
Take caution in prescription to alcoholics and patients with renal/hepatic disease
Do not start in patients with severe respiratory disease
Drug is teratogenic. Effective contraception should be used at least 3 months after treatment
What are the adverse effects of methotrexate?
Nausea, mouth ulcers, rash, transaminases elevation (stop treatment if AST or ALT is 2x normal) leucopoenia, alopecia
Why must methotrexate (given on Monday) be coadministered with folic acid?
Must give folic acid 5-30mg (on a Friday) as folic acid is still required by our normal day to day cells
What is sulphasalazine?
Amino salicylate used as a DMARD for RA with effects seen in 2 months.
However its use is limited due to side effects
How does sulphasalazine work?
It inhibits prostaglandin and Leukotriene synthesis resulting in the impairment of white cell adhesion and inhibition of cytokine synthesis
What is the adverse effects of sulphasalazine?
Nausea, vomiting (dose reduction) Rash (must stop due to risk of Steven Johnson syndrome which is toxic epidermal necrolysis) Reversible reduction in sperm count Abdominal pain Hepatotoxicity (stop if LFTs >2x normal) Leucopenia
What is leflunomide ?
A DMARD with therapeutic effects seen at 4-6 weeks and continuing to 4-6 months
How does leflunomide work?
Inhibits pyrimidime synthesis leading to decreased lymphocyte proliferation and modulation of inflammation
What are the adverse effects of leflunomide ?
Diarrhoea,
GI upset
Hypertension
Teratogenicity (contraception Required during treatment and at least 2 years after in women and 3 months after in men)
What is the purpose of the washout procedure in leflunomide use?
Aids drug elimination to stop treatment and either give colestyramin 8g tds for 11 days or activated charcoal 50g, 4x daily for 11 days
What is hydroxychloroquine?
Antimalarial used as a DMARD for rheumatoid arthritis with an onset of up to 6 weeks
How does hydroxychloroquine work?
It inhibitors TLRs which are responsible for the activation of inflammation
What are the adverse effects of hydroxychloroquine?
Headache Nausea Rash Photosensitivity Skin pigments Neuromyopathy (rare) Visual changes Hair loss
What is hydroxychloroquine contraindicated to?
Patients with pre existing retinopathy
What is sodium aurothiomalate injection?
Injections of gold used as a secondary DMARD for RA with an onset of 3 months.
A test dose of 10mg is given, then 50mg weekly until a total dose of 100mg. This is followed by a review of its efficacy
A FBC and urinalysis should be undertaken at the time of each injection
How does sodium aurothiomalate injection work?
Acts at several stages of the inflammatory pathway.
Impairs T cell activation
Inhibits TNFα, IL1 and IL12
What are the side effects of sodium aurothiomalate injection?
GI upset Rash Anemia effects Fainting Dizziness Sweating
What is azathioprine?
A second line DMARD used in RA which affects the immune response,
Its antirheumatic effects may be seen in 3-4 weeks and should be withdrawn if no effect is seen within 3 months
How does azathioprine work?
It is a purine synthesis inhibitor that interferes with DNA and RNA synthesis.
It suppresses t lymphocyte proliferation
What are the major side effects of azathioprine?
Bone marrow suppression
Why are corticosteroids used in rheumatoid arthritis?
They have anti inflammatory and immunosuppressive properties.
They interfere with antigen presenting t lymphocytes, inhibit PG and LT synthesis as well as inhibit neutrophil and monocytes superoxide radical generation.
What are the side effects of corticosteroid use ?
Peptic ulceration Acne GI effects Muscle weakness Weight gain Insomnia Nausea Malaise Headache
Why are NSAIDs used in rheumatoid arthritis?
Inhibit prostaglandins synthesis
Possess analgesic and anti inflammatory properties and reduce the stiffness
Full analgesic effect obtained within a week, anti inflammatory effect after 3 weeks.
Why are NSAIDs used adjunctive to DMARD treatment?
NSAIDs (and corticosteroids ) are only symptom modifying drugs and do not slow down disease progression, prevent bony erosions or joint deformity so they should only be used as adjunctive therapy with an appropriate DMARD
What are NSAIDs contraindicated to?
Patients with renal function and cardiac impairment
What are the treatment options for a patient which acute - high disease activity but not pregnant or planning pregnancy?
Use methotrexate as above, biological agents and corticosteroids and NSAIDs as above
What biological agents are involved in the treatment of rheumatoid arthritis?
Etanercept Infliximab Adalimumab TNFα inhibitors Abatacept Rituximab
What is etanercept?
Cytokine modulator (TNFα inhibitor) which binds to and inactivates ΤΝFα and lymphotoxin α to prevent it from interacting with cell surface TNF receptors and activating cells
Given 50mg SC weekly with or without MTX
Has a half life of 4 days
The best tolerated biologic. (No lab monitoring required)
What are the adverse effects of etanercept?
Local injection site exactions
Pancytopenia
Neurological demyelinating syndromes.
Therefore should be avoided in people with preexisting infections and those at high risk of developing infection
What is infliximab?
TNFα inhibitor like etanercept
Given as IV every 4-8 weeks
Has a half life of 8-10 days
Should be given with MTX to prevent formation of antibodies to this foreign protein which could lead to therapeutic failure or hypersensitivity.
What are the adverse reactions with infliximab?
Hypersensitivity reactions within 1-2 hours of infusion. Patient should be observed closely
What is adalimumab?
A human IgG antibody to TNF. It is less antigenic than infliximab It works by binding to and inactivating TNF to prevent it from interacting with cell surface TNF receptors and activating cells. Given 40mg SC fortnightly It has a half life of 10-20 days
What are the adverse reactions of adalimumab?
Injection site reactions Fever Infections Headache Depression
When should TNF α inhibitors be withdrawn?
If no response is seen within 6 months .
Their activity should be assessed in 12 week intervals
What are the safety concerns with TNFα inhibitors?
Injection site reactions
Reactivation of TB
Congestive heart failure
Serious opportunistic infections
Contraindicated during pregnancy and lactation
Contraindicated in patients with history of demyelinating disease
Live vaccines should not be administered
What is Abatacept?
Cytokine modulator which binds to CD80/CD86 receptors on antigen present cells and T cells.
Prevents T cells from activating to promote inflammatory process.
I.e. It is a T cell co stimulation modulator.
Given as an infusion fortnightly for the risk month, then monthly according to weight.
100kg = 1g
Can also be given as SC following an IV infusion loading dose.
Adult over 18 years: 125mg given within a day of loading dose, then 125mg weekly
What are the adverse reactions of Abatacept?
Infusion reactions Headache Dizziness Cough Back pain Hypertension UTI Rash Extremity pains
What is rituximab?
Monoclonal chimerical antibody consisting of mostly human protein to the CD20 protein found on cell surface of mature B cells.
Binding of rituximab to be less causes nearly complete depletion of B cells with gradual recovery over several months.
Useful for patients who fail TNFα and conventional therapy.
Given as 2x 1000mg IV infusions separated by a fortnightly
What are the adverse effects of rituximab?
Dyspepsia Hypertension Rhinitis Sore throat Muscle spasm Arthalgia
How can infusion related reactions form rituximab be prevented?
With co therapy of methyl prednisolone 100mg 30 min prior to rituximab
What RA treatments are used in acute cases for a patient who is pregnant?
Corticosteroids
Sulphasalazine
Hydroxychloroquine
What are some pharmacological treatments for patients which ongoing failure to reach low disease activity after 3 months of treatment and are onto pregnant or planning pregnancy?
Combination DMARD therapy
Which is a choice of 2 or 3 of the following agents:
1)Methotrexate AND sulfasalazine AND leflunomide AND hydroxychloroquine
2) DMARD (methotrexate OR sulphasalazine OR leflunomide OR hydroxychloroquine)
AND a biological agent
AND corticosteroids
AND NSAIDs
What are the nonpharmacological treatment options for RA?
Physiotherapy Exercise and rest weight reduction if obese Education on care of joints Assistant devices Splints Surgery Smoking cessation as medications (e.g. MTX) are less effective in smoking.
What sort of monitoring is invovled in RA?
Regular clinical follow up
Educate that NSAIDs are to treat symptoms only and do not affect disease progression
Glucocorticosteroids have potential for long term complications so need to monitor these.
If patient is unwell with infection usually stop DMARDS, immunosuppressants and biologicals until infection is resolved
Need specific monitoring for individual drugs especially biologicals
Hepatitis B, and C status, PPD, FBC and LFTs need to be checked before starting DMARDS
How often should patients be lab monitored?
Lab monitoring for FBC and LFT abnormalities done every 4-8 weeks at the start of treatment. Once patient is on stable dose they are checked every 3-4 months
X-rays of hands and feet every 3-5 years
How is the disease activity score used in patient monitoring?
The disease activity score should be used to ascertain whether treatment is effective based on the number of swollen and tender joints at specific locations
How does RA differ to gout in terms of speed of onset?
Gout has a sudden onset
RA is relatively rapid, but occurs over weeks to months
How does RA differ to gout in terms of joint symptoms?
In gout, joints are hot, red, swollen and extremely painful
In RA, joints are painful, swollen and stiff
How does RA differ to gout in terms of the pattern of joints that are affected?
In gout the big toe is most commonly affected. The ankle, heel, knee, wrist, fingers and elbow are also affected
In RA, the small and large joints on both sides of the body are affected. E.g. Both wrists or elbows, or the balls of both feet.
How does RA differ to gout in terms of the duration of morning stiffness?
There is no duration of morning stiffness seen in gout
Morning stiffness last longer than an hour in RA
How does RA differ to gout in terms of systemic symptoms?
In gout, chills and a mild fever, a general feeling of malaise can accompany the severe pain and inflammation
In RA, there is a frequent fatigue and a general feeling of being ill
How does RA differ from gout in terms of associated symptoms?
Tophi can form in gout, these are masses of uric acid crystals which are collected in huge joints and damage it. Can also be collected in the bones and cartilage such as the ears.
In RA, there are frequent feelings of being sick “inside” with fevers, weightloss, or involvement of other organ systems
How does RA differ from gout in terms of age of onset?
Gout usually occurs in men over 35 years of age
And sometimes in women after menopause
RA can occur at any time in life
