CPT S6 Rheumatology Flashcards
What is rheumatoid arthritis?
An autoimmune multi-system disease
Initially localized to the synovium
Cytokine involvement in inflammatory changes
Hyperplasia and proliferation of synovium
Give some diagnostic features of RA
Morning stiffness of more than one hour Arthritis of three or more joints Involvement of hand joints Symmetry Rheumatoid nodules Serum rheumatoid factor X-ray changes
What are some important factors to remember when considering a diagnosis of RA?
Need to eliminate cancer first
It’s a clinical diagnosis rather than one dictated by test results
Not all symptoms must be present to diagnose as many are late-stage
What is the basic pathogenesis of RA?
overexpression of pro-inflammatory genes in comparison to anti-inflammatory genes
What are the treatment goals for RA?
Symptomatic relief
PREVENTION OF JOINT DESTRUCTION
What are the treatment strategies for RA?
Early use of disease-modifying drugs Use of combinations of drugs Use of adequate doses Aim to achieve good disease control quickly Avoid use of long-term corticosteroids
What are the treatment goals in SLE and vasculitis?
Symptomatic relief
Mortality reduction by induction of disease remission the maintenance
Prevention of organ damage
Reduction in long term morbidity caused by disease and drugs
Give some examples of immunosuppressants
Corticosteroids Azathioprine Ciclosporin Tacrolimus Mycophenolate mofetil
Give some examples of other disease-modifying anti-rheumatic drugs (DMARDs)
Methotrexate (best) Sulphasalazine Anti-TNF agents (expensive) Rituximab Cyclophosphamide (cytotoxic though)
When is Azathioprine used in practice?
Maintenence therapy in SLE & vasculitis Rarely in RA IBD Bullous skin disease Atopic dermatitis As a 'steroid sparing' drug
What are the problems with Azathioprine?
Metabolized by TPMT, an extremely polymorphic gene, so need to test levels before prescribe because patients can develop myelosuppression
Give some azathioprine ADRs
Bone marrow suppression (so monitor FBC)
Increased risk of malignancy (as with all immunosuppressants)
Increased risk of infection
Hepatitis (so monitor LFTs)
How do ciclosporin & tacrolimus have their effect?
Both calcineurin inhibitors
So prevent IL-2 production by T-helper cells
What is the mechanism of action of mycophenolate mofetil?
Inhibits monophosphate dehydrogenase, an enzyme required for guanosine synthesis
This impairs B and T-cell proliferation but spares other rapidly dividing cells due to guanosine salvage pathways presence in other cell types.
Give some ADRs for mycophenolate
Nausea
Vomiting
Diarrhoea
Myelosuppression (not as bad as azathioprine
Metallic taste
May require monitoring
Toxicity more likely in renal and hepatic disease
When is mycophenylate used in practice?
Primarily for transplantation
Lupus Nephritis
What is the mechanism of action of cyclophosphamide?
Alkylating agent - crosslinks DNA to prevent replications
What are some indications for cyclophosphamide?
Lymphoma Leukaemia Lupus nephritis* Wegener's granulomatosis Polyarteritis nodosum *May not be as good as mycophenolate
What are the actions of cyclophosphamide?
Extremely strong anti-inflammatory
suppresses B and T cell activity
What are some ADRs for cyclophosphamide
May cause haemorrhagic cystitis
Renal excretion so adjust dose in renal impairment
Increased cancer risk
Infertility
Requires FBC monitoring
May not be the best drug for lupus nephritis and vasculitis.
What is the mechanism of action of methotrexate?
For malignancy, it works as an anti-folate, but the mechanism of action is unknown in non-malignant disease
What is methotrexate used for?
Gold standard for RA
Psoriasis
Crohn’s
Unlicensed for: inflammatory myopathies, vasculitis maintenance, steroid-sparing agent in asthma
Give some ADRs for methotrexate
Mucositis Myelosuppression Hepatitis Cirrhosis Pneumonitis Increased infection risk Highly teratogenic Abortifacient WEEKLY NOT DAILY DOSING
What toxicity monitoring is required for methotrexate?
Baseline CXR
Baseline FBC, LFT, U+Es, creatinine
Followed by regular (eg monthly) FBC, LFT, U+E
Give some actions of sulphasalazine
T cell inhibition of proliferation T cell apoptosis Inhibition of IL-2 production Reduced neutrophil chemotaxis Reduced neutrophil degranulation
Give some ADRs for sulfasalazine
Myelosuppression Hepatitis Rash Nausea Abdominal pain Vomiting
Give some positives for sulfasalazine
Safe in pregnancy Effective Favourable toxicity Long-term blood monitoring may be unnecessary Very few drug interactions Not a carcinogen
What are the effects of blocking TNF-alpha?
Inhibition of the cytokine cascade
Inhibition of leukocyte recruitent
Inhibition of elaboration of adhesion molecules
Reduced production of chemokines
Reduced angiogenesis due to reduced VEG-F and IL-8 levels
Reduced joint destruction due to reduced destructive enzyme release
What is the stepwise management of asthma in adults?
Step 1: mild intermittent asthma Step 2: regular preventer therapy Step 3: add-on therapy Step 4: persistent poor control Step 5: continuous or frequent use of oral corticosteroids
What is prescribed for each step in the stepwise management of asthmatic adults?
1: Inhaled SABA as required
2: Inhaled corticosteroid
3: Inhaled LABA
4: Increased inhaled corticosteroid dose or addition of a fourth drug (leukotriene antagonist, SR theophylline)
5: Oral corticosteroids
Describe good asthma control
Minimal symptoms Minimal need for reliever medication No exacerbations No limitation of physical activity Normal lung function (FEV1 &/or PEFR>%predicted
What should be done before initiating a stepping up of asthma control?
Check compliance with current therapies
Check inhaler technique
Eliminate trigger factors
Briefly describe the pathophysiology of asthma
Th2-driven inflammation leads to:
- Mucosal oedema
- Bronchoconstriction
- Mucus plugging
- Bronchial hyperresponsiveness
- (Potentially) Airway remodelling
Give examples of SABAs
Salbutamol
Terbutaline
What are the actions and mechanisms of SABAs?
Reversal of bronchoconstriction
Prevention of bronchoconstriction
Acts on bronchial smooth muscle to cause relaxation
Why should SABAs not be used regularly?
Results in poor asthma control
Due to reduced inhibition of mast cell degranulation in response to allergens
Give some side effects of beta 2 agonists
Tachycardia
Palpitations
Tremor
What are the actions of inhaled corticosteroids?
Improved symptoms Improved lung function Reduced frequency of exacerbations Prevention of death Due to reduced inflammation
Give examples of corticosteroids used in asthma
Beclomethasone
Fluticasone
Budesonide
Give examples of LABAs used in asthma
Formoterol
Salmeterol
Can LABAs be prescribed alone?
No. They are not anti-inflammatory alone, and MUST be prescribbed with steroids. Failure causes increased incidence of exacerbations and deaths.
How do Leukotriene receptor antagonists work?
Reduced LTC4 release by mast cells and eosinophils.
LTC4 can induce bronchoconstriction, mucus secretion and mucosal oedema, and promote inflammatory cell recruitment.
Give some ADRs of LRAs
Angioedema Dry mouth Anaphylaxis Arthralgia Fever Gastric disturbance
Give the mechanism of action of methylxanthines
We don’t really know
Could be phosphodiesterase of adenosine receptors
Give some examples of methylxanthines
Theophylline (PO)
Aminophylline (IV)
Give some methylxanthine ADRs
Narrow therapeutic window Nausea Headache Reflux Toxic compilcations; arrhythmias, seizures Many interactions
Give some ADRs for LAMAs
Dry mouth
Urinary retention
Glaucoma
Give some examples of LAMAs
Tiotropium
Ipratropium
What are the clinical uses of LAMAs?
Mainly COPD
Can be used in step 4 or 5 of asthma control too
Reduces exacerbations in both
Give some signs of severe acute asthma in adults
Any one of:
- Unable to complete sentences
- Pulse >110b/m
- Respiration rate >25/m
- Peak flow 33-50% predicted
Give some features of life-threatening asthma
PEF 4.5kPa Silent chest Cyanosis Feeble respiratory effort Hypotension Bradycardia Arrhythmia Exhaustion Confusion Coma
Give some features of near-fatal asthma
PaCO2 >6kPa
Mechanical ventilation
What is the treatment of severe acute asthma?
High flow O2 - aim for >94% sats Nebulized salbutamol Oral prednisolone 40mg for 10-14 days Can add nebulized ipratropium if poor improvement Consider aminophylline if no improvement
