Immunosuppressants Flashcards
Outline the aetiology of rheumatoid arthritis.
1% prevalence in UK
Onset at any age
Women more at risk than men
What are the X-ray changes associated with rheumatoid arthritis?
- soft tissue swelling
- periarticular osteoporosis (early) —> marginal bony erosion (late)
- narrowing of articular space
- articular destruction
- joint deformity
What are the pro-inflammatory factors associated with rheumatoid arthritis?
IL-1
IL-6 —> raised CRP
TNF-alpha
What are the joint deformities associated with rheumatoid arthritis?
Early RA
- dorsal tenosynovitis of wrist and small joints
- spindling of fingers
Ulnar deviation
Boutonnière’s deformity = fixed flexion of proximal IP
Swan-neck deformity = fixed hyperextension of proximal IP
How is rheumatoid arthritis treated? What is the aim of treatment?
Symptomatic relief + prevention of joint destruction (remission)
- early use of DMARDs (unless atypical presentation)
- achieve good disease control
- use adequate dosages (check for subclinical signs)
- avoid using long-term corticosteroids
What are DMARDs?
Disease-modifying anti-rheumatic drugs
Outline SLE
Inflammatory, multisystem autoimmune disorder
Causes arthralgia, rashes (classic malar butterfly rash), cerebral & renal disease
Outline vasculitis. What are the different subtypes?
Widespread vasculitis causing systemic symptoms and signs (systemic inflammatory vasculitides)
Large vessel e.g. giant cell arteritis, polymyalgia rheumatica
Medium vessel e.g. polyarteritis nodosa
Small vessel e.g. granulomatosis with polyangitis (Wegener’s granulomatosis), Henoch-Schönlein purpura, Behçet’s disease
What is the aim of treatment for vasculitis?
Symptomatic relief
Reduction in mortality —> induction of disease remission, then maintenance
Prevention of organ damage
Reduction in long-term morbidity caused by disease/drugs
How do corticosteroids act?
Prevent IL-1 & IL-6 production by macrophages
Inhibit stages of T-cell activation
—> reduce inflammation
Give some examples of ADRs associated with corticosteroids.
- weight gain
- fat redistribution
- striae
- growth retardation
- reduced wound healing
- hair thinning
- skin thinning & bruising
- osteoporosis
- avascular necrosis
- glucose intolerance —> hyperglycaemia
- adverse lipid profile
- increased infection risk
- increased cancer risk
- cataract formation & glaucoma
What are the indications for azathioprine? How does it work?
Indications:
- rheumatoid arthritis
- SLE & vasculitis (maintenance therapy)
- IBD
- bullous skin disease (pemphigus)
- atopic dermatitis
- “steroid sparing” drug
- transplantation
- leukaemia
Prodrug cleaved to active metabolite 6-mercaptopurine (6-MP)
Acts as anti-metabolite to decrease DNA & RNA synthesis
What are the pharmacodynamics of azathioprine?
6-MP metabolised by thiopurine methyltransferase (TPMT)
TPMT gene is highly polymorphic - those with low/absent TPMT levels are more likely to develop myelosuppression (lower dose given)
Test for TPMT activity before/immediately after prescribing
Give some examples of ADRs associated with azathioprine.
- bone marrow suppression (monitor FBC)
- increased risk of malignancy (particularly haematological)
- increased risk of infection
- hepatitis (monitor LFTs)
Give some examples of calcineurin inhibitors. How do they work? When are they indicated?
Ciclosporin (binds to cyclophilin protein)
Tacrolimus (binds to tacrolimus-binding protein)
Calcineurin exerts phosphatase activity on nuclear factor of activated T-cells —> migrates to nucleus to start IL-2 transcription —> inflammation
(therefore inhibiting calcineurin reduces inflammation)
Indications:
- transplantation
- psoriasis
- atopic dermatitis (topical formulation - Pimecrolimus)
- RA/SLE (useful, as no effect on bone marrow)
Give some examples of ADRs associated with calcineurin inhibitors.
H’s:
- nephrotoxicity —> hyperkalaemia (check eGFR)
- hypertension (check BP)
- hyperlipidaemia
- hyperemesis + nausea + diarrhoea
- hypertrichosis
- gingival hyperplasia
- hyperuricaemia (in gout)
- drug interactions (CYP450)
What is the mechanism of action of mycophenolate mofetil? When is it indicated?
Prodrug: increases oral bioavailability of mycophenolic acid
- inhibits enzyme required for de novo guanosine synthesis
- impairs B & T cell proliferation (B & T cells need to synthesise guanosine)
- spares other rapidly dividing cells (have guanosine salvage pathways)
Indications:
- transplantation (monitor levels of active metabolite)
- induction & maintenance therapy for lupus nephritis
note: toxicity may be precipitated by renal/liver disease
Give some examples of ADRs associated with mycophenolate mofetil.
- GI disturbances (usually temporary) = nausea, vomiting, diarrhoea
- metallic taste
- myelosuppression (less so than aziathioprine)
What is the mechanism of action of cyclophosphamide? When is it indicated?
Alkylating agent (cross-links DNA so it cannot replicate)
Strongest DMARD (suppresses B and T cell activity)
Indications:
- lymphoma & leukaemia
- lupus nephritis
- granulomatous poylangitis (Wegener’s granulomatosis)
- polyarteritis nodosum
Describe the pharmacodynamics and pharmacokinetics of cyclophosphamide.
Prodrug converted to active metabolite in liver
Excreted by kidney
Give some examples of ADRs associated with cyclophosphamide. How can the risk be reduced?
- metabolite (acrolein) is toxic to bladder epithelium —> haemorrhagic cystitis (prevent with aggressive hydration/Mesna)
- increased risk of bladder cancer, lymphoma, leukaemia
- infertility (related to dose and patient age)
- teratogenesis
Monitor FBCs
Adjust dose in renal impairment
What is the mechanism of action of methotrexate? What are the indications?
Antifolate: competitive, reversible inhibition of dihydrofolate reductase (catalyses step in purine and thymidine synthesis)
Cytotoxic during S-phase of cell cycle (therefore greater toxic effect on rapidly dividing cells - malignant & myeloid cells, GI & oral mucosa)
Indications:
- gold standard for RA (low dose + other DMARDs + steroids + NSAIDs)
- malignancy
- psoriasis
- Crohn’s
What are the pharmacokinetics of methotrexate?
Administered PO, IM, SC (switch to SC if nausea/partial response with PO)
Metabolite and pro-drug are both active (longer practical half life)
Weekly doses (DAILY DOSE = NEVER EVENT!)
NSAIDs displace from proteins (50% binding)
Excreted renally (dose-dependent elimination)
Give some examples of ADRs associated with methotrexate.
- mucositis (give folic acid)
- marrow suppression (give folic acid)
- hepatitis/cirrhosis
- pneumonitis (hypersensitivity)
- infection risk
- teratogenic/abortifacient
Give some examples of important drug-drug interactions with methotrexate.
Any drug with hepatic/renal ADRs e.g. azathioprine, sulfasalazine
Increased risk of myelosuppression
- other immunosuppressants
- anti-cancer drugs
- autoimmune conditions
- tetracyclines
- drugs affecting renal blood flow, renal elimination, plasma protein binding (e.g. NSAIDs)
- phenytoin
- penicillin
Give some examples of aminosalicylates. What are their mechanisms of action? When are they indicated?
Sulfasalazine (active in rheumatoid arthritis and GI conditions e.g. IBD) = sulfapyridine + salicylate
Mesalazine (GI drug)
CONTRAINDICATED IN ASPIRIN ALLERGY!
T-cells:
- inhibition of proliferation
- ?T-cell apoptosis
- inhibition of IL-2 production
Neutrophils:
- reduced chemotaxis
- reduced degranulation
DOES NOT WORK VIA COX INHIBITION
Indications:
- relieve pain and stiffness in rheumatoid arthritis
- fight infection in IBD
Give some examples of ADRs associated with aminosalicylates.
- myelosuppression
- hepatitis
- rash
- nausea
- vomiting
- abdominal pain
note: no carcinogenic potential, safe in pregnancy, few drug interactions (therefore long-term blood monitoring not always required)
Give some examples of anti-TNF agents. What is their mechanism of action?
Adalimunab, etanercept, infliximab, rituximab
- reduces inflammation
- decreased angiogenesis
- reduced joint destruction
Rituximab binds to CD20 on subset of B-cells:
- activation of complement-mediated B-cell lysis
- initiation of cell-mediated cytotoxicity via macrophages
- induction of apoptosis
Give some examples of ADRs associated with anti-TNF agents.
- hypogammaglobulinaemia —> increased risk of infection
- hypersensitivity
note: does not increase the risk of malignancy, but reduced TNF-alpha “unmasks” cancer that may have developed later/been destroyed
What is rheumatoid arthritis? How is it diagnosed?
Disease of synovial lining of joints (fingers, wrists, feet, ankles, hips)
Joints are initially painful, swollen, inflamed, and stiff (usually symmetrical)
Proliferation of synovium (pannus)
As disease progresses, ligaments are damaged and there is bone erosion (tendon sheaths can be ruptured)
Early S&S:
- morning stiffness >1hr
- arthritis of 3+ joints
- arthritis of hand joints (synovitis)
- symmetrical arthritis
Late S&S (quality of life impaired):
- rheumatoid nodules
- serum rheumatoid factor or anti-CCP
- X-ray changes
note: can mimic cancer
What is the typical presentation of temporal (giant cell) arteritis? What is the management?
Rare under 50yrs
- severe headaches
- jaw claudication whilst eating
- tenderness of scalp (hurts combing hair) or temple
- swelling of temporal/occipital arteries
- sudden painless loss of vision in one eye (once ophthalmic artery is affected; urgent referral to ophthalmologist and high dose corticosteroids)
Management:
- prednisolone = 40mg-60mg starting dose (can increase to 100mg)
- calcium, vit. D, bisphosphonates = reduce risk of osteoporosis due to long-term corticosteroids
- PPIs = reduce risk of gastric ulcers with long-term corticosteroids
