Immunosuppression Flashcards
Physiologically, what do rheumatoid factors do?
Clear old IgGs
What does RA cause?
Chronic inflammatory synovitis
Progressive erosion of articular cartilage leading to exposure of bone
Pannus - an inflamed synovium
What’s the problem with an inflamed synovium/pannus?
Damages the cartilage by restricting normal nutrient flow and released inflammatory factors
What signs/symptoms are used to diagnose RA?
Morning stiffness for less than 1 hour Arthritis in 3 or more joints Symmetrical arthritis Rheumatoid nodules Serum rheumatoid factor X-ray changes
What are the goals of treatment in RA?
Symptomatic relief
Prevent joint destruction
What is the strategy in treatment of RA?
Early use of disease-modifying drugs Achieve good disease control Use adequate dosages Use a combination of drugs Avoid long-term corticosteroids
What is SLE (in one sentence)?
An autoimmune connective tissue disease
Symptoms of SLE
Fatigue, malaise, fever, weight loss Splenomegaly, hepatomegaly, lymphadenopathy Arthralgia Oral ulcers Raynaud's phenomenon
What are symptoms/signs specific to SLE?
Erythematous, photosensitive rash seen on the face aka malar rash
What are the aims of treatment in lupus?
Symptomatic relief of eg arthralgia, Raynaud’s phenomenon
Reduce mortality - induce remission
Prevent organ damage
Reduce long-term morbidity caused by disease/drugs
What is vasculitis?
Inflammation of blood vessels
Symptoms of vasculitis?
Arthralgia and lethargy
Skin lesions such as purpura
Treatment goals of vasculitis?
Symptom relief
Reduce mortality - induce remission
Prevent organ damage
Reduce long-term morbidity caused by disease/drugs
List some types of immunosuppressants
Corticosteroids Azathioprine Ciclosporin Tacrolimus Mycophenolate mofetil (MMF)
Name some disease-modifying anti-rheumatic drugs (DMARDs)
Methotrexate (first line in RA)
Sulphasalazine (not as strong as MTX)
Anti-TNF agents
Rituximab
Mechanism of action of corticosteroids?
Prevent IL-1 and IL-6 production
Inhibit all stages of T-cell activation
Adverse effects of corticosteroids?
Weight gain Fat redistribution Striae Growth retardation Osteoporosis Avascular necrosis Glucose intolerance Adverse lipid profile Infection risk Cataract formation
What is azathioprine used for?
An immunosupressant
Used as maintenance therapy in SLE and vasculitis
Also IBD, bullous skin disease, atopic dermatitis
Steroid-sparing
Mechanism of action of azathioprine?
Cleaved to 6 mecaptopurine (6-MP)
Functions as an anti-metabolite to decrease DNA and RNA synthesis by inhibiting purine synthesis
Selectively acts on cells that are highly mitotic
How is azathioprine eliminated?
Its active form (6-MP) is eliminated by TPMT
Individuals vary in the level of TPMT activity
What can happen to those who take azathioprine with low TPMT activity? What about high TPMT?
Likely to develop myelosuppression and increased risk of infection
High - under-treatment
Adverse effects of azathioprine?
Bone marrow suppression
Increased risk of malignancy, especially in transplant patients (as with all immunosuppressants)
Increased risk of infection
Hepatitis
Name the calcineurin inhibitors?
Tacrolimus
Cyclosporin
Mechanism of action of calcineurin inhibitors?
Prevent the production of IL-2 so active against T-helper cells
- ciclosporin binds to cyclophilin protein
- tacrolimus binds to tacrolimus-binding protein
Drug-protein complexes bind to calcineurin, inhibiting it
What does calcineurin normally do?
Exerts phosphatase activity on the nuclear factor of activated T-cells
This factor then migrates to the nucleus to start IL-2 transcription
How is ciclosporin produced?
By fungus
What are calcineurin inhibitors used for?
Transplant medicine
Atopic dermatitis and psoriasis
In RA/SLE patients with cytopenias as has no clinical effects on bone marrow
How is toxicity monitored with calcineurin-inhibitors?
Blood pressure
eGFR
Adverse effects of calcineurin inhibitors?
Nephrotoxicity leading to hyperkalaemia and hyperuraemia
Hypertension
Hyperlipidaemia
Nausea, vomiting (hyperemesis), diarrhoea
Hypertrichosis
Hyperuricaemia
All the H’s
Has drug interactions due to CYP
Mechanism of action of mycophenolate mofetil?
Metabolised to mycophenolic acid
Inhibits the enzyme inosine monophosphate dehydrogenase required for guanosine synthesis
Impairs B and T proliferation
Why are other rapidly dividing cells spared with MMF?
They have guanosine salvage pathways
Adverse effects of MMF?
Nausea, vomiting, diarrhoea
Myelosuppression
What is MMF used for?
Transplants
Induction and maintenance therapy for lupus nephritis
Toxicity can be precipitated by both renal and liver disease
What causes rheumatoid arthritis?
An antibody against IgG called rheumatoid factor mediates it
They bind to form an immune complex
This activates complements and sets of the inflammatory process
Due to an imbalance of pro and anti-inflammatory factors
Mechanism of action of cyclophosphamide?
It is an alkylating agent - cross-links DNA so that it cannot replicate
Has immunological effects including suppressing B and T cell activity
Indications for cyclophosphamide?
Lymphoma and leukaemia
Lupus nephritis
Wegener’s granulomatosis (can lead to vasculitis)
Polyarteritis nodosum
Absorption and metabolism of cyclophosphamide?
Prodrug - converted in the liver by CYP450 to active form
Active metabolite is 4-hydroxycyclophosphamide
How is cyclophosphamide excreted?
By the kidney
What can acrolein, a metabolite of cyclophosphamide do?
Toxic to bladder epithelium, can lead to haemorrhage cystitis
Prevented through aggressive hydration/mesna
ADRs of cyclophosphamide?
Bladder cancer risk
Lymphoma and leukaemia
Infertility - risk relates to cumulative dose and patient age
How is cyclophosphamide monitored?
FBC
Adjust dose in renal impairment
Indications for methotrexate?
RA - first line treatment
Malignancy
Psoriasis
Crohn’s
Mechanism of action of methotrexate in malignancy?
Competitively and irreversible inhibits dihydrofolate reductase
Acts as an antifolate - stops purine and thymidine synthesis so stops DNA, RNA and protein synthesis
Greater effect on rapidly dividing cells
Mechanism of action of methotrexate in non-malignant disease?
Unknown - suggestions:
- inhibit enzymes in purine metabolism, causing accumulation of adenosine which is a regulatory autocoid generated in cellular injury/stress, interacts with GPCRs on inflammatory and immune cells to regulate function
- inhibit T cell activation
- suppress intercellular adhesin molecule expression by T cells
Bioavailability of methotrexate?
Oral - 33%
IM - 76%
How can MTX be administered?
Orally
IM
SC
When is methotrexate given? Why?
Weekly - has a very long half-life of weeks to months
Important DDI with methotrexate?
It is 50% protein bound so can be displaced by NSAIDs
How is MTX excreted?
Renally
Adverse effects of MTX?
Mucositis
Marrow suppression
-these two respond to folic acid
Hepatitis and cirrhosis
Pneumonitis (hypersensitivity reaction)
Infection risk
Teratogenic and abortifacient
How is MTX monitored for toxicity?
Baseline CXR
FBC, LFT, U&Es, creatinine (baseline and monthly)
Indications for sulfasalazine?
RA and IBD
What is sulfasalazine made up of?
5-aminosalicyclate (5-ASA) and sulfapyridine
What is the absorption of sulfasalazine?
Travels the length of the upper GI tract where it is poorly absorbed until the colon
In the colon, bacterial action causes the breakdown of sulfasalazine into 5-ASA and sulfapyridine (5-ASA is the active component)
How is sulfasalazine thought to treat RA?
Inhibit T-cell proliferation and IL-2 production, may cause T-cell apoptosis
Reduce degranulation and chemotaxis of neutrophils
ADRs of sulfasalazine?
Nashua, fatigue, headache most common
Myelosuppression, hepatitis, allergic rash
Safe in pregnancy
Why does sulfasalazine contain the sulphapyridine moiety if this is what is responsible for most ADRs?
Allows 5-ASA to get to the colon
When is anti-TNF prescribed in RA?
After they have trialled methotrexate and one other DMARD
Why would anti-TNFs be stopped?
If there are any adverse events
If there is failure to respond after 6 months
(Very expensive and bad ADR profile)
Name some anti-TNF drugs
Infliximab
Etanercept
Adlimumab
Mechanism of action of anti-TNF?
Blocks TNF-α leading to
-reduced inflammation - affects cytokine cascade, recruits leukocytes to joints leading to elaboration of adhesion molecules and production of chemokines
- reduced angiogenesis - due to reduced VEGF and IL-8 levels
- reduced joint destruction - due to less bone resorption and erosion, less MMPs and other destructive enzymes, less cartilage breakdown
ADRs of anti-TNF agents?
Increased risk of new malignancy in those with prior malignancy
Risk of infection similar to other DMARDs
Increased risk of skin/soft tissue infections
TB reactivation and other intracellular bacterial infections
Rituximab - development of hypogammaglobulinaemia
What does rituximab do?
Binds specifically to CD20 found on a subset of B cells
- leads to activation of complement-mediated B cell lysis
- initiation of cell-mediated cytotoxicity via macrophages
- induction of apoptosis
