8.2 Immunosuppressants Flashcards
Give some examples of diseases that rheumatologists manage?
inflammatory arthritis (RA) systemic lupus erythematosus systemic vasculitis (giant cell arthritis)
what is rheumatoid arthritis?
An autoimmune multi-system disease. Initially localized to synovium. Inflammatory change and proliferation of synovium (pannus) leading to dissolution of cartilage and bone
what is the inflammatory pannus?
aggregation of the inflammatory cells causing the inflammation at the level of the joint. Multiple joints can be affected. Leads to proliferation of inflammatory cells and cytokines. Can lead to erosion of the joint due to dissolution
what is the pathophysiology of rheumatoid arthritis?
Synovitis forms a pannus that releases enzymes causing destruction of cartilage bone and ligaments. Occus in 3 stages. 1. initiation phase (due to non-specific inflammation). Factors allowing an abnormal immune response, once initiated, become permanent and chronic. These factors are genetic disorders which change regulation of the adaptive immune response. 2. amplification phase (due to T cell activation). Plasma cells derived from B lymphocytes produce rheumatoid factors and ACPA of the IgG and IgM classes. These activate macrophages. This contributes to local inflammation in a joint, specifically the synovium with edema, vasodilation and entry of activated T-cells. Synovial macrophages and dendritic cells function as antigen-presenting cells by expressing MHC class II molecules, which establishes the immune reaction in the tissue. 3. chronic inflammatory phase, with tissue injury resulting from the cytokines, IL–1, TNF-alpha, and IL–6. Cytokines and chemokines attract and accumulate immune cells, i.e. activated T- and B cells, monocytes and macrophages from activated fibroblast-like synoviocytes, in the joint space.
how does the ratio of proinflammatory factors and antiinflammatory factors vary in a person with RA compared to a person without?
Greater ratio of pro-inflammatory factors ( IL-1, IL-6, TNF alpha) to anti-inflammatory factors ( Il-4, TGF beta )
what are metalloproteinases?
a catalytic protease enzyme responsible for the erosions in rheumatoid arthritis
what are the clinical criteria used in the diagnosis of RA
Morning stiffness greater than 1 hour Arthritis of greater than 3 joints Arthritis of hand joints Symmetrical arthritis Rheumatoid nodules
what are the non-clinical criteria used in the diagnosis of RA?
blood test showing serum rheumatoid factor and anti-CCP antibodies
X ray changes (erosions at the joint)
what are the treatment goals in RA?
symptomatic relief
prevention of joint destruction ( cannot reverse previous erosions, just slow progression)
what are the signs and symptoms of systemic lupus erythematosus
mallor rash ulcers sjogren's syndrome GI upset extreme fatigue arthralgia/myalgia/arthritis/myositis raynauds alopecia anaemia and other blood abnormalities pregnancy complications. oedema hypertension renal failure
what is a mallor rash?
characteristic form of facial rash. It is often seen in lupus erythematosus. butterfly shaped with sparing of the nasolabial folds. Very photosensitive rash
what is vasculitis?
Vasculitis is an autoimmune disease that causes inflammation and narrowing of blood vessels (arteries, veins and capillaries).
what are the signs and symptoms of vasculitis
general symptoms - Fever, Headache, Fatigue, Weight loss, General aches and pains
GI - Dyspepsia, Ulcers and perforations.
Ears - Dizziness, ringing in the ears and abrupt hearing loss may occur.
Eyes - Giant cell arteritis can cause double vision and temporary or permanent blindness in one or both eyes.
peripheries - Numbness or weakness. The palms of the hands and soles of the feet might swell or harden.
Lungs - SoB, haemoptysis
Skin - Bleeding under the skin can show up as red spots. Vasculitis can also cause lumps or open sores on your skin.
what are the treatment goals of LSE and vasculitis?
- Symptomatic relief e.g arthralgia, Raynaud’s phenomenon
- Reduction in mortality
- Prevention of organ damage • Reduction in long term morbidity caused by disease and by drugs
what is the mechanism of action of corticosteroids?
To prevent IL-1 and IL-6 production by macrophages. Il-6 produces CRP which stimulates inflammation
Corticosteroids inhibit all stages of T-cell activation
give some examples of non biologics disease modifying anti-rheumatic drugs
sulphasalazine - used in autoimmune GI conditions (crohns)
hydrochloroquine - used in SLE
give some examples of biologic disease modifying anti-rheumatic drugs?
Anti-TNF agents
Rituximab
IL-6 inhibitors, JAK inhibitors
what are the indications of azathioprine?
SLE and vasculitis as maintenance therapy
RA
inflammatory bowel disease
(steroid sparing drug)
what are the ADRs of azathioprine?
atopic dermatitis bullous skin disease bone marrow suppression - monitor FBC increase risk of malignancy (all immunosuppressants) increased risk of infection hepatitis - monitor LFT
why is azathioprine described as a steroid sparing drug?
as long term azathioprine can be used instead of long term corticosteroids and has less burden of treatment associated with their use.
what are some of the ADRs associated with long term steroid use?
- increased appetite – potentially leading to weight gain acne
- thinned skin that bruises easily
- increased risk of infections
- mood changes, mood swings and depression
- diabetes
- high blood pressure
- osteoporosis (weak and brittle bones)
- withdrawal symptoms caused by suppression of the adrenal glands
- glaucoma
what test must a patient have before being prescribed azathioprine?
TPMT activity test.
azathioprine is metabolised to the active metabolite 6-MP.
6-MP is metabolised by thiopurine methyltransferase (TPMT)
TPMT gene is highly polymorphic and therefore individuals can vary markedly in the activity of TPMT
In individuals with low activity of TPMT there is an increased risk of myelosuppression
what is the mechanism of action of azathioprine?
Azathioprine is metabolised to 6-MP
6-MP is metabolised to TIMP.
anti-metabolite decreases DNA and RNA synthesis
what drug class are cyclosporin and tacrolimus?
calcineurin inhibitors (immunosuppressants)
what are the indications of cyclosporin and tacrolimus?
widely used in transplantation
atopic dermatitis
psoriasis
what are the ADRs of cyclosporin?
renal toxicity - need to check BP and eGFR regularly
give some examples of CYP P450 inducers?
rifampicin
carbemazepine
phenytoin
omeprazole
give some examples of CYP P450 inhibitors?
ciprofloxacin many antifungals fluoxetine paroxetine HIV antivirals (indinavir)
what is the mechanism of action of cyclosporin and tacrolimus
- Active against helper T-cells, preventing production of
IL-2 via calcineurin inhibition - Ciclosporin binds to cyclophilin protein
- Tacrolimus binds to tacrolimus-binding protein
- Drug/protein complexes bind calcineurin
- Calcineurin exerts phosphatase activity of activated T-cells then nuclear factor migration starts IL-2 transcription
what are the indications of mycophenolate mofetil?
transplantation - may monitor mycophenolic acid
induction and maintenance therapy in the treatment of lupus nephritis and vasculitis
what is the mechanism of action of mycophenolate mofetil?
Inhibits inosine monophosphate dehydrogenase (required for guanosine synthesis)
Impairs B- and T-cell proliferation
Spares other rapidly dividing cells (due to guanosine salvage pathways in other cells)
Is a prodrug
what are the ADRs of mycophenolate mofetil?
nausea, vomiting, diarrhoea
mucositis
myelosuppression
what are the indications of cyclophosphamide?
effective in inducing remission in many autoimmune conditions
– Lymphoma, leukaemia, solid cancers
– Lupus nephritis
– Wegener’s granulomatosis (ANCA-vasculitis)
what is the mechanism of action of cyclophosphamide?
Alkylating agent -cross links DNA so that it cannot replicate
Many immunological effects:
– suppresses T cell activity
– suppresses B cell activity
what are the pharmacokinetics of cyclophosphamide?
Cyclophosphamide is excreted by the kidney so require good renal function
what is haemorrhagic cystitis?
inflammation of the urinary bladder that results in bleeding. An ADR of cyclophosphamide
how does cyclophosphamide cause haemorrhagic cystitis?
Acrolein, a metabolite of cyclophosphamide is toxic to the bladder epithelium and can lead to hemorrhagic cystitis
how is haemorrhagic cystitis prevented in cyclophosphamide use?
aggressive hydration and/or Mesna
what are the important considerations when prescribing cyclophosphamide?
• Mycophenolate mofetil safer and as effective in lupus nephritis
• Significant toxicity
– increased risk of bladder cancer, lymphoma and leukaemia
– Infertility: Risk relates to cumulative dose and patient age
– monitor FBC
– Adjust dose in renal impairment
what drugs may be co-prescribed with cyclophosphamide to reduce the occurrence of ADRs?
Mesna - reduces risk of haemorrhagic cystitis
Gonadotropin receptor antagonist - give to women to protect eggs and prevent infertility
what are the indications of methotrexate?
rheumatoid arthritis
malignancy
psoriasis
crohn’s disease
Unlicensed roles: Inflammatory myopathies, vasculitis, steroid-sparing agent in asthma
abortifacient in ectopic pregnancy - double dose
what are myopathies?
Myopathies are diseases of skeletal muscle which are not caused by nerve disorders. These diseases cause the skeletal or voluntary muscles to become weak or wasted.
what is the mechanism of action of methotrexate with cancer treatment?
• Methotrexate competitively and reversibly inhibits dihydrofolate reductase (DHFR)
• The affinity of methotrexate for DHFR is 1000X that of folate for DHFR.
• Dihydrofolate reductase catalyses the conversion of dihydrofolate to the active tetrahydrofolate the key carrier of one-carbon units in
purine and thymidine synthesis
• Methotrexate therefore inhibits the production of tetrahydrofolate and inhibits the synthesis of DNA, RNA and proteins
• Methotrexate acts during DNA and RNA synthesis hence cytotoxic during S-phase of the cell cycle. Greater toxic effect on rapidly
dividing cells which replicate their DNA more frequently
what drugs must be prescribed alongside methotrexate?
contraceptive for women of childbearing age
folic acid supplementation - helps prevent mucositis and myelosuppression
what are the pharmacokinetics of methotrexate?
- Administered PO, IM or S/C • In patients taking PO with partial response or with nausea then swap to s/c
- WEEKLY NOT DAILY DOSING, metabolites have long half lives
- 50% protein bound -NSAIDs displace
- Renal excretion
what are the benefits of treatment with methotrexate?
gold standard for treatment of RA well tolerated 50% of patients continue the drug for >5 years, longer than any other DMARD Improved QOL Slows development of joint damage Anchor drug for DMARD combinations
what are the ADRs associated with methotrexate?
- mucositis
- marrow suppression/ myelosuppression
- Highly teratogenic, abortifacient
- hepatitis, cirrhosis,
- pneumonitis
- infection risk
what is the mechanism of action of sulfasalazine
T-cell - inhibition of proliferation, possible T cell apoptosis, inhibition of IL-2 production
Neutrophil - reduced chemotaxis and reduced degranulation so cannot release cytokines and produce inflammation
what is sulfasalazine?
A conjugate of a salicylate (5aminosalicylic acid, 5ASA)
and a sulfapyridine molecule
what are the indications of sulfasalazine?
crohns disease - sulfasalazine is poorly absorbed and therefore its main activity is within the intestine so good for inflammatory bowel diseases
what are the ADRs of sulfasalazine?
• Mainly due to sulfapyridine moiety – myelosuppression – hepatitis – Rash • Milder side effects – nausea – abdo pain/vomiting
why is sulfasalazine more preferable than other immunosuppressants?
- Long term blood monitoring not always needed
- Very few drug interactions
- No carcinogenic potential • Safe in pregnancy
what are biologicals?
- Extracted from living systems e.g. whole blood + blood components, stem cell therapy
- Recombinant DNA technology producing substances that are (nearly) identical to the body’s own key signalling proteins e.g. growth hormone, erythropoietin
- Monoclonal antibodies “custom-designed“ made specifically to block any given substance in the body, or to target any specific cell type
- Receptor constructs (fusion proteins), usually based on a naturally- occurring receptor, acting to block it
what are the effects of blocking TNF-alpha?
Decrease Inflammation - decrease Cytokine cascade - decrease Recruitment of leukocytes to joint. Prevents elaboration of adhesion molecules and production of chemokines Decrease Angiogenesis - decrease VEGF levels Decrease Joint destruction - decrease MMPs and other destructive enzymes - decrease Bone resorption and erosion - decrease Cartilage breakdown
give a common indication for anti-TNF therapy
to treat latent TB - as identified by the quantiferon test.
TNF-alpha is essential for development and maintenance of granulomata. TNF-alpha is released by macrophages in response to mycobacterium Tb infection
what drug class is rituximab?
monoclonal antibody
what is the indication of rituximab?
RA
what is the mechanism of action of rituximab?
binds specifically to a unique cell- surface marker CD20, which is found on a subset of B cells but not on stem cells, pro-B cells, plasma cells or any other cell type
Rituximab causes B cell apoptosis
what is the function of B cells?
present antigen to T cells produce cytokines
produce antibodies