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
