DMARDs

Question 1

what is rheumatoid arthritis

Answer 1

rheumatoid arthritis is an autoimmune disease that attacks the synovial membranes causing it to produce a lot of fluid , which can later damage the cartilage
ligaments stabilise the joint, the fibrous capsule protects the synovial membrane which produces synovial fluid that lubricates and protects the joint
generally affect women more, affects joints symmetrically, more affects smaller joints

Question 2

cells involved in RA

Answer 2

T cells and macrophages are activated and release proinflammatory cytokines such as TNF alpha and interlukin-1, il-6, and il-8
which activate osteoclasts, chondrocytes, and fibroblasts, which break down bone and cause more fluids to form
osteoclasts produce matrix metalloproteinases which destroy bone and cartilage

Question 3

clinical manifestation of RA

Answer 3

Early on causes fatigue and whiteness. hands are usually the first joints affected. the joints swell causing them to become stiff and sore
after it progresses the disease can cause significant deformities and disability if the joints become excessively damaged
Ra is a multisystem disease that affects more than just joints, other symptoms include myopathy, Raynaud’s syndrome, pleural effusions

Question 4

psoriasis and psoriatic arthritis causes

Answer 4

although skin cells known as keratinocytes usually replace every 28-30 days, in psoriasis they replace every 3-5 days. this causes skin cells to build up on the surface of the skin
it is thought that psoriasis is caused by an immune response that releases cytokines including interferon gamma (and tnf and il-1 and il-6)

Question 5

psoriasis symptoms

Answer 5

itching, cracked skin, small scaling spots, red patches on skin, soreness, thickened nails, swollen and stiff joints

Question 6

Psoriatic arthritis

Answer 6

joint inflammation due to psoriasis
causes pain and swelling in joints and scaling skin on patches of the skin
symptoms are: joint swelling, nail lesions and pitting, grey scaly spots on scalp elbows knees or end of spine swelling of fingers or toes to look like sausages

Question 7

treatments of ra and pa

Answer 7

non-pharmacological: education, physiotherapy and orthopaedic measures (gentle exercise every day)
pharmacological: DMARDs, anti-inflammatories and analgesics
dmards can reverse or slow disease progression, and other drugs cant, but dmards take time to kick in so anti-inflammatory drugs are used in the mean time to relieve some symptoms

Question 8

Methotrexate. overview, pharmacokinetics, side effects

Answer 8

DRUG OF CHOICE FOR RA
inhibits the metabolism of folic acid, and therefore prevents the purine synthesis cells require for proliferation
at low does for ra, at high doses for cancer

can go orally, IM, IV.
33% bioavailable via oral route due to being inactivated by intestinal bacteria
75% bioavailable via intramuscular route
50% protein bound
when taken up by cell its retained for weeks
metabolised by the liver and excreted by the kidney
the day after the methotrexate dose, 5mg of folic acid is given

bone marrow toxicity (wont produce red blood cells, platelets, or leukocytes, ergo anaemia, leukopenia, thrombocytopenia)
opportunistic infections, eg TB
pulmonary toxicity - fibrosis due to lung fibroblasts being stimulated
hepatotoxicity and nephrotoxicity
increases risk of skin cancer

Question 9

Leflunomide

Answer 9

prodrug
inhibits enzyme dihydroorotate which use used in the synthesis of DNA and RNA
generally works as well as methotrexate
well tolerated but long-term research is limited

Question 10

methotrexate and leflunomide CONTRAINDICATION

Answer 10

PREGNANCY
teratogenic due to the inhibition of DNA synth
should only be given to women of childbaring age if she has no other choices and she uses effective contraceptive measures

Question 11

Hydroxychloroquine

Answer 11

not often used in ra anymore due to side effect of blindness
may inhibit lymphocyte proliferation, antigen presentation, free radical generation, and arachidonic acid cascade

Question 12

sulfasalazine

Answer 12

salicylic acid and sulphapyridine
mechanism of action unknown
given orally but very badly absorbed
side effects: gastrointestinal toxicity (from the salicylic acid), leukopenia, liver toxicity, skin reactions (from the sulphapyridine)

Question 13

cyclosporin A

Answer 13

immunosuppressant
not used for more than 3 months due to toxicity
reduces T cell activation
oral/iv route
can cause systemic and renal vasoconstriction
side effects: bone marrow toxicity, opportunistic infections, hypertension, kidney and liver toxicity, diabetes due to glucose tolerance and affected insulin production

Question 14

azathioprine

Answer 14

pro-drug. active metabolite is called 6-mercaptopurine
antimetabolite - inhibits purine synthesis necessary for cell proliferation especially leukocytes and lymphocytes
oral/iv

Question 15

cyclophosphamide

Answer 15

pro-drug
alkylating agent - puts alkyl groups onto things (cellular constituents)
forms covalent bonds with nucleotides of DNA, which interferes with transcription and replication, and leading to cell death
also treats cancer
produces two metabolites: phosphoramide mustard interacts with DNA, acrolein causes haemorrhagic cystitis which is prevented by taking Mensa

Question 16

aurotherapy

Answer 16

gold
not used often now, unknown mechanism of action
aurothiomalate is given as a deep intramuscular injection in active progressive RA
renal toxicity

Question 17

SIDE EFFECT SLIDE, IDK HOW TO DO THIS, FUTURE ME HELLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLP

Answer 17

j

Question 18

DMARD prescribing

Answer 18

depends on the patient
in newly diagnosed active RA, a combination of DMARDs (including methotrexate and at least one other DMARD) and a short term corticosteroid should be given, ideally within 3 months of symptoms
if the patient responds well after 6-12 months, then it can be reduced to the minimum clinically effective dose
if combination therapy is not possible, then monotherapy with a suitable DMARD is given. dose is rapidly increased until clinically effective

Question 19

cytokines

Answer 19

soluble low molecular weight peptides that are produced de novo synthesis by a wide variety of cell types
nomenclature: based on presumed targets (interleukin - leukocytes) or presumed functions (tumour necrosis factor)
required for normal innate and adaptive immune systems, but overexpression or action of cytokines can cause various immune, inflammatory, in infectious diseases

Question 20

closer look at
IL-1, IL-6, IL-12, IL-17, TNF-alpha

Answer 20

IL-1: receptor: IL-1R. produced by: monocytes, macrophages, B cells, epithelial cells, endothelial cells. Target: pretty much all cells. Activity: adhesion, migration, acute phase proteins, fever haematopoiesis
IL-6: receptor: IL-6R. produced by: monocytes, macrophages, B cells, epithelial cells, endothelial cells. Target: T cells, B cells, epithelial cells, monocytes, macrophages, hepatocytes. activity: acute phase protein production, B cell differentiation, osteoclast growth
IL-12: receptor: IL-12R. Produced by: activated macrophages, dendritic cells, neutrophils. target: T cells and natural killer cells. activity: Th1 (kills intracellular parasites and causes autoimmunity) cell formation, CD8 + CTL (cytotoxic T lymphocyte) activity
IL-17: receptor: IL-17R. produced by: CD4 T cells. Target: fibroblasts, endothelial cells, epithelial cells. activity: cytokine secretion promoting Th1 response
TNF alpha: receptor: TNFR. produced by: monocytes, macrophages, mast cells, basophils, eosinophils, natural killer cells, B cells, T cells, fibroblasts, epithelial cells. target: all cells except RBCs. activity: fever, anorexia, shock, enhanced leukocyte and natural killer cytotoxicity, acute phase protein and proinflammatory cytokine production by cleaveage

Question 21

spondyloarthritis

Answer 21

aka ankylosing spondylitis
spinal and peripheral joint arthritis
can cause ligaments and tendons to become inflamed where it touches the bone, ocular or cardiac manifestations, leaning forward because the vertebrae have fused together
probably caused by tnf activating interleukins that activate osteoclasts that chew up bone

Question 22

TNF receptors

Answer 22

two main types: tnf receptor 1 (p55) and tnf receptor 2 (p75)
the receptors embedded in cells Do Things, but there’s versions that float around in the blood and mop up tnf and are part of the negative feedback loop that moderates the inflammatory response

Question 23

anti-tnf alpha biologics for rheumatoid arthritis

Answer 23

ENTEROCEPT: it resembles the soluble TNF receptor. its a human tnfr2 attached to the igg constant region. stops tnf from getting to actual receptors. good for ra and IBD (which can affect joints and eyes)
all these are antibodies, and good for ra, juvenile ra, and psoriasis. can bind to both membrane bound and floating tnf, and can sometimes kill receptor cells like macrophages
infliximab - 75% human, 25% mouse. given IV infusion every 8 weeks. can cause allergic reaction so have to be observed in hospital for 4 hours after infusion
adalimumab: igg monoclonal antibody. given sc every 2 weeks, as it is human has no reaction so can be given at home
certolizumab pegol: humanised murine antibody. given subcutaneously
golimumab: sc injection 1 per month, better pka, and has very few complaints

Question 24

anakinra

Answer 24

il-1 receptor antagonist, inhibits both isoforms
for ra
adverse effect: opportunistic infections
DO NOY CO-ADMINISTER WITH TNF BLOCKERS

Question 25

tocilizumab

Answer 25

anti-IL-6 receptor antibody (recombinant) for severe RA, and when anti-tnf-alpha therapy is contraindicated or non-responsive iv infusion

Question 26

secukinumab

Answer 26

human igg that binds to IL-17A IL-17 (especially the a and f parts of the family) works synergistically with TNF to increase response for active psoriatic arthritis, ankylosing spondylitis, plaque psoriasis used when a patient has no response to TNF blockers

Question 27

ustekinumab

Answer 27

anti-il-12/23 human mab Il-12 and 23 have the same P40 subunit. so this binds to that subunit and prevents it from bind to IL-12Rb1 sc week 0, week 4, then every 12 weeks for active psoriatic arthritis that is not responding to conventional treatment

Question 28

major safety issues in biologic therapy

Answer 28

infections - due to the immunosuppressing effects of the drugs infusion/injection site reactions - more common with chimeric drugs. if infliximab must be given then the patient can be premedicated with an antihistamine or corticosteroid to reduce reaction autoimmune diseases - often by decreasing TNF you increase IGG causing psoriasis that goes away with anti-tnf treatment ends malignancy - stopped body's ability to stop cancer cell proliferation immunogenicity - forming antibodies to the antibodies. 25% of patients don't respond to infliximab after a year use in pregnancy- infliximab is not suitable in pregnancy, the others are debated. adalimumab increases risk of infections so no live vaccines should be given to babies until at least 5 weeks after last dose

Question 29

quick run down on how dendritic cells, b cells, and t cells work

Answer 29

the dendritic cell eats up an antigen and breaks it down into a smaller peptides called epitopes. this epitope is shown to the T cell b cells can also present to t cells. the b cells CD80 and CD86 receptors interact with the T cell CTLA-4 receptor. b cells can be activated by t cells or by a number of other receptors. such as by B cell activating factor (BAFF)

Question 30

Rituximab

Answer 30

chimeric (75% human) antibody that targets the CD20 b cell antigen for people with ra that do not respond to anti tnf therapies has 3 mechanisms antibody-dependant cellular cytotoxicity: macrophage does not recognise CD20 + antibody as part of the body so it kills the b cell compliment-dependant cytotoxicity: the compliment protein binds to the antibody and activates the compliment which kills the b cell direct apoptosis: kills the cell directly by binding to the receptor given as 2 infusions 2 weeks apart (with side effects mostly occurring on the first infusion). 100mg of methylprednisolone given with each dose takes 3-4 months to kick in, with possible retreatment at 6 months

Question 31

b cell depletion

Answer 31

by having fewer b cells you: have fewer activated t cells so less cytokines stop antibody, rheumatoid factor, and cytokine release, therefore stopping disease progression

Question 32

Belimumab

Answer 32

human antibody that inhibits B Lymphocyte Stimulator (BLyS) and B cell activating factor (BAFF) for systemic lupus erythematosus - chronic multisystem inflammatory disease. autoimmune. flares and remission. commonly have butterfly shaped rash on face, can affect joints, cause strokes or seizures, proteinuria, alopecia BAFF a cytokine that is required to activate B cells and turn them into plasma cells by interacting with a few different receptors, and is released by macrophages and monocytes. given in conjunction with main therapy to increase its effectiveness in patients that who are not responding adequately to the main therapy alone (aka hydroxy cloroqualone (preferred), methotrexate or azathionine) given as iv infusions, 10mg/kg every 2 weeks for 3 doses, then 10mg/kg every 4 weeks, with treatment review if no response within 6 months premedicate with antihistamines should be observed for several hours after the first 2 doses

Question 33

abatacept

Answer 33

fusion protein that is the constant region of the IGG, with the extracellular domain of CTLA-4 (t cell receptor) basically prevents t cells from binding to b cells and having antigens presented to them by that route for moderate to severe active ra in combination with methotrexate in people who are not responding to other antirheumatic drugs. do not give in conjunction with TNF inhibitors given week 0, 2, 4, and then every 4 weeks for about 1 year. infusion over 30 minutes well tolerated given at home

Question 34

osteoarthritis

Answer 34

degenerative arthritis. condition in which low-grade inflammation results in pain in the joints, caused by the wearing of the cartilage that covers and acts as a cushion in joints age related disease chondrocytes are activated by a stimulus (eg previous joint injury, obesity, inflammation) and release low grade inflammation via IL-1 and TNF, these activate matrix metalloproteinases (mmps) that break down cartilage causes joint pain, stiffness that lasts about 30 minutes in the morning, and deformities in later stages

Question 35

treatment of osteoarthritis

Answer 35

non-pharmacological: weight control, very gentle exercise pain relief: paracetamol (but no anti-inflammatory effects), nsaids (with preference for COX-2 inhibitors). opioid analgesics might be given to pain that cannot be treated with non-opioids stimulation of cartilage repair: glucosamine and chondroitin which are structural components of cartilage future treatments: anti-cytokines, mmp inhibitors surgery: arthroscopy, joint replacements (for those with deformities)