ic13 drugs for OA, RA, gout

Question 1

what is “osteoarthritis” and what is the etiology of OA

Answer 1

OA is a degenerative joint disease where there is a progressive and irreversible loss of cartilage

it is the most common inflamm joint disorder

inflamm and repetitive activity involving articular cartilage and subarticular bones with secondary effects on synovium, muscle and nerves

Question 2

what are the risk factors of OA

Answer 2

age, obesity

Question 3

what are the features of OA

Answer 3

i) joint space narrowing
ii) subchondral sclerosis (thickening of bones affected by OA)
iii) subchondral cysts (fluid filled sacs in one or both of the bones that forms a joint)
iv) osteophyte lipping (osteophytes are bone growths)
v) loose bodies (small fragments of articular cartilage that break off in the knee joint)

Question 4

what are the types of OA

Answer 4

i) primary generalised OA
ii) erosive inflamm OA
iii) hypertrophic OA

Question 5

what is the pharmacotx for OA

Answer 5

1. pain relief w/wo anti-inflamm
   i) paracetamol
   ii) non selective NSAIDs (note that diclofenac accumulates in synovial fluid in joints and have longer half life there = incr effect and decr GI s/e)
   iii) coxibs
   iv) corticosteroids
2. symptomatic slow acting drugs for OA (SYSADOA)
   i) intra-articular hyaluronic acid (HA)

Question 6

what is the func of hyaluronic acid (HA) and what is the purpose of intra-articular HA in managing OA

Answer 6

HA is a large glycosaminoglycan that is naturally found in synovial fluid

injecting exogenous HA can provide additional shock absorption, traumatic energy dissipation, protective coating of cartilage, lubrication, reduces pain and stiffness

it also induces biosynthesis of HA and extracellular matrix

Question 7

what is “gout” and what is the etiology of gout

Answer 7

gout is a metabolic disorder where there is hyperuricemia (serum uric acid level >6.8mg/dl) leading to MSU crystal depositions and tophi growths

it is a common inflamm joint disorder >40yo

it might also be attributed to drug induced hyperuricemia (thiazide, loop diuretics, low dose aspirin, cyclosporine)

Question 8

what are the two main immune system and what are the sub compartments of the immune systems (and so which is the one mainly involved in gout)

Answer 8

1. innate immunity
   i) complement
   ii) phagocytes (neutrophils, macrophages)
2. adaptive immunity
   i) B cells
   ii) T cells

phagocytes are the one mainly involved in the inflamm immune responses assoc w gout - phagocytes attempt to phagocytose uric crystals but are unsuccessful and gets damaged which leads to release of factors that recruit even more phagocytic cells which releases even more cytokines, leading to a positive feedback loop of inflamm that leads to severe inflamm and pain thus resulting in gouty arthritis

Question 9

compare the main compartments of the immune system involved with gout vs RA

Answer 9

gout: phagocyte
RA: phagocyte, Bcells, Tcells (in incr order of involvement)

Question 10

what happens when immune cells are activated (compare the actions of immune cells in gout vs RA)

Answer 10

i) proliferate
ii) produces cytokines
iii) adhesion and trafficking (eg. migration and movement for phagocytosis)

in gout: activated immune cells mainly result in ii) and iii)
in RA: activated immune cells result in all three

Question 11

what are the risk factors for gout

Answer 11

i) gender (males:women = 5:1) and tend to only happen after menopause for women and after menopause risk will catch up with men as age incr
ii) age
iii) diet (high purine)
iv) comorbs: HTN, DM, hyperlipidemia

Question 12

what are the drugs that can induce hyperuricemia

Answer 12

thiazides/ loop diuretics, low dose aspirin, cyclosporine

Question 13

what are the features of gout

Answer 13

i) high serum uric acid level >6.8mg/dl
ii) monosodium urate (MSU) crystal depositions in joint or cartilage
iii) topaceous gout: tissue growth around extracellular crystal deposits in soft tissue near joints (less common presentation)

Question 14

what is “tophi”

Answer 14

tissue growth around extracellular crystal deposits in soft tissue near joints

Question 15

what is the pathophysiology of gout

Answer 15

hyperuricemia -> precipitation of urate crystals in joint -> path 1 and path 2

PATH ONE:
urate crystals in joint lead to complement activation (immune cells are activated) that leads to neutrophil chemotaxis (movement in response to stimulus) -> phagocytosis of crystals by neutrophils [that releases LTB4 and PG and free radicals] -> lysis and activation of neutrophils along with release of crystals -> [ ] and release of lysosomal enzymes contributes to tissue injury and inflamm
*[ ] also further enhances neutrophil chemotaxis

PATH TWO:
urate crystals in joints leads to phagocytosis by monocytes -> release of IL1, TNF and IL6 which leads to neutrophil chemotaxis -> release of proteases from cartilage and synovium -> tissue injury and inflamm

Question 16

what are the goals of tx and pharmacotx for gout

Answer 16

goals:
i) relieve acute gouty attack
ii) prevent recurrent gouty episodes

pharmacotx:
1. anti inflamm to decr ongoing feedback loop of inflamm and pain during an acute gouty attack
i) non selective NSAIDs
ii) coxibs
iii) glucocorticoids
iv) colchicine (reduce leukocyte migration into joints)

2. urate lowering therapy (ULT) to prevent gouty episode
   i) xanthine oxidase inhibitors (inhibit production of urate)
   ii) uricosuric agents (incr excretion of urate through kidneys)

Question 17

list eg. of drugs for each drug class that can be used for management of gout

Answer 17

non selective NSAIDs: naproxen, indomethacin

coxibs: celecoxib

glucocorticoids: prednisolone

colchicine

xanthine oxidase inhibitors: allopurinol, febuxostat

uricosuric agents: probenecid

Question 18

what to note when wanting to start ULT (elaborate on each thing to note)

Answer 18

1. do not start ULT during acute attacks but it is to be used instead between attacks to lower plasma level of uric acid
   i) starting ULT during attacks will drastically decr plasma uric acid conc which incr the gradient from joint to plasma thus causing an incr mobilisation of crystals out of joints
   ii) when crystals are stably within the joints, they are somewhat hidden and protected from immune cell attack vs if they mobilise out of the joint they will get recognised by immune cells which leads to phagocytosis by the immune cells that causes ongoing inflamm and pain
   iii) this will make the acute attack worse since there are more mobilisation of crystals out of the cells meaning even more recognition by immune cells and exacerbation of the feedback loop
   iv) if use uricosuric agents like probenecid which works by incr excretion of urate out through the kidneys which incr the risk of uric kidney stones formation as the kidney is unable to handle the additional amount of uric acid that is to be excreted bc there is already mobilisation of uric acid out of joints into the blood and out through the kidney during the attack
2. when ULT is initiated, it is often started with NSAIDs or corticosteroids or colchicine to decr the risk of triggering an acute attack
   i) after initial period of incr risk, the agent can be slowly withdrawn and continue monotx with ULT

Question 19

what is the moa and c/i of NSAIDs for a gouty attack, also list eg. of drugs in this class and identify which would likely be most suitable

Answer 19

moa: inhibit PG synthesis that is assoc w acute inflamm and sensitisation of pain responses, thus inhibiting urate crystal phagocytosis

c/i: low dose aspirin and salicylates (bc they have anti-uricosuric actions by blocking urate secretion that can precipitate gout or make ungoing gout worse)

non selective NSAIDs incl naproxen, indomethacin
coxibs: celecoxib

naproxen has relatively long half life

Question 20

what is a glucocorticoid used to manage acute gouty attacks

Answer 20

PO or intra articular prednisolone

Question 21

what is “colchicine”, what is its moa, effect and s/e

Answer 21

colchicine is an alkaloid isolated from colchicum autumnale

moa:
i) binds to tubulin and prevents tubulin polymerisation into microtubules (preventing microtubule polymerisation disrupts the cytoskeletal structure of the cells as it affects the transport of growth factors down the nerves to the muscles)
ii) inhibits leukocyte migration and phagocytosis
iii) inhibits LTB4 and PG production

effect: relieve pain and inflamm in acute gouty attack within 24-36h

s/e: N/V/D, abdominal pain, muscle weakness, abnormal bleeding, pale lips, change in urine amount

Question 22

why does GI s/e occur due to administration of colchicine and how can we avoid this s/e

Answer 22

it arises bc colchicine is an inhibitor of microtubule polymerisation so at higher conc it will prevent division and proliferation of cells which would have greatest impact on cells along GIT since they are the most rapidly dividing cells

since GI s/e are dose limiting, they can be avoided by careful titration (helps ensure compliance)

Question 23

list the eg. of xanthine oxidase inhibitors, consider what are the structural features, moa, therapeutic target, indications, s/e and any warnings

Answer 23

first line: allopurinol, second line: febuxostat

allopurinol is a structural analog of purines while febuxostat is a synthetic competitive inhibitor of XO and does not have structural similarities to purine

moa: anti-hyperuricemia agents that decr uric acid production by inhibiting xanthine oxidase which is responsible for converting hypoxanthine to xanthine and eventually to uric acid in the purine catabolism pathway

target: <6mg/dl

indications: delibitating gout attacks, chronic erosive arthritis, urate nephrolithiasis

s/e: N/V/D, skin rash, fever, sore throat, abdominal pain, dark urine, jaundice

warning:
i) allopurinol hypersensitivity syndrome (AHS)
ii) severe cutaneous adverse reaction (SCAR)

Question 24

what are the risk factors of SCAR assoc w xanthine oxidase inhibitors

Answer 24

i) renal impairment (CrCl <60)
ii) thiazide therapy
iii) HLAB*5801 (most common in Han Chinese, Thai, Korean)

Question 25

list the eg. of uricosuric agents, indications, moa, s/e and cautions

Answer 25

probenecid is a uricosuric agent

indications:
*not first line, given 2-3w after acute gouty attack
i) when allopurinol is c/i in tophaceous gout
ii) freq gouty attacks

moa:
i) inhibits proximal tubule anion transport
ii) inhibits uric acid reabsorption
thus incr uric acid excretion

s/e: N/V, painful urination, lower back pain, allergic rxn, rash

caution:
i) drink plenty of fluid to minimise risk of renal stone formation
ii) keep urine pH >6.0 by administration of alkaline eg. potassium citrate to help decr risk of uric acid kidney stone formation

Question 26

what is “rheumatoid arthritis” and what is the etiology and risk factors of RA

Answer 26

systemic chronic infamm autoimmune disease that affects many tissues but principally attacking the joints (commonly wrist, hands, elbows, knees) and also extra articular involvement of heart, skin, blood vessels muscles and lungs

primarily targets synovial tissues, bone erosion and joint deformitis

etiology of RA:
i) genetics: strongly assoc w HLA-DR4 molecules which are MHC class II molecules
ii) environment: autoAb (like rheumatoid factor RF and citrullinated protein Ab CPA) against cyclic citrullinated peptides which may contribute to joint lesions

risk factors:
i) women:men = 3:1

Question 27

what is the pathophysiology of RA

Answer 27

major pathologic changes are caused by cytokine mediated inflamm with CD4 T cells being the principle source of cytokines (TNFalpha, IL1, IL6, IFNgamma) which have effects on osteoclasts, fibroblasts and chondrocytes to produce metalloproteinases, which are implicated in the degradation of the extracellular matrix (ECM), along with other effector molecules and the migration of these polymorphonuclear cells due to the inflamm result in bone and cartilage erosion

Question 28

what are the autoAb assoc w RA what is the key func of these autoAb

Answer 28

i) rheumatoid factor (RF)
ii) citrullinated protein Ab (CPA)

these autoAb are impt for diagnostic purposes

Question 29

what are the features of RA

Answer 29

i) bilateral, symmetrical
ii) synovial inflamm (synovitis w chronic inflamm infiltrate, exudate, fibrin) leading to swelling and villous formation of the synovium
iii) formation of the pannus and destruction of the articular cartilage
iv) destruction of adjacent bone due to pannus formation thus resulting in joint deformity
v) formation of rheumatoid nodules

Question 30

what is a “pannus” formation and “rheumatoid nodules”

Answer 30

pannus is vascular granulation tissue that grows across the cartilage tissue

rheumatoid nodules is a specific type of granuloma characterised by central zone of fibrinoid necrosis

Question 31

what are the goals of tx for RA and how would RA be managed

Answer 31

goals of tx:
i) remission of sx involving the joints
ii) return of full func
iii) maintenance of remission w DMARD tx

pharmacotx:
1. csDMARDs
i) MTX (first line)
ii) sulfasalazine
iii) leflunomide
iv) hydroxychloroquine (best tolerated)
v) cyclosporin

2. tsDMARDs
   i) JAKi (tofacitinib, baracitinib)
3. bDMARDs
   i) anti TNFmAb (infliximab, adalimumab, etanercept)
   ii) IL1RA (anakinra)
   iii) anti IL6R mAb (tocilizumab)
   iv) anti CTLA4Ig (abatacept)
   v) anti CD20 (rituximab)
4. anti inflamm
   i) NSAIDs (for short term relief of pain and stiffness + PPI to reduce GI s/e)
   ii) corticosteroids (to bridge anti-inflamm tx w DMARD tx)

Question 32

are bDMARDs more potent than csDMARDs

Answer 32

no, they are often used as adjuncts to csDMARDs to reduce dose of csDMARDs

Question 33

what is the drug class, structure, advantages, indication, formulation types, moa and s/e (what is the rationale behind the s/e and how to manage the s/e) of MTX

Answer 33

MTX is a csDMARD

structure: folic acid analog

advantages:
i) long term efficacy
ii) acceptable toxicity
iii) low cost
iv) assoc w significantly lower mortality

indication: often combined w other csDMARDs for optimal effects

formulation types: PO, SQ, IM

moa:
i) major: incr adenosine levels by inhibiting 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase or IMP cyclohydrolase (ATIC)
ii) minor: inhibits dihydrofolate reductase and thymidylate synthetase

inhibition of ATIC causes decr purine synthesis and incr adenosine synthesis thus the resulting incr in extracellular adenosine levels and subsequent activation of A2a receptor has antiproliferative effects on Tcell and macrophage func, leading to anti inflamm effects due to decr in proinflamm cytokines, adhesion molecules, chemotaxis and phagocytosis + inhibition of DHFR also decr DNA methylation, decr purine synthesis, decr pyrimidine synthesis

s/e:
i) N/V, mouth and GI ulcers
ii) hair thinning
iii) leukopenia
iv) hepatic fibrosis
v) pneumonitis
(s/e occurs due to the minor pathway of MTX moa which at high doses will decr proliferation of other normal cell types as well eg. GI and hair follicular cells which are the two most rapidly proliferating cells thus most likely to be affected)
(s/e can be minimised by concom folic acid or folinic acid 12-24h after MTX)

Question 34

what is the rescue therapy for MTX toxicity and what is the rationale behind it

Answer 34

using folate

i) MTX inhibits DHFR which converts folate into folinic acid which is impt for production of nucleic acids like adenine, guanine, thymidine, methionine, serine which are all impt for cell proliferation
ii) thus folinic acid would be the best for rescue therapy for MTX toxicity since it would be rapidly converted into N5,N10-methylene FH4 and bypass DHFR activity
iii) but folate is much cheaper than folinic acid thus more commonly used
iv) but also means folate need higher doses else it would not efficiently rescue toxicity due to the depletion of N5,N10-methylene FH4 as DHFR is inhibited by MTX

Question 35

what is the drug class, metabolism, moa and s/e of sulfasalazine

Answer 35

sulfasalazine is a csDMARD

metabolism: into sulfapyridine (active) and 5-aminosalicylic acid

moa: unknown but poorly absorbed so may be mediated by effect on gut flora and leads to
i) decr IgA and IgM rheumatoid factors
ii) suppression of T and B cells and macrophages
iii) decr in inflamm cytokines TNFalpha, IL1, IL6

s/e:
i) N/V
ii) HA
iii) rash
iv) hemolytic anemia
v) neutropenia
vi) reversible infertility in men

Question 36

what is the drug class, metabolism, moa, s/e and warning for leflunomide

Answer 36

leflunomide is a csDMARD

metabolism: rapidly converted into teriflunomide (active metabolite)

moa:
i) inhibits dihydroorotate dehydrogenase
ii) decr pyrimidine synthesis and growth arrest at G1 phase
iii) inhibits T cell proliferation and B cell autoAb production
iv) inhibits NF-KB activation pro inflamm pathway

s/e:
i) D
ii) elevation of liver enzymes
iii) alopecia
iv) weight gain
v) teratogenic

warning:
i) very long half life (for years)
ii) leflunomide is recycled through the bile (released in bile and reabsorbed through small intestine) thus can use colestyramine, a bile salt binding resin, to wash out and incr excretion of leflunomide when needed (eg. before pregnancy)

Question 37

what is the drug class, additional indication, moa and s/e of chloroquine and hydroxychloroquine

Answer 37

chloroquine and hydroxychloroquine are csDMARD

they are also antimalarial agents

moa:
i) decr MHC class II expression and thus decr Ag presentation
ii) decr TNFalpha and IL1 and cartilage resorption
iii) has antioxidant activity

s/e:
i) N/V, stomach pain
ii) dizziness
iii) hair loss
iv) ocular toxicity

*note that hydrochloroquine is the best tolerated although not best efficacy (MTX)

Question 38

what is the “JAK STAT pathway”

Answer 38

it is an intracellular signal transduction pathway that can be triggered by numerous cytokines and lead to additional production of pro and anti inflamm cytokines and destructive enzymes

many cytokine receptors involve the JAKSTAT pathway and involve a number of different functions like T cell proliferation and other aspects of immune response

involves JAK1, JAK2, JAK3, TYK2 with JAK1 being the most common receptor involved in RA

Question 39

list eg. of JAKi and note whether they are selective

Answer 39

tofacitinib inhibits JAK1, JAK2, JAK3
baracitinib inhibits JAK1, JAK2

Question 40

what is the indication, moa, s/e and caution for JAKi

Answer 40

indication:
i) combi tx with MTX for moderate to severe RA
ii) monotx in cases of intolerance to MTX
iii) psoriatic arthritis

moa: janus kinase pathway inhibitor
i) blocks cytokine production by blocking JAK STAT activation of gene transcription

s/e:
i) cytopenia (neutrophils, lymphocytes, PLT, NK)
ii) immunosuppression = opportunistic infections (incr risk of herpes zoster infection esp in asians)
iii) anemia (affects JAK2 activation by EPO)
iv) hyperlipidemia (bc incr in total, LDL, HDL, cholesterol, TG)
(immunosuppression most common s/e)

warning: do not combine w bDMARDs bc risk of great additive effect and too great of an immunosuppression

Question 41

list the types of bDMARDs that are suitable for management of RA (drug class, formulation type, structure)

Answer 41

1. TNF signalling blocker
   i) infliximab (IV): chimeric IgG1 (25% mouse)
   ii) adalimumab (SQ): human IgG1
   iii) etanercept (SQ): decoy TNFR2 receptor IgG1 fusion protein (intercepts TNF alpha and beta)
   iv) golimumab (IV): human IgG1
2. IL1 signalling blocker
   i) anakinra (SQ): modified human IL1 RA protein (differs from sequence of endogenous protein by one methionine added to N terminus and is not glycosylated)
3. IL6 signalling blocker
   i) tocilizumab (IV): humanised IgG1 (reversible antagonist of IL6)

Question 42

compare between the different naming for biologics

Answer 42

li = target immune system
xi = chimeric
mu = human
zu = humanised (but not fully human)

Question 43

what are the eg. of TNF signalling blockers (formulation type) and what are their indications, s/e, c/i and monitoring

Answer 43

TNF signalling blockers are infliximab (IV), adalimumab (SQ), etanercept (SQ)

indication: RA pts who do not respond well with csDMARD and is given in combi w MTX

s/e:
i) resp infection
ii) skin infection
iii) incr risk of lymphoma, optic neuritis
iv) exaceration of multiple sclerosis
v) leukopenia
vi) aplastic anemia

c/i:
i) live vaccination
ii) hep B

monitoring: i) screen for latent or active TB

Question 44

what are the eg. of IL1 signalling blocker (formulation type) and what are their moa and s/e

Answer 44

anakinra (SQ) is a IL1 receptor antagonist

moa: binds to IL1 receptor and blocks signalling

s/e:
i) infections
ii) inj site rxn
*note that it is less effective than anti-TNFs

Question 45

what are the eg. of IL6 signalling blocker (formulation type) and what are their moa and s/e

Answer 45

tocilizumab (IV) is a anti-IL6mAb

moa: humanised mAb directed at IL6Ralpha chain, prevents binding of IL6 to IL6Ralpha and homodimerisation of IL6Rbeta signalling

s/e:
i) infections
ii) skin eruptions
iii) stomatitis
iv) fever
v) neutropenia
vi) incr ALT/AST
vii) hyperlipidemia
viii) interacts w 3A4, 1A2, 2C9 substrates

Question 46

what is interesting about the ddi of tocilizumab

Answer 46

tocilizumab is a protein based bDMARD and thus is largely cleared by proteolytic breakdown by proteolytic enzymes and thus would not expect them to have cyp interactions

but IL6 decr expression of cyp enzymes and tocilizumab’s inhibition of IL6 will result in an incr of cyp enzymes thus give rise to potential ddi

Question 47

what is an eg. of antiCTLA4 Ig (formulation type) and what is its moa and s/e

Answer 47

abatacept is an anti-CTLA4 Ig (IV)

moa:
i) recombinant fusion protein w CTLA4-Fc IgG1, binds to and inhibits CD80 and CD86 thus preventing CD28 activation on T cells (T cell therapy)

s/e:
i) resp infection in COPD
ii) incr lymphoma incidence

Question 48

what is an eg. of antiCD20 (formulation type) and what is its moa and s/e

Answer 48

rituximab is an antiCD20 Ig (IV)

moa:
i) chimeric IgG1 directed at CD20 on pre and mature B cells thus leading to depletion of CD20 B cells (B cell therapy)
ii) blocks Ag presentation, auto Ab and cytokine levels

s/e:
i) rash in first dose
ii) resp infection in COPD