Rheumatoid Arthritis

Question 1

Differences between osteoarthritis and rheumatoid arthritis

Answer 1

Breakdown of cartilage due to unusual stress or injury vs systemic autoimmune disease with persistent inflammatory synovitis, cartilage destruction and bone erosions, symmetric polyarthritis, joint deformities, women > men

Question 2

Pathophysiology of rheumatoid arthritis - environment/genetic susceptibility

Answer 2

environment: smoking, microorganisms, stress
genotype: HLA-DR4 alleles, PTPN22, other genes

Question 3

Pathophysiology of RA - pre-articular phase/lymphoid phase

Answer 3

rheumatoid factor (alpha-IgG abs)
citrullinated cyclic peptide abs
collagen-specific abs

Question 4

Pathophys of RA - transition phase

Answer 4

microbial insult, biomechanical events, neurological events, microvascular dysfunction
T cell and B cell tolerance is breached
mechanism not well defined

Question 5

Pathophys of RA - articular phase

Answer 5

inflammation moves into synovium
destruction of cartilage and bone ensues
cardiovascular disease, osteoporosis, functional decline

Question 6

Mechanism of destruction of cartilage and erosion of bone in RA

Answer 6

Thelper17 produces IL-17 and IL-1, activating synovial fibroblasts and effecting chondrocytes
Synovial fibroblasts produce TNFalpha, IL-1 and invade cartilage
Chondrocytes produce ADAMTS (disintegrin and metalloproteinase thrombospondin) and MMP (matrix metalloproteinase) and begin to degrade matrix

IL-17, IL-7, IL-1, and TNF also activate RANKL which activate osteoclast precursor cell to differentiate into osteoclasts

Question 7

DMARDs mech of action

Answer 7

DMARD used in patients whose RA is refractory to NSAIDs

slow acting, with a delay of 1-6 months

immunosuppression of the autoimmune response

Question 8

Small molecule DMARDs vs BRMs - when to use?

Answer 8

DMARD started within 3 months of Dx

BRM +/- DMARD if unresponsive to one or more DMARDs

BRMs are generally not combined (high risk of infection)

Question 9

NSAIDs

Answer 9

used for osteoarthritis and early stage rheumatoid arthritis

Question 10

ACR20

Answer 10

American College of Rheumatology Criteria - % patients showing a 20% improvement in tender and swollen joint count, and in 3 of the following:

• acute phase reactant (sed rate)
• global patient assessment
• global physician assessment
• patient assessment of pain
• degree of disability

Question 11

radiological exam ACR criteria

Answer 11

% of patients showing no further erosion or joint narrowing as assessed by xray

Question 12

glucocorticoids

Answer 12

inhibition of gene expression

Question 13

methotrexate

Answer 13

inhibition of clonal expansion of lymphocytes (antiproliferative and proapoptotic effect)

methotrexate inhibits 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase and thymidylate synthetase –> decreases purine and pyrimidine synthesis

Question 14

rituximab

Answer 14

humanized monoclonal antibody against CD20 (a B cell marker), reduces activation of T cells

warning: serious infections, fatal infusion reactions

Question 15

abatacept

Answer 15

inhibition of co-stimulation of T cells by APCs (inhibits T cell activation)

serious infections, slightly increased risk of lymphomas

may be combined with other DMARDs but not with other BRMs

Question 16

leflunomide

Answer 16

prodrug for a pyrimidine synthesis inhibitor; depletes pyrimidines (uracil and cytosine) and inhibits T cell proliferation

once/day oral dosing; undergoes extensive enterohepatic recirculation (T1/2 = 19 days)

warning: embryo-fetal toxicity, hepatic toxicity

Question 17

methotrexate warning

Answer 17

bone marrow suppression, hepatotoxicity, pneumonitis, fetal death or developmental abnormalities, contraindicated in pregnancy

Question 18

hydroxychloroquine

Answer 18

accumulates in lysosomes and inhibits protein secretion

retinal toxicity (reversible)

usually combined with methotrexate if response is not adequate (reduces clearance of methotrexate)

Question 19

sulfasalazine

Answer 19

prodrug cleaved by colon bacteria into sulfapyridine and 5 aminosalicylic acid
suppresses release of cytokines from macrophages
delay of several months
monitor for myelosuppression

Question 20

tofacitinib

Answer 20

JAK 1,2,3 inhibitor - prevents cytokine signaling and inactivation of gene transcription
used for moderate-severe RA after inadequate response to MTX
efficacy at 6 months

Question 21

tofacitinib adverse reactions and contraindications

Answer 21

ADRs - infections, anemia, lymphopenia, neutropenia
serious infections and malignancies
may be used with methotrexate, but avoid with other immunosuppressants and other CYP3A4 substrates

Question 22

recognize TNFalpha and prevent from binding to its receptor

Answer 22

adalimumab (all human; Humira) - sub Q every 2 weeks

infliximab (human FC, mouse variable) - IV every 8 weeks

etanercept (human FC, TNF receptor extracellular domain) -sub Q every week

Question 23

TNF alpha inhibitors boxed warning

Answer 23

serious infections

Question 24

IL-1 inhibition

Answer 24

kineret (anakinra) (human/receptor combo) - 153 amino acid peptide secreted by immune cells, endothelial cells, adipocytes - for RA; monitor for neutropenia

canakinumab - IL-1 neutralizing human mAb
rilonacept - IL-1 binding fusion protein
both for juvenile idiopathic arthritis

Question 25

tocilizumab

Answer 25

IL-6 receptor antagonist; co-administered with MTX for RA

Question 26

ustekinumab, secukinumab

Answer 26

IL-12 and 23 neutralizing human mAB, IL-17 human mAB

for psoriatic arthritis

Question 27

legacy RA drugs

Answer 27

general immunosuppressants

gold
azathioprine
d-penicillamine
cyclosporine
cyclophosphamide
minoclycline