Rheumatoid Arthritis Flashcards
Differences between osteoarthritis and rheumatoid arthritis
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
Pathophysiology of rheumatoid arthritis - environment/genetic susceptibility
environment: smoking, microorganisms, stress
genotype: HLA-DR4 alleles, PTPN22, other genes
Pathophysiology of RA - pre-articular phase/lymphoid phase
rheumatoid factor (alpha-IgG abs)
citrullinated cyclic peptide abs
collagen-specific abs
Pathophys of RA - transition phase
microbial insult, biomechanical events, neurological events, microvascular dysfunction
T cell and B cell tolerance is breached
mechanism not well defined
Pathophys of RA - articular phase
inflammation moves into synovium
destruction of cartilage and bone ensues
cardiovascular disease, osteoporosis, functional decline
Mechanism of destruction of cartilage and erosion of bone in RA
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
DMARDs mech of action
DMARD used in patients whose RA is refractory to NSAIDs
slow acting, with a delay of 1-6 months
immunosuppression of the autoimmune response
Small molecule DMARDs vs BRMs - when to use?
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)
NSAIDs
used for osteoarthritis and early stage rheumatoid arthritis
ACR20
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
radiological exam ACR criteria
% of patients showing no further erosion or joint narrowing as assessed by xray
glucocorticoids
inhibition of gene expression
methotrexate
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
rituximab
humanized monoclonal antibody against CD20 (a B cell marker), reduces activation of T cells
warning: serious infections, fatal infusion reactions
abatacept
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
leflunomide
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
methotrexate warning
bone marrow suppression, hepatotoxicity, pneumonitis, fetal death or developmental abnormalities, contraindicated in pregnancy
hydroxychloroquine
accumulates in lysosomes and inhibits protein secretion
retinal toxicity (reversible)
usually combined with methotrexate if response is not adequate (reduces clearance of methotrexate)
sulfasalazine
prodrug cleaved by colon bacteria into sulfapyridine and 5 aminosalicylic acid
suppresses release of cytokines from macrophages
delay of several months
monitor for myelosuppression
tofacitinib
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
tofacitinib adverse reactions and contraindications
ADRs - infections, anemia, lymphopenia, neutropenia
serious infections and malignancies
may be used with methotrexate, but avoid with other immunosuppressants and other CYP3A4 substrates
recognize TNFalpha and prevent from binding to its receptor
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
TNF alpha inhibitors boxed warning
serious infections
IL-1 inhibition
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
