Transcript Document

Kara Kliethermes
Jim Shinaberry
December 6, 2012
What is rheumatoid arthritis?
 What are the underlying mechanisms?
 Epidemiology
 Triggers and risk factors
 What leads to the development of RA?
 Can RA be effectively treated?
 References
 Study Questions


Chronic, inflammatory and often
progressive autoimmune disease
affecting joints
 Frequently affects small
joints
 Symmetrical inflammation
 Stiff/swollen, painful joints
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 Results in:
 Deformity
 Joint destruction
 Nodules
 Disability
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 Joint space
Rheumatoid Normal Joint
Joint
narrowing
 Excessive tissue
growth
 High levels of
synovial fluid
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
Begins with inflammation of synovial joints
 Leads to excessive synovial fluid production
▪ Fluid contains metalloproteinase enzyme
▪ Attacks and erodes cartilage

Inflammation caused by infiltration of
macrophages, T-helper cells and B-plasma
cells

Worldwide prevalence  roughly 1-2% (2012)

Occurs most often between 50-60 years of age
 May begin around 30 years of age

Life expectancy of RA patients reduced 5-10 years
 Often resulting from CVD risk factors

Human leukocyte antigen (HLA)
 HLA-DRB1 is a significant risk factor gene
 Viruses may be causative agents
▪ Epstein Barr Virus (EBV)
▪ High levels of EBV in synovial fluid of RA patients

The epitope polypeptide sequence of HLADBR1 (or DBR4) is similar to that of EBV and
E-coli

Commonly found in females
 Remission during pregnancy (hormone
surge)
 Flare up after birth

Is there a link between RA and
hormones? (estrogen/progesterone)

Sex hormones
 Estrogen
▪ Estrogen activates macrophages
 Progesterone
 Other Invovled Hormones
▪ Testosterone
▪ DHEA
▪ Prolactin
▪ Promotes survival of T-cell dependent autoreactive B-cells

Unknown causes
 Genetic predisposition hypothesized
▪ Influenced by environmental risk factors

Rheumatoid Factor
 Autoantibody produced against Fc region of IgG
▪ The Fc regions of free IgG molecules are accessed easily
by these autoantibodies
 No cure
 Treatments aim to:
 Achieve remission/ Control symptoms
 Preserve structure of joints (prevent
damage/deformity)
 Improve/maintain quality of life

Rituximab (intravenous injection)
 Targets CD 20 on surface of B cells
 Results in destruction of B cells
▪ both normal and dysfunctional

Tocilizumab
 Monoclonal Ab that blocks interleukin-6 receptors
▪ IL-6 is responsible for activating inflammatory cells

Disease-modifying antirheumatic drugs
(DMARDS)
 Alleviates symptoms caused by inflammation
▪ Lessen joint distruction

Methotrexate (DMARD)
 Most widely used drug of choice
 Adenosine (active metabolite)-suppresses
expression of inflammatory cytokines
 Used in low doses to control inflammation
▪ Reduces cytokine production
 HRT (Hormone Replacement Therapy)
 Initially successful
 Controversial
▪ Shown to cause endometrial cancer
 Prevent bone loss
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Babushetty V, Sultanpur CM. 2012. The role of sex hormones in rheumatoid
arthritis. International Journal of Pharmacy and Pharmaceutical Sciences 4(1): 1521.
Clancy J, Hasthorpe H. 2011. Pathophysiology of rheumatoid arthritis: nature or
nurture? Primary Health Care 21(9): 31-38.
Holroyd CR, Edwards CJ. 2009. The effects of hormone replacement therapy on
autoimmune disease: rheumatoid arthritis and systemic lupus erythematosus.
Climacteric 2: 378-386.
Islander U, Jochems C, Lagerquist MK, Forsblad-d’Elia H, Carlsten H. 2011.
Estrogens in rheumatoid arthritis; the immune system and bone. Molecular and
Cellular Endocrinology 335: 14-29.
1. http://www.metrohealth.org/body.cfm?id=1611&oTopID=1604
2.http://images.rheumatology.org/viewphoto.php?imageId=2862487&albumId=7
5692
3. http://www.medicinenet.com/rheumatoid_arthritis/article.htm
4.http://images.rheumatology.org/viewphoto.php?imageId=2862491&albumId=7
5692

Why does estrogen inhibit Treg cells?
 A) Treg cells have a greater proportion of ERα/ERβ
receptors causing Treg cell function to be
suppressed
 B) Estrogen blocks the CD4 receptor on the
surface of the Treg cell
 C) Estrogen inhibits successful Treg development
within the bone marrow
 D) Estrogen blocks the binding of B7 on
autoreactive T cells to Treg cells, thus inhibiting
necessary suppression

In patients with RA, what specific type of
tissue is affected and why?
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