Kara Kliethermes Jim ShinaberryDecember 6, 2012

What is rheumatoid arthritis? What are the underlying

mechanisms?EpidemiologyTriggers and risk factorsWhat leads to the development of

RA?Can RA be effectively treated?ReferencesStudy 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 destructionNodulesDisability

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Joint space narrowing

Excessive tissue growth

High levels of synovial fluid

Rheumatoid Joint

Normal Joint

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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 HLA-DBR1 (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

Babushetty V, Sultanpur CM. 2012. The role of sex hormones in rheumatoid arthritis. International Journal of Pharmacy and Pharmaceutical Sciences 4(1): 15-21.

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=75692 3. http://www.medicinenet.com/rheumatoid_arthritis/article.htm 4.http://images.rheumatology.org/viewphoto.php?

imageId=2862491&albumId=75692

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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