Rheumatoid Arthritis

Nate Raines, Sonya Shadravan, Jessica Kerns, Evan Blank, Jamie Pak

Rheumatoid Arthritis
RA is a chronic systemic auto-immune inflammatory disease characterized by persistent inflammation primarily in the synovial joints

Rheumatoid Arthritis
RA can also affect other tissues:
Lungs Pericardium Pleura Sclara

Symptoms
Symmetrical polyarthritis of:
Wrists Fingers Feet Ankles Knees

Disease progression is slow, starting with minor joint pain, stiffness and fatigue. As disease progresses, joints can loose their range of motion and become eroded and deformed.

Symptoms Cont.
Other symptoms include
Pleurisy (pain when taking a breath) Sjogren syndrome (dry eyes and mouth) Burning itching and discharge in eyes Numbness, tingling or burning in hands or feet

Epidemiology
Most common type of inflammatory arthritis RA affects .5-1% of adults world wide The prevalence of RA is consistent across the globe with a few exceptions In China - .3% Pima Indians of North America 5%

Epidemiology ctd.
RA is responsible for 250,000 hospitalizations and 9 million physician visits in the US each year It may affect people at any age, with a peak incidence between 30 to 50 years of age Family history and smoking may increase risk factors

Outcomes
Most sources cite life-shortening of 5-10 years depending of severity Symptoms seem to progress more quickly for people who get RA when young Lasting joint damage can occur without adequate treatment but early treatment with new medications have decreased chronic pain and injury

Etiology
There is no established etiology for RA and all classification of the disease is currently based on clinical phenotypes However, there are molecular, genetic, and environmental factors which appear to underlie increased susceptibility to the disease These factors likely interact in a complicated and still not fully understood fashion

Physiological Basis of Susceptibility

Likely due to some alteration in t-cell selection or antigen presentation which causes the body to have an autoimmune response Type one and type 17 t-helper cells are the most commonly implicated culprits A variety of cytokines produced by these and other immune cells, as well as growth factors, signaling molecules, and transcription factors, have also been linked to the pathogenesis of the disease Presents with antibodies against the FC portion of the bodys own Immunoglobin G Also presents with antibodies against citrullinated peptides

Genetic Factors
A variety of SNPs have been indicated in rheumatoid arthritis One particularly important genetic sequence which predisposes individuals to rheumatoid arthrits is a common amino acid motif (QKRAA) in the HLA-DRB1 region of the human leukocyte antigen (HLA)DRB1 locus in patients who have already tested positive for rheumatoid factor or ACPA . This is known as the shared epitope These SNP genotypic variations interact with environmental factors to increase susceptibility in certain people

Environmental Factors
Smoking and other bronchiolar stress (such as silicosis) increase rheumatoid arthritis risk, particularly among individuals with a characteristic HLA-DR4 SNP and individuals with the common HLA-DRB1 allele. Environmental stress on lungs appears to induce post-translational modification of mucosal proteins through peptidyl arginine deiminiase type IV, increasing their citrullination and thereby eliciting a stronger response.

Clinical Diagnosis of RA
Patient must meet at least four criteria: Morning stiffness lasting at least 1 h, present for at least 6 weeks At least three joint areas simultaneously with soft-tissue swelling or fluid, for at least 6 weeks At least one area swollen in a wrist, metacarpaophalangeal, or proximal interphalangeal joint, for at least 6 weeks Simultaneous involvement of the same joint areas on both sides of the body, for at least 6 weeks Subcutaneous nodules seen by a doctor Positive rheumatoid factor Radiographic changes on hand and wrist radiographs (erosions or unequivocal bony decalcification)

Infectious Causes
Infectious agents associated with increased rheumatoid arthritis susceptibility:
EpsteinBarr virus Cytomegalovirus Proteus species E. coli

Mechanisms remain unknown, although may be a result of molecular mimicry, in which immune complexes formed in response to infection recognize and attack similar sequences in a persons own body. Peridontal disease has also been linked to Rheumatoid arthritis because it promotes the citrullination of various proteins

Laboratory Diagnosis of RA
Important Laboratory tests to help confirm diagnosis: Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibody present elevated erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) levels testing for presence of various genetic factors that can contribute to RA histological features are similar between RA and other inflammatory joint diseases and osteoarthritis, so difficult to diagnose just from that.

Histological

Normal Joint Capsule & Synovium

Synovial tissue in RA

Prominent hyperplasia of synovial lining layer. Inflamatory infiltrate in sublining is comprises of lymphocytes, plasma cells, and macrophages

Question 1

Citations
Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 2010;69:1580-1588 Firestein GS. Etiology and pathogenesis of rheumatoid arthritis. In: Kelleys Textbook of Rheumatology, 7th ed. Philadelphia, PA: W.B. Saunders; 2005:996-1042 Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis: an approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 1987;30:1205-1213 Guedes C, Dumont-Fischer D, Leichter-Nakache S, Boissier MC. Mortality in rheumatoid arthritis. Rev Rhum Engl Ed. 1999 Oct; 66(10): 492-8. Huizinga TW, Pincus T. In the clinic. Rheumatoid arthritis. Ann Intern Med. 2010 Jul 6;153(1). Majithia V, Geraci SA (2007). Rheumatoid arthritis: diagnosis and management. Am. J. Med. 120 (11): 9369. McInnes, I. B. and G. Schett (2011). "The Pathogenesis of Rheumatoid Arthritis." New England Journal of Medicine 365(23): 2205-2219. Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet. 2010 Sep 25;376(9746):1094-108. Wegner N, Wait R, Sroka A, et al. Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and -enolase: implications for autoimmunity in rheumatoid arthritis. Arthritis Rheum 2010;62:2662-2672 Images: http://www.uptodate.com/contents/synovial-pathology-in-rheumatoid-arthritis# http://www.mdconsult.com/books/figure.do?figure=true&eid=4-u1.0-B978-0-443-06850-8..50014-2-f29&sectionEid=4-u1.0-B978-0-443-06850-8..50014-2--cesec6&isbn=978-0-443-06850-8&uniqId=315046330-5 http://mulla.pri.ee/Kelley's%20Textbook%20of%20Rheumatology,%208th%20ed./HTML/340.htm