Rheumatoid Arthritis

=Objectives= The objectives are student supplied

Diagnosis of RA

 * It is a clinical diagnosis based on a collection of findings. If you have 4 of more of the following seven criteria, then you meet the criteria for diagnosis of RA.  The criteria are: morning stiffness, three or more joint areas affected, hand involvement, symmetric arthritis, rheumatoid nodules, radiologic changes, and rheumatoid factor (although anti-cyclic citrullinated Ab maybe more useful, as discussed below)

Rheumatoid factor

 * Significance of Rheumatoid Factor depends on pre-test likelihood!
 * Rheumatoid factor (RF) is non-specific marker that can support a diagnosis of RA. RF is an autoantibody that binds to the Fc-region of IgGs.
 * RF is positive in ~ 70% of patients with RA (low sensitivity) and is also be positive in many other conditions (low specificity). Patients seropositive for RF do have a worse prognosis, though.
 * False positives can occur due to variety of diseases
 * In the image below, a pentameric Rhematoid Factor (an IgM) is binding to a single Fc-region of any IgG

Anti-cyclic citrullinated peptide antibodies

 * antibody reactivity to proteins modified by citrullination, i.e., an enzyme-mediated posttranslational modification of peptidylarginine to peptidylcitrulline.
 * Sensitivity of 60%, specificity of 98%
 * Can predate RA symptoms by years, and rarely develops after onset of arthritis
 * Rarely positive in healthy individuals and rare in other inflammatory diseases!
 * There are two distinct subsets of RA patients, the anti-CCP positive vs. the anti-CCP negative patients.
 * Anti-CCP positive patients have more severe disease, correlate with smoking, correlate with erosions and have a strong DRB1 association
 * Seropositivity has strong association with HLA DRB and correlates with smoking

RA Epidemiology and Genetics

 * 2.5x more prevalent in women, 2.4x increased risk with smoking
 * First degree relatives have a 4x expected rate
 * Occurs 12-15% in monozygotic, and ~5% in dizygotic twins
 * HLA class II molecules, the DRB1 group, have been identified as susceptibility markers
 * HLA class II molecules are found on APCs (macrophages, dendritic cells, B cells, etc). The peptides they present are derived from extracellular proteins (not cystolic, which would be HLA class I).  They have made of two homologous peptides, and alpha and beta chain, both of which are encoded in the MHC.  They interact with exclusively with CD4+ T Cells, which then trigger an immune response.

Synovitis

 * Infiltration and proliferation leading to damage
 * This is a type III hypersensitivity reaction
 * There is a 25x increase in mast cells in rheumatoid synovium
 * B cells in synovium present immune complexed antigens to autoreactive T cells, B cells are very efficient APCs
 * B cells contribute the 2nd signal to T cells with CD80 and CD40 and produce cytokines TNF-alpha and IL-6
 * Fibroblasts: produce metalloproteinases, cytokines, chemokines; express toll-like receptors; support B and T cell survival; and are resistant to apoptosis
 * The rheumatoid pannus refers to the granulation tissue that is formed within the synovium by proliferating fibroblasts and inflammatory cells.
 * Fenestrated capillary walls in synovium allow for preferential trapping of immune complexes
 * Macrophages and fibroblasts are the source of cytokines in RA!

Bone Pathology in RA

 * Osteoporosis, juxta-articular osteopenia and joint erosions
 * RANK Ligand links T cells and fibroblasts with osteoclast activation
 * Invasion by proliferating pannus leads to release of proteolytic enzymes
 * Degradation of cartilage by enzymes and other mediators in synovial fluid
 * Synovial lining cells and macrophages are the main source of destructive proteinases in RA
 * Proteinase production is influenced by cytokines, growth factors and histamine

Treatment

 * Neutralization of cytokines with soluble receptors: Etanercept
 * Neutralization of cytokines with monoclonal antibodies: Infliximab, Adalimumab and Golimumab
 * There are actually a ton of different treatments it seems including immunosuppression, NSAIDs (outdated, and shouldn't be used alone), corticosteroids, etc. Not sure why he didn't go into it more...

Diagnosis

 * Diagnosis is based on the presence of 4 or more of the following 11 criteria, serially or simulateoulsy
 * Malar rash: fixed erythema, non scarring
 * Discoid rask: erythematous raised patches, freq scarring
 * Photosensitivity: rash with sun exposure
 * Oral ulcers
 * Arthritis: non-erosive but true synovitis
 * Serositis: pleuritis, pericarditis
 * Renal disorder: proteinuria and/or casts
 * Neurologic disorder: seizures or psychosis
 * Hematologic disorder: hemolytic anemia, leukopenia, lymphopenia, thrombocytopenia
 * Immunologic disorder: anti DS DNA ab, anti Sm ab
 * Antinuclear antibody

Scleroderma
=Links= Bold text
 * Scleroderma is a chronic autoimmune disease characterized by fibrosis, vascular alterations, and autoantibodies.
 * It is a spectrum of disorders. The two major types are limited systemic sclerosis and diffuse systemic sclerosis.
 * Limited systemic sclerosis is the classic CREST syndrome: Calcinosis, Raynaud's phenomenon, Esophageal dysfunction, Sclerodactyl, and Telangniectasis. Additionally, pulmonary arterial hypertension may occur and is the most serious complication.
 * Diffus systemic scleroris is rapidly progressing and affects large areas of the skin and internal organs, frequently the kidneys, esophagus, heart and lungs.
 * It can be limited or diffuse
 * It is associated with Raynaud's phenomenon. This is the vasospastic disorder caused by the discoloration of the fingers, toes and occasionally other areas. When exposed to cold temperatures, the skin in the fingers, nose, toes can turn white and become cold and numb.  When the oxygen supply is then depleted, these areas turn blue.  Since these events are episodic, once the blood supply returns, the area turns red as the blood flow returns.  So white, blue and red is the order of color changes in Raynaud's.
 * Radiology references for arthritis
 * Rheumatoid Arthritis case by European Society of Radiology