2/13 Rheumatoid Arthritis Flashcards
What is the best serological marker for RA?
ACPA (Anti-Citrullinated Protein Antibodies), an antibody detects a post-translational modification on arginine
What is the first step in the pathogenesis of RA?
When does this usually occur?
What is the sequelae of this triggering event?
tolerance broken and generation of ACPA against self proteins; occurs years before the onset of symptoms in most patients
triggering event occurs elsewhere, likely in the lung, resulting in APCA production; immune complexes made of ACPA + citrullinated proteins deposit in the synovium and triggers inflammatory events
Synovium becomes engorged with B cells (mostly plasma cells), T cells (mostly CD4) and macrophages and edematous infiltrates; neutrophils predominate later on.
Innate immunity
- Macrophages secrete TNF, IL1, IL6
Adaptive immunity response
- T cells - memory T cells activate B cells; T cells can eventually leave, but the damage continues because the ACPA still persists and deposits in the joint
- B cells - plasma cells actively producing antibodies often with RF and CCP specificity
- **PMNs and macrophages **secrete
• proteases - cause pannus (synovial inflammation), which ultimately leads to the destruction of articular cartilage, ligaments, tendons, and bone
• IL1 and TNF - activate synovial fibroblasts to secrete MMPs and streptolysin, which cause irreversible collagen breakdown at the junction of the pannus and cartilage; ultimately leads to loss of proteoglycans. With the cartilage lost, bone can be eroded and broken down or lead to fibrous/bony ankylosis. Periarticular structures (tendons/ligaments) become weakened or scarred secondary to chronic inflammation and can rupture, leading to rupture, shortening, altered joint mechanics, and deformity
What is the shared epitopes hypothesis and how does this contribute to RA?
disease risk conferred by 5 amino acids in the HLA-DR ß chain (3-4 fold increased risk for seropositive RA patients because these shared epitopes (SE) allow for binding to citrullinated forms and subsequent presentation to CD4 T cells to induce ACPA production by plasma cells against citrullinated proteins)
NOTE: HLA - ABC (Class I) are not associated with RA
Are all RA patients seropositive for ACPA?
patients can present as seropositive or seronegative, but the frequency of seropositives increase with duration and severity of RA
• Half of the seronegatives remit, never to recur
Morbidity, mortality, extra-articular diseases: Seropositive>>Seronegative
What is the typical presentation of an RA patient?
Onset: Abrupt - Insidious; sub-acute or chronic
Symptoms: stiffness/pain that improves with exercise and worsens with rest; presence of morning stiffness, especially in the hands
Sites: polyarticular joint involvement; symmetric; MCP/PIP/Wrists/MTPs
• Money is in the 2nd /3rd MCP or MTP! Do a lateral MCP/MTP squeeze
Constitutional: fatigue, perceived selective loss of strength in hands, functional limitations
When doing a PE exam for RA patient, where does the $$ lie? (3)
In the 2nd /3rd MCP or MTP (patients classically present with hand pain but not foot pain)
Do a lateral MCP/MTP squeeze
Patient winces when you shake hands
Inability to oppose distal pulp space to the base of the digit (claw maneuver), which indicates a MCP, PIP or flexor tendon inflammation
What are the sequelae of RA in terms of physical findings?
• Loss of joint motion (severe)
• Deformities (especially hands and wrists) due to weakened and unstable ligaments and erosion of the bone
• Metacarpal subluxation and ulnar drift:
- PIPs - Swan-neck (DIP hyperflexion of joints), boutonniere
- Extraarticular Disease (ninth yard) - usually late in disease
What is RF?
In what part of the hospital is RF present in every single patient?
- IgM directed against the Fc of IgG
- sensitive but not very specific for RA
- RF – encoded in germline genes; present in EVERY baby! Potentiate the effects of maternal IgG in the fetus (since they’re decreasing with time) in fixing complement
Which is a better seromarker for RA: RF or ACPA?
RF: sensitive but not very specific
ACPA: sensitive and specific
What is the typical treatment for RA?
Best DMARDs for RA?
Early use of DMARDs (MTX typical) + NSAID, low dose prednisone
Methotrexate - potent anti-inflammatory effects, but activity against destructive elements (ie erosion/cartilage destruction) is not as potent and usually emerge
What are some biologics that are also used to treat RA
What are the pros of using this? Cons?
• TNF, IL-6R antagonist
• Rituximab
• CTLA-4 Ig
Pros: used in refractory RA (to MTX)
Cons: very expensive!
RA is a disease of…?
Which joint is the most affected? How does this compare to osteoarthritis?
SYNOVIUM
AFFECTS MCP
OA: affects DIP, PIP
What are extraarticular diseases? (7)
What are they caused by?
What patients do they normally occur in?
Extraarticular diseases are caused by immune complex deposition
Usually occur in seropositive RA patients
- Anemia of Chronic Disease - common (normocytic, normochromic)
- Rheumatoid Nodules - localized form of vasculitis usually on pressure points (ie olecranon, achilles tendon); trauma -> vessel breakdown -> IC deposition
- Entrapment neuropathy (carpel tunnel syndrome)
- Atlanoaxial subluxation - rare but important to check for patients undergoing surgery/intubation, because destruction of the ligament that tethers C1 to C2 causes the odontoid to impinge on the cord or on the vascular supply of the spinal cord and brainstem
- Vasculitis - can result in peripheral neuropathy as a result of nerve root infarction; both associated with a high RF titer
- Pulmonary - fibrosis (ILD), nodules, effusions
- Eye - Sjogren’s Syndrome – exocrine gland dysfunction as a result of lymphocytic infiltration; rheumatoid nodule of the sclera (sleritis) can eventually erode through the sclera and perforate or lead to iritis, choroidis
Which extraarticular diseases are associated with a high RF titer? (3)
Rheumatoid nodules
Vasculitis
Peripheral neuropathy
What is the biggest environmental factor associated with RA?
SMOKING
