SM 234a - Rheumatoid Arthritis Flashcards
What class of medications are the mainstay of long-term RA management?
DMARDs (Disease-modifying anti-rheumatic drugs)
- Methotrexate = most effective single non-biologic DMARD
- Biologic DMARDs (-imab and -umab drugs) are very effective at modifying disease
What does a positive ACPA predict about a patients RA prognosis?
Positive ACPA = worse prognosis
- Erosive disease, extra-articular manifestations
What are the most common and severe side effects of long-term corticosteroid use?
Osteoporosis
HTN
Hyperglycemia
Characteristic of osteoarthritis or rheumatoid arthritis?
Involves PIP and DIP
Osteoarthritis
(MCP is spared in osteoarthritis, usually involved in RA)
Which antibody is most specific for RA?
Anti-citrullinated peptide antibody (ACPA)
- aka anti-cyclic citrullinated peptice (anti-CCP)
Describe the make-up of a normal synovium
- Intimal lining
- Macrophage-like synoviocytes (MLS) and fibroblast-like synoviocytes (FLS)
- Allows delicate, leaky, free movement of cells and proteins into synovial fluid
- Sublining
- Fibroblasts, adipocytes, blood vessels, immune cells
Produce lubricants for and provide nutrients to cartilage
(cartilage lacks its own blood supply)
Characteristic of osteoarthritis or rheumatoid arthritis?
Asymmetric
Osteoarthritis
What is the usual age of onset for rheumatoid arthritis?
40-60 years
How are symptoms of RA treated acutely?
- NSAIDs
- Symptomatic relief only, will not prevent disease progression
- Corticosteroids
- More effective than NSAIDs, but more side effects
- Intra-articular or systemic
What autoantibodies are most commonly seen in patients with RA?
-
Rheumatoid factor (RF)
- Specific for RA
-
Anti-citrullinated peptide antibodies (ACPA)
- Specific for RA
- Anti-nuclear antibody
- Not sensitive or specific for RA
- Positive in 20-30% of patients
Demineralization of this pattern is associated with what kind of arthritis?
Rheumatoid arthritis
- Shows ulnar styloid erosion + demineralized cortex
What is rheumatoid factor?
Autoantibody with specificty for Fc fragment of IgG
- Sensitivity = 66%, specificity = 82% for RA
- Important to check ACPA too; 35% of patients with negative RF will have positive ACPA
How does the synovium change in rheumatoid arthritis?
- Intimal lining expands
- Activated synoviocytes produce pro-inflammatory cytokines
- Sublining
- Adaptive immune cells infiltrate the sublining
- Hypervascularity
-
Pannus formation
- Invasive, destructive front of synovial tissue attached to the articular surface
- Contains activated osteoclasts that degrade bone at the edge of the pannus
What is the mechanism of methotrexate?
Inhibits dihydrofolate reductase
-> inhibition of DNA synthesis
- Inhibits vascular proliferation
- Inhibits neutrophil activation and adherance
- Inhibits IL-1, IL-8 production by mononuclear cells
- Inhibits TNF production by T cells
First-line DMARD used to manage RA
What causes bone degradation in rheumatoid arthritis?
Osteoclasts living within the pannus
- Pannus = invasive, destructive front of synovial tissue attached to the articular surface
- Interfaces with bone
- Contains osteoclasts
Characteristic of osteoarthritis or rheumatoid arthritis?
All MTPs may be involved
Rheumatoid arthritis
(Osteoarthritis usually only affects 1st MTP)
What are ACPAs?
Anti-Citrullinated Peptide Antibodies (aka anti-cyclic citrullinated peptide (Anti-CCP)
- Sensitivity 75%, Specificity 95% for RA
What are the risk factors of RA?
- Genetic
- HLA-DRB1*01, HLA-DRB1*04
- Female sex
- Environmental factors -> changes in DNA methylation
- Smoking
- Dust inhalation
- Microbiota
What is the classic radiographic finding in RA?
Juxta-articular erosions
- May not be present at presentation
- Do not wait until these appear to initiate treatment
What are the cardinal features of rheumatoid arthritis?
Synovitis + Joint damage
- Driven by IL-1, IL-6, TNF
What are the characteristics of preclinical RA?
What is happening pathogenically?
Asymptomatic autoimmunity/Early symptomatic autoimmunity
- Peptidylarginine deaminases (PADs) convert peptidylarginine to peptidylcitrulline, in a process called citrullination
- PADs can be induced by environmental factors
- Peptidylcitrulline induces an immune response
- APCs migrate to lymphoid tissues and activate T cells
- T cells stimulate B celsl to produce autoantibodies
- Rheumatoid factor (RF)
- Anti-citrullinatied peptide antibody (ACPA)
Characteristic of osteoarthritis or rheumatoid arthritis?
MCP and PIP joints involved
Rheumatoid arthritis
(DIP usually spared)
Describe the presentation of inflammatory arthritis
Insidious onset of symmetric polyarthritis (>3 joints), esp. in the small joints of hands and feet
- Joint swelling
- Decreased range of motion
- Pain and swelling is worse in the morning
- Stiffness lasts >1 hour
- Stiffness after rest
All of the following lab abnormalities might be seen in RA except:
A) Normochromic normocytic anemia
B) Positive anti-cyclic citrullinated peptide (anti-CCP) antibodies
C) Microcytic anemia
D) Positive double stranded DNA (anti-dsDNA)
E) Positive antinuclear antibody (ANA)
F) Positive rheumatoid factor (RF)
G) Neutropenia
H) Thrombocytopenia
D) Positive double stranded DNA (anti-dsDNA)
Anti-dsDNA is specific for lupus
HLA-DRB1*01 and HLA-DRB1*04 are risk factors for which disease?
Rheumatoid arthritis
Which non-biologic DMARD should never be given to women who might become pregnant now or want to become pregnant in the future?
Why?
Leflunomide
Teratogenic with a very long half-life (due to enterohepatic ciruculation)
What is the most common cause of premature death in patients with RA?
Cardiovascular disease
- Arthrosclerosis develops earlier
- May be driven by the systemic inflammation in RA
What are the goals of treatment for a patient with RA?
Reduce joint pain and swelling
Prevent joint damage
Treat to target (until remission is attained)
Which proinflammatory factors stimulate osteoclasts in RA?
IL-1, IL-6, TNF, RANKL
APCAs may also activate osteoclasts
What are the characteristics of early RA?
Undifferentiated arthritis
- The immune system is ramping up, causing inflammation in the joints
What are the common causes of mortality in patients with RA?
CVD (most common)
Infection
Cancer
Amyloidosis -> renal disease
Characteristic of osteoarthritis or rheumatoid arthritis?
Bony enlargement of joints
Osteoarthritis
(RA usually invovles swelling, not bony enlargement)
Characteristic of osteoarthritis or rheumatoid arthritis?
Insidious onset
Both
When would you add a biologic DMARD to the treatment regimen of a patient with RA?
If disease activity is still moderate-high after starting methotrexate
Describe the differences in hand involvement typically seen in RA vs. OA
- RA – MCPs and PIPs involved (DIPs spared)
- OA – PIPs and DIPs involved (MCPs spared)
Pannus formation is characteristic of which bone disease?
Rheumatoid arthritis
- Attached to the articular surface
- Interfaces with bone
- Contains osteoclasts that degrade bone
Which bacteria are associated with the development of RA?
- Periodontal: P. gingivalis
- Gut: Prevotella spp.
What is the role of citrullination in the pathogenesis of RA?
Citrullinated peptides induce the autoimmune response
- Environmental stressors at mucosal sites induce peptidylarginine deaminases (PADs)
- PADs convert peptidylarginine to peptidylcitrulline, in a process called citrullination
- Citrullinated peptides bind to HLA protein heterodimers on APCs
- APCs present citrullinated peptides to T cells
- T cells stimulate B cells to produce autoantibodies
- Rheumatoid factor
- Anti-citrullinated peptide antibody
- These antibodies can be detected up to 10 years before joint pain begins
In RA, what critical step leads to immune activation and production of RF and ACPAs?
Citrullination
Describe the differences in spine involvement typically seen in RA vs. OA
- RA – Cervical spine
- OA – Cervical or lumbar spine
What is happening pathogenically in early RA?
Recall: preclinical = production of RF and ACPA, due in part to citrullination
- Influx of inflammatory cells into the synovium
- CD4+ T cells, macrophages, APCs
- B cells and plasma cells produce autoantibodies
- Activated synoviocytes produce pro-inflammatory cytokines and proteases
- Macrophage-like synoviocytes: IL-1, IL-6, TNF
- Fibroblast-like synoviocytes: MMPs, RANKL
- Cytokines enhance and perpetuate joint inflammation
What is the first-line medication for the long-term treatment of RA?
Methotrexate
Add others (biologic) if inadequate or non-response
Describe the differences in foot involvement typically seen in RA vs. OA
- RA – All metatarsophalangeal joints as well as midfoot
- OA – Usually only the first MTP
What is atlantoaxial subluxation?
Why is this dangerous?
Partial dislocation of the atlantoaxial joint (between C1 and C2)
- Potential complication of RA
- Risk of spinal cord compression if the anterior distance between C1 and C2 is >8 mm (normal = 2.5-3 mm)
- Risk of intubation during anesthesia
Citrullination is part of the pathogenesis of which bone disease?
Rheumatoid arthritis
Which factors are produced by macrophage-like synoviocytes (MLS) in early RA?
Which factors are produced by fibroblast-like synoviocytes (FLS)?
- MLS
- IL-1, IL-6, TNF
- FLS
- MMPs
- Destroy cartilage
- RANKL
- Stimulates osteoclast differentiation
- MMPs
Characteristic of osteoarthritis or rheumatoid arthritis?
Morning stiffness lasting >1 hour
Rheumatoid arthritis
Describe the synovial fluid analysis consistent with RA
- WBC count?
- Crystals?
- Cultures?
- WBC count: 5,000 - 50,000
- >50,000 consider osteomyelitis or joint infection
- Crystals
- None
- Cultures
- Negative
What disease does this patient most likely have?
Describe the relevant radiographic findings
Rheumatoid arthritis
- Diffuse joint space narrowing
- MCP subluxation (partial dislocation), ulnar deviation
- Demineralization
- Marginal erosions at MCPs
What are the major mediators of joint damage in RA?
- Cartilage destroction
- MMPs
- Bone erosion
- Osteoclasts, stimulated by…
- IL-1, IL-6
- RANKL
- Maybe ACPAs too
- Osteoclasts, stimulated by…
What are the radiographic changes typically seen in patients with RA?
- Soft tissue swelling
- Periarticular osteopenia
- Uniform/symmetric joint space loss/deformity
- Osteoarthritis is usually not symmetric
- Marginal erosions
- Due to the osteoclast-containing pannus eating away at the bone
