RA Flashcards
DEFINITION
RA is a chronic (life-long), systemic, autoimmune disease of unknown etiology that affects the diarthrodial (movable) joints, that involves an invasion of inflammatory cells into the synovium leading to synovial hyperplasia and edema called ‘pannus’.
PANNUS : Pannus is Latin for cloth or garment. In medicine, pannus is any abnormal tissue that: Contains blood vessels (necessary for tissue growth) Covers up a normal body structure.
WHERE DOES IT AFFECT?
it affects mainly small and medium joints (of the hands and feet), and rarely large joints (e.g. shoulder, knee) and various organs, such as the lungs and vessels. Locally, inflammatory cells invade the synovium, otherwise relatively acellular, leading to hyperplasia and pannus formation that causes the damage of cartilage, erosion of bone and finally loss of function of the affected joint.
the chronic inflammation favors …
an atherosclerotic process that puts these patients at high risk of myocardial infarctions and strokes at a much younger age relatively to the general population.
PREVALANCE
● Prevalence - It is a very frequent disease. The most common polyarthritis (> 4 joints are involved) . The prevalence in western countries is 0.5-1% of the entire population. This means 1 or 2 people out of every 100 people.
INCIDENCE
16.5 cases (〖10〗^5) for year in southern Europe, 29 cases in northern Europe and 38 cases in North America.
SEX
RA is more prevalent in females (2.4:1), this ratio decreasing over time. The disease with highest emphasis on this difference is systemic lupus erythematosus where the ratio is 9:1.
AGE
The peak of the gaussian curve of incidences is found between the 4th and 5th decade (midlife), however, the disease can be found at younger or older individuals. If the disease occurs before the age of 16y it is called ‘idiopathic juvenile arthritis’ (which will be covered in another lecture).
MAIN CHARACTERISTICS
- Autoantibody production- 2 in particular:
a. Rheumatoid factor- an IgM directed against the FC portion of IgGs.
b. anti-citrullinated protein antibody (ACPA) - Synovial inflammation and hyperplasia - giving rise to a ‘Pannus’ (swelling).
- Cartilage and bone destruction n- that occurs due to the inflammatory process. If the disease is not detected and treated appropriately it can cause permanent damage, deformity and disability.
- Systemic features - additional systemic features include cardiovascular, pulmonary and psychological and skeletal problems.
Etiology
- genetic background
– HLA-DRB1 SE allele
“Shared Epitope” (SE) = five amino acid sequence motif, of which 3 (residue 70, 71 and 74) are involved in the shaping of the peptide binding pocket 4 of the HLA molecule → MHC that binds citrullinated peptides with higher affinity
etiology 2
B. Environmental Triggers
- Cigarette smoke
- Increased risk of seropositive RA among subjects who had smoked ≥20 years
- Evident at an intensity of smoking of 6-9 cigarettes/day (cumulative dose > risk)
- Remained for up to 10-19 years after smoking cessation. - Infection: periodontal infections ( Porphyromonas Gingivalis)
This is the only bacterium that has a PAD enzyme (it’s called P-PAD) and therefore citrullinate proteins at their carboxy terminal arginine (while human PADs citrullinate the peptides within the peptide) → neoantigens → breakdown of tolerance
SHARED RISK FACTORS 🡪 cigarette smoke
PATHOLOGICAL SIMILARITIES 🡪 T cell activation, inflammatory cytokine profile, resultant bone destruction and deformity
These factors are involved in the breakdown of the tolerance to the ‘self’ molecules and the production of autoantibodies that will eventually lead to the clinical manifestations.
autoantıbodies
Based on the presence of antibodies:
- seropositive (those positive for RF, ACPA or both)
- seronegative patients that have the clinical characteristics of RA but no autoantibodies (25%)
autoantibodies
- Rheumatoid factor
- IgM directed against the Fc fragment of IgG
- leads to formation of immune complexes → complement activation in the joints
- increased vascular permeability
- release of chemotactic factors
- recruitment of immune effector cells
- not very specific as it can be found in a number of other autoimmune disease (e.g. Sjogren syndrome, SLE), in other diseases (such as hepatitis) as well as is in normal healthy subjects (15%), mostly elderly
- not very sensitive as it can be found in only about 60-70% of patients with RA
autoantibodies 2
Anti-citrullinated protein antibodies (ACPA)
- very specific, as they can be found only in patients with RA
- not very sensitive as they can be found in only 70-80% of RA patients
- Negative predictive factor! → increased bone loss
- They define a subset of RA that differs in terms of pathogenesis, disease course and response to therapy when compared with ACPA-negative RA.
Citrullination is a post-translational process carried out by protein arginine deaminases (PADs): arginine → citrulline by the removal an amino group.
Proteins undergoing citrullination: vimentin, filaggrin, t2 collagen
N.B. ACPAs, RF can be present many years before disease onset, before any evidence of inflammation and immunity can be detected in the joints → RA begins outside of the joints (Lung - smoke, Periodontal - P.G.)
Citrullination
Citrullination of proteins is a process that occurs almost exclusively in dying cells (apoptosis, autophagy, netosis, necrosis) when the cell membrane becomes leaky, allowing an unlimited influx of extracellular Ca2+ ions. This modification leads to conformational alteration, possible functional alteration, change in the protein half-life, and new epitopes generation.
autoantibodies 3
- Anti-CarP (Carbamylated Protein) antibodies - new class discovered in the last years
- Carbamylation is a chemical modification of the molecules in the presence of cyanate
- Proposed targets for these antibodies are: vimentin, albumin, fibrinogen β chain, α1 anti-trypsin.
- Anti-CarP are found in about 45% of the patients with RA
- Interestingly, Anti-CarP antibodies are actually found in the 30% of the seronegative patients
- anti-CarP positivity is associated with a more erosive disease.
