Rheumatoid Arthritis Flashcards
What is inflammation classically characterised by?
Heat (calor) Redness (rubor) Swelling (tumor) Pain (dolor) Potential loss of function
What does inflammation attempt to do?
Restrict the effects/damage of the stimulus causing injury
Remove the stimulus
Promote the repair and replacement of damaged tissue
What are redness and heat caused by?
Increased blood flow due to vasodilation. Blood carries body heat so more blood in the tissue results in increased temperature
What is swelling and pain caused by?
Swelling is caused by leakage of fluid from the circulation & retention in the tissue, & pain is caused by activation of nerve endings by chemical mediators released by cells during inflammation.
What are the potential causes of inflammation?
Injury
Irritation
Infection
Autoimmune response
What are the different types of arthritis?
Osteoarthritis – mechanical Septic arthritis – infection Reactive arthritis – infection Rheumatoid arthritis – autoimmune Psoriatic arthritis – also involves skin
What are the clinical features of septic arthritis?
Deposition of live micro-organisms in the joint itself (usually bacteria)
The enter the body via the GI tract, the GU tract, the respiratory tract and the skin
Entry into the joint is via the circulation or a direct wound
Usually only one joint is affected with rapid onset
Treatment is with joint washout and antibiotics
In rare cases, it can be life threatening if it leads to septic shock
Name some of the bacteria involved in septic arthritis
Enterococcus Faecelis
Escherichia Coli
Haemophilus Infuenzae
Mycobacterium Tuberculosis
What are the clinical features of reactive arthritis?
Develops in reaction to a bacterial infection in another part of the body- usually from the GI or GU tract
Therefore the infection does not directly cause the arthritis
Name some of the bacteria involved in reactive arthritis
Campylobacter Jejuni
Chlamydia Trachomatis
Shigella Nexeri
Salmonella species
How often after infection do symptoms of reactive arthritis appear?
1-3 weeks
How is reactive arthritis treated?
NSAIDS for inflammation and is chronic then DMARDS are used
What genetic factor is reactive arthritis associated with?
HLA-B27
How may reactive arthritis be brought about?
May involve deposition of bacterial antigen fragments in the joint.
What are TLR’s and where are they located?
They are a type of pattern recognition receptor present on the surface of immune cells
What do TLR’s recognise?
Structural molecules and motifs derived from microbes
What do TLR signals activate?
NF-kB and immune/inflammatory genes
What typically activates TLR’s 4 and 5?
Gram-negative flagellated bacteria
What typically activates TLR’s 5 and 2/6?
Gram-positive and flagellated bacteria
How are TLR’s involved in arthritis?
Macrophages and fibroblasts in the joint possess TLRs which can be stimulated to induce cytokine production.
Evidence that innate immune responses mediated by TLRs to bacterial DNA (e.g. TLR9) could be involved in triggering B-cells to produce rheumatoid factor (RF).
Define RA
A systemic autoimmune disease characterised by
chronic inflammation and destruction of the synovial joints.
What can RA lead to?
Loss of function, disability, reduced quality of
life, increased co-morbidity and often premature death.
What is the ratio of women to men who develop RA?
3:1
What age is the most common to develop RA?
40-50
What happens to the bone and cartilage in the RA joint?
Bone and cartilage degradation caused by invading granulation tissue, or pannus.
How does bone erosion progress?
Soft-tissue swelling is evident, but the underlying bone is intact.
Continued soft-tissue swelling, thinning of the bone cortex on radial side.
Distinct erosion of metacarpal head, plus clear joint space narrowing
What does a pannus consist of in overgrown synovium?
Osteoblasts, fibroblasts, macrophages, dendritic cells, T-cell, plasma cells, B-cells, extensive angiogenesis, mast cells and hyperplasic synovial lining
Name the changes in the RA joint
- Increase in blood vessel formation
- Infliltartion of the synovium by leukocytes
- Thickening of the synovial layer
- Formation of pannus
- Cartilage degradation and bone erosion
Define angiogenesis
The development of new blood
vessels by endothelial-sprouting
from existing vessels.
Why does angiogenesis occur in the synovium?
A response to hypoxia and the increased metabolic demands of the synovial tissue, which induce the release of pro-angiogenic factors
What is leukocyte extravasation?
Trafficking of leukocytes out of the blood vessels
Why does leukocyte extravasation occur?
It occurs within the synovial tissue which promote a change in the adhesiveness of endothelial cells lining blood vessels. Leukocytes recruited include neutrophils, monocytes, mast cells, T-cells and B-cells.
Describe the process of selectin-mediated leukocyte rolling
Selectin-mediated adhesion to leukocytes is weak and allows leukocytes to roll along the vascular endothelial surface
Why are selectins important?
Important for lymphocyte and neutrophil interactions with the vascular endothelium – a key interaction in the process of inflammation and leukocyte extravasation.
Name the three types of selectins and where they are present?
E-selectin – present on endothelial cells
P-selectin – found on platelets & endothelial cells
L-selectin – present on lymphocytes & neutrophils
What is the structure of a selectin?
N-terminal lectin domain (carbohydrate binding)
Epidermal growth factor-like domain
Complement binding protein sequences
Why are membrane bound selectins important?
Capturing leucocytes from the circulation.
What do selectins preferentially bind to?
Complex Carbohydrates (mucins)
What can antibodies against E and P selectin prevent?
Adhesion of leucocytes to endothelium under conditions of shear from blood flow.
Why are integrins important?
Establish the strong adhesion of leukocytes to the
endothelium, essential for cell migration.
What are the characteristics of a normal synovium?
Normal synovium is a connective tissue between the joint capsule and the joint space.
It lines all inner joint surfaces, excluding the cartilage (and menisci).
It has a thin lining layer facing the joint space (1-2 cells thick).
The lining layer consists of macrophage-like and fibroblast-like synovial cells
What are the characteristics of the synovium in RA?
In RA, the lining layer becomes thickened, 6-8 cells thick:
i) increase in synovial cell proliferation (hyperplasia);
ii) increase in synovial cell size (hypertrophy).
Also, extensive infiltration of the underlying synovial tissue by macrophages and lymphocytes (mast cells, others).
Promoted by inflammatory mediators/cells.
What is a pannus?
Hyperproliferative invasive tissue mass that is observed in the RA joint
What does a pannus consist of?
Macrophage-like & fibroblast-like synovial cells within the synovial membrane
What is the cartilage-pannus junction the primary site of?
Active and progressive degradation of cartilage mediated by the release of degradative enzymes such as MMPs and ADAMTS
What is cartilage degraded by?
Activated chondrocytes/synovial fibroblasts
What is bone erosion caused by?
Activated osteoclasts
What cells are involved in RA pathogenesis in the joint?
T-Cells B-cells & plasma cells Macrophages Dendritic cells Endothelial cells Fibroblasts Osteoclasts Chondrocytes Mast cells Neutrophils
What T-cell subsets are key in RA?
Th1 and Th17 as well as Treg and Th2
What are cytokines?
Soluble signalling molecules that are essential for intercellular communication. Each binds to a specific receptor molecule on the surface of target cells. This stimulates intracellular signal transduction pathways.
How do cytokine receptors usually exist?
Cytokine receptors usually consist of 2 or 3 subunits i.e. dimers/trimers. Can be the same subunits (homo-) or different (hetero-). They may exist as membrane-bound and soluble forms.
What are chemokines?
A special class of cytokine that controls leukocyte trafficking under physiological/pathological conditions. CC class ligands recruit lymphocytes/monocytes/mast cells. CXC class ligands recruit neutrophils. 4 classes – CC, CXC, (C), (CX3C)
What are the cytokine classes?
Interleukins Interferons TNF Chemokines Growth factors CSF
What are interleukins?
Key mediators in immune/inflammatory response
Actually produced by and act on many different cell types
What are interferons?
IFN-α, IFN-β and IFN-γ
Typically produced in response to viral infection, tumours, etc
Have immuno-modulatory effects
IFN-B has anti-inflammatory properties
What is TNF?
TNF-α (& TNF-β)
TNF-α is highly pleiotropic proinflammatory cytokine, Pivotal role in RA
Produced mainly by monocytes/ macrophages
Multiple cell targets
What are growth factors?
VEGF (vascular endothelial growth factor), FGF (fibroblast growth factor), PDGF (platelet-derived growth factor), EGF (epidermal growth factor)
What are CSF?
VEGF (vascular endothelial growth factor), FGF (fibroblast growth factor), PDGF (platelet-derived growth factor), EGF (epidermal growth factor)
What pro-inflammatory cytokines are involved in RA?
IL-1, IL-6, TNF-α, IL-12, IL-15, IL-17, IL-18
IL-29, IFN- γ, IL-2, IL-32, IL-26, GM-CSF
What anti-inflammatory cytokines are involved in RA?
IL-10, IL-4, IL-1Ra, sTNFR, TGF-β, IL-11, IL-13
What chemokines are involved in RA?
IL-8, CCL2, CCL3, CCL5, CXCL5, CXCL1
What growth factors are involved in RA?
VEGF, PDGF, FGF, EGF
What is the cytokine imbalance in RA?
Predominance of pro-inflammatory mediators
What are the pleiotrophic effects of TNF-alpha in RA?
Pro-inflammatory cytokine release Hepcidin production PGE2 production Osteoclast activation Chondrocyte activation Angiogenesis Leukocyte accumulation Endothelial cell activation Chemokine release
How do TNF-alpha and IL-1beta act within the RA joint?
They act synergistically
on the same targets:
1) induce MMP production by chondrocytes
2) activate osteoclasts
3) increase adhesion molecule expression on endothelium
4) induce IL-8 by synovial fibroblasts
How are cytokines profiled in early RA?
Heatmap (and dendrograms).
Individual cytokines/MMPs are represented by columns. Patients are represented by rows. Patients are clustered (C1 – C4) according to circulating levels of the indicated cytokines/MMPs.
What is RF?
RF are IgM, IgG, IgA & IgE class antibodies all with specificity for Fc region of IgG antibody. RF in RA are characterised by their high affinity for IgG.
What is the physiological role of RF?
Enhance immune complex clearance, immune complex uptake, processing and antigen presentation by B-cells and complement fixation
How does RF behave in RA?
Produced in joint by B-cells
IgM major RF in RA
Higher affinity than normal
ACR/EULAR criteria
RF associated with severity, erosions, extraarticular
manifestations and poor prognosis (esp. high levels)
Present in 70-80% of RA patients; specifity ~80%.
What is anti-CCP?
Anti-cyclic citrullinated peptide antibodies
What does anti-CCP do?
Recognises proteins which all contain the non-standard
amino acid citrulline.
How and with what is citrulline made?
Citrulline created by post-translational modification – enzymes called peptidyl arginine deiminases (PADI) catalyse deimination of arginine to citrulline.
How does anti-CCP behave in RA?
Produced in joint by B-cells
ACR/EULAR criteria
PADI2 & PADI4 abundant in RA synovium
Anti-CCP associated with erosions, joint destruction, and poor prognosis, but not extraarticular manifestations.
Often detectable years before onset of clinical synovitis.
Present in 80-90% of RA patients; specificity >95%.
What are DMARDS?
Disease-modifying anti-rheumatic drugs.
Primary option for the treatment of RA.
Mono-therapy or combination therapy.
What are the two groups can biological therapies be separated into?
Cytokine targeted therapy:
– TNFα
– IL-1
– IL-6
Cell targeted therapy:
– B-cells
– T-cells
What is the rationale for using anti-TNF-alpha in RA?
The dis-regulated cytokine network in the RA synovium
is largely dependent on the actions of TNF-α
Both TNF-α and its receptors are present at elevated levels in the synovium – redressing this imbalance has the potential to influence multiple features of RA pathology and inflammation.
How many patients typically respond to anti-TNF-alpha therapy?
40-90%
What is Rituximab and how does it work?
B-cell depletion therapy
Targets the CD20 molecule on the surface of B-cells
Genetically engineered mouse-human chimeric mAb
Variable light and heavy chain regions from murine anti-CD20 antibody IDEC-2B8
Human IgGk constant regions
Depletes cells through Ab-dependent and complement-dependent cell lysis
What is Abatacept and how does it work?
Inhibition of T-cell co-stimulation. A mAb that targets CD80/CD86 on APCs
T-cell requires 2 signals from APC – first is TCR:MHC-antigen interaction, second is between CD28 on T-cells & CD80/CD86 on APC.
When activated, T-cell expresses CTLA4, which binds & inhibits CD80/86.
Immunoregulatory – negative feedback mechanism for T-cell activation.
Abatacept binds CD80/CD86 & blocks T-cell co-stimulation (2ndsignal)
What gene has the strongest association with RA?
MHC region, particularly the HLA
What is the shared epitope?
A sequence of 5 amino acids common to
HLA-DRB1 alleles known to confer increased risk of RA.
The sequence is QKRAA, QRRAA or RRRAA
Where is the shared epitope located?
The 3rd hypervariable region of the β1 domain, amino acids 70 – 74, and resides within the peptide-binding cleft of the class II molecule.
What environmental factors are associated with RA?
Smoking, likely the best defined environmental factor in RA. esp. seropositive RA; citrullination/PADI? HLA? Silica/asbestos Coffee--> increased frequency of seropositive RA in individuals drinking >4 cups/day (RR 2.2), independent of smoking Diet Exposure to mineral oils Hydraulic oils Infections – viral (e.g. EBV, CMV) or bacterial
How is smoking linked with TNF-alpha release?
T-cells from RA patients who smoke show increased release of TNF-α compared with cells from patients who have never smoked.
Levels increase with smoking duration and intensity.
Increased TNF-α is also seen in past smokers – they no longer smoke, but the effects of smoking on T-cell TNF-α release persist.
An increase in the ratio of TNF-α/TNFR is also evident.
Thus, there appears to be an imbalance in the ratio of TNF-a/TNFR released by T-cells that favours TNF-α activity
