Lecture 13 - biologics in arthropathies Flashcards
what is involved in the susceptibility of rheumatoid arthritis?
1) genetic susceptibility,
2) a primary exogenous arthritogen,
3) an autoimmune reaction to joint components,
4) expression/production of mediators of joint damage.
describe the immunopathogensis of ehramotid arthritis
Initial Trigger: The process starts with an antigen, possibly a microbe, which activates CD4+ T-cells.
Activation of Immune Cells: These T-cells then produce cytokines that activate other immune cells, including B-cells and macrophages.
B-cell Activation: Activated B-cells produce rheumatoid factor, leading to the formation and deposition of immune complexes in joints.
Macrophage Activation: Macrophages release tumor necrosis factor (TNF) and other cytokines, which stimulate fibroblasts, chondrocytes, and synovial cells.
Tissue Destruction: The stimulated cells release destructive enzymes (like collagenase, stromelysin, and elastase) and inflammatory mediators (like PGE2), which contribute to joint injury and the formation of pannus (inflammatory exudate).
Endothelial Activation: TNF also activates endothelial cells, leading to the expression of adhesion molecules.
Inflammatory Infiltration: The expression of adhesion molecules facilitates the accumulation of inflammatory cells in the joint area.
Chronic Inflammation and Damage: Chronic inflammation leads to the destruction of bone and cartilage, and can result in fibrosis and ankylosis (joint stiffness).
what are clinical features of early rheumatoid arthritis?
Symptoms
- Joint pain/swelling
- Stiffness following inactivity
- Systemic ‘flu-like’ features
Signs
- Synovitis
- Joint swelling/tenderness
- Extra-articular features
describe TNFA
tnfa is a critical mediator
TNFa is a multifunctional pro-inflammatory mediator
a. Induction of further cytokine production
b. Activation or expression of adhesion molecules
c. Growth stimulation
TNFa action needs to be carefully controlled by
the body
Mediates key roles in;
acute and chronic inflammation
anti-tumour responses
infection
Overproduction of TNF is associated with a wide range of pathological conditions.
Effort to find ways to down-regulate production or inhibit its effects.
what are the 2 forms of TNFa?
- membrane bound TNFa (26Da)
- Soluble TNFa (17kDa)
TACE is a TNFa converting enzyme
describe the two tnfa receptors.
TNFR1 and TNFR2 share structural similarity in extracellular domain. they have intracellular differences and different signalling pathway.
decried TNFR1
55-60 kDa TNF receptor type 1 (TNFR1) constitutively expressed in nearly all tissue
Capable of inducing cell death through a ‘death domain’ of the intracellular portion of the receptor
Binds TNF, is internalised, recruits TRADD (a death domain-containing signal transduction adapter molecule), which leads to DNA degradation and cell death (apoptosis).
describe TNFR2
75-80 kDa protein
No death domain – cannot induce apoptosis
Recruitment of TRAF2 leads to activation of the NFB pathway, production of cytokines, inhibitors of apoptosis
Differential expression of TNFR1 and TNFR2
what are TNFa signal transduction and effector mechanisms?
TNFα can signal through two different receptors, TNFR-1 and TNFR-2, which are present on the cell surface.
With TNFR2 the signalling pathway recruits TRAF2 which can allow signalling to activate the NFκB pathway.
NFκB is typically held inactive in the cytoplasm by IκB but upon activation translocates into the nucleus.
Once in the nucleus, NFκB can induce the transcription of various genes.
TNFα signaling through TNFR-1 can also lead to apoptosis.
what are the transcription products of TNFa signalling?
pro-inflammatory
TNFa
IL-1B
Upregulation of adhesion molecules (ICAM-1, VCAM-1)
Cytokines that further enhance the immune response (e.g. Il-6)
Activators of inflammatory pathways (arachidonic acid metabolites, superoxides and nitric oxide)
describe the different lines of therapy for the treatment of rheamotid arthritis
diet
NSAIDS
steroids
immunosuppressive drugs or DMARDS
biologics
what do biologics do in the immune system to help combat rheumatoid arthritis
biologics are used for the treatment of patients with rheumatoid arthritis who have been unresponsive with the treatment of DMARDS. biologics inhibit the TNFa inflammotry mediators. main anti-TNFa biologics are:
infliximab. it is a chimeric mAb. IV delivery
etancercept. it is a TNFa mimetic, not mAb, but has Ab Fc structural component. it is injected at home
adalimumab. human recombinant protein, injected at home.
golimumab. humanised mAb. injected at home.
what are biologics ie how t they work?
Biologics are antibody-like molecules. Antibodies are produced by B-lymphocytes as part of the body’s immune response to fight infections. antibodies are made in autoimmuen disease and atatck self proteins as if they are foreign or non self. antibodies are made in autoimmuen diseases and atatck self proteisn as it they are foreign or non self. Antibody producing cells are short lived
describe the structure of an antibody
variable region at top, content region at bottom half.
three globular regions of the protein form a Y shape
the two antigen binding sites are at the tips of the arms
composed two protein chains; heavy chains and light chains
what is infliximab ?
infliximab is a recombinant antibody produced and secreted from mouse myeloma cells. It is a chimeric antibody 25% mouse derived and 75% human protein. It is generated and manufactured under sterile conditions.
The antibody is manufactured by continuous perfusion cell culture. The collected harvests are clarified by filtration before further purification.
what is the mode of action of infliximab?
infliximab binds and neutralises both soluble and membrane bound TNFa and inhibits further activity so no further signal
other mechanisms of action include
1. antibody dependant cell-mediated cytotoxicity and lysis of TNFa expression cells through complement activation
descried the pharmacology of infliximab
Infliximab is administered by an intravenous infusion, used within four hours of reconstitution.
Patients are under observation for the 2 hours of the infusion and for 2 hours post-infusion and all infusions are given in the hospital
5mg/kg dose has a half life of 10 days
10mg/kg has a half life of 12 days
what is the dose of infliximab for rheumatoid arthritis
The recommended dose for RA is 3 mg/kg as a single dose.
The initial dose should be followed by additional 3 mg/kg doses 2 and 6 weeks after the first dose.
Thereafter, maintenance dose is 3 mg/kg every eight weeks.
IF USED IN COMBINATION WITH OTHER THERAPIES THE DOSE WILL REQUIRE ADJUSTMENT TO SUIT INDIVIDUAL TREATMENT REGIMES
what is the response of infliximba like in patients?
Approx. 50% of patients show a response by 2-8 weeks.
50-60% of patients achieve a clinical response at 30 weeks.
Some patients may not respond due to epitope variance – TNFa protein of a different sequence so antibody doesn’t bind, Higher doses required due to high circulating tnfa, Patient with a higher proportion of IFNb than IFNa do not respond as well
what are the safety and side effects of infliximab use?
Most common side effects are infusion reactions such as itching, flushing, nausea, headaches and abdominal pain
Short term effects in a few patients are runny nose, headaches, dizziness, flushing rash and stomach or indigestion
There is increased risk of serious infection due to immunosuppression, non Hodgkin’s lymphoma, lupus and upper respiratory tract infections such as tuberculosis
Immunogenicity: patient develops HAMA (human anti-mouse antibodies) towards Infliximab
what evidence is there of immunogenicity of infliximab?
Patients develop antibodies to Infliximab
e.g. In a trial for Crohn’s, an average of 3.9 infusions (range, 1-17) per patient was administered over an average of 10 months. Antibodies against infliximab were detected in 61% of patients.
Incidence of the formation of antibodies to Infliximab is reduced with immuno-suppressive therapy
Infliximab has been shown to be very effective in inducing remission of RA but over time may lose effectiveness
what are biologic agents used for the treatment of rheumatoid arthritis ?
infliximab
etanercept
CDO-571
CDP-870
Adalimumab
what’re attentive therapies to biologics?
The anti-interleukin 1(Il-1) inhibitor, Anakinra (KINERET)
- has had a product licence in the United Kingdom and was approved by NICE (National Institute for Health and Clinical Excellence) but now has a ‘DO NOT DO’ recommendation - not recommended for the treatment of rheumatoid arthritis (RA), except in the context of a controlled, long-term clinical study.
ABATACEPT (Orencia), which inhibits the activation of lymphocytes within the joint (blocks CD80/CD86 receptors and ability to interact with CD28)
– APPROVED BY NICE for selected use but with specific recommendations
MABTHERA (Rutiximab), which kills a specialised group of lymphocytes called B-cells – recognises CD20 - APPROVED BY NICE FOR USE IN NHS
what are potential targets for the inhibition of TNFa action?
- TNFa meolcule
- TNFa receptors
- TACE
- molecules in the TNFa signalling pathway
- NFkB, MAP kinase, and SAP kinase pathways
what are advantages of small molecule oral TNFa inhibitors?
Convenient, non-injectable with greater patient compliance
Small molecule might facilitate tissue penetration
Possibility for once a day dosing
Reduced immuno-suppression required
Non-immunogenic
Easier manufacturing and lower cost
Potential use in combination with other anti-inflammatory therapies.
may be used in ms and cross disease with conditions associated with overproduction of TNFa.
