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Biochemical Basis of Disease: Rheumatoid Arthritis Treatment
Terms in this set (122)
What does rheumatoid arthritis comprise of?
inflammation, proliferation of the bone synovium, and erosion of cartilage and bone
Which pro-inflammatory cytokines play a major role in pathogenesis of rheumatoid arthritis?
IL-1, IL-6 and TNF-alpha
What are some genetic markers for RA?
- HLA-DR4 and HLA-DRB-1
- SNPs: matrix metalloprotease 3
What are some auto-antibodies that are biochemical markers for RA?
- rheumatoid factor
- anticitrullinated protein/peptide antibodies
What are some immunological markers for RA?
- regulatory T cells
- CD28 and CD40
- Cytokines/inhibitors (K1, TNF-alpha, IL6, IL8, IL16)
What are some inflammatory markers for RA?
- Acute Serum Amyloid-associated protein (A-SAA)
What are some markers of join damage?
- hyaluronic acid
- matrix metalloprotease 3 (MMP3)
What are some markers of bone damage in RA?
- bone sialoprotein (BSP)
What imaging techniques are extensively used to find bone and joint damage from RA?
Following early diagnosis, what is used to treat RA first?
Methotrexate plus low dose glucocorticoid
What are some anti-rheumatoid drugs?
- Cytotoxic drugs
What are some NSAIDs used to reduce symptoms of RA?
aspirin, ibuprofen, celecoxib
True or False: Glucocorticoids are disease-modifying drugs
What is the major problem with treating RA patients with glucocorticoids?
serious side effects
What are some glucocoritcoids used to treat RA?
hydrocortisone, prednisone, dexamethasone
What is a cytotoxic drug used to treat RA?
What is an immunosuppressant used to treat RA?
What does DMARD stand for?
Disease modifying anti-rheumatic drugs
What do NSAIDs inhibit?
COX 1 and 2
Which NSAID blocks a balance between COX1/2?
What is an NSAID that selectively blocks COX2?
True or False: Tylenol is an NSAID
False. Weak inhibitor of COX
True or False: NSAIDs are disease modifying
False. They treat symptoms
How are glucocorticoids administered?
- oral doses
- parenterally as single intravenous injection
- intramuscular injection
- intra-articular/intrasynovial injections
How do adrenal steroids work?
They are synthesized and released as required from the adrenal cortex, under the influence of circulating adrenocorticotrophic hormone (ACTH)
Where is ACTH released from?
the anterior pituitary gland
True or False: The medulla secreted adrenal steroids and the cortex secreted catecholamines
False. Other way around
What are two examples of adrenal steroids?
What is the main endogenous hormone for mineralocorticoids?
What do glucocorticoids affect?
- carbohydrate and protein metabolism
- potent regulators of the innate and acquired immune response
Where are glucocorticoids secreted from?
What is the main hormone in humans?
hydrocortisone, aka cortisol
What is the main hormone in rodents?
What are glucocorticoids most often used for and what are their unwanted side effects?
Used for anti-inflammatory and immunosuppressive properties. All their metabilic and other actions are seen as unwanted side effects.
In humans, what is a deficiency in corticosteroid production termed as?
What results from a deficieny in corticosteroid production?
- muscular weakness
- low blood pressure
- weight loss
What is the term for excessive glucocorticoid activity in humans?
What can excessive glucocorticoid activity be caused by?
- hypersecretion from the adrenal glands (eg. tumour)
- by prolonged therapeutic glucocorticoid regimens
What are the most common glucocorticoids used?
hdyrocortisone, prednisone and dexamethasone
True or False: It has been possible to separate the glucocorticoid from the mineralocorticoid actions
True or False: It has been possible to separate the anti-inflammatory actions from the other actions of the glucocorticoids
False. It has not been possible
What are glucocorticoid effects mediated by?
intracellular glucocorticoid receptors belonging to the nuclear receptor superfamily
Glucocorticoids enter cells and bind to GRs, leading to what?
a conformational change and exposure of the DNA-binding domains of GRs
What is a possible transactivation mechanism for glucocorticoids?
- the transcriptional machiner is presumed to be operating at a low level
- the liganded glucocorticoid receptors form dimers which bind to "positive" glucocorticoid response elements within the promoter sequence and up-regulates transcription
What is the possible transrepression mechanism for glucocorticoids?
- the transcriptional machinery is driven constitutively by transcription factors
- in binding tot he negative GRE, the receptor complex displaces these transcription factors and expression falls
- AP1 and NFkB can also be involved
How does hyperglycaemia result from glucocorticoid use?
- decrease in the uptake and utilisation of glucose, increase in gluconeogenesis, hyperglycaemia
What are the main metabolic effects of glucocorticoids?
- decrease in the uptake and utilisation of glucose --> hyperglycaemia
- concomitant increase in glycogen storage, which may be a result of insulin secretion in response to the increase in blood sugar
- decreased protein synthesis and increased protein breakdown overall
What do large doses of glucocorticoids given over a long period result in?
What are some other metabolic and systemic effects of glucocorticoids?
- produce a negative calcium balance which may result in osteoporosis (decrease absorption in GI tract and increase in kidney)
- negative feedback effect on the secretion of adrenocorticotrophic hormone
What are glucocorticoids actions on inflammatory cells?
- decrease egress of neutrophils from blood vessels, and reduced activation of neutrophils and macrophages
- decreased activation of Th cells
- reduced clonal proliferation of T cells (decreased IL2 transcription)
- decreased fibroblast function
- decreased expression of COX-2
- decreased gene transcription and therefore generation of many cytokines
- reduction in the concentration of complement components in the plasma
- decreased generation of induced nitric oxide
- decreased histamine release from basophils
- decreased IgG production
- Inhibits the release of arachidonic acid from cell membrane phospholipids
- increased synthesis of anti-inflammatory factors such as IL10, IL1-soluble receptor
What are some clinical uses for glucocorticoids?
- replacement therapy for patients with adrenal failure
- anti-inflamatory/immunosuppressive therapy
- in neoplastic disease
When are glucocorticoids used as anti-inflammatory/immunosuppressive therapy?
- inflammatory conditions of skin, eye, ear or nose (topically)
- hypersensitivity states
- miscellaneious autoimmune/inflammatory diseases
- prevent graft-versus-host disease following transplant
Why are glucocorticoids used in neoplastic disease?
- to reduce cerebral edema in patients with metastatic or primary brain tumors (dexamethasone)
- treatment of specific malignancies in combination with cytotoxic drugs
How are glucocorticoid drugs transported in the blood?
by corticosteroid binding globulin
How does glucocorticoid drugs enter cells?
by diffusion (they are lipophilic)
Where are glucocorticoid drugs metabolized?
in the liver
What potentially dangerous effects can result from suppression of the response to infection or injury?
What are some unwanted effects of glucocorticoids?
- opportunistic infection
- impaired wound healing
- peptic ulceration
- metabolic actions (especially osteoporosis)
- suppression of endogenous glucocorticoid synthesis --> atrophy of adrenal cortex
- latrogenic Cushing's syndrome
What are the clinical uses for Immunosuppressants?
- to suppress rejection of transplanted organs and tissues
- to suppress graft-vs-host disease in bone marrow transplantation
- to treat conditions with an autoimmune component in their pathogenesis
specific inhibitor of T cell mediated immunity
True or False: Cyclosporin is cytotoxic
False. It is not cytotoxic
What drug is 50 to 100x more potent than cyclosporin?
How does Tacrolimus function?
by binding to FK-binding proteins and inhibting calcineurin
What is the main action of cyclosporin?
relatively selective inhibition of IL-2 gene transcription; similar efefct on interferon gamma and IL-3
What is the main action of tacrolimus?
inhibits IL2, IL3, IL4, IFN-gamma, TNF-alpha production; inhibits cell-mediated immunity without suppressing B cell or NK cell function
True or False: FK506 is antiapoptotic unlike CsA
False, other way around
How does CsA function antiapoptotically?
prevents opening of mitochondrial permeability transition pore --> inhibits cytochrome C (proapoptotic factor) release
What are some examples of DMARDs?
- gold compounds (auranofin)
What does DMARDs reduce to improve symptoms of RA?
- serum concentration of acute-phase proteins
- rheumatoid factor
True or False: DMARDs are usually slow (months) in onset
Why do almost half of the patients stop DMARDs within 2 years of treatment?
because of unwanted effects and/or lack of efficacy
What is the first choice DMARD for RA?
What is Methotrexate used to treat?
- graft versus host disease
Why does methotrexate treatment have to be closely monitored?
because of blood dyscrasias which can be fatal, and liver cirrhosis
True or False: Methotrexate antiinflammatory action is independent of its cytotoxic action
What is the MOA of Methotrexate?
- may act by increasing levels of adensosine (endogenous anti-inflammatory mediator) which inhibits neutrophil adhesion, phagocytosis and superoxide generation
- causes apoptosis of activated CD4+ and CD8+ T cells, but not resting cells
What could the versatility of MTX be due to?
its combined anti-neutrophil, anti-T-cell, and antihumoral effects
What are the two most common preparations of gold compounds?
aurothiomalate and auranofin
When does the maximum action of gold compounds occur?
develops slowly, with maximum action occurring after 3-4 months
What symptoms do gold compounds improve?
pain and joint swelling subside
What is a possible MOA for gold compounds?
possible through inhibition of IL-1 and TNF-alpha production but the MOA is not known
How is auranofin given?
What is the half life of auranofin?
How is auranofin excreted?
mostly renal, but also through GI
What are the unwanted effects for auranofin?
- effects include skin rashes, mouth ulcers, non specific flu like symptoms, proteinuria, thrombocytopenia
- if therapy is stopped when syptoms appear the incidence of serious toxic effects is relatively low
Does Penicillamine have general anti-inflammatory effects?
No, it is specific for rheumatoid diseases
How is penicillamine produced?
by hydrolysis of penicillin
True or False: The penicillamine D-isomer is used
When are therapeutic effects seen in patients that respond to penicillamine?
effects are seen within weeks but do not reach a plateau for several months
What is the putative MOA for penicillamine?
- modify rheumatoid disease partly by decreasing immune response (eg. IL-1 generation)
- partly by an effect on collagen synthesis, preventing the maturation of newly synthesized collagen
How is penicillamine given?
orally. With dosage starting low and increased gradually to minimize unwanted effects
How much of the dose of penicillamine is absorbed?
only half the dose
When do peak plasma concentrations occur for penicillamine?
How is penicillamine excreted?
in the urine
How often is penicillamine stopped?
in up to 40% of patients
What are the side effects of penicillamine?
most common are rashes and stomatitis, followed by anorexia, fever, nausea and vomiting, disturbances of taste and proteinuria
Why should penicillamine not be given with gold compounds?
because it is a metal chelator
What is Chloroquine/Hydroxychlorquine used mainly for?
in the prevention and treatment of malaria, but is no longer effective
How often to patients responsd to chloroquine?
only half the patients treated respond
What disease is treated with Chloroquine?
systemic lupus erythematosus
What disease is chloroquine contraindicated with?
psoriatic anthropathy because they make the skin lesions worse
Chloroquine as a lysosomotropic agent
accumulates preferentially int he lysosomes of cells, it is trapped there due to the low pH in lysosomes
What are the putative anti-inflammatory effects of chloroquine?
- inhibits lymphocyte proliferation
- inhibits phospholipase A2
- inhibits release of enzymes from lysosomes
- inhibits release of reactive oxygen species from macrophages
- decreases production of IL-1
What do targeted synthetic DMARDs inhibit?
What are some Janus Kinase inhibitors?
Tofacitinib and baricitinib
What results from JAK inhibition?
JAK inhibition interferes with signal transduction and thus cell activation elicited by IL6, granulocyte-monocyte colony stimulating factor, interferons, IL2 and IL15
What are some Biological DMARDs TNF inhibitor drugs?
- Anti-B-cell Rituximab
- Anti-T-cell co-stimulation
human monoclonal antibody
IgG-Fc receptor construct
chimeric monoclonal antibody
chimeric monoclonal antibody
How is Adalimumab administered?
How is etanercept administered?
How is infliximab administered?
How is Anti-B-cell Rituximab administered?
How is Anti-T-Cell co stimulation administered?
How is Anti-IL 6R administered?
What is the MOA of etanercept?
consists of teh extracellular domain of the human TNF receptor fused to the Fc region of human IgG. This decoy receptor binds TNF-alpha and TNF-beta in the circulation, preventing the access of these cytokines to target tissues
What is the infliximab antibody made of?
The variable regions are derived from mouse antihuman sequences, while the remainder of the antibody is composed of human antibody sequences
Why is infliximab variable region derived from mouse antihuman sequences and the remainder of human antibody?
This modification of the original mouse monoclonal anti-TNF-alpha antibody reduces the development of neutralizing antibodies against infliximab, whereas the humanised Fc region ensures phagocytosis
True or False: Biological DMARDs induce less adverse events than conventional synthetic DMARDs
False. Induce more adverse events
What are the adverse effects of Biological DMARDs?
- incidence of serious infections is increased
- reactivation of TB
- flares of MS
- blood dyscrasias
- demyelinating CNS disorders
- hypersensitivity reactions
- development of autoantibodies
- high risk for developing new malignancies for select biologicals
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