Rheumatoid Arthritis Flashcards
Rheumatoid Arthritis (RA) afflicts – adults in the US
2.0 million
RA afflicts ~X:X women than men characterized by daily joint pain
3:1
most patients with RA also experience some degree of
depression
anxiety
feelings of helplessness
RA can interfere with routine
daily activities
what is RA
an inflammatory disease causing pain, swelling, stiffness, and loss of function in joints
how long does RA last for
few months and disappear w/o causing any noticeable damage
are there various degrees of RA
yes, some patients have mild or moderate forms of the disease with period of worsening symptoms (flares) and period they feel better (remission)
describe the severe form of RA
-diseaseis active most of the time, lasts for many years or a lifetime, leading to serious joint damage, disability
in RA, what happens to the synovium of a joint
- it becomes inflamed causing warmth, redness, swelling and pain
- as the disease progresses, the inflamed synovium invades and damages the cartilage and bone of the joint
in RA what happens to the surrounding muscle
muscles, ligaments and tendons become weakened
what effects does RA have on bones
can cause more generalized bone loss that may lead to osteoporosis
what type of disease is RA
autoimmune disease
- a person’s immune system attacks joint tissues for unknown reasons
- WBC travel to the synovium causing inflammation, characterized by typical symptoms of RA
RA effects in other parts of the body
- anemia
- neck pain
- dry eyes and mouth
- rarely ppl have inflammation of the blood vessels, the lining of the lungs, or the sac enclosing the heart
causes of RA
- genetic factors
- environmental factors
- hormonal factors
- state of the immune system
genetic factors causing RA
-some genes, involved in the immune system, are associated with a tendency to develop RA
environmental factors causing RA
appears that some viral or bacterial infections may trigger the disease process in people genetically susceptible to RA
hormonal factors causing RA
women are more likely to develop RA than men, pregnancy may improve the disease and RA may flare after a pregnancy
how can the state of the immune system cause RA
interleukin 12 and tumor necrosis factor-alpha may contribute to RA development
how can RA be diagnosed
- difficult to diagnose in its early stages
- no single test for the disease, symptoms and their severity differ form person to person
how can laboratory test diagnose RA
- Rheumatoid factor, antibody present in the blood of most people with RA: not all people with RA test positive for rheumatoid factor, especially early in the disease
- some people test positive for R factor, yet never develop the disease
- WBC count, C-reactive protein
clinical features of RA
- tender, warm, swollen joints
- symmetrical pattern of the affected joints
- joint inflammation often affecting the wrist and finger joints closest to the hand
- joint inflammation sometimes affecting other joints (eg. neck, shoulder, elbow, hips, knees, ankles, feet)
- fatigue, occasional fevers, a general sense of not feeling well
- pain and stiffness lasting for more than 30 mins in the morning or after a long rest
how long do RA symptoms last for
many years
what are the 2 primary objectives of treating inflammatory diseases
- relief of pain
2. relief of inflammation
what drugs are used to treat RA
- NSAIDs
2. Glucocortiocids
properties of NSAIDs
-have antinociceptive and anti-inflammatory properties
NSAIDs are useful in treating
acute and chronic pain
properties of glucocorticoids
- have significant anti-inflammatory properties
- useful for the treatment of acute RA episodes
glucocorticoids have limited use as
chronic administration associated with serious toxicity
function of disease-modifying antirheumatic drugs (DMARDs)
slowing and stopping the tissue damage process
function of DMARDs in treating RA
- slow rate of RA associated bone damage
* acts upon basic aspects of the immune response
what is the downfall of DMARDs
have significant side effects
most RA patients are treated with
-salicylates and other related agents having anti-inflammatory, analgesic and antipyretic effects
pain intensity of RA is related to what
the severity of the inflammation
what may be more effective in reducing or preventing joint damage
-treating RA with more powerful drugs and the use of drug combinations instead of one medication alone
NSAIDs are effective in treating
- RA
- seronegative sponduloarthropathies (eg. psoriasis arthritis)
- osteoarthritis
- localized musculoskeletal syndromes
- gout
look at the COX-1 and COX-2 inhibitors slide 12
look at the COX-1 and COX-2 inhibitors slide 12
aspirin and select NSAIDs all have
-antipyretic, analgesic & anti-inflammatory properties
anti-inflammatory activity mediated mainly through the inhibition of
prostaglandin synthesis
when are NSAIDs found in the synovial fluid
after repeated dosing
what are the anti-inflammatory effects of aspirin
- nonselective
- irreversible COX-1 and COX-2 inhibitor
what are the analgesic effects of aspirin
decreases mild to moderate intensity pain due to its anti-inflammatory effects and its probably inhibition of pain stimuli at a subcortical site
antipyretic effects of aspirin reduces fever though
COX inhibition in the CNS as well as blocking release of interleukin-1 from macrophages
aspirin also inhibits aggregation of
platelets
see brand names of aspirin slide 15
see brand names of aspirin slide 15
see combinations of aspiring slide 16 + 17
see combinations of aspiring slide 16 + 17
other possible NSAIDS mechanism of actin include
- inhibition of chemotaxis
- down regulation of interleukin-1 production
- decreased production of free radicals and superoxide
- interference with calcium mediated-mediated intracellular events
cylooxigenase-2 selective inhibitors (COXIBS) were developed to
inhibit prostalgandin synthesis by COX-2 isoenzyme induced at sites of inflammation, without affecting the constitutively active housekeeping COX-1 isoenzyme found in the GI tract, kidneys and platelets
COXIBS bind to and block the active site of
COX-2 enzyme much more effectively than that of COX-1
COX-2 inhibitors do not have a significant effect on
- platelet aggregation, which is mediated by the COX-1 enzyme
- do not offer aspirin cardioprotective effects
where is COX-2 is constitutively active
kidneys
COX-2 inhibitors produce – toxicities
renal toxicities similar to traditional NSAIDs
why do COX-2 inhibitors have a limited use
-bc have a higher incidence of cardiovascular thrombotic effects resulting from the use of COX-2 inhibitors
glucocorticoids are used in –% of RA patients
60-70%
function of glucocorticoids in RA patients
rapid and dramatic effects, capable of slowing the appearance of new bone erosions
prolonged use of glucocorticoids results in
serious toxic effects
what is the primary function of NSAIDs
- offer mainly symptomatic relief
- have little effect on the progression of bone and cartilage destruction
DMARDs are used to
arrest or slow RA progression by modifying the disease itself
DMARDs are – acting
slow acting and their beneficial effects may take 6 weeks to 6 months to become evident
name 4 DMARDs
- methotrexate
- cyclosporine
- Azathioprine
- Sulfasalazine
what DMARDs is the choice in RA treatment
methotrexate
mechanism of action of methotrexate
- inhibits aminoimidazolecarboxamide (AICAR) ribnucleotide transformylase and thymidalate synthetase thus decreasing polymorphonuclear chemotaxis
- decreasing lymphocyte and macrophage function
how is methotrexate absorbed
-from GI, hydroxulated, and both parent drug and metabolite intracellularly polyglutamated where they remain for prolong periods
what is the plasma half life of methotrexate
6-9 hr which may go up to 24 hrs in some patients
methotrexate decreases the rate of appearance of
new erosions, and is effective to treat juvenile chronic arthritis
methotrexate also used to treat
- psoriatic arthritis
- psoriasis
- systemic lupus erythematosus
what are the side effects of methotrexate
nausea and mucosal ulcers are the common toxicities
-may cause cirrhosis
-reports of “hypersensitivity” lung reaction or RA is characterized by
-shortness of breath, as well as pseudolymphomatus rxn
what supplement is recommended to reduce GI and liver side effects of methotrexate
folic acid
what are contraindications for using methotrexate
pregnancy
mechanism of action of cyclosporine
inhibits synthesis of interleukin 1 and 2 receptors through gene transcription regulation
cyclosporine results in decreased
- macrophage T-cell interaction and T cell responsiveness
- affects T-cell dependent B cell function
why is cyclosporine involved in a # of drug interactions
- incomplete GI absorption
- metabolized by the liver P450 CYP3A
what drugs can cyclosporine interact with
potassium-sparing diuretics
FDA approved cyclosporine for the treatment of
RA; shown to delay new bony erosions
cyclosporine use is limited by
serious toxicity including nephro- and liver effects, hypertension, hirsutism, etc.
what is Azathioprine
a prodrug that is converted to its active metabolite 6-thioguanine
mechanism of action of Azathioprine
inhibits inosinic acid synthesis, as well as B and T cell function
FDA approved Azathioprine for use in the treatment of
RA
what are serious adverse effects of Azathioprine
- bone marrow suppression
- GI alterations
metabolism to 6-thioguanine is
bimodal
-slower metabolizers accumulate azthioprine, are at high risk of developing symptoms of myelosuppression
sulfasalazine is effective in treating
RA and juvenile chronic arthritis
sulfasalazine is metabolized by
bacteria in the bowel to sulfapyridine and 5-aminosalicylic acid which appears to be active agent in the treatment of RA
mechanism of action of sulfasalazine
-modify various immune response in RA patients (decreases production of IgA and IgM rheumatoid factors
what are the serious side effects of sulfasalazine
GI alterations
neutropenia
what are the tissue necrosis factor-alpha (TNF-A) Blocking Agents
Adalimumab
Infliximab
Etanercept
Leflunomide
what is Adalimumab
-recombinant human anti-TNF monoclonal antibody
what is infliximab
similar to adalimunab
etanercept interacts with
TNF-a mediated process
leflunomide interacts with
TNF-a mediated processes
cytokines play a critcal role in the immune response and in
RA
what factor appears to play a crucial role in the etiology of the inflammatory process
TNF-a
what does TNF-a modulate
cellular functions by activating specific TNFR1 and 2 membrane bound receptors
administration of soluble TNF receptors may combine with
soluble TNF, this inhibiting its effect
monoclonal aniTNF antibody inhibits
T cell and macrophage function
see diagrams 33-34
see diagrams 33-34
in RA where are cytokines expressed
in the joints of patients
what are cytokines
are a category of signalling proteins and glycoproteins that, like hormones and neurotransmitters are used extensively in cellular communication
what is Adalimumab
fully human IgG1 anti-TNF monoclonal Ab
Adalimumab is FDA approved to treat
RA, psoriatic arthritis and ankylosing spondylitis
Adalimumab given subcutaneous forms a complex with
soluble TNF preventing its interaction with p55 and p75 cell surface receptors, thus down-regulating macrophage and T cell function
methotrexate decreases the clearance of Adalimumab by
?40%
function of Adalimumab
decreases ne bone erosion formation rate when used either as monotherapy or in combination with other DMARDS
what are the adverse effects of Adalimumab
- increases the risk of macrophage-dependent infection (including TB and other opportunistic infections)
- vasculitis
- leukopenias
- evaluate for TB
what is infliximab
chimeric IgG1 monoclonal Ab, binds to soluble and possibly membrane bound TNF-a
mechanism of action of infliximab
similar to Adalimumab
infliximab used to treat
RA
inflammatory diseases
what combination simprove drug effectiveness of Infliximab
- methotrexate, DMARDS
use of Infliximab is limited by
toxic side effects
contraindications of using Infliximab
latent or active tuberculosis
-this drug is a potent macrophage inhibitor, may activate latent TB
Etanercept is used for
- surgery
- joint replacement
- tendon reconstruction
- synovectomy
purpose of surgery
- reduce pain
- improve the affected joint’s function and patients ability to perform daily activities
purpose joint replacement
- most frequently performed surgery for RA
- artificial joints not always permanent and may have to be replaced
- important for young ppl
purpose of tendon reconstruction
used most frequently on the hands, reconstructs the damaged tendon by attaching an intact tendon to it
-can help to restore hand function
function of synovectomy
-the inflamed synovial tissue is actually removed
routine monitoring and ongoing care monitors
- the course of the disease
- determines the effectiveness and any negative effects of medications, and changes therapies as needed
what are alternative and complementary therapies for treating RA
- special diets
- vitamin supplements
see health behaviour change slide 42
see health behaviour change slide 42
