Apr4 M2-DMARDS Flashcards
biologic drugs treat what
inflammatory diseases
like RA, and asthma with anti-IgE
first biologic drug made
human insulin
3 types of biologic drugs
- substances nearly identical to endogenous signaling proteins
- monoclonal Abs
- receptor constructs (fusion proteins. name = RECEPTOR DECOYS) based on naturally-occurring R linked to the Ig frame (soak up the ligand for endogenous Rs)
omalizumab (anti-IgE) effect in asthma (>12 yrs old, not controlled with CSs)
- binds IgE and removes it from circulation
- no adverse allergic effects of asthma caused by IgE
- no more signal to basophils, B cells, etc.
newer future biologic drugs in asthma do what
- target IL-4, IL-5 and IL-13 or their receptors
- can block the ligands or the receptors
- shuts down eosinophils and basophils
DMARD meaning and disease using it the most
disease modifying antirheumatic drugs
RA pathogenesis
- related to genetic but initiating event unknown
- presence of a rheumatoid factor: is an IgM that binds different IgGs
- rheumatoid factor is produced by B cells in synovial fluid (of joints) and serves as a marker of RA
what rheumatoid factor does in RA
- RF complexes trigger complement = tissue damage
- RF attracts PMNs and macrophages
- PANNUS: PMNs + macrophages + fibroblasts from scar tissue accum in joint
what pannus does in asthma
produces IL-1 and TNF-alpha causing proliferation and bone resorption by osteoclasts from macrophages
important principle in RA management
- act EARLY and AGGRESSIVELY (progresses most rapidly in first two years)
- joint damage is an EARLY phenomenon of RA
role of CSs in RA
- use to transition slowly to the DMARD
- use flare up phases of the disease
new therapeutic strategies in RA
triple therapy: methotrexate + biologic drugs
not the DMARDs only triple therapy, we use biologics nowadays
effect of DMARDs in RA
- less joint damage and deformity
- less radiographic progression
- less long-term disability
- can arrest or slow RA progression (joint erosion on XR)
1st generation DMARDs are what + good and bad
gold compounds like aurothioglucose
- good = accum macrophages + interfere with migration and phago
- bad = toxicity bc get colitis + weekly IM injections
2nd generation DMARDs: what + good and bad
cytotoxic B and T cell inhibitors like methotrexate and leflunomide
-good = S phase blocker (of pyrimidine synthesis)
+ prevents B and T cell prolif RF not produced
-bad = effects on proliferating cell populations
methotrexate effect
- inhibits dihydrofolate reductase which produces tetrahydrofolate, an important cofactor in prod of purines
- immunosuppressive and anti-cancer drug
- inhibits AICAR
(EXAM) REAL reason for which we use methotrexate in RA
inhibits the enzyme AICAR, involved in the de novo synthesis of purines
(EXAM) which mechanism of action of methotrexate is the most important one in RA
AICAR inhibition (bc is the most important one at the low dose of mtx we give in RA)
(imp?) mechanism of action of mtx related to AICAR and what AICAR does
Methotrexate’s principal mechanism of action at the low doses used in the rheumatic diseases probably relates to inhibition of aminoimidazolecarboxamide ribonucleotide (AICAR) transformylase and thymidylate synthetase, with secondary effects on polymorphonuclear chemotaxis.
what hydroxychloroquine does and mechanism of action
- classical anti-malarial drug
- useful as DMARD
- interferes with cellular ability to degrade and process proteins
main mtx and hydroxychloroquine side effects
mtx: oral ulcers, BM toxicity, infection, malignancy, NOT during pregnancy
hydroxy: retina damage, nausea, diarrhea
sulfasalazine active component and mech of action in RA
- cleaves into salcitylate and sulfinpyradone (active ingredient)
- sulfinpyradone mech of action not understood
sulfasalazine prob
- SE: malaise, nausea, hypersensitivity rx, headaches, dizziness
- microbiome issues similar to Abx. can’t use in c.diff
newer DMARD and side effects
- leflunomide
- SE like all DMARDS: diarrhea, nausea, malaise, htn, alopecia, rash, malignancy, infection
examples of biologic drugs
- TNF-a inhibitors (receptor decoy or Ab against TNF-a)
- IL-1 inhibitors
- T cell costimulatory blockade
- B cell depletion
critical cytokine found in most people in RA and why
- TNF-alpha
- triggers IL-1, IL-6 and IL-8 release
was we block TNF-a in RA
- humira (receptor decoy), binds TNF-a around
- non soluble forms of the R bind TNF-a
- engineered R floating around and binding TNF-a
the diff TNF-inhibitors
- infliximab and adalimumab = Abs against TNF
- etanercept = soluble R decoy
TNF-a i side effects
- infection
- malignancy
- autoimmune probs
- CHF
- neurologic
IL-1 fct in the body
drives fever in the brain + produced in a lot of tissues as autacoid or autocrine
how IL-1 inhibited
- Ab to IL-1 R
- decoy ligands
IL-1 i SE
- infection*
- headaches, neutropenia, infusion rx
T-cell co stim blockade (abatecept) does what
blocks coreceptor CD80 or CD86 on APC so you lose T cell activation
SE of abatecept and biologics seen
- infection
- COPD exacerbation
- malignancy
- infusion rx
immunity in RA: what happens
- *T cell mediated**
- APC presents unknown Ag to T cell
- CD4 th starts rx in genetically predisposed people
why act on B cell depletion in RA
- B cells can act as APCs
- B cell produces rheumatoid factor
- B cell releases cytokines
- stops doing all that*
B cell depletion therapy in RA done with what
rituximab, anti-CD20
molecules that ARE NOT BIOLOGICS but may be an alternative
Jak (J associated kinase) inhibitors
- downstream of many cytokines
- block them = block cytokines more downstream so block more of the immune response
jaki drug used in RA added to DMARD and bio drug mix
- tofacitinib (Xeljanz)
- used in autoimmune diseases
principle of treatment in RA nowadays (real way you should treat)
- start early and aggressively*
- start with DMARD (mtx)
- add biologic (mtx + bio)
- add 2nd line biologic (mtx + 2 biologics)
