Anti-inflammatory Biological Agents & Corticoids Flashcards
3 Goals of rheumatoid arthritis therapy
Stop inflammation (put disease in remission)
Relieve symptoms
Prevent joint and organ damage
Examples of non-drug therapies for rheumatoid arthritis
Patient education and counseling
Rest
Exercise
Physical therapy and occupational therapy
Nutrition and dietary therapy
Bone protection
Cardiovascular risk reduction (due to increased risk of coronary atherosclerosis in RA)
Therapeutic roles of NSAIDs like naproxen and celecoxib in RA
Drug of choice for RA due to efficacy and rapid onset of action
Benefits are d/t anti-inflammatory action as well as pain relief
Note that they do not alter disease progression
[acetaminophen is second choice for pain relief only]
Therapeutic role and adverse effects associated with glucocorticoids (like prednisone) used to treat RA
Role is to suppress inflammation; glucocorticoids generally should not be used on a chronic basis without concurrent DMARD therapy
Doses <5 mg/day can generally be taken without significant AEs, but no reduction in disease progression
Many adverse effects include psychosis/depression, impaired glucose tolerance, salt/water retention, osteoporosis, increased susceptibility to opportunistic infections, truncal obesity, “buffalo hump”, striae, acne, and hirsutism
Regarding the use of glucocorticoids in sicker pts with active RA, _____ is frequently added for a short period of time to the treatment regimen. This serves to rapidly reduce disease activity while awaiting clinical response to a slower-acting agent like a DMARD.
Prednisone
MOA of prednisone
Diffuses into cells to bind glucocorticoid receptor (GR)
GR complexing with NF-kB and AP-1 TFs is major indirect mechanism for immunosuppression
Lipocortin, an inhibitor or PLA2 is among genes activated
Structural differences among glucocorticoids Hydrocortisone, prednisolone, methylprednisone, betamethasone, dexamethasone, and triamcinolone
List 4 commonly used traditional (non-biologic) disease-modifying antirheumatoid drugs (DMARDs)
Methotrexate
Hydroxychloroquine
Sulfasalazine
Leflunomide
3 TNF-a blockers used to tx RA
Etanercept (two p75 TNF receptors bound to Fc portion of IgG)
Adalimumab (chimeric mAb directed against TNF)
Infliximab (recombinent human anti-TNF mAb)
[biologic DMARDs]
B cell depleter (CD20 mAb) used to treat RA
Rituximab
[biologic DMARDs]
T cell activation inhibitor used to tx RA
Abatacept
[biologic DMARDs]
IL-6 receptor mAb used to tx RA
Tocilizumab
[biologic DMARDs]
JAK3 inhibitor used to tx RA
Tofacitinib
[biologic DMARDs]
Recombinant IL-1 antagonist used to tx RA
Anakinra
[biologic DMARDs]
MOA of methotrexate
Inhibits dihydrofolate reductase —> thymineless cell death
Undergoes polyglutamation which accumulates in cells; blocks thymidylate synthase and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase —> AICAR accumulation —> adenosine efflux, which binds to purinergic GPCRs on cell surface to exert antiinflammatory effects
_______ acts faster than all other DMARDs with clinical effects evident within 3-6 weeks and works for 80% of pts
Methotrexate
Clinical applications of MTX in terms of RA
First-choice for RA due to efficacy, relative safety, low cost, and extensive use
Often used in combo with other tradiitonal DMARD
Often continued when pt is switched to a biologic DMARD
AEs of methotrexate
Bone marrow suppresion Hepatic fibrosis GI ulceration Pneumonitis Fetal death and congenital anomalies
MOA of hydroxychloroquine
Hydroxychloroquine is a lipophilic weak base and easily goes through plasma membrane
The free base form accumulates in lysosomes and is protonated, increasing pH of lysosome from 4 to 6
Higher pH of the lysosomal vesicles in APCs limits the association of peptides with class II MHC (including autoantigens!)
Clinical applications of hydroxychloroquine
Can be first choice for mild RA with LACK of poor prognostic features (extraarticular dz, positive RF, bony erosions, etc)
Often combined with MTX +/- sulfasalazine in severe cases
[note: has delayed onset of 3-6 months]
Also used for anti-malaria and SLE
Is hydroxychloroquine safe to use in pregnancy?
Yes
AEs of hydroxychloroquine
Retinal damage — rare but irreversible; directly related to dosage (low doses carry little risk)
MOA of sulfasalazine
Metabolized to sulfapyridine, which is active moiety in pts with RA (unlike IBD where its 5-ASA)
Parent molecule may also exert effects such as release of adenosine, inhibition of NF-kB, etc
Clinical applications of sulfasalazine
For RA: used alone or in combo with hydroxychloroquine and/or methotrexate (3 drug “triple therapy”)
Other uses: Crohns and UC
Seems okay to use in pregnancy but it is less studied in this context
AEs of sulfasalazine
Most common are GI side effects — N/V/D/abd pain
Dermatologic rxns to sulfa — pruritis, rash, urticaria
Serious AEs include hepatitis or bone marrow suppression (rare)
MOA of leflunomide
Inhibition of mitochondrial dihydroorotate dehydrogenase — blocks synthesis of rUMP (pyrimidine)
Leads to inhibition of T cell proliferation and Ab production as well as other anti-inflammatory effects (blocks leukocyte adhesion, DC function, NFKB activation, etc)
Clinical application of leflunomide
Alternative nonbiologic DMARD to MTX, generally a second-choice drug due to cost and more side effects
Also used in combo with MTX, sulfasalazine, or hydroxychloroquine
AEs of leflunomide
Most common are diarrhea, respiratory infection, reversible alopecia, rash, and nausea
Hepatotoxicity
Increased risk of infection
Severe AEs: pancytopenia, stevens johnson syndrome, severe HTN
T/F: Biologic DMARDs are often used in combo with other biologic DMARDs for maximum efficacy of therapy
False — biologic DMARDs should NEVER be combined
MOA of TNF-a antagonists used for RA (Etanercept, Adalimumab, Infliximab)
Work by neutralizing TNF, an important immune mediator of joint injury in RA
Highly effective at reducing RA symptoms and disease progression
Clinical applications of TNF-a antagonists
Indicated for moderate-to-severe RA, generally after traditional DMARDs have been proven ineffective
Often used in combo with MTX
Other uses: plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, and/or crohns
AEs of TNF-a antagonists used for RA
Risk of serious infections — bacterial sepsis, invasive fungal infections, hep B, TUBERCULOSIS
Severe allergic rxns, heart failure, liver failure, hematologic d/o, neuro d/o, cancer
MOA of rituximab
Antibody targets CD20 —> Loss of CD20 expression as B cells differentiate into plasma cells
Leads to plasma cell resistance and reduced levels of autoantibodies, although overall Ig levels remain normal despite B cell lymphopenia
Clinical applications of rituximab
Indicated in combination with MTX for RA in pts who have not responded to TNF antagonists
Positive testing for rheumatoid factor or anti-cyclic citrullinated peptide antibodies predicts a greater likelihood of responsiveness
[also used to tx NHL, CLL]
AEs of rituximab
Severe infusion related hypersensitivity reactions
Severe mucocutaneous reactions including stevens johnson syndrome
Hep B reactivation
Has been associated with rare virus mediated progressive multifocal leukoencephalopathy
MOA of abatacept
Prevents CD28 from binding to its counter-receptor CD80/86, thus preventing “second signal” in activation of T cells by APCs
Clinical applications of abatacept
Approved for use in moderate to severe RA, generally after TNF antagonists have failed
Can be used in combo with nonbiologic DMARDs like MTX
[also approved for polyarticular juvenile idiopathic arthritis]
AEs of abatacept
Generally well tolerated; most common AEs are HA, URI, nasopharyngitis, and nausea
Can increase risk of serious infections — usually PNA, cellulitis, bronchitis, diverticulitis, pyelonephritis, and UTI
MOA of tocilizumab
Anti-human IL-6 receptor antibody — competes for both the membrane-bound and soluble forms of IL-6R
Limits hepatic acute phase response, activation of T cells, B cells, macrophages, and osteoclasts
AEs of tocilizumab
Most commonly URI, nasopharyngitis, HA, and HTN
Serious AEs include life-threatening infections (TB, invasive fungus, opportunistic infections), GI perforation, liver injury (elevated ALT, AST), neutropenia, thrombocytopenia
MOA of tofacitinib
Inhibitor of JAK3 — directly suppresses production of IL-17 and IFN-y, as well as the proliferation of CD4 T cells
Clinical application of tofacitinib
Moderate to severely active RA in pts who had inadequate response to MTX
Can be used with or without MTX
AEs of tofacitinib
Serious and sometimes fatal infections due to bacterial, mycobacterial, or other opportunistic pathogens (PNA, cellulitis, UTI, etc)
Also increased risk of malignancy
MOA of anakinra
Recombinant non-glycosylated version of human IL-1R antagonist (levels of endogenous IL-1RA are low in RA pts)
Blocks the proinflammatory activity of naturally occurring IL-1 on many cells
Clinical applications of IL-1 antagonist anakinra
Moderate to severe RA in pts that did not respond to non-biologic DMARDs
Considered less efficacious than other bibologic DMARDs
AEs of anakinra
Increased incidence of serious infections
Hypersensitivity reactions, including anaphylaxis and angioedema
