Flashcards in RA Drugs- DMARDs Deck (75)
The treatment of RA is progressive. What do most clinicians start with?
a DMARD like METHOTREXATE with the addition of an NSAID and a corticosteroid
How is RA treated initiated in milder cases?
Hydroxychloroquine is preferred because of lower toxicity
What is considered in RA treatment after initial treatment failure?
a first-line biological agent such as Etanercept, Infliximab, Adalimumab, Golimumab, or Certolizumab
T or F. Experience shows that early, aggressive treatment with MTX and/or a biological agent results in longer disease-free remission, less joint destruction, and a better quality of life
What are the results of Methotrexate use?
inhibition of lymphocyte
proliferation and suppression of several pro-inflammatory mediators (Il-1, IFN-y, and TNF) via tonic adenosine activation.
What process does Methotrexate undergo that helps retain it in the cell?
High-dose methotrexate therapy is associated with what?
bone marrow suppression, although this may not be problematic at doses used in the treatment of arthritis.
How is Methotrexate metabolized?
hepatic (contraindicated with alcoholism, or other hepatic disease)
How is Methotrexate eliminated?
renal (hydrate and alkalination to avoid damage)
AEs of Methotrexate?
-opportunistic infection, tumor
-severe GI toxicity -irreversible pulmonary fibrosis
What can increase the risk of Gi toxicity with methotrexate use?
concurrent NSAID use
Is Methotrexate safe in pregnancy or breast-feeding?
No, category X
T or F. Vaccinations should be avoided while on methotrexate
T. Ab response may be suboptimal
How is Sulfasalazine metabolized?
to sulfapyridine and melamine by colon bacteria which are then acetylated and hydroxylated in the liver (look out for slow acetylators)
How does Sulfasalazine help in RA?
anti-inflammatory properties from melamine, an inhibitor of PG and leukotriene production
How is Sulfasalazine eliminated?
Contraindications of Sulfasalazine?
PMH of hypersensitivity to salicylate or sulfonamide drugs
AEs of Sulfasalazine?
fatal blood dyscrasia
How does Leflunomide work?
inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme that catalyzed a key step in de novo pyrimidine synthesis causing cell cycle arrest in T/B lymphocytes
Is Leflunomide safe in pregnancy?
no, category X
T or F. Leflunomide metabolites produce a uricosuric effect
T. that is, it increases the renal elimination of uric acid
How is Hydroxychloroquine used for RA treatment (note it is also used for malaria and SLE treatment)?
increases intracellular vacuole pH thus inhabiting the acidic cytoplasmic compartments required for antigenic protein digestion and peptide assembly with the alpha and beta chains of MCH class II proteins
AEs of Hydroxychloroquine?
-CNS toxicity (seizures, ototoxicity, polyneuritis)
-rarely causes coral opacities, retinopathy, or keratopathy
Contraindications to Hydroxychloroquine use?
-hepatic disease (concentrates in liver normally)
Monitoring parameters for Methotrexate?
CBC with differential, LFT, serum creatine/BUN, pregnancy test
and serum uric acid
Monitoring parameters for Sulfasalazine?
CBC with differential, LFT, serum creatine/BUN and urinalysis
Monitoring parameters for Leflunamide?
CBC with differential, LFT, pregnancy test and serum electrolytes
Monitoring parameters for Hydroxychloroquine?
CBC and opthalmalogic exam
How do corticosteroids work?
Nf-kB, activator protein (AP)-1 and NF-AT all inhibited leading to reduced production of TNF-a, IL-1, and thus IL-6 AND
Mechanism of some AEs of corticosteroids?
upregulation of receptor-activator of nuclear factor kB (RANKL) and macrophage colony-stimulating factor (MCF) and down regulation of osteoprotegerin
What does upregulation of RANKL and macrophage colony-stimulating factor (MCF) cause?
increased osteoclast production (and lifespan) leading to increased bone resorption early in GC treatment (and transiently)
How do GCs affect osteoblasts?
upregulate PPARy2 expression and decrease Wnt signaling leading to decreased osteoblastogenesis AND
upregulate caspase 3 expression
What is the effect of decreased osteoblast populations?
these effects are responsible for the LONG TERM state of decreased been formation that characteristic of GC-induced osteoporosis
T or F. In addition to suppressing symptoms/signs of early RA, GCs appear to possess disease-modifying effects, at least in early stage disease
What are some things that can be done to prevent GC-induce osteoporosis?
-advice sufficient dietary intake of calcium, protein, and vitamin D
-avoid alcohol and tobacco abuse
What treatment options are available to those chronically taking GCs to reduce risk of osteoporosis?
anti-osteoporotic therapy in those with fracture risk (measure height annually and assess BMD regularly)
AEs of high-dose GCs?
-Cushingoid (w/ HTN) syndrome
Clinical studies clearly show that patients with rheumatoid arthritis are at increased
risk of _________ compared to the general population.
cardiovascular events. This might be due to the inflammatory condition that the patient is experiencing, but it could also be
attributed to adverse effects of drugs used in the treatment of the condition.
What is one way to avoid the general systemic effects of corticosteroids?
drugs by injection, for example as intra-articular injection in the knee
T or F. Adverse effects of corticosteroids are both cumulative and daily dose dependent and can be influenced by the concurrent administration and other drugs such as DMARDs.
T. However, low-dose corticosteroids do not necessarily produce the myriad of adverse effects and may be used quite safely with routine clinical care.
Still, what should be monitored with low-dose GC?
osteoporosis, blood sugar levels, glaucoma and the presence of oedema.
What is Auranofin?
old RA drug composed of golf that suppressed inflammation but is accompanied by skin rash and GI dysfunction and is not sued anymore here
may have use in other diseases
What is Abatacept (Orencia)?
Fusion protein of human CTLA4/IgG1 Fc Fragment that binds CD80 and CD86 and prevents T-cell co-stimulatory signal engaging with CD28
What is Adalimumab (Humira)?
TNF-a monoclonal Ab, blocking its interaction with the p55 and p75 cell surface receptors
What is Anakinra?
recombinant human IL-1 receptor antagonist
What is Certolizumab peg?
Fab fragment of humanized TNF-a Ab the neutralized membrane-associated and soluble human TNF-a
What is Etancercept?
Extracellular ligand-binding portion of human p75 TNF receptor linked to part of human IgG Fc
What is the role of endogenous p75?
What is the effect of Etancercept (Enbrel)?
it binds to and inactivates TNF but does not affect TNF production or serum levels
What is Golimumab (Simponi)
Human-Derived TNF-a Ab (V and C regions) that binds to and neutralizes both soluble and transmembrane TNF-a
What is Infliximab (Remicade)?
Chimeric (mouse-human) IgGk monoclonal Ab against TNF-a that binds and neutralizes both soluble and transmembrane TNF-a
What is Tocilizumab (Actemra)?
Humanized IL-6 receptor-inhibiting monoclonal Ab that binds to soluble (serum and synovial fluid) and membrane-bound IL-6 and inhibits signaling
What is Rituximab (Rituxan)?
Chimeric monoclonal against CD20 on B cells
How does Rituximab work?
Fab domain binds CD20 and Fc domain recruits immune effectors to meidate B-cell lysis (ADCC, Ab-dependent, etc.)
Rules of thumb with biologics
-don't initiate treatment during infection
-may increase infection or malignancy risk
Which biologics can cause CHF or hypotension /angina/dysrhythmia?
Which biologics can cause a lupus-like presentation?
Stevens-Johnson syndrome (toxic epidermal necrolysis) has been infrequently reported with _____
What biologic may fuck with blood glucose tests?
Abatacept IV (contains maltose)
T or F. Women taking Rituximab must use reliable contraception while taking the drug and avoid pregnancy for 4-6 months after therapy
T. IgG crosses placenta and could deplete B-cells
Which biologics cannot be given SC?
all others have the risk for injection site reactions with repeated injection given in the same spot
CBCs should be routinely given with which biologics? Why?
-Anakinra, Certolizumab, Rituximab, Tocilizumab
due to risk of blood dyscrasia
CBCs should be routinely monitored with which biologics? Why?
Golimumab, Infliximab, and Tocilimumab
Give a serum lipid profile with which biologic?
What is Tofacitinib (Xeljanz)?
Po JAK3/JAK1 inhibitor for mild-severe RA
What interleukins are blocked by Tofacitinib?
IL-2, 4, 7, 9, 15, and 21
AEs of Xeljanz?
increased HDL and LDL cholesterol, headache, UTIs, URTIs, nasopharyngitis
BBWs of Xeljanz?
-serious infections, including Tb and opportunistic
What is Apremilast (Otezla)?
an orally (CYP) active phosphodiesterase inhibitor (PDE4), giving rise to a reduction in pro inflammatory
Uses for Apremilast?
psoriatic arthritis (improves joint tenderness and swelling) and plaque psoriasis (redness/scaliness).
AES of Otezla?
Nausea, headache, weight loss (monitor!),
depression/suicidal ideation rarely
What drugs should be avoided in G6PD deficient patients?
(look for hemolytic anemia)
What are the 4 mechanisms for the inhibition of TNF-a bearing cells by anti-TNF agents?
1. inhibition of TNF signaling
Destruction of TNFa bearing cells by:
3. ADCC and
4. outside-to-inside signal (reverse signaling)
What is TAILS?
TNF-a antagonist-induced lupus like syndrome thought to be due to release of antigenic particles during apoptosis, stimulating autoantibodies or by suppressing Th1
usually abates 1-6 months when drug stopped