2-29 Drugs for Rheumatic Diseases Flashcards
What is a disease-modifying anti-rheumatic drug?
group of agents that slow or stop the progression of rheumatic diseases
reduce pain and inflammation
reduce or prevent irreversible joint damage
resulting in longer disease-free remissions and better quality of life
2 subclasses of DMARDs: nonbiologic and biologic agents
What are the 4 nonbiologic DMARDs?
Hydroxychloroquine (HCQ)
Leflunomide (LEF)
Methotrexate (MTX)
Sulfasalazine (SSZ)
Name 9 biologic DMARDs.
TNF-α Blocking Agents
Adalimumab (Humera)
Certolizumab
Etanercept (Enbrel)
Golimumab (Simponi)
Infliximab (Remicade)
Other Agents
Abatacept (T-cell Fc-fusion)
Rituximab (anti-CD20 mAb)
Tocilizumab (anti-IL-6 mAb)
Tofacitinib (JAK inhibitor, small-molecule TKI)
What are the 2 different standard pharmacologic treatment algorithms for RA?
DMARD + NSAID +/- corticosteroid to control symptoms
Usually MTX or LEF for initial treatment, with HCQ or sulfasalazine as safer alternatives
TNF-alpha inhibitor +/- nonbiologic DMARDs
Etanercept, infliximab, adalimumab, golimumab, certolizumab
What are the indications for switching to a different TNF-alpha inhibitor or a non-TNF biologic DMARD?
Patients who do not respond to one TNF-α inhibitor may respond to another
no evidence that any one TNF inhibitor is more effective than any other
Etanercept is a common first choice because it has a rapid onset of action and short half-life resulting in short duration of toxicity, if it occurs
Some clinicians start with infliximab then switch to etanercept or adalimumab if needed
Initial treatment for RA generally consists of what classes of drugs? Why?
DMARDs - over time will control symptoms and delay/slow disease (no immediate analgesia)
NSAIDs - adjunct for pain relief (immediate analgesic/anti-inflammatory) but don’t affect disease process
Short term glucocorticoids (oral or intraarticular) - relieve joint symptoms and control systemic manifestations in moderate/severe RA (too many problems for chronic use)
What agents are added if initial treatment is inadequate?
a second nonbiologic DMARD can be added to MTX
Combinations of 2 or even 3 DMARDs can be designed rationally on the basis of complementary mechanisms of action, non-overlapping pharmacokinetics, and non-overlapping toxicities
1st line biologic therapy prescribed after an inadequate response to nonbiologic DMARDs
Patients who do not respond to one TNF-α inhibitor may respond to another, no evidence from well-controlled comparative trials that any one TNF inhibitor is more effective than any other
Why are biologic DMARDs used in treating RA?
1st line biologic therapy prescribed after an inadequate response to nonbiologic DMARDs
TNF-α inhibitors used alone may be more effective than MTX and other nonbiologic DMARDs in limiting joint destruction and act more quickly in relieving symptoms
Combination of biologic (usually anti-TNF) and nonbiologic (usually MTX) offers better disease control without substantial increase in toxicity and is commonly used to achieve remission
What are some ADRs associated with biologic DMARDs? Does combining different ones help with therapy?
Long-term safety of TNF-α inhibitors remains unclear as serious adverse events can occur in patients using these drugs
Combining different biologic agents is not recommended; it increases the risk of infections without appreciable benefit
What is the MOA, pharmacokinetics, response time, and clinical uses for methotrexate (MTX)?
MOA: high dose: dihydrofolate reductase inhibitor, no DNA synthesis = cell death
low dose (for RA): (?) lowered adenosine, apoptosis in inflammatory immune cells
Pharmacokinetics: renal (70%), bile (30%)
Response: 4-6 weeks –> months
What are the clinical uses for MTX?
first line treatment for RA - faster onset, better tolerated, high efficacy
- also for psoriasis & other rheumatic diseases, high dose in chemotherapy
What are the ADRs for MTX?
Common: nausea, upset stomah, loose stools, stomatitis, fever, alopecia, rash, HA, fatigue
Severe: hepatotoxic, pulmonary damage, myelosuppression
Monitor liver enzymes before & through treatment, get baseline chest radiograph
Folic acid supplementation/leucovorin recommended
What is a contraindication for MTX?
Pregnancy
What is the MOA, pharmacokinetics, response time for leflunomide?
MOA: metabolite inhibits dihyroorotate dehydrogenase, reduce NT synthesis & cause G1 arrest
- stops T-cell proliferation & B-cell auto-Ab production
Pharmacokinetics: completely absorbed, half life 19 days
- cholestyramine increases excretion/clearance by ~50%
Response: 6-12 weeks
What are the clinical uses for leflunomide?
as effective as MTX
used instead of MTX in initial therapy, or can replace it
Response rates better with MTX + LEF, but more hepatotoxic
What are the ADRs for leflunomide?
Common: diarrhea, elevated LFTs, alopecia, wright gain, increased BP, leukopenia, thrombocytopenia
What are the contraindications for leflunomide?
Contraindicated in pregnancy (teratogenic, embryo-lethal)
must use cholestyramine for detoxification prior to conception, otherwise it may take 2 years for serum concentrations to become undetectable
What is the MOA, kinetics, and response time of hydroxychloroquine?
MOA: (?) suppression of T-cells, decreased leukocyte chemotaxis, stabilization of lysosomes, inhibition of DNA/RNA synthesis
kinetics: extensively tissue bound, esp in melanin pigments
hepatic, blood elimination
half life 45 d
Response time: 3-6 mo
What are the ADRs for HCQ?
Ocular toxicity
opthalmalogic monitoring every 12 months is advised; drug should be discontinued immediately if signs of retinal toxicity appear
Dyspepsia, nausea, vomiting, abdominal pain, rashes, and nightmares also occur
What is the MOA, kinetics and response time for sulfasalazine?
MOA: (?) decreased IgG & IgM rheumatoid factor
suppressed T cell response, B cell proliferation
inhibition of inflamm cytokine release
kinetics: poorly absorbed, metabolized to sulfapyridine (well absorbed) and 5-ASA (unabsorbed)
response time: 1-3 mo
What are the clinical uses of sulfasalazine?
Reduces radiologic disease progression in RA
Also used for treatment of ulcerative colitis and juvenile idiopathic arthritis
Off-label uses include ankylosing spondylitis, Crohn’s disease, psoriasis, and psoriatic arthritis
What are the ADRs of sulfasalazine? Contraindications?
Causes more toxicity than HCQ; ~30% of patients discontinue use due to toxicity
Nausea, vomiting, headache, anorexia, and rash are common
Reversible infertility occurs in men; fertility is unaffected in women
Probably safe in pregnancy (category B)
What are some rarely used nonbiologic DMARDs?
Azathioprine
Cyclophosphamide
Cyclosporine
Gold salts
Minocycline
Mycophenolate mofetil
What is TNF-alpha’s role in RA? What does it do systemically?
TNF-α is a pro-inflammatory cytokine present in the synovium of patients with RA
it regulates immune cells by binding to membrane-bound receptors (TNFR)
TNF-α can induce fever, apoptotic cell death, and inflammation; it can also inhibit tumorigenesis and viral replication
What is the general MOA for TNF-alpha inhibitors, as a class?
The TNF-α inhibitors (adalimumab, certolizumab, etanercept, golimumab, and infliximab) are biologic DMARDs that prevent binding of TNF-α (and sometimes TNF-β, now called lymphotoxin-α) to TNF receptors, resulting in down-regulation of macrophages and T-cells
They exhibit different structure, pharmacokinetics, and functional effects on TNF-expressing cells (see table below)
What is the response time and clinical use of TNF-alpha inhibitors?
Response time: 1-2 weeks (instead of months for nonbiologic DMARDs)
Clinical Uses
monotherapy/combination with nonbiologic DMARDs (usually MTX) for treatment of RA
infliximab and golimumab are always combined with MTX for treatment of RA
use of a TNF inhibitor concomitant with MTX has synergistic beneficial effects
Combining different biologic agents is not recommended; it increases the risk of infections without appreciable benefit
Also used as monotherapy or in combination with nonbiologic DMARDs for a variety of other rheumatic diseases including ankylosing spondylitis, psoriatic arthritis, juvenile idiopathic arthritis, psoriasis, and inflammatory bowel disease (not all agents labeled for all indications)
What are the ADRs for TNF-alpha inhibitors?
- injection site, infusion rxns
- Cytopenia - monitor with CBCs
- Serious infections - TB, bacterial sepsis, reactivation and dissemination of infections
- Malignancies - lymphomas
- Possible auto-Ab formation
- Heart failure
- Demyelinating syndromes
Safe for pregnancy!
What is the MOA, kinetics, and response time for Abatacept?
Abatacept - Orencia
MOA: binds T-helper cells and prevents activation
Kinetics: ROA is IV/SubQ, half life 13-16 d
Response time: starts in 1 dose, up to 6 mo
What are the ADRs associated with abatacept?
abatacept/Orencia
Infusion reactions: hypertension, headache, dizziness, and, rarely, anaphylactoid reactions
increases risk of pneumonia, pyelonephritis, cellulitis and diverticulitis
Pregnancy category C due to potential risk for development of autoimmune disease in the fetus
What is the MOA, kinetics, and response time of rituximab?
rituximab/Rituxin
MOA: depletes B cells, decreasing presentation of Ag to T cells, reduced secretion of proinflamm cytokines
kinetics: IV, half life ~20 days
response time: 6 weeks to 6-9 mo
What are the ADRs of rituximab?
rituximab/Rituxin
Mild infusion reactions (rash) occur in 30% of patients; incidence decreases with each course of therapy;
severe infusion reactions (urticarial or anaphylactoid) are rare, but can occur;
incidence and severity of reactions are reduced when IV glucocorticoids are given 30 minutes before rituximab infusion
Probably increases the risk of infections such as bacterial, fungal, and new or reactivated viral infections
What is the MOA, kinetics, and response time of tocilizumab?
tocilizumab/Actrema
MOA: stops signalling of IL-6 R
Kinetics: ROA IV/SubQ, half life 11-13 d
response time: 2 weeks –> 6-12 weeks
What are the ADRs of tocilizumab?
tocilizumab/Actrema
Infusion reactions, hypertension, neutropenia, elevated transaminases, and dyslipidemia can occur and may necessitate dosage adjustment
Serious complications such as GI perforation, serious infections, and hypersensitivity with anaphylaxis have been reported
What is the MOA and kinetics of tofacitinib?
tofacitinib/Xeljanz
MOA: oral JAK in JAK/STAT, small molecule tyr-kinase inhibitor
kinetics: CYP3A4 metabolism
- reduce dose when strong CYP3A4 inhibitors co-administered
half life ~3 hours
What are the ADRs of tofacitinib?
Infections, TB screening is recommended prior to treatment initiation
diarrhea, nasopharyngitis, headache, and hypertension
Elevated liver enzymes, dyslipidemias, and cytopenias have been reported
