2-29 Drugs for Rheumatic Diseases

Question 1

What is a disease-modifying anti-rheumatic drug?

Answer 1

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

Question 2

What are the 4 nonbiologic DMARDs?

Answer 2

Hydroxychloroquine (HCQ)

Leflunomide (LEF)

Methotrexate (MTX)

Sulfasalazine (SSZ)

Question 3

Name 9 biologic DMARDs.

Answer 3

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)

Question 4

What are the 2 different standard pharmacologic treatment algorithms for RA?

Answer 4

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

Question 5

What are the indications for switching to a different TNF-alpha inhibitor or a non-TNF biologic DMARD?

Answer 5

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

Question 6

Initial treatment for RA generally consists of what classes of drugs? Why?

Answer 6

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)

Question 7

What agents are added if initial treatment is inadequate?

Answer 7

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

1^st 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

Question 8

Why are biologic DMARDs used in treating RA?

Answer 8

1^st 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

Question 9

What are some ADRs associated with biologic DMARDs? Does combining different ones help with therapy?

Answer 9

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

Question 10

What is the MOA, pharmacokinetics, response time, and clinical uses for methotrexate (MTX)?

Answer 10

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

Question 11

What are the clinical uses for MTX?

Answer 11

first line treatment for RA - faster onset, better tolerated, high efficacy

• also for psoriasis & other rheumatic diseases, high dose in chemotherapy

Question 12

What are the ADRs for MTX?

Answer 12

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

Question 13

What is a contraindication for MTX?

Answer 13

Pregnancy

Question 14

What is the MOA, pharmacokinetics, response time for leflunomide?

Answer 14

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

Question 15

What are the clinical uses for leflunomide?

Answer 15

as effective as MTX

used instead of MTX in initial therapy, or can replace it

Response rates better with MTX + LEF, but more hepatotoxic

Question 16

What are the ADRs for leflunomide?

Answer 16

Common: diarrhea, elevated LFTs, alopecia, wright gain, increased BP, leukopenia, thrombocytopenia

Question 17

What are the contraindications for leflunomide?

Answer 17

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

Question 18

What is the MOA, kinetics, and response time of hydroxychloroquine?

Answer 18

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

Question 19

What are the ADRs for HCQ?

Answer 19

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

Question 20

What is the MOA, kinetics and response time for sulfasalazine?

Answer 20

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

Question 21

What are the clinical uses of sulfasalazine?

Answer 21

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

Question 22

What are the ADRs of sulfasalazine? Contraindications?

Answer 22

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)

Question 23

What are some rarely used nonbiologic DMARDs?

Answer 23

Azathioprine

Cyclophosphamide

Cyclosporine

Gold salts

Minocycline

Mycophenolate mofetil

Question 24

What is TNF-alpha’s role in RA? What does it do systemically?

Answer 24

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

Question 25

What is the general MOA for TNF-alpha inhibitors, as a class?

Answer 25

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)

Question 26

What is the response time and clinical use of TNF-alpha inhibitors?

Answer 26

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)

Question 27

What are the ADRs for TNF-alpha inhibitors?

Answer 27

1. injection site, infusion rxns
2. Cytopenia - monitor with CBCs
3. Serious infections - TB, bacterial sepsis, reactivation and dissemination of infections
4. Malignancies - lymphomas
5. Possible auto-Ab formation
6. Heart failure
7. Demyelinating syndromes

Safe for pregnancy!

Question 28

What is the MOA, kinetics, and response time for Abatacept?

Answer 28

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

Question 29

What are the ADRs associated with abatacept?

Answer 29

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

Question 30

What is the MOA, kinetics, and response time of rituximab?

Answer 30

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

Question 31

What are the ADRs of rituximab?

Answer 31

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

Question 32

What is the MOA, kinetics, and response time of tocilizumab?

Answer 32

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

Question 33

What are the ADRs of tocilizumab?

Answer 33

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

Question 34

What is the MOA and kinetics of tofacitinib?

Answer 34

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

Question 35

What are the ADRs of tofacitinib?

Answer 35

Infections, TB screening is recommended prior to treatment initiation

diarrhea, nasopharyngitis, headache, and hypertension

Elevated liver enzymes, dyslipidemias, and cytopenias have been reported