Anti-inflammatory Biological Agents & Corticoids

Question 1

3 Goals of rheumatoid arthritis therapy

Answer 1

Stop inflammation (put disease in remission)

Relieve symptoms

Prevent joint and organ damage

Question 2

Examples of non-drug therapies for rheumatoid arthritis

Answer 2

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)

Question 3

Therapeutic roles of NSAIDs like naproxen and celecoxib in RA

Answer 3

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]

Question 4

Therapeutic role and adverse effects associated with glucocorticoids (like prednisone) used to treat RA

Answer 4

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

Question 5

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.

Answer 5

Prednisone

Question 6

MOA of prednisone

Answer 6

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

Question 7

Structural differences among glucocorticoids Hydrocortisone, prednisolone, methylprednisone, betamethasone, dexamethasone, and triamcinolone

Question 8

List 4 commonly used traditional (non-biologic) disease-modifying antirheumatoid drugs (DMARDs)

Answer 8

Methotrexate
Hydroxychloroquine
Sulfasalazine
Leflunomide

Question 9

3 TNF-a blockers used to tx RA

Answer 9

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]

Question 10

B cell depleter (CD20 mAb) used to treat RA

Answer 10

Rituximab

[biologic DMARDs]

Question 11

T cell activation inhibitor used to tx RA

Answer 11

Abatacept

[biologic DMARDs]

Question 12

IL-6 receptor mAb used to tx RA

Answer 12

Tocilizumab

[biologic DMARDs]

Question 13

JAK3 inhibitor used to tx RA

Answer 13

Tofacitinib

[biologic DMARDs]

Question 14

Recombinant IL-1 antagonist used to tx RA

Answer 14

Anakinra

[biologic DMARDs]

Question 15

MOA of methotrexate

Answer 15

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

Question 16

_______ acts faster than all other DMARDs with clinical effects evident within 3-6 weeks and works for 80% of pts

Answer 16

Methotrexate

Question 17

Clinical applications of MTX in terms of RA

Answer 17

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

Question 18

AEs of methotrexate

Answer 18

Bone marrow suppresion
Hepatic fibrosis
GI ulceration
Pneumonitis
Fetal death and congenital anomalies

Question 19

MOA of hydroxychloroquine

Answer 19

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!)

Question 20

Clinical applications of hydroxychloroquine

Answer 20

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

Question 21

Is hydroxychloroquine safe to use in pregnancy?

Answer 21

Yes

Question 22

AEs of hydroxychloroquine

Answer 22

Retinal damage — rare but irreversible; directly related to dosage (low doses carry little risk)

Question 23

MOA of sulfasalazine

Answer 23

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

Question 24

Clinical applications of sulfasalazine

Answer 24

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

Question 25

AEs of sulfasalazine

Answer 25

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)

Question 26

MOA of leflunomide

Answer 26

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)

Question 27

Clinical application of leflunomide

Answer 27

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

Question 28

AEs of leflunomide

Answer 28

Most common are diarrhea, respiratory infection, reversible alopecia, rash, and nausea Hepatotoxicity Increased risk of infection Severe AEs: pancytopenia, stevens johnson syndrome, severe HTN

Question 29

T/F: Biologic DMARDs are often used in combo with other biologic DMARDs for maximum efficacy of therapy

Answer 29

False — biologic DMARDs should NEVER be combined

Question 30

MOA of TNF-a antagonists used for RA (Etanercept, Adalimumab, Infliximab)

Answer 30

Work by neutralizing TNF, an important immune mediator of joint injury in RA Highly effective at reducing RA symptoms and disease progression

Question 31

Clinical applications of TNF-a antagonists

Answer 31

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

Question 32

AEs of TNF-a antagonists used for RA

Answer 32

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

Question 33

MOA of rituximab

Answer 33

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

Question 34

Clinical applications of rituximab

Answer 34

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]

Question 35

AEs of rituximab

Answer 35

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

Question 36

MOA of abatacept

Answer 36

Prevents CD28 from binding to its counter-receptor CD80/86, thus preventing “second signal” in activation of T cells by APCs

Question 37

Clinical applications of abatacept

Answer 37

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]

Question 38

AEs of abatacept

Answer 38

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

Question 39

MOA of tocilizumab

Answer 39

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

Question 40

AEs of tocilizumab

Answer 40

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

Question 41

MOA of tofacitinib

Answer 41

Inhibitor of JAK3 — directly suppresses production of IL-17 and IFN-y, as well as the proliferation of CD4 T cells

Question 42

Clinical application of tofacitinib

Answer 42

Moderate to severely active RA in pts who had inadequate response to MTX Can be used with or without MTX

Question 43

AEs of tofacitinib

Answer 43

Serious and sometimes fatal infections due to bacterial, mycobacterial, or other opportunistic pathogens (PNA, cellulitis, UTI, etc) Also increased risk of malignancy

Question 44

MOA of anakinra

Answer 44

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

Question 45

Clinical applications of IL-1 antagonist anakinra

Answer 45

Moderate to severe RA in pts that did not respond to non-biologic DMARDs Considered less efficacious than other bibologic DMARDs

Question 46

AEs of anakinra

Answer 46

Increased incidence of serious infections Hypersensitivity reactions, including anaphylaxis and angioedema