Pharmacological Aspects of Immunology 2 : Biological Therapies Flashcards

Question

Tofacitinib is used for RA, but what else? (2)

Answer 1

psoriatic arthritis and ulcerative colitis

Answer 2

**5 mg twice daily per os**

Answer 3

**4 mg once daily per os**

Answer 4

* Anaemia, cough, diarrhoea, fatigue, fever, gastrointestinal discomfort, increased risk of infection (**tofacitinib**) * Dyslipidaemia, herpes zoster, increased risk of infection, nausea, oropharyngeal pain, thrombocytosis (**baricitinib**)

Answer 5

* **Anaemia, cough, diarrhoea, fatigue, fever, gastrointestinal discomfort, increased risk of infection**

Answer 6

* **Dyslipidaemia, herpes zoster, increased risk of infection, nausea, oropharyngeal pain, thrombocytosis**

Answer 7

* **In RA - IL-1 production decreased** * In osteoarthritis, IL-1 production was not changed * **Shows blocking TNF-alpha could reduce the level of IL-1**

Answer 8

* In 1992, Ravinder Maini and his colleagues tested a TNF-a blocker on 20 patients with rheumatoid arthritis that was not responding to existing treatments. The results were **remarkable – nearly every patient had a rapid reduction of pain and fatigue and improved mobility, and the swelling in their joints went down.** * *Between 1993 and 1994 researchers from the Kennedy Institute carried out a larger study comparing a TNF-a blocker with a placebo. Almost 80 percent of patients receiving a high dose of the TNF-a blocker responded to treatment, compared to just 8 percent on placebo.* * *Further research at the Kennedy Institute in the late 1990s showed that combining TNF-a blockers with MTX made the treatment even more effective.* * *TNF blockade, both effective and relatively safe, has dramatically changed therapy for RA, Crohn’s disease, ankylosing spondylitis and psoriasis.* * *Anti-TNF drugs have been the biggest pharmaceutical drug class with sales exceeding $25 billion per annum.*

Answer 9

* In 1992, Ravinder Maini and his colleagues tested a TNF-a blocker on 20 patients with rheumatoid arthritis that was not responding to existing treatments. The results were remarkable – nearly every patient had a rapid reduction of pain and fatigue and improved mobility, and the swelling in their joints went down. * Between 1993 and 1994 researchers from the Kennedy Institute carried out a larger study comparing a TNF-a blocker with a placebo. Almost **80** percent of patients receiving a high dose of the TNF-a blocker responded to treatment, compared to just **8** percent on placebo. * Further research at the Kennedy Institute in the late 1990s showed that combining TNF-a blockers with MTX made the treatment even more effective. * TNF blockade, both effective and relatively safe, has dramatically changed therapy for RA, Crohn’s disease, ankylosing spondylitis and psoriasis. * Anti-TNF drugs have been the biggest pharmaceutical drug class with sales exceeding $25 billion per annum.

Answer 10

* TNF **blockade**, both effective and relatively safe, has dramatically changed therapy for RA, Crohn’s disease, ankylosing spondylitis and psoriasis. * **Anti-TNF** drugs have been the **biggest** pharmaceutical drug class with sales exceeding $25 billion per annum.

Answer 11

TNF blockade, both effective and relatively safe, has dramatically changed therapy for **RA**, Crohn’s disease, ankylosing spondylitis and **psoriasis**.

Answer 12

**Anti-TNF** drugs have been the biggest pharmaceutical drug class with sales exceeding $25 billion per annum.

Answer 13

* **Targets include IL-1, IL-6, T cell and B cell**

Answer 14

**Protein drugs administered parenterally**

Answer 15

* Biological therapy is recommended if: * Patient has failed to respond to treatment with at least two standard (synthetic) DMARDs, one of which must be **methotrexate** (unless patient cannot take **methotrexate** for medical reason) * Patient’s RA disease activity score (DAS 28) is measured as 5.1 or over, on two occasions, one month apart

Answer 16

* Biological therapy is recommended if: * Patient has failed to respond to treatment with at least **two** standard (synthetic) DMARDs, one of which must be MTX (unless patient cannot take MTX for medical reason) * Patient’s RA disease activity score (DAS 28) is measured as **5.1** or over, on two occasions, one month apart

Answer 17

* **TNF-blockers**: infliximab, etanercept, adalimumab, golimumab, * certolizumab pegol * Monoclonal antibody against **B** cells: rituximab * **T** cell co-stimulation inhibitor: abatacept * Monoclonal antibodies against IL-6R: tocilizumab, sarilumab * → Licenced in the US: IL-1R antagonist anakinra

Answer 18

* TNF-blockers: infliximab, etanercept, adalimumab, golimumab, * certolizumab pegol * Monoclonal antibody against B cells: rituximab * T cell co-stimulation inhibitor: abatacept * **Monoclonal** antibodies against IL-**6R**: tocilizumab, sarilumab * → Licenced in the US: IL-**1R** antagonist anakinra

Answer 19

* **infliximab, etanercept, adalimumab, golimumab,** **certolizumab pegol**

Answer 20

**TNF-blockers, Monoclonal antibody against B cells, T cell co-stimulation inhibitor, Monoclonal antibodies against IL-6R**

Answer 21

TNF-blockers, Monoclonal antibody against B cells, T cell co-stimulation inhibitor, Monoclonal antibodies against IL-6R are all currently licensed **biologics** for treatment of **rheumatoid arthritis** in the UK

Answer 22

Rituximab is a drug known as a **monoclonal** antibody.

Answer 23

abatacept is a **T**-cell co-stimulation inhibitor

Answer 24

* **Infliximab** – partially humanized mouse monoclonal anti-hTNF-a antibody * Etanercept – soluble TNF receptor dimer * Adalimumab – human IgG1 monoclonal anti-TNF-a antibody * **Golimumab** – human IgG1 monoclonal anti-TNF-a antibody * Certolizumab pegol – PEGylated anti-TNF-a monoclonal antibody fragment

Answer 25

* Infliximab – partially humanized mouse monoclonal anti-hTNF-a antibody * **Etanercept** – soluble TNF receptor dimer * Adalimumab – human IgG1 monoclonal anti-TNF-a antibody * Golimumab – human IgG1 monoclonal anti-TNF-a antibody * **Certolizumab** pegol – PEGylated anti-TNF-a monoclonal antibody fragment

Answer 26

* **Infliximab** – partially humanized mouse monoclonal anti-hTNF-a antibody * Etanercept – soluble TNF receptor dimer * **Adalimumab** – human IgG1 monoclonal anti-TNF-a antibody * Golimumab – human IgG1 monoclonal anti-TNF-a antibody * Certolizumab pegol – PEGylated anti-TNF-a monoclonal antibody fragment

Answer 27

When TNF-blockers are combined with MTX, they give excellent **joint** protection

Answer 28

When TNF-blockers are combined with **methotrexate**, they give excellent joint protection

Answer 29

When **TNF**-blockers are combined with MTX, they give excellent joint protection

Answer 30

* Partially humanized **mouse** monoclonal anti-human **TNF-a** antibody – first anti-TNF biologic * Neutralizes free, membrane and receptor-bound **TNF-a →** antibody-dependent cell-mediated cytotoxicity (ADCC) * Also used for the treatment of Crohn’s disease, ulcerative colitis, plaque psoriasis, ankylosing spondylitis * NICE only approves infliximab, if combined with **MTX** * Administered as **intravenous** infusion 3mg per kg of body weight, repeated 2 weeks and 6 weeks after the first infusion, then every 8 weeks.

Answer 31

* Partially humanized mouse monoclonal anti-human TNF-a antibody – first anti-TNF biologic * Neutralizes free, membrane and receptor-bound TNF-a → antibody-dependent cell-mediated cytotoxicity (ADCC) * Also used for the treatment of **Crohn’s disease, ulcerative colitis, plaque psoriasis, ankylosing spondylitis** * **NICE** only approves infliximab, if combined with MTX * Administered as intravenous infusion **3mg** per kg of body weight, repeated 2 weeks and 6 weeks after the first infusion, then every 8 weeks.

Answer 32

Infliximab dosage - Administered as intravenous infusion 3mg per kg of body weight, repeated **2** weeks and **6** weeks after the first infusion, then every 8 weeks.

Answer 33

* **Extracellular** domain of the hu p75 TNFR fused with the Fc domain of hu **IgG1** * Binds free and membrane-bound TNF, reducing the accessible TNF in **RA** → ADCC * Also used for the treatment of juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis * 25mg twice a week, or 50mg weekly by subcutaneous injection

Answer 34

* Extracellular domain of the hu p75 TNFR fused with the Fc domain of hu IgG1 * Binds free and membrane-bound TNF, reducing the accessible TNF in RA → ADCC * Also used for the treatment of juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis * **25mg** twice a week, or **50mg** weekly by subcutaneous injection * **Binds both TNF-alpha and TNF-beta**

Answer 35

* Adalimumab * Also used in juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease * **40** mg by subcutaneous injection every other week * Golimumab * In combination with MTX * Also used in psoriatic arthritis, ankylosing spondylitis * Longer half-life * **50** mg monthly by subcutaneous injection

Answer 36

* Adalimumab * Also used in juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, **Crohn’s** disease * 40 mg by subcutaneous injection every other week * Golimumab * In combination with **MTX** * Also used in psoriatic arthritis, ankylosing spondylitis * **Longer** half-life * 50 mg monthly by subcutaneous injection

Answer 37

* Adalimumab * Also used in juvenile idiopathic arthritis, plaque psoriasis, **psoriatic** arthritis, ankylosing spondylitis, Crohn’s disease * 40 mg by **subcutaneous** injection every other week * Golimumab * In combination with MTX * Also used in **psoriatic** arthritis, ankylosing spondylitis * Longer half-life * 50 mg monthly by **subcutaneous** injection

Answer 38

**Etanercept**

Answer 39

**infliximab**

Answer 40

* **PEGylated** Fab’ fragment of humanized anti-TNF-a mAb – no **Fc** portion * Also used for the treatment of Chron’s disease * 400 mg by subcutaneous injection at weeks 0, 2 and 4 (given as two injections of 200 mg), and then 200 mg every other week thereafter

Answer 41

* PEGylated Fab’ fragment of humanized anti-TNF-a mAb – no Fc portion * Also used for the treatment of **Chron’s** disease * **400** mg by subcutaneous injection at weeks 0, 2 and 4 (given as two injections of 200 mg), and then 200 mg every other week thereafter

Answer 42

* Figure shows combination of Adalimuma with MTX * Higher dose of MTX combined with Adalimumab = **higher** efficacy for RA

Answer 43

* Patients screened before starting treatment to exclude an increased risk of side effects, in particular for a past history of **tuberculosis** (TB), multiple **sclerosis**, recurrent infection, leg ulcers and a past history of cancer * **Chest** X-ray to be taken to exclude signs of previous TB and to exclude signs of heart failure * Increased risk of infections, reactivation of TB * Live vaccines, against e.g. yellow fever or polio, should be avoided * Anti-TNF therapy can be administered for as long as 10 years. * Patients can stay on the drug for as long as they continue to respond well to it.

Answer 44

* Patients screened before starting treatment to exclude an increased risk of side effects, in particular for a past history of tuberculosis (TB), multiple sclerosis, recurrent infection, leg ulcers and a past history of cancer * Chest X-ray to be taken to exclude signs of previous TB and to exclude signs of heart failure * Increased risk of **infections**, **reactivation** of TB * **Live** vaccines, against e.g. yellow fever or polio, should be avoided * Anti-TNF therapy can be administered for as long as **10** years. * Patients can stay on the drug for as long as they continue to respond well to it.

Answer 45

* Anti-TNF therapy can be administered for as long as **10** years. * Patients can stay on the drug for as long as they continue to respond well to it.

Answer 46

* Some patients may have * an **inadequate** clinical response * lose their **responsiveness** over time * experience **unacceptable** side effects * have **medical** issues * precluding the use of anti-TNF medication. * It is estimated that 30% of RA patients fail to respond adequately to a combination of a TNF inhibitor plus MTX.

Answer 47

* Some patients may have * an inadequate clinical response * lose their responsiveness over time * experience unacceptable side effects * have medical issues * precluding the use of anti-TNF medication. * It is estimated that **30**% of RA patients fail to respond adequately to a combination of a TNF inhibitor plus MTX.

Answer 48

It is estimated that 30% of RA patients fail to respond adequately to a combination of a TNF inhibitor plus **MTX**.

Answer 49

* Partially **humanized** anti-CD20 mAb * Rituximab **opsonized** B-cells are attacked and killed by three mechanisms: * 1)**Complement** mediated cytotoxicity * 2-3) Antibody-dependent cell mediated cytotoxicity (ADCC) – FcgR or CR mediated opsonic phagocytosis * 4) Apoptosis * Also used for the treatment of SLE * An intravenous infusion (1 g) on two occasions two weeks apart (although some centres give smaller weekly injections for four weeks).

Answer 50

* Partially humanized anti-CD20 mAb * Rituximab opsonized B-cells are attacked and killed by three mechanisms: * 1)Complement mediated cytotoxicity * 2-3) Antibody-dependent cell mediated cytotoxicity (ADCC) – FcgR or CR mediated opsonic phagocytosis * 4) **Apoptosis** * Also used for the treatment of **SLE** * An intravenous infusion (1 g) on two occasions two weeks apart (although some centres give smaller weekly injections for four weeks).

Answer 51

* Partially humanized anti-**CD20** mAb * Rituximab opsonized B-cells are attacked and killed by three mechanisms: * 1)Complement mediated cytotoxicity * 2-3) Antibody-dependent cell mediated **cytotoxicity** (ADCC) – FcgR or CR mediated opsonic phagocytosis * 4) Apoptosis * Also used for the treatment of SLE * An **intravenous** infusion (1 g) on two occasions two weeks apart (although some centres give smaller weekly injections for four weeks).

Answer 52

* Partially humanized anti-CD20 mAb * Rituximab opsonized B-cells are attacked and killed by three mechanisms: * 1)Complement mediated cytotoxicity * 2-3) **Antibody**-dependent cell mediated cytotoxicity (ADCC) – FcgR or CR mediated opsonic phagocytosis * 4) Apoptosis * Also used for the treatment of SLE * An intravenous infusion (1 g) on two occasions **two** weeks apart (although some centres give smaller weekly injections for **four** weeks).

Answer 53

* CTLA-4/ hu IgG1 soluble receptor fusion protein * Competitive inhibitor of **CD28** * Increases **threshold** for T-cell activation * Suppresses the **proliferation** of synovial recirculating T cells * Reduces the level of inflammatory mediators * Intravenous infusion of 500 mg, 750 mg or 1000 mg (depending on patient’s weight) over 30 to 60 minutes. After the first dose, it is given two weeks later, then two weeks after that, then monthly thereafter.

Answer 54

* **CTLA-4/ hu IgG1** soluble receptor fusion protein * **Competitive** inhibitor of CD28 * Increases threshold for T-cell activation * Suppresses the proliferation of synovial recirculating T cells * **Reduces** the level of inflammatory mediators * Intravenous infusion of 500 mg, 750 mg or 1000 mg (depending on patient’s weight) over 30 to 60 minutes. After the first dose, it is given two weeks later, then two weeks after that, then monthly thereafter.

Answer 55

Abatacept is a competitive inhibitor of CD28

Answer 56

Abatacept is a **T-cell co-stimulation inhibitor (**CTLA-4/ hu IgG1 soluble receptor fusion protein)

Answer 57

CTLA4-Ig fusion protein (IgG1) (**abatacept**)

Answer 58

* Tocilizumab: **humanized** anti-IL-6 receptor monoclonal antibody * Also used in systemic juvenile idiopathic **arthritis** * Intravenous infusion 8 mg/kg of body weight * Sarilumab: fully **human** monoclonal antibody against IL-6Ra * 200 mg once every two weeks, administered as a subcutaneous injection

Answer 59

* Tocilizumab: humanized anti-IL-6 receptor monoclonal antibody * Also used in systemic juvenile idiopathic arthritis * Intravenous infusion **8** mg/kg of body weight * Sarilumab: fully human monoclonal antibody against IL-6Ra * **200** mg once every two weeks, administered as a subcutaneous injection

Answer 60

Tocilizumab and sarilumab are the IL-**6R** inhibitors

Answer 61

Tocilizumab and **sarilumab** have been authorized for UK patients with critical COVID-19 infection.

Answer 62

* **Recombinant** IL-1ra * Differs from native human IL-1ra: it has the addition of a single **methionine** residue at its amino terminus * In RA: * Reduces bone **erosion** * Decreases osteoclast production * Blocks IL-1-induced MMP release from synovial cells * Not used in the UK to treat RA, but licensed in the US

Answer 63

* Recombinant IL-1ra * Differs from native human IL-1ra: it has the addition of a single methionine residue at its amino terminus * In RA: * Reduces bone erosion * **Decreases** osteoclast production * **Blocks** IL-1-induced MMP release from synovial cells * Not used in the **UK** to treat RA, but licensed in the **US**

Answer 64

* Increased risk of infections: * **Upper** respiratory tract infections (nasopharyngitis) * **Pneumonia** * Urinary tract infections * It is recommended to receive influenza and pneumococcal vaccines before embarking on biological therapy * Avoid **live** vaccines * Nausea * Headache * Hypertension * Allergic reactions * Contraindicated in **pregnancy** and while **breast feeding (**rituximab, tocilizumab, sarilumab, abatacept, anakinra)

Answer 65

* Increased risk of **infections**: * Upper respiratory tract infections (nasopharyngitis) * Pneumonia * Urinary tract infections * It is recommended to receive influenza and pneumococcal vaccines before embarking on biological therapy * Avoid **live** vaccines * **Nausea** * **Headache** * **Hypertension** * **Allergic reactions** * Contraindicated in pregnancy and while breast feeding (rituximab, tocilizumab, sarilumab, abatacept, anakinra)

Pharmacological Aspects of Immunology 2 : Biological Therapies Flashcards

(97 cards)