Therapeutics - biologics

Question 1

What are the anti-inflammatory drugs?

Answer 1

NSAIDs: non-selective COX-1/2 inhibitors -> aspirin, ibuprofen, diclofenac
COX-2 selective inhibitor -> celecoxib
Steroid anti-inflammatory drugs (glucocorticoids), immunosuppressants -> prednisone, prednisolone, depomedrone, triamcinolone.
Short-term use
Intramuscular injection/ injected into inflamed joints/ per os.
Slows disease progression, prevents further damage to joints.
Avoid long-term use: adverse effects can outweigh therapeutic benefit over time even at low dose → risk of infections + osteoporosis.

Question 2

What are DMARDs used for and what are the different types?

Answer 2

Slows clinical + radiographic progression of RA.
Synthetic agents: MTX, sulfasalazine, hydroxychloroquine, leflunomid.
Biologic agents: TNF-blockers, drugs targeting IL-1, IL-6 , B-cells + T-cells.

Question 3

What are the actions of methotrexate?

Answer 3

High doses treats cancer.
Antimetabolite, inhibits cell proliferation
Increases adenosine level (anti-inflammatory)
Reduces production of damaging polyamines
Induces apoptosis of activated CD4+ + CD8+ T-cells.
“Anchor drug” in combination therapies
Reduces inflammation quickly, keeps under tight control
Reduces risk of death from CV disease in people with RA
Taking supplements of folic acid reduces side-effects caused by folic acid depletion.

Question 4

What are the synthetic DMARDs?

Answer 4

Sulfasalazine (SSZ):
2-component drug -> sulfapyridine (antibiotic) + 5-amino salicylic acid (anti-inflammatory) for UC.
Hydroxychloroquine (HCQ):
antimalarial drug, used in combination with other DMARDs, possible mechanism of action -> increases lysosomal pH in (immune) cells, for SLE.
Leflunomid:
lymphocyte inhibitor, inhibits de novo pyrimidine synthesis, reduces B-cell populations (+ significant effect on T-cells).

Question 5

When is DMARD combination therapy used?

Answer 5

Treats early active RA more effectively than single drugs.
Helpful when not possible to use biologic drugs -> recent cancer / chronic infection.
Well tolerated, no more side effects than single drug.
MTX: “anchor drug” to which others should routinely be added -> SSZ, HCQ, leflunomide.
Triple combination of MTX + SSZ + HCQ most effective.
Uses steroids in some form.

Question 6

What are the adverse effects of synthesis DMARDs?

Answer 6

8-12 weeks treatment required to improve symptoms.
MTX –> 30% experience adverse effects.
Nausea, loss of appetite, diarrhoea, rash + allergic reactions, headache, hair loss, risk of infections (pneumonia), hepatotoxicity (metabolism), kidney toxicity (route of elimination).
HCQ –> accumulation of drug in eye
Leflunomid –> hypertension

Question 7

Biologics are effective at treating with conditions?

Answer 7

Anti-TNF therapy -> a-TNFa antibodies decreases IL-1 production in RA.
rapid pain reduction + fatigue, improved mobility, decreased swelling in joints.
combining TNF-a blockers with MTX makes treatment more effective.
TNF blockade effective + safe. dramatically changed therapy for RA, Crohn’s, ankylosing spondylitis + psoriasis.

Question 8

What are the targets of biologic agents in RA?

Answer 8

TNF, IL-1, IL-6, T cell, B cell

Question 9

When is biological therapy recommended and how are protein drugs administered?

Answer 9

Parenterally
Patient failed to respond to treatment with at least 2 standard (synthetic) DMARDs, 1 must be MTX (unless patient can’t take MTX for medical reason).
Patient’s RA disease activity score (DAS 28) is 5.1 or over, on 2 occasions, 1 month apart.

Question 10

What are the currently licensed biologics for treating RA?

Answer 10

TNF-blockers -> infliximab, etanercept, adalimumab, golimumab, certolizumab pegol.
Monoclonal antibody against B cells -> rituximab
T cell co-stimulation inhibitor -> abatacept
Monoclonal antibody against IL-6R -> tocilizumab
licenced in US -> IL-1R antagonist anakinra

Question 11

What are the TNF blockers?

Answer 11

Infliximab –> partially humanised 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.
Combined with MTX gives excellent joint protection.

Question 12

What are the actions and uses and of infliximab?

Answer 12

Chimeric antibody. partially humanised mouse monoclonal anti-human TNF-a antibody.
Neutralises free, membrane + receptor-bound TNF-a → antibody-dependent cell-mediated cytotoxicity (ADCC).
Crohn’s, UC, plaque psoriasis, ankylosing spondylitis.
NICE only approves if combined with MTX.

Question 13

What are the actions and uses of etanercept?

Answer 13

Soluble TNF receptor dimer.
Extracellular domain of hu p75 TNFR fused with Fc domain of hu IgG1.
Binds free + membrane-bound TNF reducing accessible TNF in RA → ADCC.
Also for juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis.

Question 14

What is the use of adalimumab?

Answer 14

Also in juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn’s.

Question 15

What is the use of golimumab?

Answer 15

Combination with MTX
Also in psoriatic arthritis, ankylosing spondylitis
Longer half-life

Question 16

What are the actions and uses of certolizumab pegol?

Answer 16

PEGylated Fab’ fragment of humanised anti-TNF-a mAb –> no Fc portion
Also for Crohn’s.
Polyethylene glycol (PEG) -> when covalently attached to drugs, reduces antigenicity, immunogenicity. prolongs circulatory time of drug.

Question 17

What are the considerations and side effects of anti-TNF therapy?

Answer 17

Patients screened to exclude increased risk of side effects -> history of TB, MS, recurrent infection, leg ulcers + cancer. chest X-ray excludes signs of previous TB + heart failure.
Increased risk of infections, reactivation of TB.
Live vaccines e.g. yellow fever or live polio should be avoided.
Anti-TNF therapy can be administered for as long as 10 years, can stay on drug as long as they respond well.

Question 18

What are the actions and uses of administration of rituximab?

Answer 18

B cell depleting agent. partially humanized anti-CD20 mAb.
Rituximab opsonized B-cells attacked + killed by 3 mechanisms:
complement mediated cytotoxicity
ADCC –> FcyR/ CR mediated opsonic phagocytosis.
apoptosis.
For SLE

Question 19

What are the actions and uses of abatacept?

Answer 19

T-cell co-stimulation inhibitor
CTLA-4/ hu IgG1 soluble receptor fusion protein
Competitive inhibitor of CD28
Increases threshold for T-cell activation
Suppresses proliferation of synovial recirculating T cells
Reduces level of inflammatory mediators

Question 20

What are the actions and uses of tociluzimab?

Answer 20

IL-6R inhibitor
Humanised anti-IL-6 receptor monoclonal antibody.
For systemic juvenile idiopathic arthritis.

Question 21

What are the actions and uses of anakinra?

Answer 21

IL-1R antagonist
Recombinant IL-1ra
Differs from native human IL-1ra -> has addition of single methionine residue at amino terminus.
In RA -> reduces bone erosion, decreases osteoclast production, blocks IL-1 induced MMP release from synovial cells.

Question 22

What are the adverse effects and contraindications of biological therapies?

Answer 22

Increased risk of infections -> upper respiratory tract infections (nasopharyngitis), pneumonia, UTIs.
Influenza + pneumococcal vaccines recommended beforehand. avoid life vaccines.
Nausea, headache, hypertension, allergic reactions.
Contraindicated in pregnancy + breast feeding (rituximab, tocilizumab, abatacept, anakinra).