Drugs used in the management of rheumatoid arthritis

Question 1

What are the different treatment plans for rheumatoid arthritis?

Answer 1

1) Non-steroidal anti-inflammatory drugs (NSAIDs)

2) Disease-modifying anti-rheumatic drugs (DMARDs)

3) Biological therapies (targeted drugs it is a drug actually an antibody which acts on specific players in the immune system often a “cytokine”)

4) Glucocorticoids

Question 2

What is the special thing about biological therapies?

Answer 2

It does not have many side effects (has a high specificity)

Question 2

What are the effects of Disease Modifying Anti-Rheumatic Drugs?

Answer 2

1) Controls the symptoms:
- controls the current inflammatory features

2) Modifies the course of the disease:
- Reduces the joint deformity and damage
- Reduces the radiographic progression
- Reduces the long-term disability

Question 3

What is the reason behind taking the NSAID for two weeks at least?

Answer 3

Because the maximal analgesic and anti-inflammatory effect is usually achieved within 10-14 days

Question 3

What NSAIDs are used to treat RA?

Answer 3

• The dose of the NSAIDs is titrated to the optimum tolerated level and it is continued for 2 weeks at least before switching to another drug

1) (3200 mg) of ibuprofen
2) (1000 mg) of naproxen
3) (20 mg) piroxicam (single daily dose)

• But usually, we do not use NSAIDs as they are usually ineffective and require very high doses until little effectiveness appears (it might be used at the beginning as a anti-inflammatory or pain reliever drug)

Question 4

What are the different DMARDs used to treat RA?

Answer 4

1) Methotrexate

2) Hydroxychloroquine

3) Sulfasalazine

4) Leflunomide

5) Minocycline

Question 5

Describe methotrexate (MTX)

Answer 5

• Can be used alone or in a combination therapy
• It has immunosuppressive and anti-inflammatory effects
• It has a relatively rapid onset of action at therapeutic doses of 6-8 weeks “once a week”
• Effective in reducing the signs and symptoms of RA in addition to slowing the radiographic damage
• It is an antimetabolite (structurally similar to endogenous compounds & an antagonist), it can be used in many diseases and medical conditions especially the ones involving rapid rate of cell division like cancer and AI diseases
• Given by injection only

Question 6

What is the main drug used to treat patients with RA?

Answer 6

Methotrexate, only in a injectable form

Question 7

What is the mechanism of action of methotrexate?

Answer 7

1) MTX is a folic acid antagonist that inhibits the enzyme dihydrofolate reductase (DHFR, responsible for thymine production)

2) Reduces monocytic cell growth and increases their apoptosis How? because the cell has n thymine to use (immunosuppressive effect)

3) It decreases IL-1 & IL-6 secretion which are inflammatory cytokines (anti-inflammatory effect)

4) It increases IL-4 & IL-10 gene expression which have an anti-inflammatory effect

5) It decreases the gene expression of proinflammatory Th1 cytokines (IL-2 “helps in cell proliferation” & IFN-y “damages the joint in RA”)

Question 8

What are the side effects of methotrexate?

Answer 8

• Methotrexate exerts its chemotherapeutic effects by being able to compete for folic acid, resulting in folic acid deficiency in the cells, this action might affect normal body cells causing significant side effects:

1) Mucosal ulceration
2) Nausea
3) Cytopenia (low blood cell count)
4) Cirrhosis
5) Acute pneumonia-like syndrome
6) Hair loss
7) Diarrhea
8) Liver, lung, nerve, and kidney damage
9) Megaloblastic anemia (due to folate deficiency)

Question 9

How can we reduce the side effects of methotrexate?

Answer 9

They can be prevented or reduced by using leucovorin which provides a source of folic acid for the body’s cells

• It is normally started 24 hours after methotrexate giving methotrexate a chance to exert its full anti-cancer effects

Question 10

What are the things you need to monitor when prescribing methotrexate?

Answer 10

1) CBC (complete blood count)
2) Liver function
3) Serum creatinine
4) Hepatitis B and C serologies
5) Chest X-rays

Question 11

What are some of the drug interactions of methotrexate?

Answer 11

1) NSAIDs block methotrexate renal excretion increasing its serum levels and increasing the risk of toxicity

2) As long as the liver function is closely monitored and the dose is adjusted, methotrexate can be given with NSAIDs and it is considered safe

Question 12

Describe hydroxychloroquine

Answer 12

• Used for early, & mild RA
• It is often combined with methotrexate, in addition to those it can also combine with sulfasalazine for a triple therapy
• Used to treat lupus and malaria
• It has an unknown mechanism of action in autoimmune disorders
• The onset of the effects take 6 weeks to 6 months

Question 12

What are the side effects of hydroxychloroquine?

Answer 12

1) Less effects on the liver and the immune system than other DMARDs

2) Ocular toxicity (irreversible retinal damage and corneal deposits)

3) Disturbance of the CNS

4) Upseting the GI

5) Skin discoloration

6) Skin eruptions (v.rare)

Question 12

Describe sulfasalazine

Answer 12

• Used in early or mild RA
• Used in combination with methotrexate and/or hydroxychloroquine in a triple therapy
• The onset of its activity takes 1-3 months
• Unclear mechanism of action

Question 13

Describe leflunomide

Answer 13

• It has an action on dihydroorotate dehydrogenase (DHODH), Arresting all cells of the autoimmune lymphocytes
• It can be used either as monotherapy (if the disease was mild) or in combination with methotrexate
• Unlike methotrexate which attacks all active cells, leflunomide has a specificity to T-cell lymphocytes as the enzyme dihydroorotate dehydrogenase is present in T-cells mainly

Question 13

What are the side effects of leflunomide?

Answer 13

1) Allergic reactions (flu-like syndrome, skin rash)

2) Alopecia (hair loss)

3) Hypokalemia

4) Headache, diarrhea & nausea (symptoms of hypokalemia)

5) Weight loss

6) Has a risk of hepatotoxicity

Question 14

Describe minocycline

Answer 14

1) It is a tetracycline antibiotic

2) It is effective in the treatment of early RA

3) It is generally not utilized as a first-line therapy

4) It can be used as monotherapy or in combination with other DMARDs

Question 15

What are the different biological therapies?

Answer 15

1) Tumor necrosis factor (TNF) inhibitors

2) Preventing full T-cell activation

3) B-cell depletion (anti-CD20 receptors)

4) Interleukin-1 receptor antagonist

5) Interleukin-6 inhibitors

Question 16

What is the most effective cytokine produced by the immune cells that attack the joints?

Answer 16

Tissue necrotic factor, so it is this that we need to attack/inhibit

Question 16

What are the different inhibitors of the TNF?

Answer 16

1) Adalimumab (human)

2) Infliximab (mouse + human)

3) Etanercept (humans)

• The suffix mab means that the shape of the antibody is a Y-shape for etanercept the antibody is horizontal

Question 16

What is the mechanism of action of TNF inhibitors?

Answer 16

• Binds to TNF in the circulation and in the joint preventing its interaction with TNF receptors on inflammatory cells surface inhibiting their activity
• Used either as monotherapy or in combination with methotrexate

Question 16

What other treatment are TNF inhibitors also used for?

Answer 16

1) Psoriatic arthritis

2) Ankylosing spondylitis (type of arthritis causing inflammation in the joint and ligaments of the spine)

3) Psoriasis

Question 17

What are the side effects of tumor necrosis factor inhibitors?

Answer 17

1) Increased risk of infection (sepsis, TB, & opportunistic infections) 2) Some patients develop positive antinuclear antibodies (ANA), lupus is reported but rare 3) Anti-infliximab antibodies occur in 10-30% of patients (suppressed by concomitant methotrexate therapy) 4) Transient neutropenia or other blood dyscrasias have been reported

Question 17

Which drug is used in preventing full T-cell activation?

Answer 17

Abatacept

Question 17

Which drug is used in depleting B-cells (Anti-CD20 receptors)?

Answer 17

Rituximab

Question 18

Which drug is used as an Interleukin-1 receptor antagonist?

Answer 18

Anakinra ( inhibits the interactions of IL-1beta and its receptor (IL-1R))

Question 18

Which drug is used as an inhibitor of interleukin-6?

Answer 18

Tocilizumab and sarilumab (bind to the IL-6 receptor and block its activity)

Question 19

What is the mechanism of action of abatacept?

Answer 19

Modulates the immune response by bonding with CD80/CD86 on an APC such as dendritic cells, preventing the costimulation of CD28 on naive T-cells and attenuating T-cell activation

Question 19

What is the mechanism of action of rituximab?

Answer 19

Eliminates B-cells via antibody and complement-mediated cytotoxicity and by apoptosis (attacks the b cell by binding to the CD 20, then the cell will go through apoptosis)

Question 20

What is the mechanism of action of anakinra?

Answer 20

It blocks IL-1a and B pathways

Question 21

What is the mechanism of action of tocilizumab?

Answer 21

It binds to IL-6R and blocks IL-6

Question 22

What are JAK inhibitors?

Answer 22

- Biological therapy - It is a set of several orally administered small-molecule Janus-kinase (JAK) inhibitors, which are considered DMARDs - They have been developed to decrease signaling by a number of cytokine and growth factor receptors

Question 23

What are some examples of Jak inhibitors drugs?

Answer 23

1) Tofacitinib 2) Baricitinib 3) Upadacitinib 4) Filgotinib

Question 23

Describe the nib drugs

Answer 23

- Protein kinases are one of the most important categories of target in oncology, due to their key role in the pathogenesis of many illnesses due to mutations, overexpression, and dysregulation of these enzymes - Over the past years a lot of drugs have been developed against protein kinase family of enzymes, The F.D.A has approved >52 protein kinase inhibitors as drugs of the 52 drugs 43 have the suffix -nib, which indicates a small-molecule inhibitor - -tinib is used for tyrosine kinase inhibitors, -anib is for angiogenesis inhibitor, -rafenib for rapidly accelerated fibrosarcoma (RAF) Kinase inhibitors

Question 23

What are some examples of other immunomodulatory and cytotoxic agents?

Answer 23

1) Intramuscular gold 2) Azathioprine 3) Cyclophosphamide 4) Cyclosporine 5) D-penicillamine - All of these drugs are considered as historical drugs

Question 23

How do we treat RA during pregnancy?

Answer 23

- RA treatment during pregnancy is complicated as none of the discussed drugs have been proven to be safe - Joint symptoms tend to diminish during pregnancy but not always - Treatment decisions must be taken carefully considering the risks and benefits to the mother and the fetus - Methotrexate can cause neural tube defects (like spina bifida and anencephaly) - Methotrexate and leflunomide are teratogenic and women who plans to get pregnant must withdraw from those drugs

Question 23

What is the safest disease-modifying anti-rheumatic drug to be used in pregnancy?

Answer 23

Hydroxychloroquine

Question 23

What is the mechanism of action of glucocorticoids?

Answer 23

- Glucocorticoid receptors regulate the transcription of genes 1) The free hormone in the plasma enters the cell 2) The hormone then will bind to the receptor inducing conformational changes 3) Hormone-receptor complex is transported into the nucleus where it binds to glucocorticoid receptor elements (GRE) on the gene 4) It will then regulate the transcription via RNA polymerase II and associated transcription factors 5) mRNA is then edited and secreted into the cytoplasm for the production of protein 6) The protein will then deliver the final hormonal response

Question 23

What are the anti-inflammatory and immunosuppressive effects of glucocorticoids?

Answer 23

1) It increases the amount of neutrophils, as it decreases their migration from the blood to the site of inflammation 2) It decreases the lymphocyte count (T & B cells), as it increases their movement from the vascular bed to the lymphoid tissue 3) It decreases phagocytosis, as it decreases TNF-a & Interleukin-1 4) It decreases the cellular immunity, as it decreases IL-12 & Interferon-y 5) It decreases prostaglandin, leukotrienes & platelet-activating factor synthesis 6) Inhibits phospholipase A2 7) Decreases the expression of cyclooxygenase II 8) Causes vasoconstriction possibly by suppressing mast cell degranulation 9) Decreases capillary permeability due to decreased amount of histamine release 10) Decreases Antibody production at dosages 11) Decreases organ rejection in tissue Transplantation

Question 23

What are some of the other side effects of glucocorticoids?

Answer 23

1) Behavioral disturbance (insomnia, euphoria & depression) 2) Increases intracranial pressure 3) Release of ACTH, TSH, GH & LH 4) Large doses can cause peptic ulcer, as it suppresses the immune response against helicobacter pylori 5) Antagonizes the effects of vitamin D on calcium absorption

Question 24

Which primary glucocorticoid is used in RA?

Answer 24

Prednisone