DISEASE-MODIFYING ANTIRHEUMATIC DRUGS

RA is a progressive immunologic disease that causes significant systemic effects, shortens life, and
reduces mobility and quality of life. The effects of disease-modifying therapies may take 2 weeks to 6
months to become clinically evident. These therapies include conventional synthetic (cs) and biologic (b)
disease-modifying antirheumatic drugs (recently designated csDMARDs and bDMARDS, respectively). All
of them increase risk to infection and vaccines must be avoided .The conventional synthetic agents
include methotrexate, azathioprine, chloroquine and hydroxychloroquine, cyclophosphamide,
cyclosporine, leflunomide,mycophenolate mofetil, and sulfasalazine. Gold salts, they have found limited
use for RA in Canada .The bDMARDs approved for RA include a T-cell modulating (T cell inhibitor)
biologic (abatacept), a B-cell cytotoxic agent which cause B lymphocyte depletion (rituximab) , an anti-IL-
6 receptor antibody (tocilizumab), IL-1-inhibiting agents (anakinra, rilonacept,canakinumab), and the
TNF-Alpha -blocking agents (five drugs );.

ABATACEPT

1. Mechanism of action: Abatacept is a modulator biologic that prevent activation of T-cell by binding
with CD28.

2. Pharmacokinetics: The recommended dose of abatacept for the treatment of adult patients with RA
is three I. V infusion (day 0-week 2-week 4) doses : 500mg-750mg-1000mg. Abatacept is also available as
a subcutaneous formulation and is given subcutancously once weekly.

3. Indications (Uses) :

a.) It can be used as monotherapy or in combination with methotrexate.

b.)in patients with moderate to severe RA or severe PJIA (polyarticular juvenile idiopathic arthritis) , and
rheumatic diseases as SLE (systemic lupus erythematosus).

4. Adverse Effects:

a.)There is increased risk of infection (as with other biologic DMARDs)predominantly of the upper
respiratory or urinary tracts.

b.) Latent tuberculosis and viral hepatitis.

c.)Live vaccines should be avoided in patients taking abatacept.

d.)Hypersensitivity reactions, including anaphylaxis but are rare.

E.) Lymphomas

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AZATHIOPRINE (Imuran)

1. Mechanism of Action: Azathioprine is a csDMARD that acts

through its major metabolte-6-thioguanine which

suppresses inosinic acid synthesis, immunoglobulin production, and IL-2 secretion.

2. Pharmacokinetics: Azathioprine can be given orally or I.V .

3. Indications:

a.)Azathioprine is approved for use in RA at 2 mg/kg per day.

b.)It is also used for the prevention of organ transplantation rejection especially kidney transplant
rejection .

c.) In PA (propionic acidemia ), reactive arthritis and SLE (systemic Lupus Erythematosus).

4.Adverse effects :

a.) Bone marrow depression or suppression.

b.) GIT disturbances &hepatotoxicity .

c.) Increase in infection risk.

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(CHLOROQUINE&

HYDROXYCHLOROQUINE)

Chloroquine and Hydroxychloroquine

are nonbiologic drugs mainly used for malaria. They increase PH (basic).Hydroxychloroquine is used
more than chloroquine.

1. Mechanism of Action: suppression of T-lymphocyte responses to mitogens, inhibition of leukocyte

chemotaxis, stabilization of lysosomal enzymes and inhibition of DNA & RNA synthesis.

2. Pharmacokinetics: Antimalarials are rapidly absorbed with elimination half-lives of up to 45 days.

3. Indications (uses) :

a.) Antimalarials are approved for RA and SLE.

b.) Hydroxychloroquine has been approved for covid19 (corona) .

4. Adverse effects: ocular toxicity and GIT disturbance.

Note : these drugs are safe in pregnancy.

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CYCLOPHOSPHAMIDE

1. Mechanism of Action: Cyclophosphamide is a csDMARD. It

cross-links DNA to prevent cell replication. It suppresses T-cell.

2. Indications : 2 mg/kg per day to treat SLE, vasculitis ,wegener’s granulomatosis and other rheumatic
diseases.

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CYCLOSPORINE (NEORAL )

1. Mechanism of Action : It inhibits IL-1 and IL-2 receptor production as well as it inhibits macrophage-T-
cell interaction and T-cell

responsiveness (calcineurin inhibitor ).

2. Pharmacokinetics: Cyclosporine absorption is incomplete and somewhat erratic. When grape juice is
taken with cyclosporine it increases it's absorption.

3. Indications : Cyclosporine is approved for use in RA , it may be useful in SLE, Wegener's

granulomatosis and organ transplantation.

4. Adverse Effects: Leukopenia, thrombocytopenia , anemia and sterility especially in women. Bladder

cancer is rare.

Note: Drugs used in organ transplantation : Azathioprine & Cyclosporine

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LEFLUNOMIDE (Avara)

20mg, loading dose and this drug can cause teratogenicity

1.Mechanism of Action: It undergoes rapid conversion, both in the intestine and in the plasma, to its
active metabolite, A77-1726 leading to the arrest of stimulated cells in the

G phase of cell growth. It also inhibits T-cell proliferation and reduces production of autoantibodies by B
cells.

2. Pharmacokinetics: Leflunomide is completely absorbed from

the gut and has a mean plasma half-life of 19 days. Cholyestyramine enhance leflunomide excretion.

3. Indications :

a.) Used in RA including inhibition of bony damage.

b.) combined treatment with methotrexate and leflunomide can also be used.

4. Adverse effects :

a.) Diarrhea occurs in approximately 25% of patients.

b.) Elevation in liver enzymes.

c.) Leukopenia and thrombocytopenia

d.) This drug is contraindicated in pregnancy.

Note : Thalidomide is the most harmful drug for pregnant women (contraindicated in pregnancy).

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METHOTREXATE

It is a synthetic nonbiologic antimetabolite, csDMARD for treating RA. It is active in cancer

chemotherapy .

1. Mechanism of Action: Inhibition of amino-imidazolecarboxamide ribonucleotide (AICAR) . AICAR,

which accumulates intracllularly leading to an accumulation of AMP.The AMP is converted to adenosine
which is a potent inhibitor of inflammation.

2. Pharmacokinetics: Methotrexate can be administered either

orally or parentally (SC or IM).

3. Dosage: 7.5 mg weekly or in Yemen (2.5 each two days during one week)

4. Indications :

a.) 50mg I.M for ectobic pregnancy and used in abortion.

b.)Used in AS ( Ankylosing Spondylitis), PA (propionic acedimia) , SLE , wegener's granulomatosis and

anti-cancer.

5. Adverse effects : Nausea , mucosal ulcers, hepatotoxicity, leukopenia, anemia, GI ulceration and
alopecia.

Note :

-Contraindicated in pregnancy .

- This drug decrease folic acid in womens

so folic acid must be taken with it to prevent teratogenicity.

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RITUXIMAB

1. Mechanism of Action: Rituximab is a chimeric monoclonal

antibody biologic agent that targets CD20 B lymphocytes. (Depletion of B lymphocytes )

2.Pharmacokinetics :

-It is given as I.V infusions of 1000 mg

- Acetaminophen, an antihistamine and glucocorticoids must be taken before the drug administration to
prevent the severity of infusion reactions.

3.Indications : Used in treatment of moderately to severity RA in combination with methotrexate.

4. Adverse effects : immunosuppression and increase risk of infection.

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SULFASALAZINE

1. Mechanism of Action: is a csDMARD and is the active moiety when treating RA while 5-
aminosalicyclic acid is the active moiety for inflammatory bowel disease.

2.Pharmacokinetics : sulfapyridine is well absorbed while 5-aminosalicyclic acid remains reabsorbed.

3.Indications :500mg it is effective in RA & inflammatory bowel disease.

4. Adverse Effects:

a.)nausea, vomiting, headache, Hemolytic anemia , pulmonary toxicity ,methemoglobinemia and

thrombocytopenia also occurs but rarely.

b.) Infertility occurs in men, but does not aftect fertility in women.

The drug does not appear to be teratogenic.

Note : Inflammatory bowel disease = Crohn's disease + ulcerative colitis.

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 TNF-ALPHA-BLOCKING AGENTS

Cytokines play a central role in the immune response and in rheumatoid arthritis.

TNF-a affects cellular function via activation of specitic mem-brane-bound TNF receptors (TNFR, TNFR).
Five “legacy” bDMARDs interfering with TNF-a have been approved for the treatment of RA and other
rheumatic diseases. Biosimilar biologics (bsDMARDs) with lower costs are available in some countries
and are being tested in other countries. Thus far, the efficacy, toxicity, and immunogenicity of the
biosimilars are equivalent to the legacy compounds. These drugs have manyadverse effects in common.

ADALIMUMAB

1.Mechanism of action : Adalimumab is a fully human IgG1 anti-TNF monoclonal antibody. It results in
down regulation of macrophage and T-cell function.

2.Pharmacokinetics : it is give subcutaneously and has half life of 10-20 days .The usual dose in RA is 40
mg every other week, but dosing is frequently increased to 40 mg weekly. In psoriasis 80mg is given at
week. The initial dose in inflammatory bowel disease is higher.

3.Indications : The compound is approved for RA, AS, PsA, Jevinile idiopathic arthritis, crohn’s disease
and ulcerative colitis (IBD).

4.Adverse effects : Increase risk of infection

Certolizumab
Taken injection and similar to adalimumab

Etanercept and Golimumab

Similar to adalimumab

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‫ صدام فاضل‬/ ‫اشراف ومراجعة الدكتور‬

‫ هاشم الدبعي‬/ ‫إعداد‬
Reference : Katzung ‫مرجع‬