Anticytokine Therapies in Rheumatoid Arthritis

Anticytokines act on the proinflammatory cytokines i.e. interleukin-1b (IL- 1b) and Tumor necrosis factor- α (TNF- α).

Gold salts

Gold compounds are of two types:

1. Those used for intramuscularly such as gold sodium thiomalate and aurothioglucose. They are made up of about 50% elemental gold.

2. Those used in oral formulation such as auranofin containing 26-29% elemental gold.

Mechanism of action:
It is thought that these gold compounds are taken up by macrophages and thus suppresses the phagocytosis and lysosomal enzyme activity.

This process is responsible for the reduction of bone and articular destruction.

Pharmacokinetics:
They tend to accumulate in the synovial fluid and bone marrow. 1/3 of the gold compounds are excreted in the urine and remaining goes through feces.

Adverse effects:
Pruritic (itching) skin rashes may occur.

D-Penicillamine

It is a metabolite of penicillin and an analog of cysteine (an amino acid).


Action:
It slows the advancement of the bone erosion and rheumatoid arthritis.

Adverse effects:
It may cause some of the very serious effects such as some of the dermatologic problems, nephritis and aplastic anemia.

Chloroquine and hydroxychloroquine

These drugs are mainly used in malaria.


Mechanism of action:
These drugs may cause the lowering of T lymphocytes for action in Rheumatoid arthritis.

Action:
These drugs are used in Rheumatoid arthritis, when NSAIDs are not effective to that extent. They may be used alone or in combination with other NSAIDs. When it is used in combination it must be used in lower doses.

These drugs slow the gradual change in the bones due to continuous wear & tear and sometimes they may cause temporary disappearance of the disease.

Adverse effects:
This may cause ocular toxicity, nausea, vomiting and dyspepsia.

Leflunomide

Leflunomide is a drug that causes modification of the immune system while undergoing treatment (this modification or alteration is a part of the treatment so that is why it is also called as immunomodulatory agent) and disease modifying anti-rheumatic agent.


Mechanism of action:
Leflunomide causes inhibition of:

1. Multiplication or propagation of T cells

2. Production of autoantibodies by B cells.

Leflunomide inhibit the enzyme Dihydroorotate dehydrogenase (DHODH). This causes Uridine 5’-monophosphate (UMP) not to be produced.

UMP is essential in two ways:

1. It is an important component of RNA synthesis.

2. It is pioneer in making nucleotide which is composed of thymidine, which is required for DNA synthesis.

As a result there is a cell arrest.

Action:

It is a reversible inhibitor of DHODH. It helps to reduce pain and inflammation and along with this function it also helps to reduce the decay or erosion cause to the bones or any other body parts due to inflammation.

It can be used alone or in combination with other drugs like methotrexate.

Pharmacokinetics:
It is well absorbed orally. Its half life is 13-19 days. The binding of this drug to serum albumin is about more than 85%. It is excreted both through biliary and renal excretion. It readily converts to metabolites and the metabolites are excreted in the urine and feces.

The metabolite which is still effective goes back to do some work. Cholestyramine enhances leflunomide excretion.

Adverse effects:
It may cause headache, diarrhea (loose bowels) and nausea. Alopecia, Weight loss or weight gain and allergic reactions like skin rash are its rare side affects.

Contraindications:
It is contraindicated in pregnancy.

Precautions:
As this drug may cause an increase in liver enzyme level so it must be used with caution in liver diseases.

Methotrexate

It is thought that methotrexate is the cornerstone of the therapy for the patients, who have not responded well to other NSAIDs in severe rheumatoid arthritis or psoriatic arthritis.


Action:
As this is an immunosuppressant, this may be responsible for its effectiveness in reducing arthritis which according to some experts is an autoimmune disease.

Methotrexate slows the decay within moving joints, which may be due to the inhibition of thymidylate synthetase and some other related enzymes.

Pharmacokinetics:
The drug is found to be absorbed about 65%-75% after oral administration. Its serum half life is about 6-9 hours.

It has been found that methotrexate shows response usually sooner than the other agents i.e. it may be within 3 to 6 weeks of treatment.

Dosage:
Small doses are effective for the treatment of Arthritis than those needed for the treatment of cancer as this drug is also useful for the treatment of cancer. The dose is reduced to once a week administration.

Adverse Effects:
In small doses it may cause mucosal ulceration and nausea. Some of the following adverse effects may also be seen:

1. Cytopenia

2. Liver cirrhosis (it is particularly dose related)

3. Pneumonia like syndrome (hypersensitivity lung reaction)

Disease modifying anti-rheumatic agents

Disease modifying anti-rheumatic drugs (DMARDs) or slow acting anti-rheumatic drugs (SAARDs)


1. Slow the course of the disease and can induce remission.

2. Reduce or prevent the joint damage.

Drugs to be choosen:
Many experts start therapy with the conventional drugs i.e. methotrexate or hydroxychloroquine. But if these do not work properly then they go to the newer agents i.e. anakinra, adalimumab, leflunomide, and infliximab. Often it is also prescribed that the combination therapy is more effective.