Drug Treatment of Rheumatoid Arthritis

Rheumatoid arthritis is an autoimmune disorder. IgG antibodies are formed which start cross-reacting against body tissues, mainly synovial membranes and joints. The disease is not confined here and can effect heart, lungs, kidneys, spleen, eye, or any other tissue.

It affects more females than males in a ratio or 3:1. Peak incidence starts within 20s, can occur between 20-40 years of age.

Disease has waxing and waning character and the person has to live with it for the rest of his life. Life span is shortened by 10-15 years.

It is treated aggressively if diagnosed early.

Signs and Symptoms

1. Morning stiffness of joints

2. As person moves about, stiffness progressively decreases. This is one sign looked into. If stiffness increases, disease is severer, if decreases it is going into remission.

If the disease is not treated well in time, joint deformity may occur.

Osteoarthritis

Wear and tear arthritis, bones appose each other at joints. They are swollen, inflamed, joint erosions and deformities are seen.

Ulnar deviation of metacarpophalangeal joints is most prominent in rheumatoid arthritis.

Boutonniere deformity is the flexion of proximal interphalageal joint and hyperextension of distal interphalangeal joint.

Swan neck deformity includes hyper-extension of proximal and flexion of distal interphalangeal joint.

Objectives Of Treatment

1. Reduction of inflammation & pain (acute relief, NSAIDS mainly)
2. Preservation of functions (disease modifying anti-rheumatic drugs)
3. Prevention of deformity
4. Prevention of extra-articular manifestations

Management

1. Patient education

Due to nature of disease, one has to live with it. One has to adhere to the instructions for normal life.

2. Rest

Initially at least. Progressively mobility is encouraged.

3. Exercise

Passive at first, gradually little harder

4. Weight reduction

5. NSAIDs
6. DMARDs
7. Combination therapies
8. Surgery –plastic joints, repair

Drug Treatment of Rheumatoid Arthritis

First Line Drugs

Non steroidal anti-inflammatory drugs

Non-selective Cox I inhibitors

	Naproxen		Fenoprofen
	Flurbiprofen		Sulindac
	Nabumetone		Etodolac
	Diclofenac		Piroxicam
	Aspirin (high dose)		Diflunisal
	Ibuprofen

Selective Cox-2 inhibitors

Celecoxib

Lumiracoxib

Roxecoxib

2nd Line Drugs or Disease Modifying Anti – rheumatic Drugs (DMARDS)

Immunosuppressive drugs

Methotrexate

Cyclophosphamide

Azathioprine

Anti Malarial drugs

Chloroquine

Hydroxychloroquine

Gold Salts (not used as toxic)

Aurothiomalate

Aurothioglucose

Auranofin

Glucocorticoids

Prednisolone

Triamcinolone

TNF Alpha Blocking Agents

Adalimumab

Infliximab

Etanercept

Miscellaneous

Sulphasalazine

Pencillamine

Levamizole

Leflunomide

Abatacept

Rituximab

Methotrexate

Much lower dose is required on weekly basis. Starting dose is 7.5 mg/week. It is gradually increased depending upon the response up to 300 mg/week.

Effects are slow to appear for all DMARDs taking about 6 weeks to 6 months to appear.

Mechanism Of Action

a. At low dose, blockage of two enzymes occurs:

1. Amino imidazole carboxamide ribonucleotide (AICAR) transformylase

2. Thymidylate synthetase

These enzymes are required for DNA and RNA synthesis. Their blockage causes blockage of neutrophil chemotaxis which is important for inflammation.

b. Dihydrofolate reductase is inhibited at slightly higher dose. It is also required for DNA and RNA synthesis and blockage of  lymphocyte and macrophage functions and chemotaxis occurs.

c. Apart from this, there is evidence that methotrexate also blocks proinflammatory cytokines like interleukins, which are proinflammatory.

d. Decreases proliferation of immune inflammatory cells

e. Apoptosis of immune inflammatory cells.

Side – Effects

1. Nausea
2. Stomatitis
3. Mucosal ulcers
4. Hepatotoxicity, chances of cirrhosis are minimal
5. Bone marrow suppression (thrombocytopenia, neutropenia)
6. Hypersensitivity lung reaction leading to shortness of breath, managed by withdrawing the drug.
7. Pseudolymphomatous reactions.

GI and liver function abnormalities can be decreased by:

1. Using leucovorin -24 hours after weekly dose
2. Using folic acid daily, but may also decrease efficacy of methotrexate

Uses

50-70% of patients diagnosed with rheumatoid arthritis –main stay

Not only for these, but also for other connective tissue disorders like:

1.  SLE,
2. Wegener granulomatosis
3. Psoriatic arthritis

Gold Salts

Two parenteral preparations are available:

1. Aurothiomalate
2. Aurothioglucose, contains 50% elemental content of gold.

Oral auranofin contains 29% elemental gold.

Gold combines with sulfhydryl groups, its affinity may be responsible for actions. It is also present in the tissues.

Mechanism Of Action

Various steps in inflammatory cascade are blocked by gold preparations.

1. Alteration of morphology and function of neutrophils and macrophages
2.   Lysozomal enzyme inhibition
3.   Inhibition of release of histamine
4.   Inactivation of complement system
5.   Inhibit release of PGE₂ and leukotriene b₄

Various aspects of inflammatory chemical mediators are blocked by gold salts.

Pharmacokinetics

Can be given I/M or orally (auranofin).

Tend to adhere to body tissues and get deposited in:

1. Synovial membranes of joints
2. Liver
3. Spleen
4. Kidneys
5. Lymph nodes

Because of this terminal half life is increased to one year.

Two-thirds of these gold preparations are excreted through kidneys

One-third through faeces (liver).

Side – Effects

Most patients exhibit some side effects. These include:

1. Skin rashes
2. Hematological (bone marrow) suppression
3. Proteinuria
4. Stomatitis
5. Mouth ulcers
6. metallic taste
7. corneal gold deposits
8. Nitritoid reaction, like nitrates, flushing because of vasodilatation of blood vessels of face, dizziness and hypotension. This is not because of gold, but because of the additives in preparation.

Auranofin causes dermatitis and diarrhea.

Sulfasalazine

Mechanism Of Action

Sulfapyridine and Sulfasalazine 5- amino salicylic acid combination splits in colon by bacteria, 5-amino salicylic acid exerts local inflammatory reaction in gut, used in inflammatory bowel disease.

In rheumatoid arthritis, both exert their effects. They do so by suppression of T and B cell function. One evidence is that when sulfasalazine is used, the antibodies levels decrease.

Decreased I_gA and I_gM.

Side Effects

1. GI symptoms -Nausea vomiting
2. Skin rashes
3. Hematological suppression (aplastic anemia, thrombocytopenia, leucopoenia)
4. Hypersensitivity (with drugs having sulfa moiety)
5. Reversible infertility in males

Chloroquine And Hydroxychloroquine

Antimalarial drugs.

Mechanism Of Action

Quite different from antimalarial actions:

1. Decrease T cell responses (T lymphocytes)
2. Decrease chemotaxis (neutrophils, macrophages)
3. Stabilization of lysosomal membranes
4. Inhibition of DNA and RNA synthesis
5. Trapping of free toxic radicals

Used orally in arthritis.

Protein binding is low (about 50-60%).

Volume of distribution is very large, about 13000 liters because have special affinity for melanin containing tissues, where they get deposited.

Long term use, because of this effect, leads to retinopathy.

Antimalarials are used for short time.

Side effects

1. GI symptoms –nausea, vomiting, diarrhea
2. Ocular examination is recommended every 6-12 months, because of retinopathy.

Glucocorticoids

Used parentally, orally and locally (intra-articular injections) depending upon conditions.

Mechanism of Action

Have lot of anti-inflammatory actions, main are:

1. Block phospholipase A2

When disruption of cell membrane occurs, arachidonic acid is formed, utilized in lipo-oxygenase or cyclooxygenase pathways. Both are blocked.

Cyclooxygenase II isoform is not constitutive in most body tissues. It needs to be  induced by stimuli.

2. Block expression of cyclooxygenase II.
3. Prevent antigen antibody reaction
4. Inhibit release of histamine by mast cells
5. Stabilize lysosomal membrane
6. Lymphoid tissues regress under action of glucocorticoids (involution)

Side effects

Effect every tissue.

Cushing syndrome (moon like face)

TNF-alpha inhibitors

Etanercept- TNF inhibition- suppression of T-cell & macrophage function

Infliximab- chimeric antibodies

TNF alpha is one of the most important cytokine of chronic inflammation, modulates monocyte macrophage functions. As these drugs block this cytokine, they are very important for severe rheumatoid arthritis.

They can be given alone or in combination with methotrexate.

Inhibition leads to suppression of T cells (as activation requires antigen presenting cells, which are macrophages, so stimulation blocked) and macrophage functions.

Infliximab is also used subcutaneously (monoclonal)

Infliximab has 75% human and 25% mouse origin, thus consists of three chimeric monoclonal antibodies. It gets bound to both soluble and membrane bound TNF-alpha. Varied genetic origin, given slow I/V. It causes demyelinated syndrome and also infusion site reactions (due to anti-infliximab antibodies)

The problem is that TNF is very important cytokine involved in immune response to chronic inflammation. Bacterial infection (T.B) is aggravated by these agents. If there is a need to use one of these, person is thoroughly scanned for tuberculosis.

Chances of malignancy, lymphopoenia are enhanced by use of these agents.

These agents are recommended if all other drugs fail to bring remission. They are then given alone, or in combination with methotrexate.

Leflunomide

Prodrug, converted to active metabolite in liver. It inhibits dihydroorotate dehydrogenase. When inhibited, DNA and RNA synthesis is blocked.

T and B cell functions are also blocked.

Adverse effects

1. GI symptoms
2. Hepatotoxicity
3. Hypertension
4. Mild alopecia
5. Weight gain
6. Increased blood pressure

Cholestyramine increases excretion and clearance.

Abatacept

It decreases the activation of T cells by binding to CD 80 and CD 86 inhibiting CD 28 binding. Its dose depends on body weight:

1. Less than 60 kg -500 mg
2. 60-100 kg -750 mg
3. Above 100 mg -1000 mg

Adverse Drug Reactions

Increased risk of infections esp. URTI

Infusion site reactions

Anaphylaxis

Anti-abatacept antibody

Increased chances of lymphomas

Azathioprine

Its metabolite is 6-thioguanine which:

1. Decreases ionisinic acid synthesis
2. Decreases B cell and T cell functions
3. Decreases Ig production
4. Decreases IL-2 secretion

Pharmacokinetics

In presence of thiopurine methyltransferrase it is converted to active metabolite.

Uses

1. Rheumatoid arthritis.
2. Psoriatic arthritis
3. Reactive arthritis
4. SLE
5. Polymyositis
6. Behcet’s disease

Adverse effects

1. Bone marrow suppression
2. GI upset
3. Increased infection risk
4. Increased lymphomas

Cyclosporine

It regulates gene transcription and decreases IL-1 and 2 production, this inhibits macrophage T cell interaction, decreases T cells responsiveness and T cell dependent B cell functions

Pharmacokinetics

Incomplete and erratic absorption

Microemusion -20-30% bioavailability

Grapefruit juice increased bioavailability up to 62%

Metabolized by CYP3A.

Uses

1. Rheumatoid arthritis
2. SLE
3. Polymyositis
4. Dermatomyositis
5. Wegener’s granulomatosis