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Infliximab (Remicaide in USA) / (Revellex in South Africa), is a Chimeric antibody including human and mouse component.It acts by blocking the molecular system that drives the immune response - Tumour necrosis factor. This prevents binding to receptor and triggering the immune response. They constitute one of several new Biologic agents available for the treatment of inflammatory Rheumatic diseases, such as Rheumatoid arthritis and the seronegative spondyloarthropathies.These Biologics include Infliximab, Etanercept (Enbrel), Adalimumab anti TNF agents, and Anakinra, an IL-1 receptor antagonist.

Cytokines in immune disease

	The immune response is characterised by a balance of chemical messengers called cytokines, that are made by inflammatory cells that promote other cells to increase or decrease the immune cascade respectively. Hence there is a proinflammatory as well as an antiinflammatory effect. In autoimmunity there is a predominance of the cytokines that increase inflammation, as opposed to those that reduce the inflammatory response.
TNF is one of the main promoters of the immune cascade. The TNF molecule binds to a specific receptor at the cell surface that then triggers a response within that cell, thereby activating it and promote the cell to either divide or to produce further cytokines that direct even further cells to activate. The result is an enhanced immune response.
Infliximab is an antibody designed to bind to TNF that is in circulation, thereby preventing TNF from binding to the surface receptors and hence preventing the immune response.
Etanercept is a fusion protein of two receptor molecules in solution, soluble TNF receptor, that thereby prolongs the half life or survival time of the circulation receptor, and binds TNF in solution, hence preventing the immune response

There were an estimated 365201 people on Infliximab by August 2002.

Trials done since 1995. The 102 week data have been released and look extremely attractive.
These trials were done originally on resistant patients looking at several criteria for improvement.

Patient assessment
Physician assessment
HAQ - health assessment questionnaire - looking at function in daily life
ACR 20 - an index endorsed by the American college of rheumatology - looking at activity of disease
Radiological progression.

Results show a dramatic improvement in:

CRP
ESR
Joint tender and swollen counts
Stiffness
Improvement in the HAQ.
Radiological progression

Response tends to plateau at 1 year and then persists with maintenance infusions.

Radiological scores of patients with early Rheumatoid arthritis over 102 weeks

Dose studies suggest:

Standard recommended dose 3mg/ kg
Given as a initial infusion and then repeat infusions after 2 wks...after a further 4 wks....then 8 weekly

However the lack of response can be addressed by either increase in dose to 10mg / kg or increasing dose frequency to monthly instead of 2 monthly. There is however problems with price and funding by medical funds.

Antibody to drug:

Because the drug has a foreign protein content - related to the mouse component, there is a resulting development of an antibody to the drug itself. This has several clinical relevancies.
1. Incidence of the antibody seems to increase with intermittent use as opposed to regular maintenance infusions.
2. The use of maintenance dosing results in lower antibody production over time.
3. The co-use of immunosuppression therapy or cortisone reduces the development of antibodies.
4. There is a link between the incidence of reactions to the drug and the levels of antibodies.
5. There is no clear link between serious reactions i.e. anaphylaxis / collapse, and the levels of antibodies.
6. There does not seem to be a reduction in clinical response and level of antibody.

Antibody production and time on drug

Antibodies and clinical response

Reactions over 102 weeks

Serious reactions over 102 weeks

Infusion reactions over 102 weeks comparing background medications

Adverse events

Drug reactions

Serious infusion reaction - rate is approximately  0.8%
Overall infusion reaction 4.8%
Over time there is no increase and the overall potential for reaction remains the same. Previous reaction does not clearly increase risk of another reaction although caution may be required.

Delayed reactions (delayed hypersensitivity reaction) can occur rarely - arthralgia, myalgia, fever, and rash - approximately 2-4% of patients

Headaches
Upper respiratory infections
Sinusitis
Lupus like syndrome is reported infrequently, but is reversible. There is no relationship between those people who are antibody positive and those who develop the syndrome. In those patients who have ANF positive there is no contraindication to use. In fact studies are published regarding treatment of lupus by infliximab. There appears to be a difference between drug induced Lupus and primary Lupus.

Serious adverse events include

Pneumonia 0.9%
Tuberculosis 0.2%
Congestive heart failure 0.4%
Deep vein thrombosis 0.4%
Mortality 0.5% (TB / Pneumonia / CCF)
No cases of demyelination and aplastic anaemia.
Lymphoma and malignancy 

Lymphoma is reported.:
4 / 555 patients on infliximab in the Rheumatoid studies
3 / 1106 in the Crohns studies. 
However, these diseases are associated themselves with this disease and there is no direct causative association with the drug. Rheumatoid arthritis is reported alone to increase risk of lymphoma by up to 23 fold (in one study), compared to average population. 
Most studies show approximately 2-3 times average risk. 
This increases with immunosuppression. However ongoing studies and vigilance continues.
The risk therefore remains a possibility but not confirmed.

In 18000 patients followed in an open follow up study there was a marginally increased rate compared to patients off biologic drugs (although the patients on biologics were suffering from much worse disease).

Incidence of lymphoma in 18000 patients over 4 years

Drug status	Number of patients	Cases with lymphoma	Increased risk
No Methotrexate / Etanercept/Infliximab	3504	5	1.3
Methotrexate	6396	10	1.5
Infliximab	6465	9	2.6
Etanercept	3381	8	3.8

Increased mortality is not observed, compared to the background observed level in average patients not on therapy.

Tuberculosis

Tuberculosis (TB), is an ongoing concern especially in the third world such as south Africa where there is a high incidence of Tuberculosis. Of the estimated 554372 patient years experience on infliximab there are increased numbers of TB reported. 2/3 of cases occur within the first 3 infusions. There is a 11% mortality. 
There is an inability to form tuberculous granulomata -and hence reduced defense to the TB. 

63% are pulmonary TB
23% Miliary widespread TB.
22% lymph gland involvement.

Screening is hence required before starting as most cases are REACTIVATION of latent previous disease. Since screening commenced, the incidence has dropped. This is noted in the USA where incidence of TB is now dropping in patients on infliximab.

Guidelines are provided by the South African Rheumatism and arthritis association (SARAA) regarding aspects of TB and the biological drugs such as infliximab.
(Go to guidelines on the use of infliximab)

Use in Other disease.

1. Ankylosing Spondylitis.

Approval has been obtained by US and European health regulatory authorities for use in Ankylosing spondylitis. Psoriatic arthritis data is also positive, but not yet licensed for "on label" use. 
Clear effect is seen in reduction in stiffness, swollen joints and enthesitis points.
Onset of benefit is rapid by 6 weeks and then maintained.

2. Psoriatic arthritis.

Excellent responses are seen in almost 100 percent of cases with response to skin disease.
50% improved by at least 75% improvement at week 10.
100% improved by at least 20 and 50% at week 10. 
Responses seem particularly impressive in psoriasis.

No increased adverse events were noted.

3. Inflammatory bowel disease.

Use in Crohns disease and ulcerative colitis is now well established at a higher infusion dose 5mg / kg.

4. Juvenile arthritis.

Phase 3 studies are in progress but there is not a lot of data other than anecdotal studies. Efficacy however appears excellent.