Biologic Drugs - by drdoc on-line
Infliximab - Remicade, Revellex
Biologic therapy has been the major development in the field of Rheumatology over the last 10 years. Several different drugs are now available. To understand the mechanism of these drugs, an understanding of the immune system is ideally required.(Click here to go to immune system review).
Monitoring of biologic therapy is required to assess response. Accordingly, we do joint counts and use questionnaires such as the health assessment questionnaire, and patient and physician global scoring. We measure, the C-reactive protein and sedimentation rate as an objective measure of inflammation. Various scores have been designed including the disease activity score --DAS, and disease activity index -SDAI. We follow these responses serially over time. This process is critical as an objective measure of response to the drugs.
Response scores have had been used in trials include the American College of rheumatology -- ACR, 20, 50, 70 percent responses. These imply that at least, that percentage of patients respectively will respond to the drug.
The responses of biologic drugs in trials have been largely consistent across all classes of drug. No major competitive trials have been done comparing individual agents, that shows superiority of one versus another. Almost all trials show approximately 70% ACR 20 response, 50% ACR 50 response and 20% ACR 70 response. What does differentiate the drugs however is side effect, administration mechanism, frequency of application and therefore choice of drug depends on individual factors. In addition, there are cost differences. However, all the drugs have considerable cost.
Reduction in radiological damage is now well documented in several trials of these drugs with a reduction in erosions and the effect on bone. This has been one of the most interesting benefits of the use of biologic drugs.
Drug Mechanism Administration Infliximab, Remicade, Revellex Anti TNF chimeric antibody Intravenous infusion Etanercept, Enbrel Recombinant soluble TNF receptor fusion protein Subcutaneous injection. Adalimumab, Humira anti-TNF Subcutaneous Injection Anakinra, Kineret Interleukin-1 receptor antagonist Subcutaneous injection Abatacept, Orencia Co-stimulant antagonist CTLAV4-Ig fusion protein Intravenous infusion Tocilizumab, RoActemra, Actemra Interleukin 6 receptor antagonist Intravenous infusion Rituximab, Mabthera Anti CD20- B-cell antagonist Intravenous Infusions
Agents that oppose the action of tumour necrosis factor
The introduction of Tumor necrosis factor / monoclonal antibody therapy has been extremely exciting. tumour necrosis factor is one of the key mechanisms of inflammation (Click here to go to immune system review). Mechanisms to antagonize the effect of tumour necrosis factor, include either a direct binding of a synthetic molecule or antibody to Tumour necrosis factor. Or secondly, prevention of tumour necrosis factor reaching the receptor of the cell by utilizing circulating receptor.
The drugs in this class of drugs have a potential to cause potent immunosuppression. This provides long-term issues such as susceptibility to infection. These infections include the potential for unusual infections such as tuberculosis or fungal infections. In Africa we have high levels of tuberculosis in our community. Here and even worldwide, we screen for tuberculosis before considering using this form of treatment. This includes x-ray of the chest and skin testing. If skin testing is positive, we initiate treatment for latent tuberculosis, ideally, for one to two months before starting treatment. This includes isoniazid -- INH and possibly rifampicin therapy. This treatment would then be continued for up to six months concurrent with the anti-tumor necrosis factor therapy. Other infections, that may be aggravated by the drugs include upper respiratory infections, sinus infections, fungal infections, and histoplasmosis and pneumocystis lung infections.
Other side effects, and to this group include the potential for malignancy, such as lymphoma. This is controversial, as multiple studies suggest that the underlying autoimmune diseases such as rheumatoid arthritis, also potentially cause lymphoma. Concurrent use of these drugs with pre-existing malignancy is controversial, and has to be considered depending on the individual patient.
Infliximab is a antibody to the tumour necrosis factor itself. However, it consists of mainly human construction, but there is a small mouse component to the antibody. This aggravates allergy problems. The drug is given as a fusion at baseline, two weeks, four weeks, eight weeks and then every eight weeks thereafter. Infusion centres are required as the is a potential for allergy during the infusion, which can be either mild such as rashes or severe. This includes a potential for anaphylaxis, including bronchospasm wheezing or circulatory collapse. Therefore I personally premedicate the patient with hydrocortisone 100 mg and phenergan 25mg intravenous antihistamine. This prevents an infusion reaction. The use of Phenergan does cause some drowsiness, and therefore I instruct the patient not to drive home afterwards. Successive infusions, frequently are associated with reduced risk, but a healthy respect for the drug is required by the practitioner.
The dose is 3 mg per kilogram for rheumatoid arthritis and 5 mg per kilogram for spondyloarthropathy or inflammatory bowel disease.
The drug is given with a biological filter. It is given as a slow infusion. Supervision of the patient is required at all times. The results of the treatment excellent and noticed rapidly by the patient. Some people even notice some benefit within hours.
However over time, the effect of the drug sometimes reduces and more frequent infusions or higher doses may be required.
An additional problem is the development of antibodies to the drug. Therefore, to prevent this co-use of methotrexate with infliximab is recommended. The methotrexate is used in the standard weekly oral method. Blood tests are therefore required to monitor the methotrexate, as per usual. Trials show superiority of methotrexate with infliximab compared to infliximab alone.
Further, if patients stop infliximab for whatever reason, the effect of antibodies on the drug builds up and reintroduction of the drug after several months fails frequently to produce any response.
An alternative to direct anti- tumour necrosis factor antibody a natural mechanism exists, of soluble Tumor necrosis factor receptors circulating in solution to oppose circulating tumour necrosis factor. Synthetic production of this circulating tumour necrosis factor receptor has been successfully processed by joining two molecules together as a fusion protein.
Enbrel consists of 2, P-75 TNF receptor proteins and human immunoglobulin, joined at the Fc portion. The process of joining two receptor molecules effectively increases the half life of the molecule. Natural circulating TNF receptor has an extremely short half life and cannot be used therapeutically.
Enbrel is given as an injection subcutaneously, twice a week. The drug is provided as a powder and fluid that requires to be mixed by the patient before injection. Co-use with methotrexate, has also been shown to be beneficial.
Side-effects of the drug concluded standard anti-TNF concerns, such as risk of infections. Injection site reactions and allergies are common and are usually minor. Sinus and upper respiratory tract infections are relatively common, but usually mild. Severe infections require cessation of drug. Other extremely rare side effects include a demyelination syndrome similar to multiple sclerosis.
On the whole, the drug is easy to use and patient friendly. Response rates are excellent and similar to other anti-tumor necrosis factor drugs. The drug has been used in rheumatoid arthritis and spondyloarthropathy including ankylosing spondylitis and psoriasis. It has been used with wide experience in juvenile arthritis.
Humira is a humanised antibody to Tumor necrosis factor, and has no mouse or foreign component, and therefore has less allergy. It is given as an injection of 40 mg subcutaneous every two weeks. The pre-filled syringe requires no reconstitution by the patient and is very easy to give by the patient. The injection has some problems with local allergy and has been described as slightly painful by some patients. Results however are excellent, rapid and similar to other anti-TNF drugs. Side-effects are also similar with chronic infection such as tuberculosis recurrence the major concern, as with other anti-TNF drugs. co-use with methotrexate is not thought to be as important as compared to etanercept or infliximab. The drug has been used in both rheumatoid arthritis as well as the spondyloarthropathy and juvenile forms of arthritis.
This is a B-cell targeting therapy. It is a genetically engineered anti CD 20 monoclonal antibody that selectively targets CD 20 positive B-cells. CD 20 positive B-cells do not include the stem cells or the mature of plasma cells which make the antibodies. Therefore existing immune response persists. Binding to the B-cell triggers damage and apoptosis or death of CD 20 positive B-cells.
The drug has largely been used after a failure of tumour necrosis factor drugs, and therefore is thought to be a second line of biologic therapy. Recent evidence however suggests that the failure of response still allows reintroduction of anti-TNF therapy.
Trials of Rituximab have been done in patients with rheumatoid arthritis in particular. The drug is given as an infusion of 1000 mg on day 1 and a day 15, and is usually followed with a second series of infusions after six months.
The drug has a allergic potential, including that of anaphylaxis, and requires supervision and monitoring in an infusion centre or high care facility. Because of the risk of allergy, I premedicate my patients with hydrocortisone 100 milligrams and Phenergan -- antihistamine 25 mg before the infusion. This prevents incidence of allergy. Subsequent infusions produce reduced risk of allergy.
Side effects include infection risks. However, the risk of chronic infection such as tuberculosis does not exist with this group of therapy, which gives it a major advantage in areas of high tuberculosis prevalence.
Studies showed that the B-cell levels drop within three weeks. Response to treatment is similar overall to the anti-TNF drugs, with 70% ACR 20, 50% ACR 50 and 20% ACR 70 responses. Radiographic progression is inhibited. The response to the drug may last several months before repeat infusion is required.
This drug has a different mechanism to other biologic drugs. This opposes co-stimulatory molecules which assist with binding of immune cells to T-cells. CDs, 28 is one of the surface markers on a T-cell, that assist with binding of CD 80/CD 86 surface markers of antigen presentation cells to the T-cell. This facilitates the immune response. Abatacept consists of immunoglobulins bound to CTLA4, which binds to CD80/CD86, and prevents or suppresses T-cell activation. The drug is given as a 30 minute infusion at baseline, two weeks, and thereafter every four weeks. Responses are similar to other biologics. It is largely used for patients with inadequate response to anti-tumor necrosis factor therapy -- as a second line approach. Side effects include infections such as respiratory or urine tract infections, and also tuberculosis is a potential problem similar to other anti-tumor necrosis factor drugs. The side effects are therefore similar to all other biologic drugs.Tocilizumab -- RoActemra
Tocilizumab is one of the newest biologic drugs, and one of the most exciting. It consists of an anti-IL-6 mechanism. Tocilizumab is an anti-IL-6 monoclonal antibody. IL-6 is closely involved in the cytokine or immune mechanism network in inflammatory arthritis. It is also associated with the mechanisms of osteoporosis, and erosion formation by the stimulation of RANK Ligand. (Receptor activator of NF Kappa beta), which stimulates the osteoclast activity in bone. It also stimulates the liver to produce acute phase proteins such as C. reactive protein, CRP.
Therefore, IL6 antagonism is theoretically a direct opposer of the immune mechanism of rheumatic disease, and associated bone damage. Trials show and confirm a reduction in joint inflammation activity, with good response to rheumatoid arthritis inflammation. There is a 70% ACR 20, 40% ACR 50 and 20% ACR 70 response in trials.
The dose is 4 mg per kilogram to 8 mg per kilogram of Tocilizumab. It is given as an infusion every four weeks. Reduction in CRP levels is noted. Improvement in hemoglobin is observed and a reduction in bony erosions and joint damage confirmed.
However, as expected, the same side effects are observed as with other biologic drugs, with infections being the major concern. Elevation in lipid and cholesterol parameters are observed. A reduction in white cell and platelet counts has also been observed. Caution is therefore required in patients with low white cell count and low platelet count. Mild increases in liver enzymes have been observed and liver function test monitoring for the first six months is advised on two monthly basis.
Remission data suggest that long-term remission is possible.
Because this drug is used in patients who have failed anti-tumor necrosis factor therapy, studies have shown that responses to Tocilizumab reduced the greater the number of TNF drugs that had been used and failed in the past.
Co-treatment with methotrexate is not required, but preferable. If used with methotrexate, standard monitoring of methotrexate is required over time..
Once every 4-8 weeks
Once every 1-2 weeks
Twice every 6-12 months
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