Biologic drugs

History of biologic drugs and why they are important


In the last 15 years there have been great advances in the way that we treat inflammatory diseases, including many forms of arthritis such as rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis.
This is important for patients who do not have a good response to more traditional medications for inflammatory arthritis (eg DMARDs; see BSR Patient Information on DMARDs). It gives new hope to those with very severe and aggressive disease.


What are ‘biologic’ drugs?


Biologic drugs are large complex protein molecules designed to block aspects of the immune system, depending on what disease they are treating. There are a number of different types of biologic drugs used in various branches of medicine including cancer treatment, rheumatology, gastroenterology, dermatology and increasingly other areas. Biologics are expensive to produce and therefore only used in severe disease after other more traditional drugs have not worked or are not tolerated.


Who can take biologic drugs?


Whilst biologic drugs are often very effective they do not cure any of the conditions mentioned and the treatment is long term. Biologic drugs are expensive and can cost up to £10,000 per patient for one year of treatment for each person treated. There are strict NHS rules for prescribing biologic drugs. The National Institute for Health and Care Excellence (NICE) provides guidelines to which each Rheumatology Department and Hospital must adhere.


How will I be assessed specifically for biologic drug treatment in the NHS?


To be eligible for treatment with biologics in the UK, NHS patients must have tried and not responded to traditional treatments and have persistently bad arthritis. Your Rheumatologist then has to consider if it is safe for the specific biologic to be prescribed. You and your Rheumatologist will then have to balance the risks and benefits of biologic drug treatment for you. Furthermore, detailed assessments will need to be made regularly to ensure the biologic drug is still working sufficiently against your arthritis. If not there are rules that it should be stopped.


What different types of biologic drugs are there?


This is an area of constant research and development and it is one of the most exciting areas of medicine. Biologic drugs are designed to target small molecules which are important in causing the diseases.


How do you take Tumor Necrosis Factor alpha inhibitors (TNFi) drugs?


Most TNFi drugs are given by injection under the skin on either the upper leg or tummy. Patients learn to do this at home using a pen device or needle and syringe. The injections are given at different intervals depending on which drug is used (Humira and Cimzia once a fortnight, Enbrel once a week and Simponi once every month). Remicade (and the new generic Infliximab versions) is given by an intravenous infusion via a cannula in the arm and therefore can only be given in a hospital. In rheumatoid arthritis TNFi drugs are usually taken in combination with methotrexate.


Will TNFi drugs work immediately or is there a delay like with Disease Modifying Antirheumatic Drugs (DMARDs)?


Typically people who benefit from TNFi drugs, do so reasonably quickly, within the first few weeks. This is unlike with DMARDs which can take 2-3 months to start working well.


Types of biologics


Rituximab


Rituximab (Mabthera) is a monoclonal antibody, which works by blocking a protein on B (lymphocyte) cells. B cells are often abnormally overactive in some inflammatory and autoimmune conditions and they can start to interact with other parts of the immune system to attack the body causing inflammation which then causes symptoms such as joint inflammation and stiffness in rheumatoid arthritis for example. Treatment with rituximab leads to deactivation and removal of some of these overactive B cells.


How is Rituximab given?


Rituximab is given by intravenous infusion and therefore can only be given in hospital. Two infusions are given – once a fortnight after the other. Usually Rituximab treatment is combined with a small dose of intravenous glucocorticoid (methylprednisolone) and an antihistamine. The treatments, each visit, takes about half a day but they can be speeded up for later infusions if all goes well.


What are the side effects of Rituximab?


Sometimes blood pressure can drop during the infusions and other side effects like aching, itching, sore throat, or dizziness can happen during the infusion or soon after. Infusion nurses will monitor the situation carefully. Often slowing the rate of the infusion can help.


Will Rituximab work immediately or is there a delay before it’s effect?


After the first two infusions, the response to the medicine is reviewed at 3 months. If there is a good result rituximab can be given again after at least 6 months. Often the rheumatologist will wait until the return of some rheumatoid symptoms before redosing and the effects of one course can be as long as 9 months or a year. According to guidelines rituximab is always recommended to be given with methotrexate. Sometimes other medicines like sulfasalazine will be given instead of methotrexate.


Abatacept


Abatacept (Orencia) is the only biologic drug of its type approved in the UK for rheumatoid arthritis. It blocks inflammation by attaching to the surface of specific cells of the immune system (T cells). This stops the immune cell from signalling other parts of the immune system to create inflammation.


How is Abatacept taken?


It can be given either as a drip or infusion into the vein in hospital every 4 weeks or as an injection under the skin in either the upper leg or tummy by the patient at home each week using a needle and syringe. Abatacept should usually be given in combination with methotrexate.


Tocilizumab


Tocilizumab (Roactemra) is another unique biologic; it blocks a cytokine (chemical messenger) called interleukin 6 (IL6). IL6 is an important cytokine in rheumatoid arthritis which switches on inflammatory immune cells and switches off antiinflammatory cells. Tocilizumab stops IL6 from binding to immune cells in the first place therefore reducing inflammation. This has an effect on the joint inflammation in RA, the stiffness, tiredness and also helps correct the anaemia (low red blood cells) associated with RA.

Tocilizumab also works and is approved for some forms of juvenile idiopathic arthritis (JIA) in children. There is evidence that tocilizumab can reduce and stop the bone damage associated with RA.


How is Tocilizumab given?


Tocilizumab can be given either by infusion into a vein every four weeks or by injections under the skin of the upper leg or tummy every week.


Is infection the most common side effect of biologic drugs?


Yes. All the biologic drugs work by altering a patient’s immunity and all increase the risk of infection. They can also mask the signs of infection, such as fever, and in the case of tocilizumab the blood tests (CRP) which normally goes up during infection can remain normal. It is important to report to any doctor what drugs you are on, including DMARDs but especially biologics, which are prescribed by the hospital and not by the GP.


What should I do if I get an infection while taking a biologic drug?


If you have an infection it is recommended that you stop your biologic drug and discuss the matter with your Rheumatologist either directly or through the Multidisciplinary Rheumatology team (e.g. via the Helpline telephone talking to a practitioner).


Do I need the winter vaccinations if I am taking a biologic drug?


It's advisable for patients taking biologics to have the winter flu vaccination each year and if necessary to be brought up to date with the pneumovax vaccination. Please discuss this with your GP surgery staff. Your Rheumatology practitioner can advise further.


Is any blood test monitoring required?


Periodically there will be a need for blood tests to monitor for any (usually infrequent) problems of bone marrow suppression (low white cell count or platelets for example). There are guidelines your Rheumatology Department will follow in determining when to do these tests – which you should be used to from when you have been taking other Rheumatology drugs. For Tocilizumab tests can initially be quite frequent, but for all Biologics, the frequency of testing is not great once you are established on the Biologic.

Other infection risk issues with biologic drugs


Tuberculosis (TB risk). There are some specific infection risks with individual drugs. With TNFi drugs there is an increased risk of becoming unwell if exposed to TB and of TB becoming active if a patient was exposed to it before and has not cleared it properly. The rheumatology team will assess the risk of this before you start your biologic drug. Patients who have been fully treated for TB can still be treated with TNFi drugs.

Chicken Pox and Shingles. If you have never had chicken pox and you then come into contact with someone with chicken pox or think you have it, you should contact your GP and rheumatology multidisciplinary team immediately as a special treatment HVZ Ig may be recommended. If you have previously had Chicken Pox and you develop shingles (your old chicken pox reactivating) then prompt treatment with acyclovir is needed and your biologic will probably need stopping temporarily, so talk immediately to your GP and Rheumatology Multidisciplinary team.


Are there specific side effects from the self injected biologic drugs?


Injection site reactions are not uncommon for the biologic drugs self-administered (subcutaneous injection). The reactions are often mild and may lessen with repeated doses. The symptoms are often redness, itching, bruising, pain and swelling at the injection area. Simple measures such as a review of injection technique with the nurse, application of ice, taking pain killers, the use of mild steroid cream, tea tree oil and rotating the site of injection usually help. Rarely do patients need to stop their drug and switch to a different biologic because of this.


The risk of Progressive Multifocal Leucoencephalopathy (PML) with Rituximab


PML is a viral infection of the brain called progressive multifocal leucoencephalopathy (PML). It is very rare. The risk of PML can be increased with rituximab treatment; however, it is still a very rare finding in patients having treatment. Symptoms of PML include severe dizziness, altered vision and confusion. After each infusion you will be given an alert card about the risk of PML.


Is there a risk of cancer from biologic drugs?


There is a theoretical increased risk of cancer with some biologic drugs. The issue is being monitored in the UK as elsewhere in the world by registering the details of some people taking biologics on a central database (eg in the UK, the BSR-BR). However, there is no evidence in the registries (of thousands of patients receiving biologic drugs over the last 10 years) of an increased risk of the major cancers (solid tumours e.g. breast, prostate, lung, bowel) specifically for TNFi drugs. There is however a small increased risk from certain types of skin cancer with TNFi drugs, which can be treated successfully when diagnosed early.

It is important to remember that rheumatoid arthritis itself is linked with an increased risk of cancers compared with the general population and that is why the proper data is vital in informing the answer to our questions about cancer in Rheu-matological disease and from its treatment. Because we don’t know the effects of very long term treatment with biologics their use is considered only for patients who have not responded to other treatments and who have severe disease.


Can I have a biologic drug if I have a history of cancer?


In the UK it is recommended that patients who have had a cancer within the last 10 years do not start TNFi drugs, abatacept or tocilizumab. Rituximab is allowable however, and is in fact used to treat some forms of cancer – specifically lymphoma.


New biologic drugs are being developed all the time. Is there on going surveillance for cancer from these new drugs?


UK Doctors are continuing to provide information on cancer in patients taking TNFi drugs to the UK registry (BSR-BR). Data about some new biologics is being added as drugs are approved. The main UK database for this has been for patients treated for Rheumatoid Arthritis. There is now also a database for TNFi treatment for Ankylosing Spondylitis and for Psoriatic Arthritis. Other countries around the world have similar databases and the data from all of these is published regularly.


Can biologic drugs cause other diseases?


TNFi drugs have been linked with causing a type of Systemic Lupus Erythematosis (‘lupus’), and form of demyelination like multiple sclerosis. The risks of these are very low overall. If these conditions develop then typically when the TNFi is stopped the condition stabilises or resolves and effects from it are usually minimal.


What are other side effects of biologic drugs?


There are other less common side effects associated with each of the biologic drugs. Your doctor or nurse will go through these with you and they are in the patient information leaflets for each drug. Side effects may include: rashes, raised cholesterol, temporarily abnormal liver function, low white blood cells and infusion reactions.


Do biologic drugs affect fertility?


As far as we know biologic drugs do not affect future fertility potential of a man or a woman. If you wish to get pregnant (or if male want a family with your partner) then discuss the matter as early as you can with your Rheumatologist.


What is the evidence for use of biologic drugs in pregnancy?


There are reports of some of the biologic drugs being used in pregnancy (ie women falling pregnant without planning while taking a drug) with no problems for the mother or baby. The decision to continue or withdraw biologic drug treatment for a woman is made between the patient and Rheumatologist. The decision is based on the balance of biologic drug risk and the increased risks of the arthritis flaring up severely again during or just after pregnancy without the drug.


Are there any special dietary precautions if I am taking a biologic drug?


There is an increased infection risk with biologic drugs. Infection can be food-borne and particular care is advised when preparing, cooking and storing food. To reduce the risk of Listeria and Salmonella infections:

  • Only eat soft cheeses if the labels clearly states they are made from pasteurized milk;
  • Avoid refrigerated pâtés or meat spreads. Canned or shelf-stable pâtés and meat spreads are OK;
  • Avoid drinking unpasteurized milk and eating raw eggs;
  • Cook the food to the recommended temperatures;
  • Avoid eating hot dogs, luncheon meats or delicatessen meats, unless reheated until steaming hot.

To conclude, if you are in any doubt speak with your Rheumatology team.