Anti-TNFa Treatment in Rheumatoid Arthritis

What is TNFα?

Tumour necrosis factor alpha or TNFα is a cytokine. Cytokines are substances released by the body during inflammation. Inflammation is a normal process generated by the body to fight against harmful bacteria and viruses. Normally, this inflammation is controlled and regulated. In rheumatoid arthritis this process breaks down, therefore the joints of patients with rheumatoid arthritis become inflamed. An excessive amount of TNFα is present in the blood and joints of patients with rheumatoid arthritis. Research has shown that excessive production of TNFα can lead to inflammation and damage to joints. TNFα is a particularly powerful cytokine because it causes the release of other cytokines from the body (such as IL1 and IL6). Blocking TNFα can reduce inflammation and joint damage.

Currently, there are five licenced treatments, etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia) and golimumab (Simponi) that can block the effect of TNFα.

NICE Guidelines

The National Institute for Clinical Excellence (www.nice.org.uk) has assessed and approved the use of these TNFα inhibitors to treat patients with rheumatoid arthritis in accordance with the British Society for Rheumatology guidelines. As these drugs are very expensive, NICE have looked at the cost versus the effectiveness of the drugs, and though they have approved them, patients need to meet the following criteria to be deemed eligible to start anti-TNF treatment:

  1. The patient must have tried at least 2 of the standard DMARDs (such as methotrexate, sulfasalazine, hydroxychloroquine and leflunomide) and one of these must be methotrexate.
  2. The level of disease (measured using an assessment called ‘disease activity score’ or ‘DAS’) should be above 5.1 on two occasions, one month apart. DAS is calculated by a combination of factors, including assessing 28 joints to see if they are swollen/tender and looking at the levels of inflammation showing up in your blood. (click here for more information on DAS).

Etanercept (Enbrel)

1.What is etanercept (Enbrel)?

Etanercept is a man-made protein that is made by joining two human proteins together. One of the proteins is normally found in the joints of patients with rheumatoid arthritis. It binds to TNFα and stops it from causing inflammation although it is not present in sufficient quantity to neutralise all the TNFα in the joint. Furthermore, it only stays in the body for a short time. Therefore, it was joined to another human protein so that it stays longer in the body to neutralise the effect of TNFα.

2. What is the benefit of taking etanercept (Enbrel)?

Etanercept (Enbrel) is used to reduce signs and symptoms of rheumatoid arthritis and to reduce joint damage in patients with moderate to severe disease. In clinical trials, two thirds of patients receiving etanercept had at least a 20% improvement after treatment for 3 months, which included reduction in pain, stiffness and the number of inflamed joints. Many patients were better able to perform daily activities such as dressing, walking, getting out of bed and performing daily chores. In some patients, it can work as early as two weeks but in most people maximum benefits occur within three months.

3. How is etanercept (Enbrel) given?

Etanercept (Enbrel) is given by subcutaneous injection (injection underneath the skin) twice a week or weekly. Injections can be given by patients or their carers after a period of training. Etanercept (Enbrel) can also be given together with methotrexate, especially in patients whose disease is inadequately controlled by methotrexate alone.

4. What are the possible side effects of etanercept (Enbrel)?

One of the most frequent side effect of etanercept (Enbrel) is mild local skin irritation at the injection sites.

Serious infections have been reported in a few patients using etanercept (Enbrel). Patients who were particularly prone to infections, such as those with advanced or poorly controlled diabetes are more at risk. Etanercept (Enbrel) should be stopped immediately if a patient develops a serious infection. It is also inadvisable to start on etanercept when a patient has an infection of any type. If you develop an infection while receiving etanercept (Enbrel), you should contact your physician.

There have also been rare reports of serious blood disorders. Please inform your doctor immediately if you develop symptoms such as persistent fever, bruising, bleeding, paleness, pain, muscle weakness, numbness and blurred vision. It is unclear whether etanercept (Enbrel) is the cause of these disorders but your doctor may advise you to stop using etanercept (Enbrel).

Other rare side effects that have been reported include the development of conditions such as systemic lupus erythematosus (SLE) and multiple sclerosis (MS).

5. Caution in taking etanercept (Enbrel)

We do not know the long term side effects of etanercept (Enbrel). Usually, your doctor would try you on standard treatments first before considering using etanercept (Enbrel). There are other situations when your doctor would advise against giving you etanercept (Enbrel). These include patients with severe heart failure, pregnancy or mothers who are breast-feeding, infection and tuberculosis or cancer in the past. Etanercept (Enbrel) can reduce the effectiveness of vaccines: if you are planning to have vaccinations, please inform your doctor first.

6. What if I am thinking of getting pregnant?

No one knows the risk of etanercept (Enbrel) to an unborn baby (though reports of unexpected pregnancies while on Enbrel have resulted in normal births). If you are a woman of child-bearing age, you must use contraception while on etanercept (Enbrel). If you are thinking of becoming pregnant in the near future or if you are not using contraception, please discuss treatment with etanercept (Enbrel) with your doctor.

Infliximab (Remicade)

1.What is infliximab (Remicade)?

Infliximab (Remicade) is a manufactured "antibody". Antibody is normally produced by the body to fight against harmful bacteria but infliximab (Remicade) has been designed to bind to TNFa and prevent it from causing inflammation.

2. What is the benefit of taking infliximab (Remicade)?

Infliximab (Remicade) is used to suppress inflammation in patients with active rheumatoid arthritis. It must be given together with methotrexate. If you cannot take methotrexate because of side effects, your doctor may not be able to prescribe infliximab (Remicade).

3. How is infliximab (Remicade) given?

Infliximab (Remicade) is given by intravenous infusion (by a drip into a vein) and must be given in a hospital. Each treatment is given over 2 hours and you will need to wait for another two hours afterwards before you can go home. You will have further doses of infliximab (Remicade) 2 and 4 weeks after the first treatment. Thereafter, you will have treatment every 8 weeks.

4. What are the possible side effects of infliximab (Remicade)?

Common side effects of infliximab (Remicade) include a blocked or runny nose, headache, dizziness, flushing, rash, abdominal pain or indigestion. Rarely, people may be allergic to infliximab in which case the drug will have to be stopped.

Serious infections, including tuberculosis, have been reported in a few patients using infliximab (Remicade). Patients who were particularly prone to infections, such as those with advanced or poorly controlled diabetes are more at risk.

Infliximab (Remicade) should be stopped immediately if a patient develops a serious infection. It is also inadvisable to start on infliximab (Remicade) when a patient has an infection of any type. If you develop an infection while receiving infliximab (Remicade), you should contact your doctor.

Rare side effects that have been reported include the development of conditions such as systemic lupus erythematosus (SLE) and multiple sclerosis (MS).

5. Caution in taking infliximab (Remicade)

We do not know the long term side effects of infliximab (Remicade). Usually, your doctor would try you on standard treatments first before considering using infliximab (Remicade). There are other situations when your doctor would advise against giving you infliximab (Remicade). These include patients with severe heart failure, pregnancy or mothers who are breast-feeding, infection and tuberculosis or cancer in the past. Infliximab (Remicade) can reduce the effectiveness of vaccines. If you are planning to have vaccinations, please inform your doctor first.

6. What if I am thinking of getting pregnant?

No one knows the risk of infliximab (Remicade) to an unborn baby. Since infliximab (Remicade) is given together with methotrexate, which is harmful to an unborn baby, if you are a woman of child-bearing age, you must use contraception while on infliximab (Remicade) and methotrexate. If you are thinking of becoming pregnant in the near future or if you are not using contraception, please do not take infliximab (Remicade) and methotrexate. It is recommended that women do not become pregnant and men do not try for a baby with their partner for at least six months after the last dose of infliximab (Remicade) and methotrexate.

Since infliximab (Remicade) could pass into the breast milk, mothers should not breast feed while on infliximab (Remicade).

Biosimilars: Since 2015, two “biosimilar infliximabs”, “Inflectra” and “Remsima” have become available in the UK. Both Inflectra and Remsima are monoclonal antibodies which are highly similar but not exactly identical to Remicade. Hence they are classified as “infliximabs”. In clinical trials in rheumatoid arthritis, Inflectra and Remsima produced the same benefit as Remicade. 

Adalimumab (Humira)

1.What is adalimumab (Humira)?

Similar to infliximab, adalimumab (Humira) is an antibody but it is fully human which means that it can be taken without methotrexate, though if methotrexate can be tolerated it will often be given alongside Humira.

2. What is the benefit of taking adalimumab (Humira)?

As with etanercept (Enbrel) and infliximab (Remicade), Adalimumab reduces pain and joint inflammation.

3. How is adalimumab (Humira) given?

Adalimumab (Humira) is given by subcutaneous injection (injection underneath the skin) either fortnightly or weekly. Your doctor will advise you on the correct dose.

4. What are the possible side effects of adalimumab (Humira)?

Common side effects of adalimumab (Humira) include injection site reaction. Rarely, people may be allergic to adalimumab in which case, the drug will have to be stopped.

Serious infections, including tuberculosis, have been reported in a few patients using adalimumab (Humira). Similar to other anti-TNF medicines, adalimumab (Humira) should be stopped immediately if a patient develops a serious infection. If you develop an infection while receiving adalimumab (Humira), you should contact your doctor.

Rare side effects that have been reported include the development of conditions such as systemic lupus erythematosus (SLE) and multiple sclerosis (MS).

5. Caution in taking adalimumab (Humira)

Similar to etanercept (Enbrel) and infliximab (Remicade), the same caution applies to adalimumab (Humira), in that the long term side effects of adalimumab (Humira) are unknown. Your doctor would advise against giving you adalimumab (Humira) if you have severe heart failure, pregnancy or mothers who are breast-feeding, infection and tuberculosis or cancer in the past. Adalimumab (Humira) can also affect vaccines: if you are planning to have vaccinations, please inform your doctor first.

6. What if I am thinking of getting pregnant?

No one knows the risk of adalimumab (Humira) to an unborn baby (though reports of unexpected pregnancies while on Enbrel have resulted in normal births). If you are a woman of child-bearing age, you must use contraception while on adalimumab (Humira). If you are thinking of becoming pregnant in the near future or if you are not using contraception, please do not take adalimumab (Humira). Mothers should not breast feed while on adalimumab (Humira).

Certolizumab Pegol (Cimzia)

1.What is certolizumab (Cimzia)?

Certolizumab pegol binds to the TNF cells in the same way as the other anti-TNF drugs, but uses a slightly different structure known as ‘PEGylation’. It can be given with or without methotrexate.

2. What is the benefit of taking certolizumab (Cimzia)?

As with the other anti-TNF medications, Certolizumab (Cimzia) reduces pain and joint inflammation.

3. How is certolizumab (Cimzia) given?

Certolizumab (Cimzia) is given by prefilled syringe injection underneath the skin. Normally, treatment starts with two (200mg) injections. This is followed by a further two injections at the same dose, two and four weeks later. After this, a maintenance dose of 200 mg given as one injection, every fortnight. Your doctor will advise you on the correct dose.

4. What are the possible side effects of certolizumab (Cimzia)?

Common side effects of certolizumab (Cimzia) are similar to other anti-TNFa medicines. Injection site reaction seems less frequent than etanercept (Enbrel) and adalimumab (Humira). Rarely, people may be allergic to certolizumab (Cimzia) in which case, the drug will have to be stopped.

Serious infections, including tuberculosis, have been reported in a few patients using certolizumab (Cimzia). Similar to other anti-TNFa medicines, certolizumab (Cimzia) should be stopped immediately if a patient develops a serious infection. If you develop an infection while receiving certolizumab (Cimzia), you should contact your doctor.

Rare side effects that have been reported include the development of conditions such as systemic lupus erythematosus (SLE) and multiple sclerosis (MS).

5. Caution in taking certolizumab (Cimzia)

Similar to etanercept (Enbrel) and adalimumab (Humira), the same caution applies to certolizumab (Cimzia), in that the long-term side effects of certolizumab (Cimzia) are unknown. Your doctor would advise against giving you certolizumab (Cimzia) if you have severe heart failure, pregnancy or mothers who are breast-feeding, infection and tuberculosis or cancer in the past. Certolizumab (Cimzia) can also affect vaccines: if you are planning to have vaccinations, please inform your doctor first.

6. What if I am thinking of getting pregnant?

Cimzia is the only anti-TNFa medicine that is thought not to travel from the blood stream of the mother into a baby growing in the womb. However, the use of any medication during pregnancy must be discussed very carefully with your specialist in light of your other medications and overall activity of your disease. Mothers should not breast feed while taking certolizumab (Cimzia).

Golimumab (Simponi)

1.What is golimumab (Simponi)?

Similar to adalimumab (Humira), golimumab (Simponi) is a fully human antibody, which means that it can be taken with or without methotrexate.

2. What is the benefit of golimumab (Simponi)?

Golimumab (Simponi) reduces pain and joint inflammation in patients with rheumatoid arthritis.

3. How is golimumab (Simponi) given?

Golimumab (Simponi) is given by injection underneath the skin either using a pre-filled syringe or injection pen every month. In some patients, the dose may need to be increased. Your doctor will advise you on the correct dose.

4. What are the possible side effects of golimumab (Simponi)?

The side effects of golimumab (Simponi) are similar to other anti-TNFa medications. Rarely, people may be allergic to golimumab (Simponi) in which case, the drug will have to be stopped.

Serious infections, including tuberculosis, have been reported in a few patients using golimumab (Simponi). Similar to other anti-TNF medicines, golimumab (Simponi) should be stopped immediately if a patient develops a serious infection. If you develop an infection while receiving golimumab (Simponi), you should contact your doctor.

Rare side effects that have been reported include the development of conditions such as lupus-like syndrome and multiple sclerosis (MS). 

5. Caution in taking golimumab (Simponi)

Similar to other anti-TNF medicines, the same caution applies to golimumab (Simponi). The long term side effects of golimumab (Simponi) are unknown. Your doctor would advise against giving you golimumab (Simponi) if you have severe heart failure, are pregnant or breastfeeding, have an infection, or have had tuberculosis or cancer in the past. Golimumab (Simponi) can also affect vaccines: if you are planning to have vaccinations, please inform your doctor first. 

6. What if I am thinking of getting pregnant?

No one knows the risk of golimumab (Simponi) to an unborn baby. If you are a woman of child-bearing age, you must use contraception while on golimumab (Simponi). If you are thinking of becoming pregnant in the near future or if you are not using contraception, please do not take golimumab (Simponi). Mothers should not breast feed while on golimumab (Simponi). 

British Society for Rheumatology Biologics Register (BSRBR)

The British Society for Rheumatology Biologics Register was established to protect patients by detecting, at the earliest opportunity, the long-term and rare side-effects of TNFα inhibitors. The register will follow up the progress of patients who are started on TNFα inhibitors and DMARDs by questionnaires and clinical assessments. The data is sent to a central computer register and analysed regularly. The British Society for Rheumatology Biologics Register have studied the short-term and medium-term side-effects of TNFα blockers, and over 10,000 patients have provided favourable data on the benefit and risk of these agents in rheumatoid arthritis.

It is important that as many patients as possible agree to take part in this study since the ability of the register to detect long-term and rare side effects depends on the total number of patients taking part in the register. Therefore the more patients who agree to take part in the Biologic Register, the earlier the Register can detect long-term and rare side effects.

Biosimilar anti-TNF Treatment

Since 2015, two “biosimilar infliximabs”, “Inflectra” and “Remsima” have become available in the UK. Both Inflectra and Remsima are monoclonal antibodies which are highly similar but not exactly identical to Remicade. Hence they are classified as “infliximabs”. In clinical trials in rheumatoid arthritis, Inflectra and Remsima produced the same benefit as Remicade. In future more biosimilars of different anti-TNF agents will become available.

Conclusion

TNFα blockers are highly effective treatments for patients with active rheumatoid arthritis. Their short and medium-term side-effects are relatively well established, and evolving research is encouraging with regards to the long-term effects of these drugs. They are therefore only used in patients who have tried conventional "second-line" treatments.

References available on request

Prof Ernest Choy, Professor of Rheumatology and Head of Department at Cardiff University

Original article: 17/09/2001
Reviewed: 14/01/2016
Next review due: 14/01/2019

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