| How is anti-TNF different from other drugs used for AS?
Drugs like aspirin and ibuprofen act on the symptoms of AS but do not change the actual disease itself. General immune-suppressing treatments like sulfasalazine and methotrexate may be effective in people with AS in the hands and feet (i.e. non-spinal disease) but have only minimal effects on severe AS and arthritis mainly in the spine. The anti-TNF drugs specifically block one of the chemicals involved in AS and therefore have the potential to modify the course of the disease. By reducing inflammation, TNFa-blockers can reduce pain, swelling and fatigue, improve mobility and potentially prevent further damage. High levels of TNFa are found in the sacroiliac joints of patients with AS. If this excess TNFa is blocked, then this could prevent damage to these joints and so actually alter the disease progression.
Is there evidence that anti-TNF does decrease the inflammation involved in AS?
There have been dramatic and impressive results in the people with AS who have been involved in clinical trials of anti-TNF agents. These drugs result in significantly better function, lower disease activity and reduced pain when compared to placebo. In all trials to date there has been a dramatic reduction in symptoms of AS and in the progression of joint destruction. Both spinal symptoms and peripheral (i.e. hands, feet, knees etc) joint involvement show fast and significant improvement. Even in people with advanced spinal fusion from AS, there can often still be significant improvement with these drugs.
Anti-TNF agents also have beneficial effects on several disorders associated with AS such as psoriasis, uveitis and Crohn’s disease. These drugs have been used for over 10 years in patients with rheumatoid arthritis and in these patients the improvement in symptoms is generally sustained.
Does everyone who takes it get this dramatic reduction in disease?
No, the effect does vary with different individuals. There are some non-responders in all trials (i.e. no change in disease). Continued, long-term use of these drugs requires evidence of clinical improvement (see later).
It should also be noted that these drugs are not a cure but are a very effective treatment for AS. Some inflammation does appear to remain as it is likely that other chemicals (apart from TNFa) are also involved in the inflammatory process and are not affected by anti-TNF drugs. When the anti-TNF therapy is stopped, the inflammation from AS usually comes back. Therefore a person needs to continue taking the TNFa-blockers long-term, usually for life. However, complete remission of disease is occasionally seen in patients with rheumatoid arthritis.
There is also the possibility that the type of inflammation may change after a time and the anti-TNF therapy may no longer work as well. Therefore, it is possible that anti-TNF may not always work for life.
Are there any problems with taking anti-TNF drugs? 
Yes. There is some need for caution and these drugs may not be appropriate for all patients. The main side-effects of these drugs are described below.
Many of these side effects are rare and some of the risks are theoretical. However, because of these risks anti-TNF is currently only considered for people with severe and active ankylosing spondylitis.
Which anti-TNF drugs are effective in AS?
Currently, there are three licensed anti-TNF treatments; etanercept (Enbrel), adalimumab (Humira) and infliximab (Remicade) which have been shown to be effective in AS.
Etanercept and adalimumab are given by regular self injection, in much the same way as people who are diabetic inject themselves. In contrast, infliximab needs to be given as an intravenous infusion every 6-8 weeks.
Are all 3 anti-TNF agents available for AS in the NHS?
No. In May 2008 the National Institute for Clinical Excellence (www.nice.gov.uk) approved the use of etanercept and adalimumab to treat patients with severe AS on the NHS, but not infliximab. The decision not to recommend infliximab, despite its proven effectiveness, was based on cost-benefit assessments, and has already been the subject of an unsuccessful appeal. Patients already receiving infliximab at the time of the NICE recommendations can continue to receive this.
Treatment should only be started and supervised by a specialist who is experienced in diagnosing and treating AS (this will usually be a rheumatologist).
 NICE has recommended adalimumab or etanercept for patients with severe AS who:
- have active spinal disease (assessed on 2 separate occasions 12 weeks apart) AND
- have tried at least 2 NSAIDs (non-steroidal anti-inflammatory drugs, such as ibuprofen, diclofenac) that have not worked.
NICE has stated that treatment with either of these anti-TNF drugs should only continue if the person’s AS shows an adequate improvement in response to therapy. Treatment can continue as long as the person is responding to the treatment without any unacceptable side effects. If the improvement is not maintained or if the drug stops working, then the treatment should be stopped.
If a person has to stop taking adalimumab or etanercept during the first 12 weeks of treatment because of unwanted side-effects, then their specialist may offer them the other drug as an alternative (if considered safe by the specialist). However, NICE has stated that if treatment with adalimumab or etanercept does not work or stops working, then the other drug should not be offered.
What is etanercept (Enbrel) and how is it given?
Etanercept is a man-made substance that is made by joining two human proteins together. One of the proteins binds to TNFa and stops it from causing inflammation. The second protein helps keep this first protein in the body for longer.
Etanercept is given by injection under the skin (“subcutaneous”) twice a week. The injections are given by patients, or their carers, after a short period of training.
What is adalimumab (Humira) and how is it given?
Adalimumab is an antibody (protein) that is fully human. This antibody binds to TNFa (in a different way to etanercept) and stops it from causing inflammation.
Adalimumab is given by injection under the skin (like etanercept) fortnightly (i.e. every second week).
What are the possible side effects of adalimumab or etanercept?
The most frequent side effect of these drugs is local skin irritation at the site of injection. This is usually mild. Rarely, people may be allergic to these drugs in which case the drug has to be stopped.
Serious infections, some involving death, have been reported in a few patients taking anti-TNF medications. Your specialist’s team will carefully assess your risk of developing serious infections, including tuberculosis, prior to starting you on these drugs. It is possible they may decide the treatment is too risky for you at that time. If you develop an infection while taking adalimumab or etanercept, you should stop your treatment temporarily and contact your specialist or their team.
There are a few conditions that can potentially be worsened by these drugs (such as severe heart failure, previous cancers) and your specialist team may chose not to give you adalimumab or etanercept, on safety grounds, if you have one of these conditions.
There have been rare reports of conditions such as multiple sclerosis, serious blood disorders, inflammation of the nerves of the eyes, lupus-like conditions. Some of these may resolve completely on stopping the drug, but this is not necessarily the case.
As the anti-TNF agents are still relatively new drugs, their long-term side effects are not fully known. As the immune system is involved in protecting against cancers, there is a theoretical risk of developing certain kinds of cancers in the future. Some studies have suggested there might be an increased risk of malignancies with higher doses of anti-TNF. Your specialist team should discuss this, and the other potential side-effects with you before starting treatment.
As with all new drugs, the regulatory authorities, including NICE, require close surveillance of all side effects associated with these drugs to ensure that trends in increasing side effects are picked up early. In addition, the British Society for Rheumatology has a Biologics Register that has been collecting data on patients with Rheumatoid Arthritis receiving anti-TNF therapy to detect and report on side effect patterns. It is anticipated that a similar register will be established for AS.
What if I am thinking of getting pregnant?
No one knows the risk of adalimumab or etanercept to an unborn baby. If you are a woman of child-bearing age, you must use contraception while on these drugs. If you are thinking about becoming pregnant in the near future, please discuss this with your specialist or doctor first.
What if I require an operation or a vaccination?
Most specialists and authorities will recommend stopping your adalimumab or etanercept for 2 weeks before, and 2 weeks after major surgery (including joint replacements) to minimise the risk of surgical infections. This advice is not based on any definite evidence, and you should discuss this with your specialist if you have surgery planned.
The anti-TNF agents can affect some vaccines, so you should inform your doctor if you are planning to have any vaccinations. It may be best to have some of these before starting on anti-TNF therapy.
Conclusion
In summary, anti-TNF therapy is very new and exciting, and represents the first disease modifying therapy to have a significant effect in AS. However, it is expensive and it is not currently clear which people will benefit most from anti-TNF. As a result, this treatment is currently only available in the NHS for use in people whose AS has not responded to other disease-modifying drugs.
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