Immunisation for people with rheumatoid arthritis
Immunisation is an important issue for people with rheumatoid arthritis (RA) as they experience infections more frequently than the general population, and these infections tend to be more serious. This may be in part due to the abnormal activity of the immune system which is an inherent feature of RA, but infection is also a recognised occasional complication of treatment with some of the drugs used to treat the disease. The image of immunisation has been tarnished in recent years by sensationalist and often inaccurate press reports. The benefits of immunisation are perhaps too easily forgotten – for instance the elimination of polio in this country and most of the world during my lifetime has saved many people from paralysis and occasionally death. The World Health Organisation champions universal immunisation programmes to protect individuals and the community from serious infections. Vaccines are very effective and generally safe, especially in comparison with the diseases they prevent.
Which drugs used to treat rheumatoid arthritis increase the risk of infection?
It is not as easy to give a clear answer as one might expect. Analgesics (e.g. paracetamol, codeine, tramadol) and non-steroidal anti-inflammatory drugs including COX-2 drugs (e.g. ibuprofen, diclofenac, naproxen and celecoxib) do not increase the risk of infection. By contrast steroids (even in small, regular doses) and powerful cytotoxic drugs such as cyclophosphamide have long been recognised to increase the risk of infection. Older disease-modifying drugs such as sulfasalazine, gold and hydroxychloroquine do not seem to have a significant effect on the infection rate. Although methotrexate (MTX) is generally considered to be an immunosuppressive drug it is doubtful that it suppresses the immune system significantly at the doses used to treat RA. Most large studies of the infection rate in people with RA on methotrexate have been re-assuring although there are case reports of people developing unusual infections, as there have been with leflunomide. TNF-α inhibitors (adalimumab, etanercept, infliximab, certolizumab pegol and golimumab) have profound effects on the immune system which is what makes them so effective in RA. However TNF-α helps the body to fight off infection and some evidence suggests that the use of TNF-α inhibitors may increase the risk of serious infection up to two-fold, particularly in the early stages of its administration. Use of TNF-α inhibitors may lead to re-activation of tuberculosis (TB) which is why people starting the drugs are now routinely screened for any evidence of TB in the past. Rituximab, tocilizumab and abatacept are also likely to be associated with a small increase in the risk of infection. Any increase in the risk of infection with these drugs has to be set against the benefits of disease control in RA.
Who should not be immunised?
Immunisation is usually avoided during pregnancy. Serious reactions are extremely rare but people who have had a confirmed anaphylactic reaction (rash, wheezing and sharp fall in blood pressure) to a vaccine or one of its components should not have it again. Those who have had a confirmed anaphylactic reaction to egg should not receive yellow fever or influenza vaccines.
What types of vaccine are there?
There are two types of vaccine, known as 'live' or 'inactivated' vaccines. Immunisation involves exposing someone to a component of an infective agent, which is not in itself harmful, in order to stimulate the body’s immune system to mount a protective response against the infection. Importantly the immune system has the capacity of memory, so that on subsequent exposure to the infective agent a protective response can occur quickly to prevent or reduce the severity of the infection.
Which immunisations should be avoided when taking drugs for rheumatoid arthritis?
Live vaccines should not be given to people who are having, or have had, cancer chemotherapy or radiotherapy within the past six months as they are likely to have suppression of their immune system. The Department of Health also recommends that people on the following drugs with the potential for immunosuppression should avoid live vaccines: methotrexate, leflunomide, azathioprine, ciclosporin, cyclophosphamide, TNF-α inhibitors and the newer cytokine inhibitors (eg tocilizumab) or high-dose steroids (greater than 40mg prednisolone daily). Rituximab and abatacept should probably be regarded similarly. Live vaccines include measles, mumps, rubella, varicella (chicken pox/shingles) and yellow fever. BCG is a living, attenuated form of TB and this too should be avoided in people who are immunosuppressed. (See table below for summary).
|Examples of live vaccines||Examples of inactivated, non-live vaccines|
|Measles, Mumps, Rubella
Hepatitis A & B
Polio (injection, combined with diptheria)
Human Papilloma virus (HPV)
* Guidance issued by the British Society for Rheumatology (BSR), based on the Department of Health ‘Green Book’ on immunisation suggests that until further evidence of safety is established for the Zostavax shingles vaccination, it would not be recommended to anyone taking a biologic drug for rheumatoid arthritis. Patients on some of the non-biologic DMARDs (such as methotrexate) may be able to have the vaccine, but if you are invited to have this vaccination, please check with your rheumatologist first. If your rheumatologist is considering treating you with a biologic drug you should ask your rheumatologist whether you should have the Zostavax shingles vaccine before starting this type of treatment. Further details about this guidance can be found here.
How long a gap should there be between starting/stopping a DMARD and having a vaccine?
There is little hard evidence on which to base advice on how long an interval should elapse between immunisation and the start or finish of DMARD or biologic therapy, although some authors have made suggestions. People should not start a biologic drug within one month of being immunised with a live vaccine, although a fortnight is probably acceptable for conventional disease-modifying drugs including MTX which have a more gradual effect on the immune system.
It is generally regarded as safe to give a live vaccine six months after the biologic drug has been stopped and some suggest three months. The British Society for Rheumatology has suggested that to reduce the risk of post-operative infection in people with RA who are having surgery, a TNF-inhibitor should be stopped 3-5 times the half-life (the time it takes for a drug to reduce by half) of the relevant drug before the operation. If one considers it reasonable to extend that advice to the safe interval between stopping an anti-TNF drug and giving a live vaccine one gets the following estimates: 9-15 days after stopping etanercept; 4-6 weeks after infliximab, 5-8 weeks after golimumab and 6-10 weeks after adalimumab and certolizumab. If the same can be said for the other biologic drugs this would mean that the intervals would be 6-10 weeks after tocilizumab and abatacept, and 9-15 weeks after rituximab.
Cancer experts recommend that BCG should not be given during the six months following cancer chemotherapy, although given the much lower doses of MTX used in rheumatology a shorter interval might be reasonable for this drug.
Despite these concerns about the use of live vaccines, influenza and pneumococcal vaccines are recommended for those who are immunosuppressed. Thus many people with RA should not receive live vaccines, but they should receive regular influenza and pneumococcal vaccination.
What should people unable to have live vaccines do?
People who come into contact with measles can be treated with human normal immunoglobulin, and those in contact with shingles or chickenpox with varicella zoster immunoglobulin; these contain protective antibodies to the relevant infections. People exposed to chickenpox may also benefit from treatment with the anti-viral drug acyclovir. As regards yellow fever, some countries require a certificate of immunisation in order to permit entry to the country. It is possible to get a certificate of exemption which explains why you have not been immunised and this may satisfy the immigration authorities of some countries, but you will of course be at risk of catching yellow fever.
Is immunisation effective if you are taking drugs for rheumatoid arthritis?
The strength of the protective response may not be as great as it is in the general population following immunisation of people taking methotrexate, TNF-α inhibitors or other biologic drugs. Most people will however generate a useful protective response which should at least reduce the severity of any subsequent infection with the relevant microbe. Ideally immunisation would be carried out before people start MTX or other disease-modifying treatment, but this should not result in significant delay in starting disease-modifying treatment for RA. It certainly makes sense to ensure that people who are about to start treatment with TNF-α inhibitors or other biologic drugs are up to date with their immunisation schedule (including influenza and pneumococcal) and to consider immunisation against haemophilus (Hib) which is another cause of pneumonia.
In conclusion, immunisation against infection is highly desirable in people with RA, although certain modifications to the usual schedule may be required depending on the drugs one is taking for the arthritis.
Further advice can be found in the “The Green Book” published by the Department of Health
References available on request
Dr Robin Butler MD FRCP. Consultant Rheumatologist, Robert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry, Shropshire and NRAS Medical Advisor
Original article: 25/09/2008
Next review due: 28/10/2018