Introduced by Professor David Blake, Royal National Hospital for Rheumatic Diseases.
'Arthritis' simply means inflammation in a joint. The suffix -'itis' means inflammation, and can be used for inflammation in any organ, for example pharyngitis, a sore throat. A common cause of inflammation is infection caused by microbes. Inflammation is a bodily process for fighting infection. It is highly evolved in humans but happens in all living creatures. Inflammation has a major impact on how we treat the disease. With advancing age, osteoarthritis is the most common inflammatory disease affecting joints. Here, the inflammatory reaction, often quite mild, is caused by a breakdown in structures within the joint; for instance, the cartilage that lines them and allows them to move slowly. Of course, there is no infection here and the body is responding to the little bits of debris. It tries to destroy these using the same cells and products from these cells, often enzymes, to get rid of them. So inflammation doesn't always mean infection.
RA is also an example of inflammation (-itis) not triggered by infection. Before discussing how this might come about, let's describe how it affects a person.
People vary in how their RA starts but a fairly common story is like this.
A woman between 30 and 50 goes to bed perfectly well and in the morning has an unpleasant aching and stiffness of the joints, most likely to be in the hands or the front of the feet. It may start in one joint area, but then, over weeks or months, may jump to another joint area. Often it jumps to the same joints on the opposite side. The knuckles are the most common place for it to start, especially the second and third knuckles. It's painful and stiff, and a big worry. Most people know someone who has the disease and most people worry that they will be crippled. Fear of the unknown sends people quickly to their GP for reassurance and advice and here the difficulties start for both the doctor and the patient.
The first problem is that though it may look like RA to the doctor, at this stage one cannot be sure, because some viruses can cause an identical form of arthritis with the same pattern that can last for weeks or months, occasionally up to a year. So doctor must be uncertain and cautious. The right thing to say is that it is arthritis, but without further tests and the passage of time one cannot be certain what sort of arthritis. Reassurance just cannot be given at this stage. Anxiety is bound to increase even if the doctor gives the information clearly and sympathetically. Patients who then ask relatives and friends often get very inappropriate advice.
At the first visit the doctor will probably order some blood tests, to measure the amount of inflammation and look for 'rheumatoid factor', and perhaps screen for viruses. While awaiting the results of these tests he may give you painkillers and anti-inflammatory drugs. A common one would be ibuprofen which one can buy without prescription. It works quite well but it is not a cure and its effects are usually partial. Almost all patients say that they don't like taking tablets. No one likes to be ill. Some will seek complementary cures. Many are advertised but none with any proof of working. Others may seek to change their diet, but no diets are known to work. If any complementary medicine or diet were known to work, doctors would recommend them - they are no keener to give drugs than patients are to take them.
A few weeks later the doctor has the results of the tests and also the advantage of knowing what has happened since you were last seen. Three things could have happened. You could be exactly the same or you could be a lot better, even completely normal; or you could be worse, possibly much worse. Taking the last first, the disease may now be jumping from one joint to another. One day it's a knee or both knees, a few days later a shoulder or both shoulders. By the end of the week an elbow or both elbows and they don't quite straighten as well as they should. No sooner has one joint appeared to get better than another pops up in its place. Medical short-hand for this is an intermittent, flitting, peripheral polyarthritis - a fairly bland way of describing something that everyone would find frightening. (The word poly- here just means 'many'.) But sometimes the disease stays in one joint (a monoarthritis) or in a few joints (an oligoarthritis). Each of these patterns suggests a possible diagnosis and also the outlook or prognosis.
Let's now take the best option - that it's gone away. RA can do this early on; coming for a week or two, going for a few weeks or months and then popping back again. This pattern is called palindromic arthritis. These attacks can be very painful but aren't always. If the arthritis has gone it may suggest that it was a viral arthritis, a so-called post-viral or reactive arthritis. The doctor also has the blood test results and will have measured the amount of inflammation, using either the ESR, plasma viscosity, or CRP. If the values have gone above the normal range of values found in healthy people, it suggests inflammation (-itis) somewhere, and how high it has gone up, tells the doctor how active it is. Clearly, the lower the better. This is purely a measure of inflammation, not a specific test for RA. Many things can make it go up including even rotten teeth (periodontitis). A more useful specific test is the rheumatoid factor test, which measures a part of the immune inflammatory reaction, though sometimes even this does not go up in someone with rheumatoid arthritis. It is necessary to understand it to understand how other treatments work.
The inflammatory reaction is divided into a fast system generated by cells called white blood cells, or neutrophils, and a slower system generated by more immune-based T cells and B cells. It doesn't matter at the moment what these stand for. In RA the immune cell system responds more strongly than expected i.e. the immune response is exaggerated. Some doctors call this an autoimmune reaction. Auto- just means 'self' and that contrasts it with the immune response that occurs, for instance, after vaccination.
This slow immune response is also how the body deals with more tricky infective insults such as viruses, which hide in cells and are not easily attacked by the fast acting neutrophils. RA is an example of a disease that is at least partly triggered by our slow immune system. The rheumatoid factor test measures an immunoglobulin which is an antibody produced by the B cell, and it seems to be attacking another sister immunoglobulin. We don't know why, and are trying to find out; it seems to have no useful purpose and that is very odd.
So the doctor has found inflammation and a positive test for rheumatoid factor, and he is most likely to refer the patient to a specialist. You might expect him to x-ray the joints but at this stage this would not help him and would delay specialist advice. X-rays do help in making a diagnosis of RA but the changes take a few months to appear. The changes that the specialist is looking for are called erosions. An eroded bone is one that has been nibbled away at by the inflammatory fast-acting and immune long-acting cells that move from the blood into the lining of the joint, the synovium or synovial membrane. This is normally very thin structure, much like the clear lining layer of your eye, the conjunctiva. The synovium gets inflamed and starts off looking like conjunctivitis, red and oozing. The cells keep coming into the synovium and it becomes swollen, starts to organise itself all on its own and nibbles away at the bone edges and the cartilage.
The GP refers the patient to a specialist, usually a consultant rheumatologist, a physician who deals especially with diseases affecting the muscles and joints. Unfortunately waiting lists to see the specialist can be quite long. Serious diseases are of course given priority to over those that are not, but all patients in pain rightly think their problem is serious, particularly if they cannot work. This is as frustrating for the specialist as it is for the patient. The consultant has about 30 minutes for a patient, and will ask various detailed questions to help clarify the diagnosis and to separate it from other conditions that resemble it. He will examine the patient as a whole, because RA occasionally spreads outside the joints to other organs, so-called systemic disease. He may get x-rays at this stage, and may well also repeat and extend the earlier blood tests. If everything appears clearly the right pattern for RA - the blood tests suggest it, the disease is not settling but is slightly advancing - he may decide to start a different type of drug, or he may delay a little further to arrange more sophisticated immune tests and x-rays. At this stage he needs to explain what these drugs are about, his responsibilities to you and your responsibilities to him and to yourself. This can often not be done in 30 minutes. The patient is worried about work prospects, or about relationships with spouse and family who are frustrated by the disability and the lack of 'getting on top of it'. Many other anxieties may also surface. (See 'Work' and 'Personal life and changes to home'.)
Everyone at this point wants to voice their own individual fears and anxieties, and a sense of loss of control. The specialist knows he needs to discuss the drugs in detail and all feel frustration that all the problems can't be dealt with. He or she may at this point, get support from the team of nurses, physiotherapists, occupational therapists and patient advisers. If you are uncomfortable about the drugs, by all means ask for further information and time to think about it and perhaps discuss it again with your own doctor or the nurse in the local surgery. The doctors will, however, be anxious to start you on something else soon because the longer the delay, the more likely there is to be damage and the less likely he is to be able to suppress the disease or stop it. He will probably suggest an immune suppressant agent, or possibly a short course of steroids.
Steroids, discovered in the 1950s, do not cure RA but suppress the inflammatory reaction at all points: the fast-acting cells and the slow-acting cells, and they do so extremely well at high doses. These doses however, cause serious side effects within months to years. The discovery of steroids was a fantastic advance, but they were definitely not the cure for RA. Steroids in high doses cause high blood pressure, diabetes, thinning of the bones (osteoporosis) and reduce the ability to fight infections. These side effects attack all who take a high enough dose for long enough. The doctor, if he does prescribe a steroid, is prescribing it in a low dose for a short time, to improve mobility whilst the immune suppressant slow-acting anti-rheumatic drugs are starting to work. These are also known as disease-modifying anti-rheumatic drugs or 'immune-normalisers'.
What these drugs do is to damp down the exaggerated inflammatory response, particularly at the slow or immune end of the system that occurs in people with RA. All the drugs that the consultant is now thinking about are immune-normalisers. The first ones that were discovered, more or less by chance, were gold and penicillamine, which are now little used. Since then other drugs with variable immune normalising properties have been discovered - sulfasalazine, methotrexate and leflunomide are the most useful. Careful long-term trials on lots of people have been done. Methotrexate is the most widely used. It is taken once a week - taking more causes a lot of trouble. At low doses and for RA it has good immune normalising properties. At much higher doses it is a major immune suppressant in everyone and is used to treat some cancers. For many, though not all people with RA, it can more or less stop the disease in its tracks, but the doctor must find the right dose. That dose will be different for each person. It seems better to push the dose up high, get on top of the disease and then, when it is nicely suppressed, start reducing the dose. Being over-cautious and always not quite being there, seems to lead to a higher dose being needed. This is now where the patient's responsibilities really matter. To get the right dose the specialist and the GP need to see regular blood tests including a measure of inflammatory activity (that's the ESR, CRP or viscosity) to make sure that it is doing the trick but has not immune-suppressed the patient, giving all the advantages of immune normalisation but none of the dangers of immune suppression. The blood test has to be done monthly. A doctor or other professional needs to check the result, but an interested patient can easily learn to do it. Ideally, the result is put on a card for the patient and the doctors to use. Most GPs will do this - it is very important. The drug takes at least three months to work, often another three months or a little more to get the ideal maximum dose and then six months to a year to get the minimum stabilising dose. This is done on the basis of the blood tests and the symptoms, and requires regular medical checks. A working person may need time off for this.
If after six months the response has not been good enough, and attacks and tiredness continue. Tiredness is a very important symptom that is often not discussed in clinics but has a major impact on life, behaviour and relationships. It is hard to see the tiredness of RA in another person - it is not obvious. Partners often become extremely intolerant. The patient wants to go to bed early, the partner to go out. The partner would like to have sex but the patient doesn't. You're at work and a small matter that would not normally trouble you leads to a response that is just one step too far. The husband comes home, wants his tea, doesn't say it nicely and normally this would have been no trouble but you go upstairs and burst into tears and truly don't understand why. There is hardly a patient whether man or woman with RA who hasn't gone through these problems on many occasions and it is very important that everyone understands that with this disease, these problems unfortunately come free. Your understanding and that of your partner, your employer or your children's understanding is very important for making sure this doesn't get on top of all of you.
We think we understand the mechanism. There are a series of short proteins in your joints that can leave your blood, cross into the brain and stimulate an area that causes this fatigue and irritability. For a normal person the closest we get to feeling something like it, is with flu. (See 'Ongoing Symptoms' and 'Self-management'.)
Let's jump another six months to a year and again presume the worst though this is unlikely. The fatigue is getting worse, the joints aren't settling and the doctor will have probably already added another immuno-normaliser in. Sulfasalazine and methotrexate are a common combination. If they haven't worked, he will now consider anti-cytokine therapy, a relatively new treatment which can be remarkably effective. It is, however, extremely expensive.
It was developed after the discovery of TNF, a very small protein produced by some of the slow-acting immune cells, which then acts on others producing different molecules which then interact with the same cells and with different cells and create an avalanche-type reaction. TNF can cause local joint damage and at the same time many of the more widespread features of arthritis. It was therefore selected as a potential target. To block TNF, investigators have produced either an antibody or a different kind of coupling device, a receptor. These drugs worked very well in animals with arthritis, and showed promise in small numbers of patients. Much larger controlled trials were then performed. The trial results were very encouraging, near-miraculous in some people. In others, it was effective but not perfect, but in some the effect was disappointingly small. Anti-TNF has to be given by injection under the skin or into a vein. It is very expensive to make and the supply is restricted. One cannot yet predict who will do very well. People who respond well lose their tiredness within a few days of the first injection and many only then realise how down the disease had made them. They had accepted life at this level. People who respond by losing their tiredness usually then get a good anti-arthritis effect and some recent trials indicate that the erosive bone damage stops or heals a little. It is also becoming clear that the earlier this treatment is started, the better the results are. But unfortunately we lack the money to try this drug on everybody with early arthritis; now the drug may be used only in people with active disease (by strictly defined criteria) who have failed on at least two of the immune normalisers (for more information see 'Biological treatments: anti-TNF and b-cell therapy').
A drug that can so dramatically reduce the inflammatory reaction is unlikely to do this without a side effect: inflammatory reaction is designed to fight infection. That is the down side of anti-TNF. Certain infections are more common. For instance, if a patient has tuberculosis, even if it is sealed off in the body, this drug will expose it. It is a brilliant advance but it needs careful handling. But it does point towards a new range of anti-rheumatic treatments.
Final words. RA can be a mild inconvenience or a devastating illness - everyone is different. An individual patient has little control over the eventual outcome. However, a positive attitude and a desire to get on with it, not only helps to prevent disabilities and handicaps, but also mysteriously affects our immune system for the better.
We hope you enjoy this module. We're very grateful to all the patients who've contributed their time and effort to putting it together. It is worth your while concentrating on it and coming back to it. You will certainly get a lot more information and a well-informed patient gets better treatment.
Thank you very much.
Last reviewed August 2010.
