Introduced by Professor David Blake, Royal National Hospital for Rheumatic Diseases and updated by Dr Catherine Swales, Nuffield Orthopaedic Centre
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 doesnt always mean infection.
RA is also an example of inflammation (-itis) not triggered by infection. Before discussing how this might come about, lets 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 wrists and knuckles are the most common place for it to start, especially the second and third knuckles. Its 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 the doctor may be uncertain and cautious. The right thing to say is that it is arthritis, but without further tests and the passage of a little more time one cannot be certain what sort of arthritis. Complete reassurance on diagnosis cannot be given at this stage, although it should be stressed that we now have many more (and more successful) treatments for rheumatoid arthritis. Anxiety may increase even if the doctor gives the information clearly and sympathetically. Patients who then ask relatives and friends may get 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 or other antibodies, and perhaps screen for viruses. While awaiting the results of these tests they 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 dont 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 its 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 dont 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.
Lets now take the best option – that its 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 arent always. If the arthritis has gone it may suggest that it was a viral arthritis, a so-called post-viral or post-infectious arthritis. The doctor also has the blood test results and will have measured the amount of inflammation, using either the ESR 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). More useful specific tests are the rheumatoid factor and anti-CCP tests (see below), which measures antibodies in your bloodstream, though sometimes even these do not go up in someone with rheumatoid arthritis.
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 doesnt 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 dont know why, and are trying to find out; it seems to have no useful purpose and that is very odd. There is also another antibody, which specialists test for called anti-CCP, in which people with RA produce antibodies against proteins that have been changed in some way.
So the doctor has found inflammation and a positive test for rheumatoid factor, and they are most likely to refer the patient to a specialist. You might expect them to x-ray the joints but at this stage this would not help and would delay specialist advice. X-rays do ultimately contribute to 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 a 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 although more hospitals are developing fast-track early arthritis clinics where patients with a possible new inflammatory arthritis are seen quickly, ideally within 2-4 weeks of referral. 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. They will examine the patient as a whole, because RA occasionally spreads outside the joints to other organs, so-called systemic disease. They 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 ‚Äì they will decide to start a different type of drug. At this stage they need to explain what these drugs are about, their responsibilities to you and your responsibilities to them 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 they need to discuss the drugs in detail and all feel frustration that all the problems cant be dealt with. At this point they‚Äôll also offer 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 they are to be able to suppress the disease or stop it. They will probably suggest a ‚Äúdisease modifying‚Äù drug, and some steroid to get the disease under control quite quickly (probably a Depomedrome injection).
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 they do prescribe a steroid, will do so at a low dose for a short time, to improve mobility whilst the immune suppressant slow-acting anti-rheumatic drugs are starting to work. The latter drugs are also known as disease-modifying anti-rheumatic drugs DMARDs 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 DMARDs. 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, hydroxychloroquine, 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 has been nicely suppressed for a few years, start considering a reduction 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 patients 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 (thats the ESR, CRP) 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 fortnightly initially and then 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. In general DMARDs take about three to four months at full dose to work and then changed according to T2T (treat to target) goals. You are likely to be started on two different DMARDs at the beginning to try to get things under control quickly.
Tiredness is a very important symptom that is often not discussed in clinics but has a major impact on life. It is hard to see the tiredness of RA in another person – it is not obvious ‚Äì but can put strain on relationships. A significant number of people with RA, both male and female, experience personal problems due to their disease, and it is very important that everyone understands that with this disease, these sort of problems can arise. Your understanding and that of your partner, your employer or your childrens understanding is very important for making sure this doesnt get on top of all of you.
At this stage the doctor may add in another third DMARDs. Sulfasalazine, hydroxychloroquine and methotrexate are a common combination; or they may substitute one for another. If after six months they havent worked and you still have severe disease activity, they now consider so-called biologic therapy. These are antibodies that are made in a lab, and they are designed to attack and destroy/affect important cells or proteins that drive RA. Although they can be remarkably effective, they are extremely expensive and sometimes not without risk. As a result they are currently reserved for patients who have severe disease activity despite six months use of standard DMARDs, including methotrexate.
The first biologic treatment was against TNF, a 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. Anti-TNF antibodies either destroy the TNF protein or are joined to its receptor and act as a decoy, preventing the TNF from binding to cells are causing the inflammatory avalanche. Anti-TNF has to be given by injection under the skin or, very occasionally, into a vein. 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 the erosive bone damage may slow dramatically or stop altogether. (For more information see Biological therapies: anti-TNF, B-cell therapy, abatacept and tocilizumab).
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, most notably TB with the use of anti-TNF, which is why every patient starting it is screened for the disease.