Rheumatoid Arthritis

Written by Dr. Furrat Amen

What is Rheumatoid Arthritis (RA)?

There are many different types of arthritis – in fact RA is the second most common arthritis after osteoarthritis which is characterised by thinning of cartilage that coats the ends of the bones, in a joint, and formation of osteophytes, bony growths. Other forms of arthritis include gout and psoriatic arthritis and all these diseases have varying traits which distinguish them from one another. It starts suddenly in ten per cent of patients whilst the rest develop the disease slowly.

The meaning of arthritis is ‘inflammation of a joint’ and in the context of RA this inflammation is long term (i.e. chronic), systemic (affects other body systems – not only the joints), and tends to be symmetrical. It is however the joints – and in particular their lining (the synovial membranes) which are affected by the inflammation. Less frequently, patients may present with problems of the kidneys, lungs, cardiovascular systems etc.

RA is an autoimmune disease which is commonly begins from thirty to forty years of age. It is caused when a B or T cell, which attacks self, escapes apoptosis. This may be activated by a bacteria or virus which has and amino acid sequence similar to that of protein in human tissue. Macrophages and lymphocytes are attracted to the site of inflammation. T cells produce cytotoxins and cytokines which activate B cells to produce destructive antibodies.

So why do some people get RA while others do not. Well, the answer is partly genetic – the HLA DR4 antibody indicates a predisposition to develop the disease. This may account for 30% of the disease. It seems to be passed through families but tends to skip a generation. At the moment the cause of RA is not known. The remaining cause may be attributed to an, as yet, unidentified environmental factor – probably a bacteria or virus which triggers the disease in a genetically predisposed individual.

RA is present in roughly equal proportions worldwide with a prevalence of two per cent. More women develop the disease – outnumbering men three to one.

It is, unfortunately, rare for the disease to remit spontaneously although this has been known to happen, rather the disease is likely to follow a the route of exacerbation and remissions which are marked out by the occurrence of ‘flare-ups’. RA may damage the joints as well as causing persistent inflammation. Many patients with RA find that their arthritis worsens when there are sudden changes in weather, although research does not support this being a major factor.

RA may affect any synovial joint and tends to concentrate on the small joints of the hand (not the distal interphalangeal joint), the foot, and wrist. Swelling of the joint occurs and the joint becomes tender. Effusion(fluid) may collect in the joint. It causes early morning stiffness and may also be associated with tiredness. All this together results in restriction of movement of the affected joint. Other joints such as the shoulder, elbow, knee may be affected. If it is not treated it may involve other parts of the joint.

In RA of long standing duration the atlantoaxial joint may sublux and spinal cord compression may occur. Osteoporosis is an added complication of RA.

The first part of the joint to be affected is the synovium, with hyperplasia and oedema comes the formation of a ‘pannus’. A pannus is a disruptive element in a joint and destroys cartilage and the bone beneath that is exposed as a result. RA also brings about a change in the composition of synovial fluid because of antibody-antigen complex formation and it becomes destructive, rather than lubricating and providing material for cartilage survival. Eventually the ligments and tendons may be affected, even resulting in rupture. All this taken together results in deformities characteristic of RA such as Boutonnière, Swan necking, and Mallet fingers. The weight bearing joints grate and without protective cartilage cause bony destruction. The range of movement of joints becomes compromised and instability may follow.

A pannus may compress a sensory nerve causing loss of sensation or a motor nerve causing dropped foot or hand. Other features may include anaemia, fever, loss of appetite and associated weight loss especially when the disease is more serious. Anaemia is particularly common in Still’s disease. Twenty percent may develop rheumatoid nodules over the elbows, sacrum, and back of the heel, i.e. areas exposed to pressure. The back of the knee may develop a Baker’s cyst. An chronic obstructive pulmonary disease may occur, as might pericarditis, and Felty’s syndrome (fever, fatigue, weight loss, and anorexia).

Vasculitis, Sjörgren’s syndrome (causing dry eyes and mouth), pleurisy, carpal tunnel syndrome are other recognised complications.

How is RA diagnosed?

History and examination are key with a clear-cut symmetrical, multiple small joint disease with effusion or swelling being diagnostic. Any swelling (tumor), warmth (calor) or redness (rubor), crepitus or pain(dolor) should be noted.

Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) may be present in raised levels in the blood. A full blood count may confirm anaemia.

There is also an association of RA with the presence of Rheumatoid Factor in the blood, which consists of antibodies of the IgG variety, in about 70% of those with RA. It is however possible, rarely, to have Rheumatoid Factor without RA.

X rays in patients exhibiting RA of moderate duration may show erosion of bone. Other tests might be required, in respect of any treatments that are administered, in order to check progress and minimise side-effects.

Treatment

Many different health professionals have a role to play in the treatment of RA. When the patient first attends a clinic and is discovered to have RA a course of nonsteroidal antiinflammatory drugs (NSAID) may be prescribed and this may be accompanied by advice on bed rest and physical exercise routines. After the trial of NSAIDs, the RA may go into complete remission or may require second line treatments or corticosteroids.

Corticosteroids do have toxicity effects and some patients may have reduced benefical effects if they are used over a long period of time and so their popularity is declining. They reduce inflammation and can be used to control flare-ups. They may be injected into the offending joint or injected intramuscularly during a flare-up to have a longer duration of action to minimize side-effects. If the flare-up is associated with systemic effects and extra-articular involvement then it is advisable to give intravenous therapy using a large dose of methylprednisolone which may be administered over a couple of hours. Later on in the disease process prednisolone tablets may be prescribed in doses of 7.5mg daily to reduce disability and increase ranges of movements of joints, although this regimen is not advised for younger patients who would be likely to suffer from long term side-effects.

Second-line antirheumatic drugs are disease modifying and change the disease process rather than just dealing with symptoms. Methotrexate is an example of such an agent. It is an antiinflammatory folate antagonist and so must be stopped several months before a pregnancy for ladies and three months before a man considers starting a family. It acts after a month or two of treatment by injection or tablet. It works by blocking the synovial fibroblast and endothelial cell proliferation, changes the expression of a collagenase-coding gene, and cuts down levels of leukotrienes which are involved in inflammation. In the short-term its usage compares favourably with other second line drugs listed below. A dose of 7.5mg to 17.5mg methotrexate is administered every week to combat confirmed RA and the associated synovitis. Notable liver disease occurs with five out of one thousand patients treated, so it is necessary to check ALT, AST, and serum albumen levels every four to eight weeks, with a biopsy only necessary if half the blood tests, in one calendar year, show abnormalities. Biopsies are recommended for patients who have hepatitis B or C, have a high alcohol intake, or have persistently abnormal levels of the enzymes mentioned.

Other side-effects include a decrease in the number of white blood cells, gastrointestinal upset and oral ulceration. It is avoided in cases of heart failure, lung, kidney or liver disease (hepatic fibrosis and cirrhosis). Haematological abnormalities and pneumonitis are less frequent complications of treatment. All these side effect are predisposed to by the following factors:

• Renal dysfunction
• Liver disease
• Chronic hepatitis B or C
• Diabetes mellitus
• Obesity
• Reduced serum albumen
• Trimethoprim – sulphamethoxazole treatment

Methotrexate has not be found to generate cancers (1) but there is information regarding lymphoma which indicates the need for long term study of the situation. Treatment with methotrexate alone is often not as successful as combined treatment. Combinations include addition of sulphasalazine 500mg bd, and hydroxychloroquine 200mg bd. 77% of patients in a study showed improvement on the triple combined therapy comparing with improvements of 33% in those who took methotrexate alone and 40% in those taking the sulphasalazine and hydroxychloroquine combination (2).

Sulphasalazine is a combination of sulphapyridine and salicylic acid which is safe but has been noted to cause oligospermia. It is also used in ulcerative colitis. Side-effects include low blood counts, stomach disturbance and rashes and so it is necessary to have frequent blood and liver function tests.

Hydroxychloroquine is an antimalarial drug which may be used for RA in those with slowly progressing disease which is mild in nature. It may cause eye problems so it is sensible to have an annual eye check-up. Azathioprine is an immunosuppressant used if methotrexate and gold have been ineffective. It is necessary, however, to follow up the patient with liver function tests, looking for hepatitis, other blood tests for pancreatitis and to check for bone marrow toxicity. It may also increase the likelyhood of some infections.

Gold Salts are injectable and have been in use since the 1920s. They are given weekly for three to five months and then the frequency of administration is reduced. Side-effects include skin rashes, mouth ulcers, proteinuria, and abnormal blood counts. The oral form has less in the way of side-effects but is widely thought to be less effective. There is a significant reduction of radiologically detectable progression of RA, and indeed although erosion surface areas increase in the first six months of treatment, the following six months show a halt in the erosion size, and six months later the erosions heal (RR0.38, 95% CI 0.23-0.64) (3). With early treatment in the course of RA and adequate dosage good progress may be made in RA – although little difference exists between the use of gold and methotrexate (4). It is most useful and coincidentally most toxic in the first two years of treatment (3).

D-Penicillamine is a slow acting drug to combat RA. It has similar benefits to gold administration although once again careful monitoring is required with blood and urine tests. It must be taken in increasing doses an hour before breakfast. A non-permanent feature is alterations in taste sensation.

Other drugs include cyclophosphamide, chlorambucil, and cyclosporin. These are effective but have serious side-effects which by default limit the use to resistant cases of RA. Cyclosporin is also used in organ transplantation so as to prevent rejection. Side effects include a possible increase in blood pressure, a change in kidney function which is unimportant, and the growth of thin hair on the face.

Other factors, in addition to drug treatment, include aerobic exercise, psychological intervention, education about RA, home physiotherapy, occupational therapy, and rehabilitation programs. GPs are particularly important in these respects and have an important role to play as educators and co-ordinators (5).
The response to all these treatments may be monitored by checking the range of movements of involved joints and any associated pain. ESR and CRP may also provide useful information about the progress of the disease. Changes for the better on treatment may take up to six months, but if there is none a change in treatment may be necessary.

It is necessary to minimise disability and increase function when treating RA patients and the best way to do this is to develop a moderate exercise programme which does not leave the patient fatigued. It is also necessary to encourage rest between the routines. Any pain should not be too great and should not exceed an hour after finishing the routine. It is necessary to continue the exercises twice a day for life even on days when there are flare-ups, albeit a reduced set of exercises. It may be necessary to change jobs, and whilst at work to move frequently and mobilise affected joints.

Splinting may reduce inflammation, pain and the relevant joint destruction. Splints also help to support unstable joints in good positions for everyday use, but it must be remembered to remove the splints in order to exercise and to check for any possible skin irritation. Immobilisation of joints leads to atrophy of the muscles surrounding the joints and this in turn leads to a loss of function. To avoid this isometric exercise can be performed when a joint flares, isotonic exercise with small weights are useful for unaffected joints, whilst isokinetic joints increase pressure and damage to weight bearing joints.

What does the future hold for sufferers?

Pfizer is currently researching ‘Tenidap’, a lipooxygenase/cyclooxygenase inhibitor which has been shown to stop neutrophil collagenase release. Capsaicin cream is underdevelopment which will be rubbed into the joint affected by RA to relieve pain. The tetracyclic antibiotic minocycline and the fatty acid gamma linolenic acid (fish oil) also seem successful in relieving the symptoms of RA. Hormone replacement therapy (oestradiol) also relieves the symptoms of pain, as well as reducing the ESR.

Research is continuing a pace into HLA class II sensitivity, monoclonal antibodies, recombinant cytokines, cytokine antagonists, small peptides, oral tolerance therapy, bone marrow transplantation , T-cell vaccination and drugs to block interleukins, T-cells and neutrophils. In particular leumedins (N-fluorenyl-9 methoxycarbonyl amino acids) are likely to be useful as they show little toxicity in trials. They work by blocking the recruitment of neutrophils into the inflammatory region and have been shown to inhibit T-cell activation.

Monoclonal antibodies may be raised against cell surface antigens on T-cells but results are disappointing thus far. More promising are those raised against ICAM-1 or the cytokines IL-6 and TNF alpha. A trial in seven patients for flare-ups in RA showed an 80% improvement in symptoms and CRP levels (6). Further to this a trial was conducted with 73 patients and low and high dose regimens of anti-TNFalpha antibody. The results in comparison to the placebo control group were very good (7). There is an immediate suppression of the acute phase response in open studies.

Oral tolerance therapy, thus far, has involved feeding patients type n collagen, a joint cartilage protein. This has produced encouraging results with complete remission in some cases. Any symptoms show a reduction in severity, time-span, and frequency. The advantages are of the non-toxicity of ingested proteins and the simple oral administration.

References:

1) Bologna C et al. Study of eight cases of cancer in 426 rheumatoid arthritis patients treated with methotrexate Ann Rheum Dis, 1997 Feb, 56:2, 97-102

2) O’Dell JR et al. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxycholorquine, or a combination of all three medications N Engl J Med, 1996 May 16, 334:20, 1287-91

3) Jones G, Brooks PM. Injectable gold compounds: an overview Br J Rheumatol, 1996 Nov, 35:11, 1154-8

4) Rau R. [Does parenteral gold inhibit roentgen progression of chronic polyarthritis?] Z Rheumatol, 1996 Sep-Oct, 55:5, 307-18

5) Glazier R. Managing early presentation of rheumatoid arthritis. Systematic overview Can Fam Physician, 1996 May, 42:,913-22

6) Elliot MJ et al Lancet, 1994, 334: 1125-1127

7) Elliot MJ et al Lancet, 1994, 334: 1105-1110

8) Jawad A Rheumatoid arthritis a patient’s guide. London: Martin Dunitz,1996

9) ARC An introduction to the musculoskeletal system. Chesterfield: ARC, 1991