An immunosuppressant drug used to treat severe rheumatoid arthritis and other autoimmune disorders. It is also used to prevent organ rejection after transplant surgery. Increased susceptibility to infection is a side effect.
There has been a rapid introduction in recent years of monoclonal antibodies which prevent T-cells from proliferating. They can be recognised by the su?x ‘mab’ (standing for monoclonal antibody) and include rituximab and alemtuzumab. In?iximab, used in CROHN’S DISEASE and RHEUMATOID ARTHRITIS, inhibits tumour necrosis factor alpha.... immunosuppression
Causes There is a major immunogenetic predisposition to rheumatoid arthritis in people carrying the HLA-DR4 antigen (see HLA SYSTEM). Other minor immunogenetic factors have also been implicated. In addition, there is a degree of familial clustering which suggests other unidenti?ed genetic factors. Genetic factors cannot alone explain aetiology, and environmental and chance factors must be important, but these have yet to be identi?ed.
Epidemiology Rheumatoid arthritis more commonly occurs in women from the age of 30 onwards, the sex ratio being approximately 4:1. Typical rheumatoid arthritis may occur in adolescence, but in childhood chronic SYNOVITIS usually takes one of a number of di?erent patterns, classi?ed under juvenile chronic arthritis.
Pathology The primary lesion is an in?ammation of the synovial membrane of joints. The synovial ?uid becomes diluted with in?ammatory exudate: if this persists for months it leads to progressive destruction of articular CARTILAGE and BONE. Cartilage is replaced by in?ammatory tissue known as pannus; a similar tissue invades bone to form erosions. Synovitis also affects tendon sheaths, and may lead to adhesion ?brosis or attrition and rupture of tendons. Subcutaneous and other bursae may be involved. Necrobiotic nodules also occur at sites outside synovium, including the subcutaneous tissues, the lungs, the pericardium and the pleura.
Clinical features Rheumatoid arthritis varies from the very mild to the severely disabling. Many mild cases probably go undiagnosed. At least 50 per cent of patients continue to lead a reasonably normal life; around 25 per cent are signi?cantly disabled in terms of work and leisure activities; and a minority become markedly disabled and are limited in their independence. There is often an early acute phase, followed by substantial remission, but in other patients gradual step-wise deterioration may occur, with progressive involvement of an increasing number of joints.
The diagnosis of rheumatoid arthritis is largely based on clinical symptoms and signs. Approximately 70 per cent of patients have rheumatoid factor ANTIBODIES in the SERUM but, because of the large number of false positives and false negatives, this test has very little value in clinical practice. It may be a useful pointer to a worse prognosis in early cases if the level is high. X-RAYS may help in diagnosing early cases and are particularly helpful when considering surgery or possible complications such as pathological fracture. Patients commonly develop ANAEMIA, which may be partly due to gastrointestinal blood loss from antiin?ammatory drug treatment (see below).
Treatment involves physical, pharmacological, and surgical measures, together with psychological and social support tailored to the individual patient’s needs. Regular activity should be maintained. Resting of certain joints such as the wrist with splints may be helpful at night or to assist prolonged manual activities. Sound footwear is important. Early use of antirheumatic drugs reduces long-term disability. Drug treatment includes simple ANALGESICS, NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS), and slow-acting drugs including GOLD SALTS (in the form of SODIUM AUROTHIOMALATE), PENICILLAMINE, SULFASALAZINE, METHOTREXATE and AZATHIOPRINE.
The non-steroidal agents are largely e?ective in reducing pain and early-morning sti?ness, and have no e?ect on the chronic in?ammatory process. It is important, especially in the elderly, to explain to patients the adverse effects of NSAIDs, the dosage of which can be cut by prescribing paracetamol at the same time. Combinations of anti-rheumatic drugs seem better than single agents. The slow-acting drugs take approximately three months to act but have a more global e?ect on chronic in?ammation, with a greater reduction in swelling and an associated fall in erythrocyte sedimentation rate (ESR) and rise in the level of HAEMOGLOBIN. Local CORTICOSTEROIDS are useful, given into individual joints. Systemic corticosteroids carry serious problems if continued long term, but may be useful under special circumstances. Much research is currently going on into the use of tumour necrosis factor antagonists such as INFLIXIMAB and etanercept, but their precise role remains uncertain.... rheumatoid arthritis
Treatment Any major de?ciencies, such as thyroxin or insulin lack, should be corrected. The activity of the immune system should then be reduced. CORTICOSTEROIDS and, in more severe cases, strong immunosuppressant drugs – AZATHIOPRINE, CYCLOPHOSPHAMIDE or METHOTREXATE – should be administered. Treatment is di?cult because of the need to control the autoimmune condition without damaging the body’s ability to combat other diseases.... autoimmune disorders
Crohn’s disease is rare in the developing world, but in the western world the incidence is increasing and is now 6–7 per 100,000 population. Around 80,000 people in the UK have the disorder with more than 4,000 new cases occurring annually. Commonly Crohn’s disease starts in young adults, but a second incidence surge occurs in people over 70 years of age. Both genetic and environmental factors are implicated in the disease – for example, if one identical twin develops the disease, the second twin stands a high chance of being affected; and 10 per cent of sufferers have a close relative with in?ammatory bowel disease. Among environmental factors are low-residue, high-re?ned-sugar diets, and smoking.
Symptoms and signs of Crohn’s disease depend on the site affected but include abdominal pain, diarrhoea (sometimes bloody), ANOREXIA, weight loss, lethargy, malaise, ANAEMIA, and sore tongue and lips. An abdominal mass may be present. Complications can be severe, including life-threatening in?ammation of the colon (which may cause TOXAEMIA), perforation of the colon and the development of ?stulae between the bowel and other organs in the abdomen or pelvis. If Crohn’s disease persists for a decade or more there is an increased risk of the victim developing colon cancer. Extensive investigations are usually necessary to diagnose the disease; these include blood tests, bacteriological studies, ENDOSCOPY and biopsy, and barium X-ray examinations.
Treatment As with ulcerative colitis, treatment is aimed primarily at controlling symptoms. Physicians, surgeons, radiologists and dietitians usually adopt a team approach, while counsellors and patient support groups are valuable adjuncts in a disease that is typically lifelong. Drug treatment is aimed at settling the acute phase and preventing relapses. CORTICOSTEROIDS, given locally to the affected gut or orally, are used initially and the effects must be carefully monitored. If steroids do not work, the immunosuppressant agent AZATHIOPRINE should be considered. Antidiarrhoeal drugs may occasionally be helpful but should not be taken during an acute phase. The anti-in?ammatory drug SULFASALAZINE can be bene?cial in mild colitis. A new generation of genetically engineered anti-in?ammatory drugs is now available, and these selective immunosuppressants may prove of value in the treatment of Crohn’s disease.
Diet is important and professional guidance is advisable. Some patients respond to milk- or wheat-free diets, but the best course for most patients is to eat a well-balanced diet, avoiding items that the sufferer knows from experience are poorly tolerated. Of those patients with extensive disease, as many as 80 per cent may require surgery to alleviate symptoms: a section of affected gut may be removed or, as a lifesaving measure, a bowel perforation dealt with.
(See APPENDIX 2: ADDRESSES: SOURCES OF INFORMATION, ADVICE, SUPPORT AND SELFHELP – Colitis; Crohn’s disease.)... crohn’s disease
The drugs work by suppressing the production and activity of white blood cells called lymphocytes. Side effects vary, but all the drugs increase the risk of infection and of the development of certain cancers.... immunosuppressant drugs
Cytotoxic drugs are used either singly or in combination, when an enhanced response is the aim. Chemotherapy of cancer is a complex process and should be supervised by an oncologist in co-operation with physicians, surgeons, radiotherapists and radiologists as appropriate.
The cytotoxic drugs include:
(1) The alkylating agents which act by damaging DNA, thus interfering with cell reproduction. Cyclophosphamide, ifosfamide, chlorambucil, kelphalan, busulphan, thiotepa and mustine are examples of alkylating agents.
(2) There are a number of cytotoxic antibiotics used in the treatment of cancer – doxorubicin, bleomycin, dactinomycin, mithramycin and amsacrine are examples. They are used primarily in the treatment of acute leukaemia and lymphomas.
(3) Antimetabolites – these drugs combine irreversibly with vital enzyme systems of the cell and hence prevent normal cell division. Methotrexate, cytarabine, ?uorouracil, mercaptopurine and azathioprine are examples.
(4) Another group of cytotoxic drugs are the vinca alkaloids such as vincristine, vinblastine and vindesima.
(5) Platinum compounds such as carboplatin, cisplatin and oxaliplatin are e?ective. All of them are given intravenously, but the latter two tend to have more unpleasant side-effects. Carboplatin and cisplatin are useful in the treatment of solid tumours. Carboplatin, a derivative of cisplatin, is given intravenously in ovarian cancer and in small-cell lung cancer. Better tolerated than cisplatin, the drug causes less nausea and vomiting, nephrotoxicity, neurotoxicity and ototoxicity. Where platinum-containing therapy has failed, intravenous treatment with paclitaxel may be tried. With only a limited success rate, it is relatively toxic and should be carefully supervised; responses, however, are sometimes prolonged.
Also of increasing importance in treating cancer are interferons. These are naturally occurring proteins with complex effects on immunity and cell function. Although toxic, with numerous adverse effects, they have shown some anti-tumour e?ect against certain lymphomas and solid tumours.... cytotoxic
It is a classical example of an autoimmune disease (see AUTOIMMUNITY). The body develops ANTIBODIES which interfere with the working of the nerve endings in muscle that are acted on by ACETYLCHOLINE. It is acetylcholine that transmits the nerve impulses to muscles: if this transmission cannot be e?ected, as in myasthenia gravis, then the muscles are unable to contract. Not only the voluntary muscles, but those connected with the acts of swallowing, breathing, and the like, become progressively weaker. Rest and avoidance of undue exertion are necessary, and regular doses of neostigmine bromide, or pyridostigmine, at intervals enable the muscles to be used and in some cases have a curative e?ect. These drugs act by inhibiting the action of cholinesterase – an ENZYME produced in the body which destroys any excess of acetylcholine. In this way they increase the amount of available acetylcholine which compensates for the deleterious e?ect of antibodies on the nerve endings.
The THYMUS GLAND plays the major part in the cause of myasthenia gravis, possibly by being the source of the original acetylcholine receptors to which the antibodies are being formed. Thymectomy (removal of the thymus) is often used in the management of patients with myasthenia gravis. The incidence of remission following thymectomy increases with the number of years after the operation. Complete remission or substantial improvement can be expected in 80 per cent of patients.
The other important aspect in the management of patients with myasthenia gravis is IMMUNOSUPPRESSION. Drugs are now available that suppress antibody production and so reduce the concentration of antibodies to the acetylcholine receptor. The problem is that they not only suppress abnormal antibody production, but also suppress normal antibody production. The main groups of immunosuppressive drugs used in myasthenia gravis are the CORTICOSTEROIDS and AZATHIOPRINE. Improvement following steroids may take several weeks and an initial deterioration is often found during the ?rst week or ten days of treatment. Azathioprine is also e?ective in producing clinical improvement and reducing the antibodies to acetylcholine receptors. These effects occur more slowly than with steroids, and the mean time for an azathioprine remission is nine months.
The Myasthenia Gravis Association, which provides advice and help to sufferers, was created and is supported by myasthenics, their families and friends.... myasthenia gravis
BURSITIS, TENDINITIS and non-speci?c back pain (see BACKACHE).
Osteoarthritis (OA) rarely starts before 40, but by the age of 80 affects 80 per cent of the population. There are structural and functional changes in the articular cartilage, as well as changes in the collagenous matrix of tendons and ligaments. OA is not purely ‘wear and tear’; various sub-groups have a genetic component. Early OA may be precipitated by localised alteration in anatomy, such as a fracture or infection of a joint. Reactive new bone growth typically occurs, causing sclerosis (hardening) beneath the joint, and osteophytes – outgrowths of bone – are characteristic at the margins of the joint. The most common sites are the ?rst metatarsal (great toe), spinal facet joints, the knee, the base of the thumb and the terminal ?nger joints (Heberden’s nodes).
OA has a slow but variable course, with periods of pain and low-grade in?ammation. Acute in?ammation, common in the knee, may result from release of pyrophosphate crystals, causing pseudo-gout.
Urate gout results from crystallisation of URIC ACID in joints, against a background of hyperuricaemia. This high concentration of uric acid in the blood may result from genetic and environmental factors, such as excess dietary purines, alcohol or diuretic drugs.
In?ammatory arthritis is less common than OA, but potentially much more serious. Several types exist, including: SPONDYLARTHRITIS This affects younger men, chie?y involving spinal and leg joints. This may lead to in?ammation and eventual ossi?cation of the enthesis – that is, where the ligaments and tendons are inserted into the bone around joints. This may be associated with disorders in other parts of the body: skin in?ammation (PSORIASIS), bowel and genito-urinary in?ammation, sometimes resulting in infection of the organs (such as dysentery). The syndromes most clearly delineated are ankylosing spondylitis (see SPINE AND SPINAL CORD, DISEASES AND INJURIES OF), psoriatic or colitic spondylitis, and REITER’S SYNDROME. The diagnosis is made clinically and radiologically; no association has been found with autoantibodies (see AUTOANTIBODY). A particularly clear gene locus, HLA B27, has been identi?ed in ankylosing spondylitis. Psoriasis can be associated with a characteristic peripheral arthritis.
Systemic autoimmune rheumatic diseases (see AUTOIMMUNE DISORDERS). RHEUMATOID ARTHRITIS (RA) – see also main entry. The most common of these diseases. Acute in?ammation causes lymphoid synovitis, leading to erosion of the cartilage, associated joints and soft tissues. Fibrosis follows, causing deformity. Autoantibodies are common, particularly Rheumatoid Factor. A common complication of RA is Sjögren’s syndrome, when in?ammation of the mucosal glands may result in a dry mouth and eyes. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) and various overlap syndromes occur, such as systemic sclerosis and dermatomyositis. Autoantibodies against nuclear proteins such as DNA lead to deposits of immune complexes and VASCULITIS in various tissues, such as kidney, brain, skin and lungs. This may lead to various symptoms, and sometimes even to organ failure.
Infective arthritis includes: SEPTIC ARTHRITIS An uncommon but potentially fatal disease if not diagnosed and treated early with approriate antibiotics. Common causes are TUBERCLE bacilli and staphylococci (see STAPHYLOCOCCUS). Particularly at risk are the elderly and the immunologically vulnerable, such as those under treatment for cancer, or on CORTICOSTEROIDS or IMMUNOSUPPRESSANT drugs. RHEUMATIC FEVER Now rare in western countries. Resulting from an immunological reaction to a streptococcal infection, it is characterised by migratory arthritis, rash and cardiac involvement.
Other infections which may be associated with arthritis include rubella (German measles), parvovirus and LYME DISEASE.
Treatment Septic arthritis is the only type that can be cured using antibiotics, while the principles of treatment for the others are similar: to reduce risk factors (such as hyperuricaemia); to suppress in?ammation; to improve function with physiotherapy; and, in the event of joint failure, to perform surgical arthroplasty. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) include aspirin, paracetamol and many recently developed ones, such as the proprionic acid derivatives IBUPROFEN and naproxen, along with other drugs that have similar properties such as PIROXICAM. They all carry a risk of toxicity, such as renal dysfunction, or gastrointestinal irritation with haemorrhage. Stronger suppression of in?ammation requires corticosteroids and CYTOTOXIC drugs such as azathioprine or cyclophosphamide. Recent research promises more speci?c and less toxic anti-in?ammatory drugs, such as the monoclonal antibodies like in?iximab. An important treatment for some osteoarthritic joints is surgical replacement of the joints.... joints, diseases of
Pancreatic cancer The incidence of pancreatic cancer is rising: around 7,000 cases are now diagnosed annually in the UK, accounting for 1–2 per cent of all malignancies. There is an established association with heavy cigarette-smoking, and the cancer is twice as common in patients with diabetes mellitus as compared with the general population. Cancer of the pancreas is hard to diagnose; by the time symptoms occur the tumour may be di?cult to treat surgically – with PALLIATIVE bypass surgery the only procedure.
Chronic pancreatitis may be painless; it leads to pancreatic failure causing MALABSORPTION SYNDROME and diabetes mellitus, and the pancreas becomes calci?ed with shadowing on X-RAYS. The malabsorption is treated by a low-fat diet with pancreatic enzyme supplements; the diabetes with insulin; and pain is treated appropriately. Surgery may be required.
Acute pancreatitis An uncommon disease of the pancreas which may start gradually or suddenly, usually accompanied by severe abdominal pain which often radiates through to the back. Biliary tract disease and alcohol account for 80 per cent of patients admitted with acute pancreatitis, while other causes include drugs (see AZATHIOPRINE and DIURETICS) and infections such as MUMPS. Patients are acutely ill with TACHYCARDIA, fever and low blood pressure; many go into SHOCK. The condition may be mistaken for a perforated PEPTIC ULCER, except that in acute pancreatitis the blood concentration of AMYLASE is raised. The main complication is the formation of a PSEUDOCYST. Treatment includes intravenous feeding, ANTICHOLINERGIC drugs and ANALGESICS. Regular measurements of blood GLUCOSE, CALCIUM, amylase and blood gases are required. Abdominal ULTRASOUND may identify gall-stones (see under GALL-BLADDER, DISEASES OF). If the patient deteriorates, he or she should be admitted for intensive care as haemorrhagic pancreatic necrosis may be developing. LAPAROTOMY and DEBRIDEMENT may be called for. Mortality is 5–10%.... pancreas, disorders of
In autoimmune disorders, disease is due to damage wrought by circulating ANTIBODIES or sensitised lymphocytes (see LYMPHOCYTE). If the disease is due to circulating humoral antibodies, removal of these antibodies from the body should theoretically relieve the disorder. This is the principle on which plasma exchange was used in the management of autoimmune diseases due to circulating antibodies. Such disorders include Goodpasture’s syndrome, SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) and MYASTHENIA GRAVIS. One of the problems in the use of plasma exchange in the treatment of such diseases is that the body responds to the removal of an antibody from the circulation by enhanced production of that antibody by the immune system. It is therefore necessary to suppress this homeostatic response with cytotoxic drugs such as AZATHIOPRINE. Nevertheless, remissions can be achieved in autoimmune diseases due to circulating antibodies by the process of plasma exchange.... plasma exchange
Treatment is with immunosuppressant drugs, such as cyclophosphamide or azathioprine, combined with corticosteroids to alleviate symptoms and attempt to bring about a remission.
With prompt treatment, most people recover completely within about a year, although kidney failure occasionally develops.
Without treatment, complications may occur, including perforation of the nasal septum, causing deformity of the nose; inflammation of the eyes; a rash, nodules, or ulcers on the skin; and damage to the heart muscle, which may be fatal.... wegener’s granulomatosis
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