The term connective tissue disease is used for three diseases systemic lupus erythematosus (SLE), systemic sclerosis, and polymyositis and dermatomyositis, whose relationship is illustrated in Fig. 8.16. The collective term ‘connective tissue disease’ means little but, since the aetiology of these conditions is unknown, it is difficult to suggest a better alternative. The diseases have a number of features in common, including the occurrence of arthritis or arthralgia, multisystem involvement, vasculitis and immunological abnormalities such as circulating autoantibodies and immune complex deposition. Features of all three diseases appear in mixed connective tissue disease.
Systemic lupus erythematosus
SLE is the commonest of the connective tissue disorders and is characterized by the presence in the serum of antibodies against nuclear components. It is a multisystem disease, with arthralgia and rashes as the commonest clinical features, and cerebral and renal disease as the most serious problems.
The disease probably affects about 0.1% of the population and is thus about 20 times less common than RA. It is much commoner in black women in the USA, with a prevalence of up to 1 in 250. It is about nine times as common in women as men, with a peak age of onset between 20 and 40 years.
The cause of SLE is unknown but is probably ultifactorial, including a variable genetic predisposition and environmental factors that trigger the disease. In some cases, genetic predisposition is so strong that minor additional triggers are sufficient. Known predisposing factors include:
HEREDITY: the identical twin of a patient with SLE has a 30% chance of developing the disease; first-degree relatives have a 5% chance. Certain races are especially prone, including Sioux Indians, Africans and Polynesians.
COMPLEMENT DEFICIENCIES of all types.
SEX HORMONE STATUS: women are much more often affected than men. Known environmental triggers include:
DRUGs such as hydralazine.
IN FECT10 N: a virus infection is a popular theory for the cause of lupus and it is easy to see how a DNA virus could lead to the production of antibodies to nuclear material.
The immunological mechanisms of the disease include:
POLYCLONAL B-CELL ACTIVATION. Increased numbers of B cells lead to hyperglobulinaemia.
ANTINUCLEAR ANTIBODIES AND OTHER AUTOANTIBODIES are produced.
IMPAIRED T-CELL REGULATION of the immune response.
FAILURE TO REMOVE IMMUNE COMPLEXES FROM THE CIRCULATION. Circulating immune complexes cause arthralgia; deposition of immune complexes in tissues causes vasculitis and many other features of the disease, including glomerulonephritis. Many immunological abnormalities are seen, including antibodies to human IgG, nuclear protein, smooth muscle,
cytoplasm, organ-specific antibodies, e.g. thyroid, leucocytes, platelets, red cells, clotting factors and cryoglobulins with varying clinical effects. Their role in the pathogenesis, if any, is unknown.
SLE is characterized by a widespread vasculitis affecting capillaries, arterioles and venules. Fibrinoid (an eosinophilic amorphous material) is found along blood vessels and tissue fibres. The synovium of joints may be oedematous and may contain fibrinoid deposits. Haematoxylin bodies (rounded blue homogeneous haernatoxylinstained deposits) are seen in inflammatory infiltrates and are thought to result from the interaction of antinuclear antibodies and cell nuclei. Lesions of other organs are described in the appropriate chapters.
SLE is extremely variable in its manifestation and most of the clinical features are due to the consequences of vasculitis. Mild cases may present only with arthralgia, whilst in severe cases there may be multisystem involvement.
GENERAL FEATURES. Fever is common in exacerbations, occurring in up to 80% of cases. Patients comlain of malaise and tiredness.
HE JOINTS. Joint involvement is the commonest clinical feature (>90%). Patients often present with symp- . ms that sound like RA. Joints are painful but characteristically appear clinically normal, although sometimes there is slight soft-tissue swelling surrounding the joint. Aseptic necrosis affecting the hip or knee is a rare complication of the disease.
THE SKIN. This is affected in 80% of cases. Erythema in a butterfly distribution on the cheeks of the face and across the bridge of the nose is characteristic. Vasculitic lesions on the fingertips and around the nail folds, purpura and urticaria occur. In one-third of cases there is photosensitivity and prolonged exposure to sunlight can lead to exacerbations of the disease. Livedo reticularis, palmar and plantar rashes, pigmentation and alopecia may be seen. Raynaud’s phenomenon is common and may precede the development of arthralgia and other clinical problems by years. Immunofluorescence of ‘normal’ skin will show immunoglobulin and complement deposition at the dermo-epiderrnal junction, which is known as the positive band test.
THE LUNGS. Up to two-thirds of patients will have lung involvement sometime during the course of the disease. Recurrent pleurisy and pleural effusions (exudates) are the commonest manifestations. Pneumonitis and atelectasis may be seen; eventually a restrictive lung defect develops. Rarely, pulmonary fibrosis occurs. THE HEART. This is involved in over 40% of cases. Pericarditis, with small pericardial effusions detected by echocardiography, is common. A mild myocarditis also occurs. Aortic valve lesions and a cardiomyopathy can rarely be present. Endocarditis involving the mitral valve (Libman-Sacks syndrome) is very rare.
THE KIDNEYS. These are affected in 30-50% of cases. Proteinuria (>1 g per 24 hours) is common. The renal histological lesions consist of minimal change, proliferative changes (either focal, diffuse or crescentic) or a membranous glomerulonephritis. Most patients with or without renal disease have immune complex deposits in their kidneys.
Hypertension may occur owing to progression to either the nephrotic syndrome or renal failure.
THE NERVOUS SYSTEM. Involvement of the nervous system occurs in 60% of cases. There may be a mild depression but occasionally more severe psychiatric disturbances occur. Epilepsy, cerebellar ataxia, aseptic meningitis, cranial nerve lesions, cerebrovascular accidents or peripheral neuropathy may be seen. These lesions may be due to vasculitis or immune-complex deposition.
THE EYES. Retinal lesions include cytoid bodies, which appear as hard exudates, and haemorrhages. Blindness is uncommon. Secondary Sjogren’s syndrome may be seen.
THE GASTROINTESTINAL SYSTEM. SLE often causes gastrointestinal symptoms, although these are usually not a major presenting feature. Symptoms include nausea, vomiting, anorexia and diarrhoea.
DISCOID LUPUS. is a benign variant of the disease in which skin involvement is often the only feature, although systemic abnormalities may occur with time. The rash is characteristic and appears on the face as welldefined erythematous plaques that progress to scarring and pigmentation.
DRUG-INDUCED SLE. This is usually characterized by arthralgia and mild systemic features, rashes and pericarditis, but seldom renal or cerebral disease. It usually disappears when the drug causing it is stopped. Hydralazine and procainamide are the most likely causes, but other drugs have occasionally been implicated.
MIXED CONNECTIVE TISSUE DISEASE.
A FULL BLOOD COUNT usually shows an anaemia (usually normochromic normocytic), neutropenia and thrombocytopenia. An autoimmune haemolytic anaemia may occur. The ESR is raised in proportion to the disease activity. In contrast, the eRP is normal.
SERUM ANTINUCLEAR ANTIBODIES ARE POSITIVE in almost all cases. dsDNA binding is specific for SLE, although it is only present in 50% of cases, particularly those with severe systemic involvement, e.g. renal disease.
SERUM RHEUMATOID FACTOR is positive in half of the patients.
SERUM COMPLEMENT LEVELS are reduced during active disease. Immunoglobulins are raised (usually IgG and IgM).
CHARACTERISTIC HISTOLOGICAL ABNORMALITIES are seen in biopsies from, for example, the kidney.
Systemic corticosteroid therapy is the mainstay of treatment in SLE, although patients with mild disease and arthralgia can be managed with NSAIDs. In cases where steroids are required, they should be used in small doses for short periods just sufficient to suppress the disease in order to minimize complications. Active SLE, with fever and pleurisy, should be treated with prednisolone 30 mg daily, the dose being reduced over the course of a few weeks to a maintenance level of around 5-10 mg daily. It may be possible to stop treatment in such a patient within a few months.
Two other types of drug are used in the management of SLE:
1 The antimalarial drug hydroxychloroquine (400 mg daily) is useful for suppressing the disease activity in patients with minor manifestations such as arthralgia that cannot be controlled with NSAIDs or troublesome skin lesions. Ocular toxicity may occur.
2 Immunosuppressive drugs are used for patients with more serious disease manifestations such as renal disease, usually in combination with steroids. Azathioprine (2 mg kg:’ daily) is most often used; chlorambucil is an alternative and cyclophosphamide is reserved for patients with life-threatening disease. Immunosuppressive drugs also have a useful steroid-sparing effect.
Patients should be told about their disease and its management. Patients with photosensitivity problems should avoid excessive exposure to sunlight. There is no major contraindication to pregnancy. However, there is an increased rate of fetal loss and complications may arise during the pregnancy; specialist care should therefore be available.
COURSE AND PROGNOSIS
An episodic course is characteristic, with exacerbations and complete remissions that may last for long periods of time. These remissions may occur even in patients with renal disease. A chronic course is occasionally seen. Earlier estimates of the mortality in SLE were exaggerated; 5- year survival rate is about 95%. In most cases the pattern of the disease becomes established in the first few years;
if serious problems have not developed in this time, they are unlikely to do so. The arthritis is usually intermittent. Chronic progressive destruction of joints as seen in RA and OA does not occur, but a few patients develop deformities such as ulnar deviation.
This condition was first described in a small proportion of patients with SLE but over the years it has become clear that it is much commoner than SLE and that most patients do not have SLE. The syndrome is characterized by the presence of antiphospholipid antibodies, which are thought to playa role in thrombosis by an effect on platelet membranes, endothelial cells and on clotting compounds such as prothrombin, protein C and protein S.
The major features are:
ARTERIAL AND VENOUS THROMBOSES-17% of strokes occurring under the age of 45 years are thought to be due to the antiphospholipid syndrome. Thromboses of different types occur and cause other features of the disease including the Budd-Chiari syndrome and Addison’s disease.
ABORTIONS-27% of women who have had more than two abortions have the antiphospholipid syndrome.
CHOREA, MIGRAINE AND EPILEPSY.
VALVULAR HEART DISEASE.
ATHEROMA. The syndrome may also be important In the development of accelerated atheroma.
Anti-cardiolipin antibodies are diagnostic. The ESR is usually normal and antinuclear antibodies are usually negative.
Anticoagulants: small doses of aspirin in mild cases; warfarin in severe cases; heparin in early pregnancy because warfarin is toxic to the fetus.
Systemic sclerosis is a multisystem disease that predominantly affects the skin and presents with Raynaud’s phenomenon in over three-quarters of cases. It is less common than SLE. The major features distinguishing systemic sclerosis from polymyositis and SLE are shown . It is commoner in women than men (3 : 1) and can appear at any age under 50 years.
The aetiology of systemic sclerosis is unknown. Abnormalities in both humoral and cellular immunity have been documented. A positive speckled or nucleolar antinuclear antibody is found in up to 60% of patients. Familial cases have been documented and HLA-B8, DR3 has been reported to occur with greater frequency in systemic sclerosis. A similar syndrome can be produced by certain chemicals, including polyvinyl chloride and in poisoning with adulterated oil (toxic epidermal syndrome).
In the early phase the skin is oedematous, with perivascular lymphocyte infiltration and degeneration of collagen fibres. Later there is an increase in collagen. Small blood vessels show intimal proliferation and obliteration. Progressive fibrosis is the major feature of visceral involvement.
The involvement of various organs is shown.
The cutaneous changes that occur are described . Sclerosis of the skin can lead to beaking of the nose and difficulty in opening the mouth. Other changes seen in the skin include telangiectasis, pigmentation or depigmentation, ulceration and calcinosis. Raynaud’s phenomenon often occurs; it is described
The gastrointestinal system
Oesophageal involvement is almost invariable, although only half of these patients will have symptoms of heartburn or dysphagia. A barium swallow may show delayed peristalsis, dilatation or stricture formation, but oesophageal manometry is the most sensitive test. This shows lack of distal oesophageal peristalsis and a reduced oesophageal sphincter pressure.
The small bowel can be involved, producing malabsorption from bacterial overgrowth due to dilatation and atony. Dilatation and atony may also affect the colon. The joints and muscles The fibrotic process can affect tendons, causing flexion deformities of the fingers. The small joints of the hands are affected in 25% of patients, particularly in the early stages of the disease. Soft-tissue swelling of the fingers produces ‘sausage fingers’. Progressive changes in joints are not seen. Myopathy and myositis occur and electromyogram EMG abnormalities are common.
Lower-lobe fibrosis leads to cyst formation and honeycombing in advanced cases. Gas transfer and restrictive ventilatory defects are seen. Aspiration pneumonia and pulmonary hypertension may occur.
Diffuse myocardial fibrosis with arrhythmias (in 25%) and conduction defects may occur. Effusions accompany pericardial disease.
This is the most serious manifestation of the disease and is caused by an obliterative endarteritis of renal vessels. It can cause renal failure and malignant hypertension. The eyes Sjogren’s syndrome with keratoconjunctivitis sicca may be seen.