Br.J. Anaesth. (1979), 51, 13
AUTOIMMUNITY AND AUTOIMMUNE DISEASE A. J. REES
TABLE I. Classification of autoimmunity. {Cell-mediated response is not included because its role in autoimmune disease is uncertain)
Auto-antibody responses Immune complex disease Unknown mechanism
Normal, e.g. anti-idiotypes Pathological, e.g. •••••_ such as SLE. More recently, autoantibodies have been described in life-threatening bullous disease. Pemphigus vulgaris. Pemphigus affects the middleaged. It is characterized by generalized flaccid blisters which show little tendency to heal. Before the advent of steroids, the disease was uniformly fatal and even now mortality is high. Diagnosis is clinical and confirmed by histology and immunofluorescent examination of the skin which shows IgG (autoantibody) deposits in the inter-cellular space. 5 13 Pemphigoid. Pemphigoid affects older patients and SEPTEMBER the bullae are more resiliant. Antibodies to skin basement membrane can be demonstrated in 80% of FIG 2. Record of an individual patient with Goodpasture's syndrome. patients. High-dose steroids are the mainstay of therapy, but azathioprine and methotrexate have also been used. creases after pulmonary haemorrhage (Ewan et al., 1976). Pulmonary haemorrhage is exacerbated by An autoimmune basis of some less severe skin fluid overload, so that great care must be taken when diseases such as herpes gestationes has also been transfusion is used to correct severe anaemia, which is demonstrated; standard texts should be consulted for a feature of this disease. details about them. Muscle disease (Walton, 1977) Renal disease Myasthenia gravis is caused by an antibody to Antibody-mediated glomerulonephritis (Wilson and acetylcholine receptors on the post-synaptic memDixon, 1973; Rees, Lockwood and Peters, 1978). brane, which either blocks receptors or accelerates Antibodies to glomerular basement membrane (GBM} their degradation. Young women are most commonly are a rare but usually devastating cause of disease. affected and abnormalities of the thymus, either Although subacute forms do occur, the nephritis is hyperplasia or adenoma, are found in 80% of patients. usually fulminant and renal function may be lost in a Cardinal symptoms are muscle weakness and fatigumatter of hours (fig. 2). Examination of urine reveals ability; the severity varies greatly and exacerbations an abnormal sediment and proteinuria, plasma urea follow intercurrent infection. Involvement of bulbar and creatinine reflect renal function whilst renal or respiratory muscles may lead to respiratory failure. biopsies show focal necrotizing glomerulonephritis Clinical diagnosis is confirmed by the tensilon test. with crescents. Immunofluorescent preparations re- A favourable response to this short-acting antiveal characteristic linear staining of the GBM with cholinesterase should be seen within minutes of i.v. IgG. Anti-GBM antibodies also cross-react with injection. Laboratory investigations are usually alveolar basement membrane and about 90% of normal, except for the presence of anti-receptor antipatients have pulmonary haemorrhage which may bodies. Patients with IgA deficiency have been precipitate respiratory failure. Even severe pulmonary described occasionally. haemorrhage may not cause haemoptysis, in which Conventional treatment is with long-acting anticase confirmation of the radiological diagnosis can be cholinesterases, such as pyridostigmine. Improveaccomplished by measurement of uptake of carbon ment may follow thymectomy, even when the gland is monoxide per unit volume of lung (&CO) which in- histologically normal. High-dose steroids are a useful
18 adjunct in refractory cases, but must be introduced gradually to avoid the risk of acute exacerbations. Recently, the benefits of plasma exchange and immunosuppressive drugs have been shown fPinching, Peters and Newsome-Davies, 1977). They are discussed elsewhere in this issue (p. 21).
BRITISH JOURNAL OF ANAESTHESIA TABLE III. Systemic lupus: cardinal features Musculo-articular Cutaneous Fever Neuro-psychiatric Renal Pulmonary Haematological
Investigations
DNA binding increased Positive ANF LE cells Complement reduced Immune complexes present
Immune complex disease
As alluded to above, immune complex (IC) disease is much more variable than that resulting from antibodies. This reflects the sites where complexes deposit; the joints, skin and kidney seem peculiarly vulnerable. Several distinct syndromes have been defined, these divisions are arbitrary but are retained for clinical convenience rather than from scientific merit. Techniques for measuring IC in sera have recently been developed. There is as yet not one ideal assay and current assays detect different properties of the complexes. Consequently the proportion of "positive" patients with a particular disease depends on which assay is used (fig. 3). Despite this, results from
prominently affected. Additional features result from autoantibodies to red cells, platelets, lymphocytes and cerebral tissue. Common presenting features are a photosensitive rash and arthralgia, but more severe disease, for example glomerulonephritis or cerebral disease, may be manifest from the outset. Pulmonary haemorrhage is an unusual but severe complication. Investigation should include a full blood count and a thorough search for renal involvement, including microscopy of a fresh specimen of urine. Immunological tests reveal the hallmark of the disease—antiDNA antibodies—and their detection has replaced LE cells as the arbiter of diagnosis. Anti-nuclear factor (ANF) is also positive, but less specific. Immune complexes are present in about 50% of patients. Low serum concentrations of complement (low C2, C4, C3) are almost invariable in active disease. Treatment of mild disease is with simple antiinflammatory drugs. More severe disease requires steroids, or sometimes immunosuppressive drugs and plasma exchange. FIG. 3. Detection limitations of different IC assays in Rheumatoid arthritis (Bluestone and Bacon, 1977). connective tissue disease. Positive immune complex assays Rheumatoid arthritis is a chronic deforming disease within the circles Clq, Raji and RhF are three separate assays. RA = rheumatoid arthritis; SLE = systemic lupus thought to be caused by immune complexes. Women erythematosis; PSS = scleroderma; MCTD = mixed con- are mainly affected and the frequency increases until nective tissue disease. the sixth decade. Initial symptoms are confined to joints, especially the hands, wrists, knees and hips. some assays can be clearly correlated with intensity of Subcutaneous nodules are pathognomic and are disease activity (Pussell et al., 1978). However, it still found in 20-25% of patients. Extra-articular has to be proved in human disease—as opposed to manifestations are less common, but haemolytic experimental analogues—that the complexes detected anaemia caused by hypersplenism (Feltys Syndrome), in the circulation are pathogenic. With this caveat, lung disease with effusions, nodules and fibrosis, and systemic vasculitis may occur. some individual diseases will now be considered. Rheumatoid factors—antibodies to immunoSystemic lupus erythematosis (Hughes, 1977) (table III). SLE is often regarded as the archetypal immune globulins—are a hallmark of the disease, but are only complex disease. Signs and symptoms are protean: positive in 60% of patients when tested by conskin, joints, kidney and central nervous sytem are ventional means. Immune complexes are found in
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 7, 2015
Clinical
AUTOIMMUNITY AND AUTOIMMUNE DISEASE most patients, but complement concentrations are normal. Treatment is with simple anti-inflammatory drugs and steroids are used only when vasculitis is present. Polyarteritis nodosa (PAN) (Rose and Spencer, 1957) (table IV). PAN is characterized by widespread TABLE IV. Polyarteritis: cardinal features Clinical
Leucocytosis Hyperglobulinaemia Rheumatoid factor Biopsy: vasculitis, glomerulonephritis Arteriography: aneurisms.
vasculitis that may affect any organ. In some parts of the world it is associated with chronic carriage of hepatitis B antigen, but this does not seem to be true in the U.K. Typical presenting symptoms are fever, arthralgia, myopathy and weight loss with progression to include peripheral neuropathy, pulmonary vasculitis and renal disease. Severe hypertension and abdominal pain are prominent in those with involvement of medium-sized vessels, whilst a necrotizing glomerulonephritis is found in those in whom smaller vessels are affected. There are no pathognomic laboratory tests. Neutrophilia and eosinophilia are common; urinary investigations provide evidence of nephritis. Immunological investigations are similarly non-specific and results of muscle biopsies are usually equivocal. Renal biopsies reveal the nephritis, but when severe hypertension is present, visceral arteriography is the most important investigation. It may reveal multiple aneurysms and should be regarded as an emergency. Treatment is discussed elsewhere in the issue (Pinching, p. 21). Wegener's granulomatosis (Fauci and Wolff, 1973).
Wegener's should probably be regarded as a variant of the microscopic form of PAN. Most of the clinical features are identical, but in addition granulomata in the upper respiratory tract and lungs cause local symptoms. There are no pathognomonic immunological features; the treatment is discussed by Pinching (p. 21). Other vasculitides. Henoch-Schonlein purpura (Meadow et al., 1972) predominantly affects children;
and is characterized by arthritis vasculitis and glomerulonephritis. The rash is characteristic. There are no special serological features, but IgA deposited, in kidney and skin offers a useful confirmation cf diagnosis. Mixed cryoglobulinaemia (Brouet et al., 1974) affects the elderly. Cryoglobulins (proteins that precipitate in the cold) are found in serum and are associated with severe cutaneous vasculitis and some times glomerulonephritis. Plasma exchange may be beneficial. Diseases of unknown aetiology
Scleroderma (systemic sclerosis) (Cannon et al., 1974). This disease chiefly affects women and is characterized by diffuse sclerosis of the skin, gastrointestinal tract, heart and lungs. Raynaud's phenomenon is found in 80% of patients. The sudden development of accelerated hypertension and irreversible renal failure is the commonest cause of death. Treatment is unsatisfactory, but recently isolated reports suggest that vigorous control of the hypertension may allow the kidneys to recover in some patients. Polymyositis and dermatomyositis (Pearson, 1974).
This disease is characterized by progressive muscle weakness that may be accompanied by a rash; proximal muscles are particularly severely affected but pharyngeal and respiratory muscles may also be involved. Careful monitoring of respiratory function (for example vital capacity) is mandatory. Forty per cent of patients have skin changes which are frequently diagnostic. They consist of a purplish rash on the upper eyelids which is associated with periorbital oedema. Development of the disease is frequently associated with an occult neoplasm. Investigations show increased concentrations of muscle enzymes (cp.k., s.g.o.t. and aldolase); e.m.g. and muscle biopsy may also be diagnostic. Treatment is unsatisfactory and involves large doses of steroids; plasma exchange does not seem to be beneficial. CONCLUSIONS
Experimental studies have provided clear, although as yet incomplete, ideas of the basis of autoimmunity and have identified novel approaches to therapy such as plasma exchange combined with immunosuppressive drugs. Unfortunately, despite this, numerous immediate clinical problems remain, especially in the management of life-threatening disease. One of the most pressing of these is to distinguish between infection and fulminant immune
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 7, 2015
Investigations
Fever Rash Glomerulonephritis Hypertension Acute abdomen Neuropathy (mononeuritis multiplex) Pulmonary haemorrhage
19
20
BRITISH JOURNAL OF ANAESTHESIA
Fauci, A. S., and Wolff, S. M. (1973). Wegener's granulomatosis: studies in eighteen patients and a review of the literature. Medicine, 52, 535. Gell, P. G. H., and Coombs, R. R. A. (eds) (1962). Clinical Aspects of Immunology. Oxford: Blackwell. TABLE V. Autoimmune disease: aims in the critically ill Haakenstad, A. O., and Mannik, M. (1977). The biology of immune complexes; in Autoimmunity (ed. N. Talal). New (1) Distinguish disease activity from infection York: Academic Press. (2) Establish definite diagnosis Hughes, G. V. R. (1977). The Connective Tissue Diseases. (3) Start specific therapy Oxford: Blackwell. Jerne, N. K. (1973). The immune system. Set. Am., 229,52. immunosuppressive drugs which increase suscepti- Lachman, P. J., and Hobart, M. J. (1978). Complement genetics in relation to HLA. Br. Med. Bull., 34, 247. bility to infection, and second, infection itself can Meadow, S. R., Glasgow, E. F., White, R. M. R., Moncreiff, exacerbrate the underlying disease. The choice is M. W., Cameron, J. S., and Ogg, C. S. (1972). Schonleinoften between more immunosuppression, or less. Henoch nephritis. Q.J. Med., 41, 241. Under these circumstances early invasive investiga- Pearson, C. M. (1974). Polymyositis and related disorders; in Disorders of Voluntary Muscle (ed. J. N. Walton). tions, especially with regard to possible chest inEdinburgh and London: Churchill Livingstone. fections require early bronchoscopy and lung biopsy, Pinching, A. J., Peters, D. K., and Newsom-Davis, J. which should be mandatory where uncertainty exists. (1976). Remission of myasthenia gravis following plasma Currently there are few reliable indices of disease exchange. Lancet, 2, 1373. activity and many judgements need to be purely Pussell, B. A., Lockwood, C. M., Scott, D. M., Pinching, A. J., and Peters, D. K. (1978). The value of immune clinical. complex assays in diagnosis and management. Lancet, 2, Finally, it must be stressed that, without excellent 359. basic medical care of cardiorespiratory and other Rees, A. J., Lockwood, C. M., and Peters, D. K. (1977). Enhanced allergic tissue injury in Goodpasrure's syndrome systems, attention to asceptic techniques and good by intercurrent infection. Br. Med. J., 2, 723. nursing, complex and potentially dangerous modern (1978). Nephritis due to antibodies to approaches to therapy are little more than an extravaglomerular basement membrane; in Progress in Glomerugant waste of time. lonephritis (eds P. Kincaid-Smith and A. J. F. d'Apice). New York: John Wiley. REFERENCES Roitt, I. M. (1977). Essential Immunology. Oxford: Blackwell. Bluestone, R., and Bacon, P. A. (eds) (1977). Extra-articular Rose, G. A., and Spencer, K. (1957). Polyarteritis nodosa. manifestations of rheumatoid arthritis. Clin. Rheum. Dis., Q.J. Med., 26, 43. 3,3. Rose, N. R., Bacon, L. D., Sundick, R. S., Kong, Y. M., Bodmer, W. F. (ed.) (1978). The HLA system. Br. Med. Esquivel, P., and Bigazzi, P. E. (1977). Genetic regulation Bull., 34, 213. in autoimmune thyroiditis; in Autoimmunity (ed. N. Brouet, J.-C, Clauvel, J.-P., Danon, F., Klein, M., and Talal), p. 63. New York: Academic Press. Seligman, M. (1974). Biological and clinical significance of Soothill, J. (1975). Immunodeficiency; in Clinical Aspects of cryoglobulins. Am. J. Med., 57, 775. Immunology (eds P. G. H. Gell and R. R. A. Coombs). Cannon, P. J., Hassan, M., Case, D. B., Casarella, W. J., Oxford: Blackwell. Sommers, S. C , and Leroy, E. C. (1974). The relationship Talal, N. (ed.) (1977). Autoimmunity. New York: Academic of hypertension and renal failure in scleroderma (systemic Press. sclerosis) to structural and functional abnormalities of Volpe, R. (1977). The role of autoimmunity in hypoendocrine and hyperendocrine function. Ann. Int. Med., renal cortical circulation. Medicine, 53, 1. Cochrane, C. G.5 and Koffler, D. (1973). Immune complex 87, 86. disease in experimental animals and man. Adv. Immunol., Walton, J. N. (1977). Brain's Diseases of the Nervous System, p. 1017. Oxford: Blackwell. 16, 185. Dacie, J. V., and Worlledge, S. (1975). Auto-allergic blood Weigle, W. O. (1973). Immunological unresponsiveness. Adv. Immunol., 16, 61. diseases; in Clinical Aspects of Immunology (eds P. G. H. Weissman, G. (ed.) (1975). Mediators and Inflammation. Gell and R. R. A. Coombs). Oxford: Blackwell. New York: Plenum. Dresser, D. W. (ed.) (1976). Tolerance. Br. Med. Bull, 32,2. Ewan, P. W., Jones, H. A., Rhodes, C. G., and Hughes, Wilson, C. B., and Dixon, F. J. (1973). Anti-glomerular basement membrane-induced nephritis. Kidney Int., J. M. B. (1976). Detection of intrapulmonary haemorrhage 3,74. with carbon monoxide uptake. N. Engl.J. Med., 295, 139.
complex disease (table V). This difficulty is made worse by two factors; first, treatment of severe autoimmune disease almost invariably involves steroids or
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 7, 2015
AUTOIMMUNITY AND AUTOIMMUNE DISEASE A. J. REES
TABLE I. Classification of autoimmunity. {Cell-mediated response is not included because its role in autoimmune disease is uncertain)
Auto-antibody responses Immune complex disease Unknown mechanism
Normal, e.g. anti-idiotypes Pathological, e.g. •••••_ such as SLE. More recently, autoantibodies have been described in life-threatening bullous disease. Pemphigus vulgaris. Pemphigus affects the middleaged. It is characterized by generalized flaccid blisters which show little tendency to heal. Before the advent of steroids, the disease was uniformly fatal and even now mortality is high. Diagnosis is clinical and confirmed by histology and immunofluorescent examination of the skin which shows IgG (autoantibody) deposits in the inter-cellular space. 5 13 Pemphigoid. Pemphigoid affects older patients and SEPTEMBER the bullae are more resiliant. Antibodies to skin basement membrane can be demonstrated in 80% of FIG 2. Record of an individual patient with Goodpasture's syndrome. patients. High-dose steroids are the mainstay of therapy, but azathioprine and methotrexate have also been used. creases after pulmonary haemorrhage (Ewan et al., 1976). Pulmonary haemorrhage is exacerbated by An autoimmune basis of some less severe skin fluid overload, so that great care must be taken when diseases such as herpes gestationes has also been transfusion is used to correct severe anaemia, which is demonstrated; standard texts should be consulted for a feature of this disease. details about them. Muscle disease (Walton, 1977) Renal disease Myasthenia gravis is caused by an antibody to Antibody-mediated glomerulonephritis (Wilson and acetylcholine receptors on the post-synaptic memDixon, 1973; Rees, Lockwood and Peters, 1978). brane, which either blocks receptors or accelerates Antibodies to glomerular basement membrane (GBM} their degradation. Young women are most commonly are a rare but usually devastating cause of disease. affected and abnormalities of the thymus, either Although subacute forms do occur, the nephritis is hyperplasia or adenoma, are found in 80% of patients. usually fulminant and renal function may be lost in a Cardinal symptoms are muscle weakness and fatigumatter of hours (fig. 2). Examination of urine reveals ability; the severity varies greatly and exacerbations an abnormal sediment and proteinuria, plasma urea follow intercurrent infection. Involvement of bulbar and creatinine reflect renal function whilst renal or respiratory muscles may lead to respiratory failure. biopsies show focal necrotizing glomerulonephritis Clinical diagnosis is confirmed by the tensilon test. with crescents. Immunofluorescent preparations re- A favourable response to this short-acting antiveal characteristic linear staining of the GBM with cholinesterase should be seen within minutes of i.v. IgG. Anti-GBM antibodies also cross-react with injection. Laboratory investigations are usually alveolar basement membrane and about 90% of normal, except for the presence of anti-receptor antipatients have pulmonary haemorrhage which may bodies. Patients with IgA deficiency have been precipitate respiratory failure. Even severe pulmonary described occasionally. haemorrhage may not cause haemoptysis, in which Conventional treatment is with long-acting anticase confirmation of the radiological diagnosis can be cholinesterases, such as pyridostigmine. Improveaccomplished by measurement of uptake of carbon ment may follow thymectomy, even when the gland is monoxide per unit volume of lung (&CO) which in- histologically normal. High-dose steroids are a useful
18 adjunct in refractory cases, but must be introduced gradually to avoid the risk of acute exacerbations. Recently, the benefits of plasma exchange and immunosuppressive drugs have been shown fPinching, Peters and Newsome-Davies, 1977). They are discussed elsewhere in this issue (p. 21).
BRITISH JOURNAL OF ANAESTHESIA TABLE III. Systemic lupus: cardinal features Musculo-articular Cutaneous Fever Neuro-psychiatric Renal Pulmonary Haematological
Investigations
DNA binding increased Positive ANF LE cells Complement reduced Immune complexes present
Immune complex disease
As alluded to above, immune complex (IC) disease is much more variable than that resulting from antibodies. This reflects the sites where complexes deposit; the joints, skin and kidney seem peculiarly vulnerable. Several distinct syndromes have been defined, these divisions are arbitrary but are retained for clinical convenience rather than from scientific merit. Techniques for measuring IC in sera have recently been developed. There is as yet not one ideal assay and current assays detect different properties of the complexes. Consequently the proportion of "positive" patients with a particular disease depends on which assay is used (fig. 3). Despite this, results from
prominently affected. Additional features result from autoantibodies to red cells, platelets, lymphocytes and cerebral tissue. Common presenting features are a photosensitive rash and arthralgia, but more severe disease, for example glomerulonephritis or cerebral disease, may be manifest from the outset. Pulmonary haemorrhage is an unusual but severe complication. Investigation should include a full blood count and a thorough search for renal involvement, including microscopy of a fresh specimen of urine. Immunological tests reveal the hallmark of the disease—antiDNA antibodies—and their detection has replaced LE cells as the arbiter of diagnosis. Anti-nuclear factor (ANF) is also positive, but less specific. Immune complexes are present in about 50% of patients. Low serum concentrations of complement (low C2, C4, C3) are almost invariable in active disease. Treatment of mild disease is with simple antiinflammatory drugs. More severe disease requires steroids, or sometimes immunosuppressive drugs and plasma exchange. FIG. 3. Detection limitations of different IC assays in Rheumatoid arthritis (Bluestone and Bacon, 1977). connective tissue disease. Positive immune complex assays Rheumatoid arthritis is a chronic deforming disease within the circles Clq, Raji and RhF are three separate assays. RA = rheumatoid arthritis; SLE = systemic lupus thought to be caused by immune complexes. Women erythematosis; PSS = scleroderma; MCTD = mixed con- are mainly affected and the frequency increases until nective tissue disease. the sixth decade. Initial symptoms are confined to joints, especially the hands, wrists, knees and hips. some assays can be clearly correlated with intensity of Subcutaneous nodules are pathognomic and are disease activity (Pussell et al., 1978). However, it still found in 20-25% of patients. Extra-articular has to be proved in human disease—as opposed to manifestations are less common, but haemolytic experimental analogues—that the complexes detected anaemia caused by hypersplenism (Feltys Syndrome), in the circulation are pathogenic. With this caveat, lung disease with effusions, nodules and fibrosis, and systemic vasculitis may occur. some individual diseases will now be considered. Rheumatoid factors—antibodies to immunoSystemic lupus erythematosis (Hughes, 1977) (table III). SLE is often regarded as the archetypal immune globulins—are a hallmark of the disease, but are only complex disease. Signs and symptoms are protean: positive in 60% of patients when tested by conskin, joints, kidney and central nervous sytem are ventional means. Immune complexes are found in
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 7, 2015
Clinical
AUTOIMMUNITY AND AUTOIMMUNE DISEASE most patients, but complement concentrations are normal. Treatment is with simple anti-inflammatory drugs and steroids are used only when vasculitis is present. Polyarteritis nodosa (PAN) (Rose and Spencer, 1957) (table IV). PAN is characterized by widespread TABLE IV. Polyarteritis: cardinal features Clinical
Leucocytosis Hyperglobulinaemia Rheumatoid factor Biopsy: vasculitis, glomerulonephritis Arteriography: aneurisms.
vasculitis that may affect any organ. In some parts of the world it is associated with chronic carriage of hepatitis B antigen, but this does not seem to be true in the U.K. Typical presenting symptoms are fever, arthralgia, myopathy and weight loss with progression to include peripheral neuropathy, pulmonary vasculitis and renal disease. Severe hypertension and abdominal pain are prominent in those with involvement of medium-sized vessels, whilst a necrotizing glomerulonephritis is found in those in whom smaller vessels are affected. There are no pathognomic laboratory tests. Neutrophilia and eosinophilia are common; urinary investigations provide evidence of nephritis. Immunological investigations are similarly non-specific and results of muscle biopsies are usually equivocal. Renal biopsies reveal the nephritis, but when severe hypertension is present, visceral arteriography is the most important investigation. It may reveal multiple aneurysms and should be regarded as an emergency. Treatment is discussed elsewhere in the issue (Pinching, p. 21). Wegener's granulomatosis (Fauci and Wolff, 1973).
Wegener's should probably be regarded as a variant of the microscopic form of PAN. Most of the clinical features are identical, but in addition granulomata in the upper respiratory tract and lungs cause local symptoms. There are no pathognomonic immunological features; the treatment is discussed by Pinching (p. 21). Other vasculitides. Henoch-Schonlein purpura (Meadow et al., 1972) predominantly affects children;
and is characterized by arthritis vasculitis and glomerulonephritis. The rash is characteristic. There are no special serological features, but IgA deposited, in kidney and skin offers a useful confirmation cf diagnosis. Mixed cryoglobulinaemia (Brouet et al., 1974) affects the elderly. Cryoglobulins (proteins that precipitate in the cold) are found in serum and are associated with severe cutaneous vasculitis and some times glomerulonephritis. Plasma exchange may be beneficial. Diseases of unknown aetiology
Scleroderma (systemic sclerosis) (Cannon et al., 1974). This disease chiefly affects women and is characterized by diffuse sclerosis of the skin, gastrointestinal tract, heart and lungs. Raynaud's phenomenon is found in 80% of patients. The sudden development of accelerated hypertension and irreversible renal failure is the commonest cause of death. Treatment is unsatisfactory, but recently isolated reports suggest that vigorous control of the hypertension may allow the kidneys to recover in some patients. Polymyositis and dermatomyositis (Pearson, 1974).
This disease is characterized by progressive muscle weakness that may be accompanied by a rash; proximal muscles are particularly severely affected but pharyngeal and respiratory muscles may also be involved. Careful monitoring of respiratory function (for example vital capacity) is mandatory. Forty per cent of patients have skin changes which are frequently diagnostic. They consist of a purplish rash on the upper eyelids which is associated with periorbital oedema. Development of the disease is frequently associated with an occult neoplasm. Investigations show increased concentrations of muscle enzymes (cp.k., s.g.o.t. and aldolase); e.m.g. and muscle biopsy may also be diagnostic. Treatment is unsatisfactory and involves large doses of steroids; plasma exchange does not seem to be beneficial. CONCLUSIONS
Experimental studies have provided clear, although as yet incomplete, ideas of the basis of autoimmunity and have identified novel approaches to therapy such as plasma exchange combined with immunosuppressive drugs. Unfortunately, despite this, numerous immediate clinical problems remain, especially in the management of life-threatening disease. One of the most pressing of these is to distinguish between infection and fulminant immune
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 7, 2015
Investigations
Fever Rash Glomerulonephritis Hypertension Acute abdomen Neuropathy (mononeuritis multiplex) Pulmonary haemorrhage
19
20
BRITISH JOURNAL OF ANAESTHESIA
Fauci, A. S., and Wolff, S. M. (1973). Wegener's granulomatosis: studies in eighteen patients and a review of the literature. Medicine, 52, 535. Gell, P. G. H., and Coombs, R. R. A. (eds) (1962). Clinical Aspects of Immunology. Oxford: Blackwell. TABLE V. Autoimmune disease: aims in the critically ill Haakenstad, A. O., and Mannik, M. (1977). The biology of immune complexes; in Autoimmunity (ed. N. Talal). New (1) Distinguish disease activity from infection York: Academic Press. (2) Establish definite diagnosis Hughes, G. V. R. (1977). The Connective Tissue Diseases. (3) Start specific therapy Oxford: Blackwell. Jerne, N. K. (1973). The immune system. Set. Am., 229,52. immunosuppressive drugs which increase suscepti- Lachman, P. J., and Hobart, M. J. (1978). Complement genetics in relation to HLA. Br. Med. Bull., 34, 247. bility to infection, and second, infection itself can Meadow, S. R., Glasgow, E. F., White, R. M. R., Moncreiff, exacerbrate the underlying disease. The choice is M. W., Cameron, J. S., and Ogg, C. S. (1972). Schonleinoften between more immunosuppression, or less. Henoch nephritis. Q.J. Med., 41, 241. Under these circumstances early invasive investiga- Pearson, C. M. (1974). Polymyositis and related disorders; in Disorders of Voluntary Muscle (ed. J. N. Walton). tions, especially with regard to possible chest inEdinburgh and London: Churchill Livingstone. fections require early bronchoscopy and lung biopsy, Pinching, A. J., Peters, D. K., and Newsom-Davis, J. which should be mandatory where uncertainty exists. (1976). Remission of myasthenia gravis following plasma Currently there are few reliable indices of disease exchange. Lancet, 2, 1373. activity and many judgements need to be purely Pussell, B. A., Lockwood, C. M., Scott, D. M., Pinching, A. J., and Peters, D. K. (1978). The value of immune clinical. complex assays in diagnosis and management. Lancet, 2, Finally, it must be stressed that, without excellent 359. basic medical care of cardiorespiratory and other Rees, A. J., Lockwood, C. M., and Peters, D. K. (1977). Enhanced allergic tissue injury in Goodpasrure's syndrome systems, attention to asceptic techniques and good by intercurrent infection. Br. Med. J., 2, 723. nursing, complex and potentially dangerous modern (1978). Nephritis due to antibodies to approaches to therapy are little more than an extravaglomerular basement membrane; in Progress in Glomerugant waste of time. lonephritis (eds P. Kincaid-Smith and A. J. F. d'Apice). New York: John Wiley. REFERENCES Roitt, I. M. (1977). Essential Immunology. Oxford: Blackwell. Bluestone, R., and Bacon, P. A. (eds) (1977). Extra-articular Rose, G. A., and Spencer, K. (1957). Polyarteritis nodosa. manifestations of rheumatoid arthritis. Clin. Rheum. Dis., Q.J. Med., 26, 43. 3,3. Rose, N. R., Bacon, L. D., Sundick, R. S., Kong, Y. M., Bodmer, W. F. (ed.) (1978). The HLA system. Br. Med. Esquivel, P., and Bigazzi, P. E. (1977). Genetic regulation Bull., 34, 213. in autoimmune thyroiditis; in Autoimmunity (ed. N. Brouet, J.-C, Clauvel, J.-P., Danon, F., Klein, M., and Talal), p. 63. New York: Academic Press. Seligman, M. (1974). Biological and clinical significance of Soothill, J. (1975). Immunodeficiency; in Clinical Aspects of cryoglobulins. Am. J. Med., 57, 775. Immunology (eds P. G. H. Gell and R. R. A. Coombs). Cannon, P. J., Hassan, M., Case, D. B., Casarella, W. J., Oxford: Blackwell. Sommers, S. C , and Leroy, E. C. (1974). The relationship Talal, N. (ed.) (1977). Autoimmunity. New York: Academic of hypertension and renal failure in scleroderma (systemic Press. sclerosis) to structural and functional abnormalities of Volpe, R. (1977). The role of autoimmunity in hypoendocrine and hyperendocrine function. Ann. Int. Med., renal cortical circulation. Medicine, 53, 1. Cochrane, C. G.5 and Koffler, D. (1973). Immune complex 87, 86. disease in experimental animals and man. Adv. Immunol., Walton, J. N. (1977). Brain's Diseases of the Nervous System, p. 1017. Oxford: Blackwell. 16, 185. Dacie, J. V., and Worlledge, S. (1975). Auto-allergic blood Weigle, W. O. (1973). Immunological unresponsiveness. Adv. Immunol., 16, 61. diseases; in Clinical Aspects of Immunology (eds P. G. H. Weissman, G. (ed.) (1975). Mediators and Inflammation. Gell and R. R. A. Coombs). Oxford: Blackwell. New York: Plenum. Dresser, D. W. (ed.) (1976). Tolerance. Br. Med. Bull, 32,2. Ewan, P. W., Jones, H. A., Rhodes, C. G., and Hughes, Wilson, C. B., and Dixon, F. J. (1973). Anti-glomerular basement membrane-induced nephritis. Kidney Int., J. M. B. (1976). Detection of intrapulmonary haemorrhage 3,74. with carbon monoxide uptake. N. Engl.J. Med., 295, 139.
complex disease (table V). This difficulty is made worse by two factors; first, treatment of severe autoimmune disease almost invariably involves steroids or
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 7, 2015
