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  30.6.2 Cervical malignancy

GAVIN P. SPICKETT AND JOHN G. G. LEDINGHAM

  INTRODUCTION

The term vasculitis embraces a wide variety of conditions in which inflammatory damage to blood vessels is a principal component. The clinical consequences of vasculitis depend on the size and nature of vessels involved, the organs they supply, and the nature of the underlying diagnosis. Most patients with vasculitides will present to physicians in the first instance, but patients with vasculitis affecting major arterial trunks may present to surgeons with, for instance, acute ischaemia of the limbs or abdominal organs. Wegener's granulomatosis is commonly first seen by ear, nose, and throat surgeons since it frequently affects the upper airways and eustachian tubes. Early recognition of a systemic vasculitis is important: most patients respond relatively favourably to medical treatment but have a poor prognosis if left untreated. The diagnosis is often difficult to prove, and in such cases delay in treatment can be particularly hazardous.

The vasculitides can be classified in a number of ways depending on clinical syndromes or histopathological features and size of vessels involved  (see Section 7.3) 35. None of these is yet very satisfactory and a retreat to the use of the simple term ‘vasculitis’ is increasingly favoured. It is important to recognize the considerable overlap which exists between the primary vasculitides, particularly with regard to the size of vessel affected.  Table 1 192 lists the primary and secondary vasculitides. Primary vasculitides can be roughly subdivided by the size of the predominantly affected vessel and by the presence or absence of granulomata. Such a pathological classification as illustrated in  Section 7.3 35 has little intrinsic merit and does not relate to the underlying triggering event.

MECHANISMS OF VASCULAR DAMAGE

The heterogeneous nature of the vasculitides indicates that there is no single explanation for the vascular damage; few primary vasculitic syndromes have a well understood cause. Epidemiological studies and circumstantial evidence suggest that Wegener's granulomatosis, microscopic polyarteritis, and Kawasaki disease may be triggered by infection, but the nature of the agent(s) is unknown. In the secondary vasculitides the mechanisms of vascular damage are related to the immunological products released as a result of the underlying disorder. The specificity of the disease processes for vessels of particular sizes has not been satisfactorily explained.

The inflammatory response involves non-specific phagocyte cells, macrophages, and neutrophils, which are attracted to areas of vascular damage by specific chemotactic factors. These may be released from the vascular endothelium itself, from adherent platelets, or by activation of the complement cascade. Complement is activated locally either by antigen and antibody (classical pathway) or by the damaged endothelium (alternative pathway). The natural amplification of complement activation means that deposition of a small quantity of immune complex rapidly leads to further complement breakdown, release of chemotactic factors, and cellular recruitment. The complement system is linked to the kinin system and the clotting cascade, both of which are activated, leading to increased vascular permeability and thrombus formation. As inflammation progresses, specific T lymphocytes may be recruited: these release lymphokines, further amplifying the cellular response and promoting systemic effects, including the release of acute-phase proteins and fever. Vascular occlusion leads to local tissue infarction, which may be extensive when a major artery is involved. Healing of the vasculitic lesion may lead to local fibrosis.

The role of antibody in the vasculitis syndromes is poorly defined. Autoantibodies directed against various components of the cytoplasm of neutrophils and against endothelial cells have been described in primary vasculitis: although such antibodies may play a primary pathogenetic role in the disease, rather than being secondary markers of tissue damage, the evidence is far from conclusive. Antibody is more obviously involved in the pathogenesis of secondary vasculitis, as in cryoglobulinaemia and the connective tissue disorders.

INVESTIGATION OF POSSIBLE VASCULITIS

Presentations of vasculitis are protean: features which may lead to a surgical consultation are listed in  Table 2 193. The diagnosis is often difficult to prove, and key investigations required to take a suspected diagnosis further are detailed in  Table 3 194.

The inflammatory nature of the major vasculitides is manifest by an elevation in plasma levels of the acute-phase response proteins. C-reactive protein, which has a short half-life and rapid response time, is the most useful of these proteins for both diagnosis and monitoring therapy. For reasons that are unclear, certain closely related conditions such as systemic lupus erythematosus and systemic sclerosis tend to be associated with the production of very little C-reactive protein, while bacterial infection leads to substantial rises in the C-reactive protein levels. Infections masquerading as vasculitis and intercurrent infection in patients with established vasculitic illness may therefore make interpretation of high levels of C-reactive protein difficult. The erythrocyte sedimentation rate (ESR), an established marker of inflammation, is useful for diagnosis but of little value in monitoring therapy as it is largely dependent on the serum concentration of fibrinogen, which has a long half-life and a long response time. It is also affected by red cell morphology and the degree of anaemia. The ESR will nevertheless be raised in most vasculitides.

Serum immunoglobulins tend to be non-specifically elevated; monoclonal immunoglobulins (paraproteins) may be detected in Type II cryoglobulinaemia and also in Cogan's syndrome (ocular interstitial keratitis, often associated with various combinations of systemic vasculitis, aortitis, aortic valve disease, and musculoskeletal disease) and, less commonly, in the connective tissue disorders. A paraprotein can be identified rapidly by serum electrophoresis. Some abnormal immunoglobulin molecules (cryoglobulins) precipitate from the serum when it is cooled: if the peripheral skin temperature falls below this critical level in vivo precipitation may then damage cutaneous vessels. To identify a cryoglobulin, a sample must be taken at 37°C and transported at that temperature to the laboratory, where the clot is allowed to retract at the same temperature. The serum is then removed and then allowed to cool.

Complement levels are valuable indicators which can be used to monitor the activity of systemic lupus erythematosus; in addition, levels are low in some types of cryoglobulinaemia. Both C3 and C4 are acute phase-proteins and their concentrations may be normal even when complement is being consumed; identification of C3 breakdown products may be helpful in demonstrating complement consumption.

Certain syndromes that are accompanied by vasculitis are characterized by the presence of autoantibodies which may be considered to be markers of the disease. This is mainly applicable to the connective tissue disorders  (Table 4) 195. In assessing the importance of these autoantibodies when making a diagnosis, it is important to recognize that, as the immune system ages, spontaneous production of raised levels of autoantibodies becomes more common: in middle-aged and elderly patients low levels are not necessarily indicative of disease. Autoantibody production may also occur transiently following infection, particularly with Epstein-Barr virus.

Rheumatoid factors are autoantibodies directed against the Fc region of human immunoglobulin. High levels are present in seropositive rheumatoid arthritis, and this is associated with the development of nodular and systemic disease. However, they are very poor specific indicators of rheumatoid arthritis since they are produced in response to other inflammatory stimuli and infections, and in the elderly. Their presence does not therefore indicate rheumatoid arthritis unless clinical features are also compatible with this diagnosis.

Antibodies to various neutrophil cytoplasmic antigens have been detected in the plasma of patients with vasculitis syndromes, particularly Wegener's granulomatosis, microscopic polyarteritis, and Churg–Strauss syndrome. In Wegener's granulomatosis and microscopic polyarteritis, the antibody which produces a coarse speckled staining of cytoplasm appears to be directed against a lysosomal serum protease (proteinase 3), whereas in necrotizing glomerulonephritis the perinuclear staining antibody probably recognizes myeloperoxidase, lactoferrin, or elastase in polymorphs. Although it has been suggested that these antibodies mediate tissue damage by activating neutrophils, this is as yet unproven. Rather stronger, but still inconclusive, evidence has been gathered to suggest that titres of cytoplasmic staining antibodies may confirm a suspected diagnosis of Wegener's granuloma, and may also be used to monitor progress and detect incipient relapse. These IgG antibodies have a half-life of some 3 weeks, so that when following response to treatment it is not useful to repeat assays at intervals of less than 4 to 6 weeks.

The high frequency of renal disease in vasculitis syndromes means that examination of the urine for protein and blood by stick testing, and careful microscopic examination for casts and red cells, is imperative. Plasma creatinine and urea measurements are crude but useful indices of glomerular filtration rate; when progressive renal disease is suspected, sequential measurements of 24-h urine protein and creatinine clearance should be performed. Renal biopsy may confirm vasculitis if an involved vessel is sampled, or if the histology is compatible with the renal manifestations of a systemic vasculitis illness. A negative biopsy of renal tissue, however, by no means excludes an arteritic illness.

Arteritis may be confirmed by biopsy of other tissues: those most commonly sampled include skin, muscle, temporal or occipital artery, sural nerve, epididymis, or liver; again it is essential to recognize the patchy distribution of vascular lesions and the need to examine the whole length of any biopsied vessel and to remember that negative findings do not exclude the diagnosis.

Imaging techniques have advanced substantially in the last 10 years. CT scanning or, better, magnetic resonance imaging, may allow accurate detection of vasculitic lesions in areas such as lungs and brain, which were previously difficult to investigate. Angiography has a major role in delineating the extent of vascular damage, particularly in patients with large vessel diseases such as Takayasu's disease and in polyarteritis nodosa, where the detection of characteristic aneurysms may be diagnostic. Echocardiography is the diagnostic test of choice in Kawasaki's disease and should be performed sequentially to monitor the size of the coronary artery aneurysms that are a characteristic feature of this illness.

VASCULITIS SYNDROMES

Giant cell arteritis

This condition, also known as temporal arteritis in view of its predilection for the temporal arteries, was first described in a hospital porter who was unable to tolerate his bowler hat because the pressure it exerted on the inflamed temporal vessels caused severe pain. This disease usually presents with severe headaches, accompanied by localized tenderness of the vessel in its course over the temple and scalp, and sometimes by fever and malaise. It is predominantly a disease of the elderly, particularly women, and is probably the most common form of vasculitis. It is not restricted to the temporal arteries but may involve other major vessels: in the scalp, occipital vessels are occasionally affected. Vasculitis of the facial artery may lead to severe jaw pain which is exacerbated by eating (jaw claudication), while vasculitis of the coronary arteries may cause myocardial ischaemia. Classically, vasculitis may affect the retinal artery, leading to sudden blindness. Vasculitis of arteries of the upper limb may lead to arm claudication, digital ischaemic lesions, and the need for a vascular surgical opinion.

Atypical presentations almost always cause diagnostic delay. There is usually tenderness over the inflamed artery if it can be palpated, C-reactive protein levels and the ESR are almost always raised, and there is usually a normochromic normocytic anaemia. Biopsy of an affected vessel shows characteristic giant cell granulomata, comprising mainly CD4⫀ T lymphocytes, but a negative biopsy does not exclude the diagnosis. Angiography may be helpful when upper limb vessels are affected  (Fig. 1) 325.

The response to steroid therapy is rapid, but large doses (60–80 mg prednisolone/day) may be required. Immunosuppressive drugs such as cyclophosphamide (2 mg/kg.day) or azathioprine (2 mg/kg.day) have been used on occasions, but there is little evidence to suggest that the combination of prednisolone and these agents convey substantial advantages over prednisolone alone. The chief value of adding cyclophosphamide or azathioprine is in reducing the total dose of prednisolone needed to control chronic or unresponsive disease. Immediate therapy is mandatory, in view of the risk of visual impairment which occurs in up to 40 per cent of patients with temporal artery disease. The disease tends to regress in activity and may ultimately ‘burn out’, and steroids can usually be tailed off after some 1 to 2 years. The disease may relapse, however, and may persist for many years.

The aetiology is obscure: there is an association with polymyalgia rheumatica, and the two conditions may develop sequentially or even coexist in some patients. Polymyalgia rheumatica is a much milder illness, characterized by limb girdle stiffness, and it generally responds to lower doses of corticosteroids.

Takayasu's arteritis

Takayasu first described this disease following observations of retinal changes in a young Japanese woman in 1908. The disease is indeed predominantly one of young women, and although it was first described in Asian women and is still much more common in females, it is by no means racially restricted. It affects particularly the aortic arch and the large vessels of the branches arising from it, but it may extend to or affect only the descending thoracic and abdominal aorta and its primary branches. The pulmonary artery may also be involved.

The illness presents with a generalized inflammatory prodrome in around 70 per cent of patients, with fever, malaise, myalgia, and arthralgia. This is followed after a variable period by symptoms and signs of vascular occlusion including claudication of arms or legs, which commonly present to the vascular surgeon. Chest and back pain, breathlessness, and syncopal attacks may lead to medical consultation. The absence of peripheral pulses and the presence of bruits over affected vessels are characteristic. The renal artery is affected in over one-half of patients: hypertension is therefore common, and renal failure may be a late complication. Visual disturbance and ultimately blindness occurs in chronic cases. Death is usually due to congestive cardiac failure and/or myocardial infarction. The vessel most frequently affected is the subclavian artery (85 per cent).

The pathological features are those of a panarteritis, involving all layers of the elastic arteries. Secondary thrombosis and stenotic and aneurysmal lesions are common. Secondary atherosclerotic changes also occur in the damaged vessels.

There is usually evidence of an acute phase response with elevated levels of C-reactive protein and a rise in ESR, but there are no other specific markers. Duplex Doppler ultrasound will demonstrate reduced flow and arteriography will document the extent and nature of the lesions.

Medical treatment with 30 to 50 mg/day of prednisolone will reduce some of the inflammatory response, but it is uncertain whether the overall prognosis is affected. A few patients appear to have benefited from cyclophosphamide treatment, but studies of the effects of this drug are confused by the occurrence of spontaneous remission and sudden relapse. Surgical treatment involving appropriate vascular reconstruction is not contraindicated and may be successful in some cases, particularly when local inflammatory change has been damped down or abolished by corticosteroid or other immunosuppressive treatment.

Wegener's granulomatosis

Wegener's granulomatosis can be separated from other forms of arteritis by its characteristic clinical features, by its histopathology, and by its serological marker, the classical antineutrophil cytoplasmic antibody. None of these is, however, specific; even the histopathology is ‘compatible with’ rather than ‘diagnostic of’ the disease. Firm diagnosis, therefore, rests on the coincidence of typical clinical, histological, and serological features.

The pathology is that of a vasculitis affecting predominantly small arteries and veins, and is marked by a neutrophil and mononuclear cell infiltrate, accompanied by fibrinoid necrosis. Granulomata occur within these vessels and in the surrounding tissues and these have an abundance of multinucleate giant cells. The ESR and C-reactive protein levels are invariably raised in the acute phase. Serum immunoglobulin levels are also increased, while complement levels are invariably normal. Antineutrophil cytoplasmic antibodies, usually at high titre, are present in some 90 per cent of patients.

Most patients with Wegener's granulomatosis present with malaise, fever, and arthralgia; other features depend on the distribution and activity of the vascular lesions. The upper airways (nose, nasal sinuses, postnasal space, or eustachian tubes) are affected in 90 per cent of patients. These usually present to the ear, nose, and throat surgeon with chronic sinusitis, nasal discharge, usually with crusting and blood, nasal ulceration, and otitis media. Saddle nose deformity, due to erosion of nasal cartilage, is said to be a typical feature, but it occurs late in the disease.

Parenchymatous lesions in the lung may appear solid on chest radiographs, resembling neoplasms. Central necrosis may lead to fluid levels and the diagnosis of lung abscess or breaking down neoplasm. Infiltrative lesions are commonly misdiagnosed as tuberculosis. These manifestations present with cough, breathlessness, haemoptysis, and chest pain. Reduction of lung diffusing capacity is evidence of generalized interstitial disease, even in the absence of radiographically obvious lesions. Less commonly, submucosal granulomatous lesions sited in the sublaryngeal region may present with the features of extrathoracic obstruction, while localized airways obstruction is caused by lesions lower in the trachea or main bronchi. The clinical presentation of Wegener's granulomatosis affecting the kidney may vary from an abnormal microscopic deposit and modest proteinuria through to rapidly progressive glomerulonephritis, with or without nephrotic features. The disease may be confined to the upper airways, to the lungs, or to the kidney but, in many cases, lesions are found in all three sites. Ocular involvement has been documented with scleritis  (Fig. 2) 326, uveitis, and even scleromalacia perforans. When the upper nasal sinuses are affected, granulomata may spread to the retro-orbital space, causing proptosis or disorders of external ocular movement. Cutaneous evidence of vascular damage occurs in around 40 per cent of patients. The disease occurs predominantly in the middle-aged.

The treatment of Wegener's granulomatosis is medical. In patients with life-threatening disease presenting with rapidly progressive glomerulonephritis and/or lung haemorrhage, pulsed methyl prednisolone (1 g daily for 3 days) and intravenous cyclophosphamide (2–2.5 mg/kg) can be effective, when followed by continued immunosuppression with prednisolone 30 to 40 mg/day and cyclophosphamide 2.5 mg/kg.day or azathioprine 2.5 mg/kg.day. When the presentation appears less immediately dangerous the same combination of high-dose steroids and cyclophosphamide or azathioprine can be used without the parenteral induction.

The disease appears to be suppressed by such treatment, rather than eradicated, though it may occasionally regress completely and not recur when treatment is withdrawn. More commonly there is a relapse sometimes after many years. Response to treatment is best monitored by a serial measurement of C-reactive protein and antineutrophil cytoplasmic antibody levels. There is laboratory and clinical evidence that relapse may be precipitated by intercurrent infection. The possibility that infusions of pooled immunoglobulin 0.5 g per kg per day for 4 days might be helpful as in idiopathic thrombocytopenic purpura is being explored in controlled clinical trials.

POLYARTERITIC SYNDROMES

Both microscopic polyarteritis (commonly) and polyarteritis nodosa (less often) may give rise to systemic manifestations, as in Wegener's granulomatosis, of malaise, fever up to 40°C (sometimes the only feature), myalgia, and weight loss. When the disease is confined to these manifestations diagnosis can be particularly difficult, even when it is suspected. Other presenting features, which are mostly medical, depend on the site and severity of the vasculitic process: some are more typical of the nodosa types, while others represent the microscopic categories of the condition. Surgical presentations are not uncommon.

Peripheral vascular disease may occur due to involvement of small vessels, which results in ischaemic lesions or frank gangrene of fingers or toes  (Fig. 3) 327. Ischaemic arteritic ulcers may occur particularly in the lower limbs, and there may be associated Raynaud's phenomenon. Embolic lesions or claudication may occur, as in giant cell arteritis, when vasa vasorum vasculitis results in stenosis or aneurysmal lesions of medium sized vessels.

Abdominal pain is a well-recognized presentation and probably results from vasculitis in the vessels of the splanchnic circulation. Symptoms are often rather vague and non-specific with ill-defined abdominal pain and occasionally modest diarrhoea or occult blood loss. An area of ischaemic gut or acute appendicitis of vascular origin may perforate, and mesenteric arterial vasculitis may result in a presentation of acute abdomen secondary to infarction of bowel or pancreas.

Renal manifestations present largely to physicians but infarction of the kidney (in polyarteritis nodosa) may result in loin pain, fever, vomiting, and blood and protein in the urine. This syndrome is often diagnosed as pyelonephritis, despite negative urine cultures, or of renal stone disease, despite the absence of firm evidence of a stone. The condition is rare and is best diagnosed by detection of the wedge-shaped infarcts by CT scanning of the kidneys. Clinical vasculitis involving ureter, bladder, epididymis, and testis is rare but may result in haematuria or local pain and inflammation.

Obstructive uropathy due to retroperitoneal fibrosis may be quite commonly associated with a periaortitis (microscopic polyarteritis) surrounding the lower abdominal aorta. Vasculitis is sometimes evident from examination of biopsy material. CT scanning or magnetic resonance imaging in this situation shows soft tissue swelling as well as ureteric obstruction responsive to treatment with corticosteroids; mobilization of obstructed ureters into the peritoneum may be necessary.

The thoracic aorta, particularly the ascending arch, may be affected not only by giant cell arteritis and Takayasu's disease but also in relapsing polychondritis. In this rare condition, vasculitis surrounds tissues in which the glycosaminoglycan content is high. There may, therefore, be inflammation and vasculitis lesions over the cartilage of the ear, nose, trachea, larynx and, more rarely, the sclera and aortic collagen. As well as aortic aneurysm or dissection, perichondritis can result in collapse of tracheal tissue. Thoracic aortitis is not a common feature of microscopic or nodosa arteritis.

Although coronary arteries are probably rarely affected, this certainly occurs especially in giant cell arteritis. Vasculitis of the lung, particularly in Wegener's granulomatosis, may be misdiagnosed as a tumour and may present to a surgical team for biopsy or excision. In the Churg–Strauss variant, pulmonary infiltrates, asthma, and eosinophilia predominate and mononeuritis multiplex, which occurs in all forms of vasculitis, is perhaps especially common. Both forms of antineutrophil antibody have been found in this group of patients.

The eye is commonly affected by all vasculitis illnesses, presenting with episcleritis or scleritis more seriously, with vasculitis involving the retinal vessels or the optic nerve, diagnosed by ophthalmoscopy or fluorescein angiography. Anterior uveitis can also occur, but this is much less common. Cranial nerve lesions of the vasa nervorum may produce mononeuritis multiplex of the nerves supplying the external ocular muscles.

Diagnosis of these protean syndromes is often difficult. There are no absolutely diagnostic serological tests but the C-reactive protein level and ESR are almost always increased and a normochromic normocytic anaemia, together with polymorphonuclear leucocytosis, is common. Complement levels are normal or raised. Selective angiography is often valuable and may demonstrate characteristic small aneurysms, the structures which originally gave rise to the term ‘nodosa’.

Polyarteritis nodosa is considered to be a ‘immune complex disease’ based on the link, in some parts of the world, with the presence of hepatitis B virus surface antigen. However, this is not a universal association and most patients in the Western world are not infected with this virus. The treatment is identical to that used in Wegener's granulomatosis, comprising high-dose corticosteroids and immunosuppression with cyclophosphamide or azathioprine. Again, the response to therapy is best monitored by review of clinical manifestations supported by regular review of haemoglobin, white cell count, C-reactive protein level, and ESR, although the latter is less sensitive.

Systemic sclerosis—scleroderma and CREST syndrome

Although in some patients manifestations of scleroderma are confined to the skin, there is often overlap with the more general organ involvement characteristic of systemic sclerosis. Not all clinicians would classify these disorders as vasculitic in origin, but they are associated with inflammatory cell infiltration and obstruction of small blood vessels with excessive collagen deposition. Again the many manifestations present very largely to physicians. Some particular features often lead to surgical consultations.

Raynaud's phenomenon is particularly common and may be the earliest feature of the disease. It may progress to ischaemic damage of fingers or toes, necrotic ulceration and ultimately the need for amputation. Other presentations which may be seen by the surgeon include dysphagia due to oesophageal disease; reflux oesophagitis may lead to stricture formation, and a barium swallow study shows the characteristic poor oesophageal motility. Less commonly, sclerosis of the small bowel may lead to disordered mobility, bacterial overgrowth, and malabsorption. Such patients may present with weight loss, nausea, vomiting, and diarrhoea. A small bowel enema shows characteristic local areas of dilatation and pseudodiverticula formation  (Fig. 4) 328. In advanced disease there may be complete loss of peristalsis, effectively intestinal obstruction, and some patients progress to a stage at which their survival is dependent on chronic parenteral nutrition. Perforation of the gut has been described and large bowel disease may also present with obstruction or infarction of the colon.

These syndromes rarely present any difficulty in diagnosis, which is usually obvious clinically. Serologically, they are characterized by a high level of antinuclear antibodies of speckled or nucleolar pattern and a specific autoantibody, Scl–70, which is found particularly in patients with systemic sclerosis. The anticentromere antibody is particularly associated with the CREST syndrome (C for Calcinosis circumscripta; R for Raynaud's; E for (o)esophageal disease; S for sclerodactyly; T for telangiectasia) an entity which, although often presenting as a discrete syndrome, also commonly overlaps with other manifestations of systemic sclerosis. No pharmacological agent is of any proven value in the treatment of systemic sclerosis. Management, therefore, revolves around the amelioration of symptoms and such immediate treatment as the particular clinical manifestations require. Sympathectomy or prostacyclin infusion may be of value, although limited in both time and effect, in the treatment of peripheral ischaemia. Broad spectrum antimicrobial (oxytetracycline) therapy is useful in controlling the gastrointestinal manifestations, which depend on overgrowth of bacteria. H&sub2;-receptor antagonists or related agents may be helpful in the treatment of reflux oesophagitis and dysphagia, and pacemakers may be needed when disease affects the bundle of His and causes heart block. Total parenteral nutrition can be given if intestinal disease is sufficiently severe.

Systemic lupus erythematosus

The protean manifestations of this disorder almost always present to the physician, although Raynaud's phenomenon, with or without vasculitis of digital vessels of the upper or lower limbs, may be the only clinical feature in some women, who thus present to a surgical team. The diagnosis is suggested by the pattern of manifestations of the illness. Serological markers include a raised titre of antinuclear antibody, low concentrations of the third and fourth components of complement, increased binding of double-stranded DNA and/or the presence of anti-Ro, anti-La, and anti-SM antibodies. Elevated levels of antibodies to cardiolipin or antibodies interfering with clotting in vitro, the so-called ‘lupus anticoagulant’, are not infrequent findings. These phospholipid antibodies are mainly associated with otherwise unexplained venous or even arterial thrombosis, and perhaps with a history of recurrent abortion, possibly related to abnormal coagulation in the circulation of the pregnant uterus and resultant placental insufficiency.

Behçet's disease

Behçet's disease is a particularly poorly understood illness in which the pathology has a vasculitic component. It is classically characterized by recurrent orogenital ulceration, iridocyclitis with or without retinal vasculitis, and a number of cutaneous lesions. Although it may be more common in Japan and in the countries surrounding the Mediterranean, it is becoming increasingly recognized in the Caucasian population, most commonly in people in the third decade of life. There is a strong immunogenetic background to the disease: it is strongly associated with the HLA-B51 antigen in Turkey, Israel, France and the United Kingdom. HLA-DR7 in addition to B51 has been reported to be associated with retinal and neurological manifestations of the disease.

Histopathologically, affected tissues show a lymphomonocytic infiltration around affected epithelia and associated small blood vessels. The latter may be occluded by proliferation of endothelium and associated fibrinoid necrosis.

Mouth ulcers may be difficult to distinguish from those of lesser pathological significance. Ulcers in the genitalia may affect classically the labia, vagina, penis, and scrotum, and there may be an associated epididymo-orchitis. Skin manifestations include classical erythema nodosum as well as pustular lesions which are widely distributed but most common on the face and back. A characteristic feature is the development of pustular lesions at the sites of minor skin damage (‘pathergy’).

Among the most important manifestations presenting to surgeons will be those affecting the eye. Uveitis with or without hypopyon, iridocyclitis, retinal vascular lesions including infarction, optic atrophy, and choroidoretinitis are all dangerous complications and may lead to blindness. Neurological manifestations occur in up to 25 per cent of patients. Any part of the central nervous system may be affected, often in a series of episodes with focal neurological signs. If these arise in the hemispheres they may resemble stroke, but manifestations may also occur in the brain stem and cord. On occasion, the findings suggest inflammatory disease of the nervous system, meningitis, or encephalitis with pleocytosis of the cerebrospinal fluid.

Arthralgia and, on occasion, arthritis are commonly reported. Thrombophlebitis of superficial and deep veins may occur and more serious vascular complications include thrombosis, particularly of veins, sometimes such major vessels as the superior and inferior vena cava. Gastrointestinal manifestations are common and include diarrhoea, nausea, anorexia, and abdominal pain. On rare occasions ulceration of both colon and small bowel has been described, as have both malabsorption and pancreatitis. Aneurysmal changes in the aorta and its large branches may also occur. Pulmonary manifestations include shadows on chest radiographs, sometimes associated with haemoptysis and believed to be due to pulmonary vasculitis. Renal manifestations are very rare but both proteinuria and microscopic haematuria have been reported.

Treatment of mouth and genital ulcers with topical ointments or sprays containing both corticosteroids and tetracycline is often very effective, and uveitis may also respond to prednisolone eye drops. The more serious manifestations, particularly those of neurological or retinal disease, are best treated by a combination of corticosteroids and immunosuppressive agents, but the response is uncertain and often disappointing. There are also reports of apparently successful use of colchicine and of aspirin for thrombotic problems. High doses of prednisolone (up to 60 mg a day) appear to be necessary at the onset of serious complications; these are subsequently supplemented by azathioprine in a dose of 2 to 2.5 mg/kg.day. Cyclophosphamide has been used in the same dosage instead of azathioprine, but there is no convincing evidence that it is superior. Cyclosporin may have a particular role to play in the treatment of retinal manifestations, and thalidomide, although contraindicated in women of child-bearing age, has been reported to be beneficial in the treatment of skin and orogenital manifestations in occasional patients.

Kawasaki's disease

This is a systemic illness of children characterized in its onset by lymphadenopathy and mucosal ulceration, with vasculitis sometimes affecting the coronary arteries. The illness presents with fever, conjunctivitis, a skin rash, cervical lymphadenopathy, and oral ulceration. Desquamation of the skin may occur as a late feature. Although originally described in Japan, it occurs worldwide. The cause is likely to be infective, although no pathogen has been identified. The diagnosis is clinical, supported by a non-specific rise in the ESR and in C-reactive protein levels. Cardiac manifestations of the disease may be detected by electrocardiography (QT prolongation and ST segment changes with or without arrhythmias), and two-dimensional echocardiography or coronary angiography are mandatory to monitor the formation of coronary artery aneurysms and their progress. The pathology of coronary artery aneurysms is characterized by a panarteritis with fibrinoid necrosis and local aneurysm formation. Lymph node biopsy may show necrosis of the node with small vessel vasculitis and proliferation of immunoblasts.

In the acute phase of the disease, symptoms may be settled by high dose aspirin (30–50 mg/kg.day); corticosteroids are probably of no benefit and may even be harmful. Infusions of intravenous immunoglobulin at doses of 0.5 g/kg daily for 4 days are effective, but only if given within the first week of the onset of the disease.

Buerger's disease (thromboangiitis obliterans)

Whether or not this disorder exists as a specific entity is controversial, especially in the Western world. However it is a relatively common vascular condition in south-east Asia. The syndrome that suggests its diagnosis most commonly occurs in young men (male to female predominance 9 : 1) who are smokers. In the lower limb, ischaemic symptoms may produce clinical features ranging from claudication, sometimes felt in the arch of the foot, to ischaemic ulceration of the toes. Less commonly there may be Raynaud's phenomenon or claudication sometimes affecting the hand rather than musculature higher up the limb. Angiography reveals the presence of distal disease, such as obliteration of tibial and/or peroneal arteries in the leg. Histological examination of affected vessels does not reveal atheromatous change, but both arteries and neighbouring veins are characteristically infiltrated with neutrophils and small branches may have thrombosed. The only useful therapy is to persuade the patient to abandon smoking.

Lymphomatoid granulomatosis

This condition may be mistaken for Wegener's granulomatosis: the differentiation depends on the report of an experienced histo-pathologist. In both conditions there is granulomatous vasculitis in affected tissues, which are heavily infiltrated with atypical lymphocytes and plasma cells. Laboratory tests are unhelpful and the sedimentation rate is commonly normal. This disease which, in a significant but uncertain proportion of patients may proceed to malignant lymphoma, may respond well to immunosuppressive treatment with prednisolone and cyclophosphamide or azathioprine.

IMMUNOSUPPRESSIVE TREATMENT IN THE MANAGEMENT OF VASCULITIS

The mainstay of treatment for most primary inflammatory vasculitides is immunosuppression with high-dose prednisolone and either cyclophosphamide or azathioprine in a dose of 2 to 2.5 mg/kg.day. High dose methylprednisolone (500 mg to 1 g daily for 3 days) may be used in conjunction with intravenous cyclophosphamide (1 g/m²) in patients with life-threatening complications, but the evidence demonstrating the superiority of this approach to high-dose oral therapy is uncertain. Both cyclophosphamide and azathioprine may cause a profound leucopenia and weekly blood counts are mandatory, at least in the initial stages of management. After high-dose and prolonged immunosuppression, administration of prophylactic septrin should be considered, since this is known to be useful in preventing Pneumocystis pneumonia in transplant recipients. Cyclophosphamide may also cause alopecia (reversible) and haemorrhagic cystitis, which may be prevented by the concomitant use of Mesna. Cyclophosphamide is also toxic to the gonads in both sexes, although the degree of toxicity is variable between individuals. Appropriate warnings must be given to patients, who should be offered the opportunity for sperm banking if a future family is to be considered. Long-term use of cytotoxic drugs, particularly chlorambucil and cyclosphosphamide, have been associated with an increased incidence of lymphoid malignancy later in life. Plasmapheresis, which has proven effective in myasthenia gravis, antiglomerular basement membrane disease, and in Guillain–Barré syndrome, has also been found useful by some groups, particularly when vasculitis affects the kidney.

FURTHER READING

Berstein RM. Humoral autoimmunity in systemic rheumatic disease. J R Coll Phys, 1990; 24: 18–25.

Chajek T, Fainaru M. Behçet's disease: a report of 41 cases and a review of the literature. Medicine, 1975; 54: 179–96.

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