Sessa A, Meroni M, Battini G (eds): Systemic Lupus erythematosus: Renal Vasculitis. Contrib Nephrol. Basel, Karger, 1992, vol 99, pp 17-25
Vascular Disease and Thrombosis: Relationship to the Antiphospholipid Antibodies Ronald A. Asherson, G.R.V. Hughes
Antiphospholipid antibody (aPL) production does not seem to occur in primary vasculitidies, although the presence of the lupus anti-coagulants and/or antibodies to cardiolipin (aCL) may be found in association with diseases such as SLΕ. The production of aPL appears to be associated with very specific conditions, and, in some of these, may correlate with thrombotic occlusions of vessels (veins more than arteries). There seems to be no relationship of the production of aPL to vasculitis in those patients with systemic lupus erythematosus (SLE)/other `lupus-related' conditions such as Sjögren's syndrome [ 1] where vasculitis is a well-recognized complication. In the vast majority of patients with thrombotic disease associated withe aPL who have been studied histopathologically, there has been no evidence of inflammatory cell infiltration in the vessel walls. However, some investigators have commented upon and stressed the appearance of `vasculitis' or `vasculopathy' both in patients with the `primary' and/or secondary antiphospholipid syndromes (APS). As vasculitis is a not uncommon complication of SLΕ it is not surprising that a minority of patients with proven histopathological vasculitis might demonstrate aPL. It is also unlikely that aPL production is in any way influenced or precipitated by vascular damage per se, as in other conditions with extensive vasculitis and/or vascular damage (e.g. atherosclerotic vascular disease, diabetes mellitus or the `primary' vasculitidies), there is minimal evidence of aPL production. The `vasculopathy' with intimal hyperplasia and, ín some, medial hypertrophy, may be related to previous vascular occlusion and subsequent recanalization of vessels.
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The Lupus Arthritis Research Unit, The Rayne Institute, St Thomas' Hospital, London, UK
Asherson/Hughes
t8
Antiphospholipid Antibodies and Vasculitic Conditions
Behfet's Syndrome Seventy patients with Behçet's syndrome were studied and l3 positives were found [8]. Eight of the 13 had a history of retinal vascular disease. In a subsequent study, raised aCL levels were found in only 2 of 25 patients with Behçet's syndrome and thrombophlebitis and the isotype was IgM alone [9].
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Giant Cell Arteritis/Polymyalgia rheumatics (GCA/PMR) Several publications have recently drawn attention to the presence of aPL in GCA/PMR. A single patient with occlusion of a major arterial vessel and GCA/PMR was reported by Cid et al. [2] from Spain, and this group subsequently reported high titres of aCL in 3 of 40 patients with the condition (7.5%). Two had elevated titres of both IgG and IgM isotypes whilst the third had elevations of the IgM isotype. Late ischaemic complications occurred in the latter and in one of the former [3]. Another study [4] found IgG aCL in 11 of 22 patients (17%) with the condition, more frequently in those with acute GCA and also in those with PMR/GCA. In 1990, Watts et al. [5] reported 10 consecutive patients presenting with acute ischaemic optic neuritis. In 5, the neuropathy was secondary to a `non-arterític' form and to previously undiagnosed GCA in the others. The IgG aCL was increased in all the patients with GCA and levels were not increased in the 'non-arteritic' group. Espinoza et al. [6] studied 50 patients, 30 with PMR alone and 20 with associated GCA. They also measured von Willebrand factor (vWF) antigen, C-reactive protein and ESR. In the group with PMR alone 26.6% had aCL elevations, whilst 80% of those with GCA were positive (p = < 0.1). Both isotypes were seen in patients with GCA and 5 of these patients had severe complications consisting of cerebrovascular accident (1), myocardial infarction (1), blindness (1), diplopia (1) and transient ischaemic attacks (2). One patient with vascular complications was seen in the absence of elevated aCL levels. On further analysis of the levels of aCL, titres were usually low, moderate positives of IgG aCL being seen only in the GCA group (5 patients). A high percentage (62.5%) of those patients with both antibodies had vascular complications. High levels of vWF antigen associated with GCA compared with PMR suggested that both aCL elevations and the presence of vWF antigen could be a reflection of endothelial cell injury. As the pathogenesis of the `vasculopathy' in GCA is unknown, it was suggested by the authors of this paper that it was possible that the endothelial cell injury might be mediated by immunological mechanisms. As a result of this, aCL is one of the practical markers which could be measured in patients with PMR, and its elevation might indicate the presence of GCA.
Vascular Disease and Thrombosis
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Takayasu's Arteritis IgG aCL elevations were found in 1 patient with Takayasu's arteritis. This patient had developed complete occlusion of the left subclavian artery as well as tapering of the left brachiocephalic artery [4]. Elevated aCL levels in patients with Takayasu's arteritis have also been confirmed in a larger unpublished series of patients from South Africa [ 10]. Relapsing Polychondritis One patient with relapsing polychondritis in a series of 8 was found to have a positive lupus anticoagulant test. This patient subsequently developed acute thrombosis of the abdominal aorta and iliac arteries during a flare of disease activity. Aortic replacement was performed and histology of the resected artery showed an increase in thickness of the intima as a result of thrombosis, but no evidence of vasculitis was seen. The lupus anticoagulant disappeared after 2 months' of treatment with high-dose prednisolone treatment [11]. Primary Sjögren's Syndrome and Vasculitis A recent paper evaluated 65 patients with primary Sjögren's syndrome [1]. Increased aPL levels (predominantly IgA aCL) were found in 13 (21%). aCL elevations were not significantly associated with arterial/ venous thromboses or with vasculitis in this group of patients. The lupus anticoagulant was negative in all.
Conditions Mimicking Vasculitis In some patients with elevations of the aPL, the clinical presentation may suggest `vasculitis'. However, it has become clear that microvascular thrombotic disease may superficially resemble vasculitis clinically. Two such examples are:
Subungual `Splinter' Haemorrhages Subungual splinters are often an accompaniment of vasculitic lesions such as digital infarcts, and may be seen with infective endocarditis or rheumatoid vasculitis. Recently, these lesions have also been described in
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Ophthalmic Vaso-Occlusive Phenomena These include retinal and `optic neuritis' leading to optic atrophy. Extensive sheathing of vessels, exudates and neovascularization may lead clinicians to the conclusion that the patients are suffering from retinal or choroidal vasculitis [ 12-14].
Asherson/Hughes
20
patients with elevations of the aPL and may be seen during pregnancy, following the administration of oral contraceptives, with transient ischaemic attacks particularly resulting in amaurosis fugax [ 15], as well as in patients with other concurrent thrombotic events such as adrenal vascular occlusion [ 16]. Skin Lesions Florid vasculitic skin lesions have been documented as occurring infrequently in patients with primary APS [ 17]. However, skin vasculitis is distinctly unusual. A patient recently documented from our own unit with high levels of IgM aCL and on long-term anti-coagulation therapy with warfarin developed a superficial macular rash over the lower limbs, which closely resembled a vasculitic eruption. Skin biopsy revealed only fibrin thrombi in the small dermal vessels [20]. Other authors have also documented macular skin lesions in their patients with aPL elevations which superficially resembled vasculitis, but which, on biopsy, showed only microthrombosis in the dermal vessels without any evidence of vasculitis [21]. The histopathology of 13 specimens obtained from patients with the lupus anticoagulant and skin ulceration seen at the Mayo Clinic recently [23] showed vascular thrombosis in 10, capillary proliferation in 8, endarteritis obliterans in 7 and vascular infiltration in 1. Reyes and Alarcon-Segovia [22] reported vascular proliferation `glomerulus-like' nodular structures in the subcapillary dermis. Within the fibrous tissue there was a moderate mixed infiltrate of polymorphonuclear cells and lymphocytes. The lumen of the proliferated vessels was irregular and a few were occluded by fibrin thrombi. Some vessels had fibrin deposition within the walls. It is likely that multiple recanalization of vessels is responsible for this picture.
Histopathological examination of tissue obtained from amputations and reported by Alarcon-Segovia et al. [24] showed striking intimal and medial proliferation as well as some increase in the adventitia. There was little evidence of thrombosis, but in 2 of the patients reported who had required early amputation, there was a mononuclear infiltrate of the large arteries accompanied by evidence of leucocytoclastic vasculitis in skin and/or muscle. One patient had developed cutaneous modules which on subsequent biopsy were also found to be due to leucocytoclastic vasculitis. There has been some controversy regarding the histopathological interpretation of these changes, but it is probable that the inflammatory changes
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Arterial Vasculopathy
Vascular Disease and Thrombosis
21
are mainly those seen following thrombosis at varying stages of organization and not due to vasculitis per se [25] as mentioned earlier.
The importance of disturbances in the coagulation mechanism was first recognized in the early 1970s [26], and attempts were made to influence the course of glomerulonephritis by the use of anticoagulants such as heparin [27, 28], or by defibrinating agents such as Ancrod [29]. In 1975, Kincaid-Smith [ 30] stressed the participation of intravascular coagulation in the pathogenesis of kidney disease. Over a 15-year period, her group studied 4,860 biopsy specimens and demonstrated the presence of fibrin deposition within vessels in a range of conditions including acute tubular necrosis thrombotic microangiopathy, scleroderma, pre-eclamptic toxaemia, and malignant hypertension. They suggested that all might have a similar pathogenesis and proposed that fibrin deposition within vessels was the first step in the formation of the intimal lesions with resultant narrowing of interlobular arteries. Different stages, i.e. fibrin deposition alone, fibrin with commencing organization and epithelialization and narrowing by cellular intimal proliferation, were all present in the same biopsy specimens. Kant et al. [31] in 1981 analyzed the clinical, serological, coagulation and histological findings in 71 patients with SLΕ. One hundred and five renal biopsy specimens were analysed. Thrombin and fibrin were detected using light microscopy and immunoflourescence. Thrombi were detected in 50% of biopsies with diffuse and focal proliferative glomerulonephritis. In patients with glomerular thrombi, factor VIII levels were significantly increased and circulating platelets decreased. Thrombosis in a first biopsy appeared to be an excellent predictor of increased glomerulosclerosis in the second. There was a striking association between the occurence of a circulating anticoagulant and the occurrence in the renal biopsy of glomerular thrombosis without necrosis. The same group subsequently reported renal thrombosis in 14 of 18 SLΕ patients with a circulating lupus anticoagulant [32]. Another study [33] correlated the clinical features of 12 women with circulating lupus anticoagulant with renal biopsies. Four of the 12 had serological evidence of SLΕ. As the vascular glomerular lesions were present in 8 patients without evidence of SLΕ, these authors concluded that the thrombotic lesions previously described in the renal circulation in lupus nephritis were not, as previously associated, a manifestation of so-called
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Glomerular Thrombosis and Relationships to Antiphospholipid Antibodies
Asherson/Hughes
22
`lupus vasculitis', but represented a form of thrombotic microvascular complication associated with the presence of a circulating lupus anticoagulant. The patients studied were referred because of recurrent abortions or impaired renal function in pregnancy. Biopsies of these patients carried out at a time remote from pregnancy showed persisting double contours in glomeruli, with narrowing of arteries due to recanalizing thrombi and cellular intimal proliferation. These findings are in keeping with `organization of the thrombi. In 1991. Leaker et al. [34] documented 4 patients with raised aCL levels and insidious loss of renal function in the absence of overt nephritis and with normal urinary findings. Three had defined SLΕ, although clinical and laboratory evidence of lupus activity was minimal in these patients. The fourth patient had a `primary' APS. All had previous episodes of thrombosis and all were receiving maintenance immunosuppressive therapy at the time of renal biopsy. In all, renal biopsies showed ischaemic changes with no evidence of active lupus nephritis. Arteriolar hyalinosis was prominent. Small to medium-sized vessels were abnormal with narrowing of the vessel lumen secondary to cellular intimal proliferation. One biopsy showed fibrin thrombi in glomerular capillaries. Three further very similar patients were recently documented by Agati et al. [35], one with a primary APS, one with SLΕ and one with `lupus-like' disease. All had a clinical course dominated by repeated multi-organ thrombosis. The renal presentation varied from asymptomatic, mild proteinuria to nephrotic syndrome, renal insufficiency and hypertension. Frampton et al. [36] recently studied 76 patients with SLΕ and clinically evident nephritis, most of whom were taking prednisolone and azathioprine at the time of the study. Renal biopsies were performed on all patients. Although an association between the presence of intra-glomerular thrombi and elevations of IgG aCL was found, no association between aPL and renal histological pattern or long term renal function was discovered. The authors speculated that this could have been a result of the small numbers of patients with worsening renal function studied (n = 7) or perhaps that the follow-up period was too short (8-89 months). These authors suggested that the aPL-mediated glomerular thrombi might contribute in some patients to the pathogenesis of the nephritis.
In summary, glomerular thrombi and vascular lesions may be seen in a variety of conditions, including SLE, scleroderma, microangiopathic diseases (e.g. the haemolytic uraemic syndrome), pregnancy-associated
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Conclusions
Vascular Disease and Thrombosis
23
renal failure, pre-eclampsia and malignant hypertension. There is no associated vasculitis in the renal biopsies of these patients, but progressive narrowing of the renal vessels consequent on organization of fibrin thrombi may give rise to glomerulosclerosis and loss of insidious renal function. aPL-associated vascular disease consisting of thrombotic lesions affecting large and small vessels, veins as well as arteries, occurs mainly in patients with SLE and closely related conditions such as `lupus-like' disease (`probable' lupus), the `primary' APS and the recently defined `catastrophic' antiphospholipid syndrome [37, 38]. Thrombotic events are uncommonly associated with the aPL in patients with vasculitis, the exceptions being conditions such as giant cell temporal arteritis, and very rarely Takayasu's arteritis or relapsing polychondritis. Small vessel occlusions may mimic vasculitic disorders in certain circumstances.
References Asherson RA, Fei HM, Staub HL, et al: Antiphospholipid antibodies and HLA associations in primary Sjogren's syndrome. Ann Rheum Dis 1992;in press. 2 Cid MC, Cervera R, Font J, et al: Recurrent arterial thrombosis in a patient with giant cell arteritis and raised anticardiolipin antibody levels. Br J Rheumatol 1988;27:264-266. 3 Cid MC, Cervera R, Font J, et al: Late thrombotic events in patients with temporal arteritis and anticardiolipin antibodies. Clin Exp Rheumatol 1990;8:359-363. 4 McHugh NJ, James IE, Plant GT: Anticardiolipin and antmeutrophi! antibodies in giant cell arteritis. J Rheumatol 1990;17:916-912. 5 Watts MT, Grenues M, Clearkin L, et al: Antiphospholipid antibodies and ischaemic optic atrophy. Lancet 1990335:613-614. 6 Espinoza LR, Jara LJ, Silveira L, et al: Anticardiolipin antibodies in polymyalgia rheumatics/giant cell arteritis: Association with severe vascular complications. Am J Med 1991;90:474-478. 7 Case records of the Massachusetts General Hospital: Case 23-19990. N Engl J Med 1990322:1656-1665. 8 Howell RG, Harris EN, Gharavi A, et al: Anticardio!ipin antibodies: Occurrence in Behcet's syndrome. Ann Rheum Dis 1984;43:746-748. 9 Efthimiou J, Harris EN, Hughes GRV: Negative anticardiolipin antibodies and vascular complications in Behcet's syndrome. Ann Rheum Dis 1985;44:725. 10 Dessein P: Personal communication 1991. 11 Balsa-Criado S, Gonzales-Hernandez T, Cuesta MV, et al: Lupus anticoagulant in relapsing polychondritis. J Rheumatol 1990;17:1426. l2 Levine SR, Crofts JW, Lesser R, et al: Visual symptoms associated with the presence of a lupus anticoagulant. Ophthalmology 1988;95a:686-692 13 Asherson RA, Merry P, Acheson JF, et al: Antiphospholipid antibodies: A risk factor for occlusive ocular vascular disease in systemic lupus erythematosus and the 'primary' anti-phospholipid syndrome. Ann Rheum Dis 1989;48:358-361.
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1
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Hall S, Beuttner Η, Luthra HA: Occlusive retinal vascular disease in systemic lupus erythematosus. J Rheumatol 1984;11:846-850. 15 Asherson RA: Subungual splinter haemorrhages: A new sign of the antiphospholipid coagulopathy. Ann Rheum Dis 1990;49:268. 16 Ames D, Asherson RA, Ayres B, et al: Bilateral adrenal infarction, hypoadrenalism and splinter haemorrhages in the `primary' antiphospholipid syndrome. Br J Rheumatol 1992;3 L:177-120. 17 Asherson RA, Khamashta MA, Ordi-Ros J, et al: The `primary' antiphospholipid syndrome: Major clinical and serological features. Medicine, Baltimore 198968:366374. 18 Alarcon-Segovia D, Sanchez-Guerrero J: Primary antiphospholipid syndrome. J Rheumatol 1989;16:482-488. 19 Mackworth-Young C, Loizou S, Walport MJ: The primary antiphospholipid syndrome: Features of patients with raised anticardiolipin antibodies and no other disorder. Ann Rheum Dis 1989;48:362-367. 20 Asherson RA, Jacobelli S, Rosenberg Η, et al: Skin nodules and macules resembling vasculitis in the `primary antiphospholipid syndrome. Clin Exp Dermatol 1992;in press. 21 Grob JJ, Bomerandi JJ: Cutaneous manifestations associated with a presence of the lupus anticoagulant. J Am Acad Dermatol 1986;15:211-219. 22 Reyes E, Alarcon-Segovia D: Leg ulcers in the primary antiphospholipid syndrome. Report of a case with a peculiar proliferative small vessel vasculopathy. Clin Exp Rheumatol 1991;9:63-66. 23 Alegre BA, Winkelmann RA: Histopathologic and immune fluorescence study of skin lesions associated with circulating lupus anticoagulant. J Am Acad Dermatol 1988;19:117-124. 24 Alarcon-Segovia D, Cardiel ΜΗ, Reyes E: Antiphospholipid arterial vasculopathy. J Rheumatol 1989;16:762-767. Lie JT: Vasculopathy in the antiphospholipid syndrome: Thrombosis or vasculitis, or 25 both (editorial)? J Rheumatol 1989;16:713-715. 26 Bassalli P, McCluskey RG: The pathogenetic role of the coagulation process in glomerular diseases of immunologic origin. Advances in nephrology, vol I, Chicago, Yearbook, 1971, p 47. 27 Bone JM, Valdes AJ, Germuth FG, Lubowitz Η: Heparin therapy in anti-basement membrane nephritis. Kidney Int 1975;8:72-79. 28 Border WA, Wilson CV, Dickson FJ: Failure of heparin to affect two types of experimental glomerulo-nephritis. Kidney Int 1975;8:140-148. 29 Thompson NM, Simpson IJ, Evans DJ, Peters DK: Defibrination with ancrod in experimental chronic immune complex nephritis. Clin Exp Immunol 1975;19:301. 30 Kincaid-Smith P: Participation of intravascular coagulation in the pathogenesis of glomerular and vascular lesions. Kidney Int 1975;7:242-253. Kant KS, Pollak VE, Weiss MA, et al: Glomerular thrombosis in systemic lupus 31 erythematosus: Prevalence and significance. Medicine, Baltimore 1981;16:71-86. 32 Glueck HI, Kant KS, Weiss MA, et al: Thrombosis in systemic lupus erythematosus. Arch Intern Med 1985;145:1389-1397. 33 Kincaid-Smith P, Fairley KF, Kloss M: Lupus anticoagulant associated with renal thrombotic microangiopathy and pregnancy related renal failure. Q J led 1988;69:795815. 34 Leaker B, MacGregor A, Griffith M, Snaith M, Neild GH, Isenberg D: Insidious loss of renal function in patients with anticardiolipin antibodies and absence of overt nephritis. Br J Rheumatol 1991;30:422-425.
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Agati V, Kunis C, Williams G, Appel GB: Anticardiolipin antibody and renal disease: A report of three cases. J Am Soc Nephrol 1991;1:777-784. Frampton G, Hicks J, Cameron JS: Significance of antiphospholipid antibodies in 36 patients with lupus nephritis. Kidney Int 1991;39:1225-1231. 37 Asherson RA: The catastrophic antiphospholipid syndrome (editorial). J Rheumatol 1992, in press. 38 Harris EN, Bos K: An acute disseminated coagulopathy-vasculopathy associated with the antiphospholipid syndrome. Arch Intern Med 1991;151:231-233.
Ronald A. Asherson, MD, Director of Clinical Research, Lupus Arthritis Research Unit, The Rayne Institute, St. Thomas' Hospital, London SEl 7EH (UK)
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35
Vascular Disease and Thrombosis: Relationship to the Antiphospholipid Antibodies Ronald A. Asherson, G.R.V. Hughes
Antiphospholipid antibody (aPL) production does not seem to occur in primary vasculitidies, although the presence of the lupus anti-coagulants and/or antibodies to cardiolipin (aCL) may be found in association with diseases such as SLΕ. The production of aPL appears to be associated with very specific conditions, and, in some of these, may correlate with thrombotic occlusions of vessels (veins more than arteries). There seems to be no relationship of the production of aPL to vasculitis in those patients with systemic lupus erythematosus (SLE)/other `lupus-related' conditions such as Sjögren's syndrome [ 1] where vasculitis is a well-recognized complication. In the vast majority of patients with thrombotic disease associated withe aPL who have been studied histopathologically, there has been no evidence of inflammatory cell infiltration in the vessel walls. However, some investigators have commented upon and stressed the appearance of `vasculitis' or `vasculopathy' both in patients with the `primary' and/or secondary antiphospholipid syndromes (APS). As vasculitis is a not uncommon complication of SLΕ it is not surprising that a minority of patients with proven histopathological vasculitis might demonstrate aPL. It is also unlikely that aPL production is in any way influenced or precipitated by vascular damage per se, as in other conditions with extensive vasculitis and/or vascular damage (e.g. atherosclerotic vascular disease, diabetes mellitus or the `primary' vasculitidies), there is minimal evidence of aPL production. The `vasculopathy' with intimal hyperplasia and, ín some, medial hypertrophy, may be related to previous vascular occlusion and subsequent recanalization of vessels.
Downloaded by: National Univ. of Singapore 137.132.123.69 - 3/27/2017 5:06:45 AM
The Lupus Arthritis Research Unit, The Rayne Institute, St Thomas' Hospital, London, UK
Asherson/Hughes
t8
Antiphospholipid Antibodies and Vasculitic Conditions
Behfet's Syndrome Seventy patients with Behçet's syndrome were studied and l3 positives were found [8]. Eight of the 13 had a history of retinal vascular disease. In a subsequent study, raised aCL levels were found in only 2 of 25 patients with Behçet's syndrome and thrombophlebitis and the isotype was IgM alone [9].
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Giant Cell Arteritis/Polymyalgia rheumatics (GCA/PMR) Several publications have recently drawn attention to the presence of aPL in GCA/PMR. A single patient with occlusion of a major arterial vessel and GCA/PMR was reported by Cid et al. [2] from Spain, and this group subsequently reported high titres of aCL in 3 of 40 patients with the condition (7.5%). Two had elevated titres of both IgG and IgM isotypes whilst the third had elevations of the IgM isotype. Late ischaemic complications occurred in the latter and in one of the former [3]. Another study [4] found IgG aCL in 11 of 22 patients (17%) with the condition, more frequently in those with acute GCA and also in those with PMR/GCA. In 1990, Watts et al. [5] reported 10 consecutive patients presenting with acute ischaemic optic neuritis. In 5, the neuropathy was secondary to a `non-arterític' form and to previously undiagnosed GCA in the others. The IgG aCL was increased in all the patients with GCA and levels were not increased in the 'non-arteritic' group. Espinoza et al. [6] studied 50 patients, 30 with PMR alone and 20 with associated GCA. They also measured von Willebrand factor (vWF) antigen, C-reactive protein and ESR. In the group with PMR alone 26.6% had aCL elevations, whilst 80% of those with GCA were positive (p = < 0.1). Both isotypes were seen in patients with GCA and 5 of these patients had severe complications consisting of cerebrovascular accident (1), myocardial infarction (1), blindness (1), diplopia (1) and transient ischaemic attacks (2). One patient with vascular complications was seen in the absence of elevated aCL levels. On further analysis of the levels of aCL, titres were usually low, moderate positives of IgG aCL being seen only in the GCA group (5 patients). A high percentage (62.5%) of those patients with both antibodies had vascular complications. High levels of vWF antigen associated with GCA compared with PMR suggested that both aCL elevations and the presence of vWF antigen could be a reflection of endothelial cell injury. As the pathogenesis of the `vasculopathy' in GCA is unknown, it was suggested by the authors of this paper that it was possible that the endothelial cell injury might be mediated by immunological mechanisms. As a result of this, aCL is one of the practical markers which could be measured in patients with PMR, and its elevation might indicate the presence of GCA.
Vascular Disease and Thrombosis
19
Takayasu's Arteritis IgG aCL elevations were found in 1 patient with Takayasu's arteritis. This patient had developed complete occlusion of the left subclavian artery as well as tapering of the left brachiocephalic artery [4]. Elevated aCL levels in patients with Takayasu's arteritis have also been confirmed in a larger unpublished series of patients from South Africa [ 10]. Relapsing Polychondritis One patient with relapsing polychondritis in a series of 8 was found to have a positive lupus anticoagulant test. This patient subsequently developed acute thrombosis of the abdominal aorta and iliac arteries during a flare of disease activity. Aortic replacement was performed and histology of the resected artery showed an increase in thickness of the intima as a result of thrombosis, but no evidence of vasculitis was seen. The lupus anticoagulant disappeared after 2 months' of treatment with high-dose prednisolone treatment [11]. Primary Sjögren's Syndrome and Vasculitis A recent paper evaluated 65 patients with primary Sjögren's syndrome [1]. Increased aPL levels (predominantly IgA aCL) were found in 13 (21%). aCL elevations were not significantly associated with arterial/ venous thromboses or with vasculitis in this group of patients. The lupus anticoagulant was negative in all.
Conditions Mimicking Vasculitis In some patients with elevations of the aPL, the clinical presentation may suggest `vasculitis'. However, it has become clear that microvascular thrombotic disease may superficially resemble vasculitis clinically. Two such examples are:
Subungual `Splinter' Haemorrhages Subungual splinters are often an accompaniment of vasculitic lesions such as digital infarcts, and may be seen with infective endocarditis or rheumatoid vasculitis. Recently, these lesions have also been described in
Downloaded by: National Univ. of Singapore 137.132.123.69 - 3/27/2017 5:06:45 AM
Ophthalmic Vaso-Occlusive Phenomena These include retinal and `optic neuritis' leading to optic atrophy. Extensive sheathing of vessels, exudates and neovascularization may lead clinicians to the conclusion that the patients are suffering from retinal or choroidal vasculitis [ 12-14].
Asherson/Hughes
20
patients with elevations of the aPL and may be seen during pregnancy, following the administration of oral contraceptives, with transient ischaemic attacks particularly resulting in amaurosis fugax [ 15], as well as in patients with other concurrent thrombotic events such as adrenal vascular occlusion [ 16]. Skin Lesions Florid vasculitic skin lesions have been documented as occurring infrequently in patients with primary APS [ 17]. However, skin vasculitis is distinctly unusual. A patient recently documented from our own unit with high levels of IgM aCL and on long-term anti-coagulation therapy with warfarin developed a superficial macular rash over the lower limbs, which closely resembled a vasculitic eruption. Skin biopsy revealed only fibrin thrombi in the small dermal vessels [20]. Other authors have also documented macular skin lesions in their patients with aPL elevations which superficially resembled vasculitis, but which, on biopsy, showed only microthrombosis in the dermal vessels without any evidence of vasculitis [21]. The histopathology of 13 specimens obtained from patients with the lupus anticoagulant and skin ulceration seen at the Mayo Clinic recently [23] showed vascular thrombosis in 10, capillary proliferation in 8, endarteritis obliterans in 7 and vascular infiltration in 1. Reyes and Alarcon-Segovia [22] reported vascular proliferation `glomerulus-like' nodular structures in the subcapillary dermis. Within the fibrous tissue there was a moderate mixed infiltrate of polymorphonuclear cells and lymphocytes. The lumen of the proliferated vessels was irregular and a few were occluded by fibrin thrombi. Some vessels had fibrin deposition within the walls. It is likely that multiple recanalization of vessels is responsible for this picture.
Histopathological examination of tissue obtained from amputations and reported by Alarcon-Segovia et al. [24] showed striking intimal and medial proliferation as well as some increase in the adventitia. There was little evidence of thrombosis, but in 2 of the patients reported who had required early amputation, there was a mononuclear infiltrate of the large arteries accompanied by evidence of leucocytoclastic vasculitis in skin and/or muscle. One patient had developed cutaneous modules which on subsequent biopsy were also found to be due to leucocytoclastic vasculitis. There has been some controversy regarding the histopathological interpretation of these changes, but it is probable that the inflammatory changes
Downloaded by: National Univ. of Singapore 137.132.123.69 - 3/27/2017 5:06:45 AM
Arterial Vasculopathy
Vascular Disease and Thrombosis
21
are mainly those seen following thrombosis at varying stages of organization and not due to vasculitis per se [25] as mentioned earlier.
The importance of disturbances in the coagulation mechanism was first recognized in the early 1970s [26], and attempts were made to influence the course of glomerulonephritis by the use of anticoagulants such as heparin [27, 28], or by defibrinating agents such as Ancrod [29]. In 1975, Kincaid-Smith [ 30] stressed the participation of intravascular coagulation in the pathogenesis of kidney disease. Over a 15-year period, her group studied 4,860 biopsy specimens and demonstrated the presence of fibrin deposition within vessels in a range of conditions including acute tubular necrosis thrombotic microangiopathy, scleroderma, pre-eclamptic toxaemia, and malignant hypertension. They suggested that all might have a similar pathogenesis and proposed that fibrin deposition within vessels was the first step in the formation of the intimal lesions with resultant narrowing of interlobular arteries. Different stages, i.e. fibrin deposition alone, fibrin with commencing organization and epithelialization and narrowing by cellular intimal proliferation, were all present in the same biopsy specimens. Kant et al. [31] in 1981 analyzed the clinical, serological, coagulation and histological findings in 71 patients with SLΕ. One hundred and five renal biopsy specimens were analysed. Thrombin and fibrin were detected using light microscopy and immunoflourescence. Thrombi were detected in 50% of biopsies with diffuse and focal proliferative glomerulonephritis. In patients with glomerular thrombi, factor VIII levels were significantly increased and circulating platelets decreased. Thrombosis in a first biopsy appeared to be an excellent predictor of increased glomerulosclerosis in the second. There was a striking association between the occurence of a circulating anticoagulant and the occurrence in the renal biopsy of glomerular thrombosis without necrosis. The same group subsequently reported renal thrombosis in 14 of 18 SLΕ patients with a circulating lupus anticoagulant [32]. Another study [33] correlated the clinical features of 12 women with circulating lupus anticoagulant with renal biopsies. Four of the 12 had serological evidence of SLΕ. As the vascular glomerular lesions were present in 8 patients without evidence of SLΕ, these authors concluded that the thrombotic lesions previously described in the renal circulation in lupus nephritis were not, as previously associated, a manifestation of so-called
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Glomerular Thrombosis and Relationships to Antiphospholipid Antibodies
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`lupus vasculitis', but represented a form of thrombotic microvascular complication associated with the presence of a circulating lupus anticoagulant. The patients studied were referred because of recurrent abortions or impaired renal function in pregnancy. Biopsies of these patients carried out at a time remote from pregnancy showed persisting double contours in glomeruli, with narrowing of arteries due to recanalizing thrombi and cellular intimal proliferation. These findings are in keeping with `organization of the thrombi. In 1991. Leaker et al. [34] documented 4 patients with raised aCL levels and insidious loss of renal function in the absence of overt nephritis and with normal urinary findings. Three had defined SLΕ, although clinical and laboratory evidence of lupus activity was minimal in these patients. The fourth patient had a `primary' APS. All had previous episodes of thrombosis and all were receiving maintenance immunosuppressive therapy at the time of renal biopsy. In all, renal biopsies showed ischaemic changes with no evidence of active lupus nephritis. Arteriolar hyalinosis was prominent. Small to medium-sized vessels were abnormal with narrowing of the vessel lumen secondary to cellular intimal proliferation. One biopsy showed fibrin thrombi in glomerular capillaries. Three further very similar patients were recently documented by Agati et al. [35], one with a primary APS, one with SLΕ and one with `lupus-like' disease. All had a clinical course dominated by repeated multi-organ thrombosis. The renal presentation varied from asymptomatic, mild proteinuria to nephrotic syndrome, renal insufficiency and hypertension. Frampton et al. [36] recently studied 76 patients with SLΕ and clinically evident nephritis, most of whom were taking prednisolone and azathioprine at the time of the study. Renal biopsies were performed on all patients. Although an association between the presence of intra-glomerular thrombi and elevations of IgG aCL was found, no association between aPL and renal histological pattern or long term renal function was discovered. The authors speculated that this could have been a result of the small numbers of patients with worsening renal function studied (n = 7) or perhaps that the follow-up period was too short (8-89 months). These authors suggested that the aPL-mediated glomerular thrombi might contribute in some patients to the pathogenesis of the nephritis.
In summary, glomerular thrombi and vascular lesions may be seen in a variety of conditions, including SLE, scleroderma, microangiopathic diseases (e.g. the haemolytic uraemic syndrome), pregnancy-associated
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Conclusions
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renal failure, pre-eclampsia and malignant hypertension. There is no associated vasculitis in the renal biopsies of these patients, but progressive narrowing of the renal vessels consequent on organization of fibrin thrombi may give rise to glomerulosclerosis and loss of insidious renal function. aPL-associated vascular disease consisting of thrombotic lesions affecting large and small vessels, veins as well as arteries, occurs mainly in patients with SLE and closely related conditions such as `lupus-like' disease (`probable' lupus), the `primary' APS and the recently defined `catastrophic' antiphospholipid syndrome [37, 38]. Thrombotic events are uncommonly associated with the aPL in patients with vasculitis, the exceptions being conditions such as giant cell temporal arteritis, and very rarely Takayasu's arteritis or relapsing polychondritis. Small vessel occlusions may mimic vasculitic disorders in certain circumstances.
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Ronald A. Asherson, MD, Director of Clinical Research, Lupus Arthritis Research Unit, The Rayne Institute, St. Thomas' Hospital, London SEl 7EH (UK)
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