The major manifestations of antiphospholipid syndrome (APS) are caused by thrombosis within the venous or arterial vasculature, whereas the vascular lesions in systemic vasculitis result from an inflammatory infiltrate in the vessel wall. There is an association between vascular thrombosis and inflammation, however, as vasculitis can occur in APS and thromboembolic complications are seen in systemic vasculitis. Although differentiating between vasculitis and antiphospholipid-associated thrombosis can be difficult, it may be crucial to do so given the different therapeutic implications for immunosuppression or anticoagulation. This article explores the relationship between thrombosis and inflammation as it relates to APS and systemic vasculitis.
Key points
- •
Systemic vasculitis may rarely coexist with antiphospholipid syndrome (APS), despite the fact that the classic APS manifestations are thrombosis and vasculopathy.
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Vasculitic-like manifestations attributed to antiphospholipid antibodies (aPL) include livedoid vasculitis, retinal vasculitis, and diffuse alveolar hemorrhage.
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Antiphospholipid antibodies are increased in certain primary vasculitic disorders; a causative association of aPL with thrombosis in these patients has not been shown, however, and routine testing for aPL in primary vasculitis is not recommended.
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Differentiating between vasculitis and antiphospholipid-associated thrombosis, especially in patients with known primary vasculitis or systemic lupus, is critical in determining appropriate immunosuppressive or anticoagulant therapy.
Introduction
Antiphospholipid syndrome (APS) is an autoimmune disease characterized by vascular thrombosis and/or pregnancy morbidity occurring in conjunction with serologically detectable antiphospholipid antibodies (aPL). aPL, defined as autoantibodies directed against phospholipid-binding plasma proteins, include lupus anticoagulant (LAC), anticardiolipin antibody (aCL), and anti–β2-glycoprotein I (aβ2GPI), and should be persistently positive when measured at least 12 weeks apart to meet the criteria for APS ( Box 1 ). Detection of positive aPL in the absence of characteristic clinical events does not equate to a diagnosis of APS; many individuals with positive aPL remain asymptomatic indefinitely. Because transient aPL positivity can be triggered by certain infections, malignancies, or medications, demonstration of persistent serologic positivity is critical when considering a diagnosis of APS. APS may occur alone or in the setting of another autoimmune disease, most commonly systemic lupus erythematosus (SLE).
Clinical Criteria
- 1.
Vascular thrombosis:
At least 1 clinical episode of arterial, venous, or small vessel thrombosis, in any tissue or organ
- 2.
Pregnancy morbidity:
- a.
At least 1 unexplained death of a morphologically normal fetus at or beyond the 10th week of gestation, or
- b.
At least 1 premature birth of a morphologically normal neonate before the 34th week of gestation because of eclampsia, severe preeclampsia, or recognized features of placental insufficiency, or
- c.
At least 3 unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities, and paternal and maternal chromosomal causes excluded
- a.
Laboratory Criteria a
- 1.
Lupus anticoagulant present in plasma
- 2.
Anticardiolipin antibody of immunoglobulin (Ig)G and/or IgM isotype, in medium or high titer (>40 IgG or IgM phospholipid units)
- 3.
Anti–β2-glycoprotein I antibody of IgG and/or IgM isotype in medium or high titer (>99th percentile)
Definite APS is present if at least 1 of the clinical and 1 of the laboratory criteria are met.
a Laboratory criteria must be present on 2 or more occasions at least 12 weeks apart.
Although venous or arterial thrombosis and fetal loss are the commonest clinical manifestations of APS, this is a multisystem disease with many noncriteria manifestations including thrombocytopenia, skin ulcers, nephropathy, and cardiac valvular disease. The pathogenic vascular lesions in APS are predominantly related to thrombosis or microangiopathy and not inflammation. However, vascular inflammation, namely, vasculitis, may rarely be a component of APS. Furthermore, aPL positivity or secondary APS may occur in patients with an underlying primary systemic vasculitis.
Introduction
Antiphospholipid syndrome (APS) is an autoimmune disease characterized by vascular thrombosis and/or pregnancy morbidity occurring in conjunction with serologically detectable antiphospholipid antibodies (aPL). aPL, defined as autoantibodies directed against phospholipid-binding plasma proteins, include lupus anticoagulant (LAC), anticardiolipin antibody (aCL), and anti–β2-glycoprotein I (aβ2GPI), and should be persistently positive when measured at least 12 weeks apart to meet the criteria for APS ( Box 1 ). Detection of positive aPL in the absence of characteristic clinical events does not equate to a diagnosis of APS; many individuals with positive aPL remain asymptomatic indefinitely. Because transient aPL positivity can be triggered by certain infections, malignancies, or medications, demonstration of persistent serologic positivity is critical when considering a diagnosis of APS. APS may occur alone or in the setting of another autoimmune disease, most commonly systemic lupus erythematosus (SLE).
Clinical Criteria
- 1.
Vascular thrombosis:
At least 1 clinical episode of arterial, venous, or small vessel thrombosis, in any tissue or organ
- 2.
Pregnancy morbidity:
- a.
At least 1 unexplained death of a morphologically normal fetus at or beyond the 10th week of gestation, or
- b.
At least 1 premature birth of a morphologically normal neonate before the 34th week of gestation because of eclampsia, severe preeclampsia, or recognized features of placental insufficiency, or
- c.
At least 3 unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities, and paternal and maternal chromosomal causes excluded
- a.
Laboratory Criteria a
- 1.
Lupus anticoagulant present in plasma
- 2.
Anticardiolipin antibody of immunoglobulin (Ig)G and/or IgM isotype, in medium or high titer (>40 IgG or IgM phospholipid units)
- 3.
Anti–β2-glycoprotein I antibody of IgG and/or IgM isotype in medium or high titer (>99th percentile)
Definite APS is present if at least 1 of the clinical and 1 of the laboratory criteria are met.
a Laboratory criteria must be present on 2 or more occasions at least 12 weeks apart.
Although venous or arterial thrombosis and fetal loss are the commonest clinical manifestations of APS, this is a multisystem disease with many noncriteria manifestations including thrombocytopenia, skin ulcers, nephropathy, and cardiac valvular disease. The pathogenic vascular lesions in APS are predominantly related to thrombosis or microangiopathy and not inflammation. However, vascular inflammation, namely, vasculitis, may rarely be a component of APS. Furthermore, aPL positivity or secondary APS may occur in patients with an underlying primary systemic vasculitis.
Antiphospholipid antibodies, antiphospholipid syndrome, and vasculitis
The mechanistic interplay between aPL and vascular inflammation is complex. Although the pathogenesis of thrombosis in APS is not entirely understood, the interactions of aPL with antigenic components of the phospholipid complex are essential in mediating the pathologic prothrombotic phenotype. Subsequent endothelial cell activation and damage contributes to the vasculopathy of APS.
Despite the persistent presence of aPL, clinically evident thrombosis occurs only occasionally, suggesting that a “second hit” is required for the development of thrombosis. Inflammation driven by the nuclear factor κB pathway and/or complement activation has been hypothesized as a link between the aPL-induced hypercoagulable state and frank thrombus development. Endothelial cell activation, production of inflammatory cytokines, and upregulation of vascular adhesion molecules promote the recruitment of neutrophils and monocytes to the vascular lumen. Thus, an inflammatory cell infiltrate may coexist with thrombosis in APS; however, this is a reactive process and does not represent true vasculitis with the pathognomonic inflammation of the vessel wall.
When histopathologic vasculitis is found in APS, it is usually a contemporaneous phenomenon and is not causally related to the APS. Concurrent vasculitis and APS most commonly occur in a patient with SLE or another underlying connective tissue disease. Vasculitis occurs in approximately 10% to 35% of SLE patients, with small-vessel cutaneous vasculitis accounting for 80% of cases; aPL antibodies are found in 40% of SLE patients. Albeit infrequently, SLE patients can develop medium-vessel or large-vessel vasculitis that affects the central or peripheral nervous system or visceral organs. In characterizing vasculitis in large cohorts of SLE patients, a correlation between vasculitis, aPL, and APS-related manifestations such as livedo reticularis, venous thrombosis, and thrombocytopenia has been reported. Despite the association between vasculitis and aPL in SLE, however, there is no evidence to support a causative role of aPL in the development of vasculitis.
The link between aPL positivity and SLE vasculitis may relate to damage of the vascular endothelium by the vasculitic process. Disruption of the vascular endothelium exposes phospholipids that, together with phospholipid-binding proteins, can serve as an antigenic stimulus for aPL production and/or a binding target for circulating aPL. This same mechanism of vasculitic damage may also explain the association of aPL and APS with primary systemic vasculitis. Prevalence estimates of definite APS occurring in the primary systemic vasculitides range from 0.7% to 6%, although the prevalence of aPL positivity in these conditions is much higher. APL have been reported in association with all of the primary systemic vasculitides, including those affecting small, medium, and large vessels.
The sequelae of vascular occlusion, whether thrombotic or inflammatory, are tissue ischemia and end-organ damage, and can be clinically indistinguishable. There is an obvious need to differentiate between thrombotic and vasculitic lesions to guide therapy and choose between anticoagulation and immunosuppression. The remainder of this article focuses first on a discussion of the reported vasculitic manifestations of APS itself, then on the significance of aPL in the individual vasculitic syndromes.
Vasculitic manifestations of antiphospholipid syndrome
Cutaneous Lesions
A variety of dermatologic manifestations have been described in APS. Cutaneous lesions occur in approximately half of patients with APS, with livedo reticularis being the most frequent dermatologic manifestation. Livedoid vasculitis, also known as livedo reticularis with ulceration, has been described in APS and is characterized by purpuric lesions of the lower extremities that progress to ulceration and atrophie blanche ( Fig. 1 ). Despite the name, the histopathology of livedoid vasculitis lacks evidence of true vasculitis, without perivascular inflammatory infiltrate or leukocytoclasia, and is more properly termed livedoid vasculopathy. Patients with APS can also present with painful cutaneous nodules resembling cutaneous vasculitis. However, these lesions are typically refractory to immunosuppression and demonstrate thrombosis of superficial dermal vessels on biopsy without vasculitis; thus, these nodules are termed pseudovasculitis. There have been several reports of APS patients with histopathologic leukocytoclastic vasculitis on biopsy, but most of these patients had concurrent SLE. In a small cohort of patients with underlying connective tissue disease, immunoglobulin (Ig)A but not IgG aCL positivity was associated with cutaneous vasculitic lesions in 9 patients who did not have any other manifestations of APS.
Retinal Vasculitis
Ocular manifestations are not uncommon in APS ; most of these are caused by occlusive ocular vascular disease, which may also be associated with central nervous system involvement. Frank retinal vasculitis, with or without concurrent retinal thrombosis, can occur in APS. In a cohort of patients presenting with ocular inflammatory disease who were found to have aCL positivity, retinal vasculitis was diagnosed in 60% of aCL-positive patients. However, only 3 of the 13 patients with retinal vasculitis in this cohort had high-titer aCL IgG (>40) and repeat aCL testing was not available, making the diagnosis of definite APS difficult to establish.
A diagnosis of retinal vasculitis is made on the basis of characteristic fluorescein angiographic findings of vascular leakage and capillary nonperfusion. Thus, retinal vasculitis in APS is not based on histopathologic evidence, so the presence of microthrombi as the underlying etiologic trigger cannot be excluded. The cases of reported retinal vasculitis in APS were all treated successfully with anticoagulation without immunosuppression, further supporting a thrombotic etiology.
Diffuse Alveolar Hemorrhage
Diffuse alveolar hemorrhage (DAH), disruption of the alveolar-capillary basement membrane resulting in bleeding into the alveolar space, is a rare but serious manifestation of APS. DAH occurs more frequently in the catastrophic antiphospholipid syndrome (CAPS) than in classic APS. Presentation of DAH can vary from dyspnea and cough to hemoptysis and acute respiratory failure. The histopathologic lesion of DAH in APS/CAPS is pulmonary capillaritis, which is believed to be immune mediated. In the largest reported series of primary APS-associated DAH, 18 patients were described; histologic evidence of capillaritis was noted in all 3 patients who underwent surgical lung biopsy. Bronchial alveolar lavage demonstrates neutrophilia, and neutrophils are often present in the alveolar space on biopsy specimens even if capillaritis is not seen. These inflammatory pathologic findings in APS-associated DAH occur in the absence of thrombosis; thus, DAH is considered to be a nonthrombotic manifestation of APS.
The pathogenic mechanism leading to capillary damage or capillaritis in APS-associated DAH is not well understood. Circulating aPL are believed to be pathogenic in this inflammatory manifestation of APS and may induce upregulation of endothelial cell-adhesion molecules, with ensuing neutrophil recruitment and migration into the alveolar space and resultant tissue destruction and hemorrhage.
The presumed inflammatory nature of DAH in APS has important therapeutic implications. Experts recommend prompt initial treatment of DAH with high-dose corticosteroids and temporary cessation of anticoagulation. Additional immunosuppression is often needed, as recurrences and mortality are common. No controlled or prospective data are available to guide treatment of APS-related DAH; however, borrowing from the treatment of capillaritis in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cyclophosphamide (CYC) or rituximab (RTX) are often the first-line agents used. In a recent retrospective series from the Mayo Clinic of 18 patients with primary APS-associated DAH, complete remission was achieved in 3 of 7 patients treated with CYC and 5 of 8 patients treated with an RTX-based regimen, whereas uncontrolled disease was observed in patients treated with azathioprine, mycophenolate mofetil, intravenous Ig, or plasmapheresis.
Miscellaneous Case Reports
Biopsy-proven vasculitis in association with primary APS has been reported in a variety of organ systems ( Table 1 ). There are case reports of cerebral vasculitis, diagnosed on brain biopsy, in patients with persistent LAC positivity and no signs of underlying SLE. These patients were uniformly treated with high-dose corticosteroids, although 1 of the 3 reported cases proved fatal despite immunosuppression. Vasculitic involvement of peripheral nerves has also been reported in a woman with aCL and recurrent pregnancy loss who developed mononeuritis multiplex with sural nerve biopsy confirming vasculitis. Arteritis in the coronary arteries with concurrent thrombosis was identified in the autopsy of a woman with LAC and aCL positivity and recurrent venous thromboembolism who suffered a fatal myocardial infarction. Occlusive involvement of the renal artery resulting from vasculitis presenting as hypertension has also been reported in primary APS.
| Organ System | Clinical Manifestation | Histopathology | Comments |
|---|---|---|---|
| Skin | Livedoid vasculitis, pseudovasculitis | Fibrinoid changes, fibrin plugs along vascular channels, thrombi in superficial dermal vessels | Despite term livedoid vasculitis, this is believed to be a thrombotic vasculopathy |
| Ocular | Retinal vasculitis | No abnormality, diagnosed on basis of fluorescein angiography | May be related to microthrombosis in retinal vasculature |
| Pulmonary | Diffuse alveolar hemorrhage | Capillaritis and/or neutrophilia in alveolar space | Considered to be a nonthrombotic manifestation of APS |
| Cardiac a | Myocardial infarction | Coronary arteritis and thrombosis | |
| Renal a | Hypertension | Immune-complex vasculitis reported in one case | |
| Central nervous system a | Stroke, encephalopathy | Granulomatous angiitis | |
| Peripheral nervous system a | Mononeuritis multiplex | Necrotizing arteritis with thrombosis |
Antiphospholipid antibodies and antiphospholipid syndrome in systemic vasculitis
The systemic vasculitides are a heterogeneous group of disorders characterized by the common feature of vascular inflammation. The 2012 revised Chapel Hill Consensus Conference provides a useful classification for the primary vasculitides based chiefly on the caliber of the vessels involved in the inflammatory process. Although aPL have been reported in conjunction with all of the systemic vasculitides, the pathogenic significance of these autoantibodies in vasculitis is under debate.
Small-Vessel Vasculitis
Antineutrophil cytoplasmic antibody–associated vasculitis
The ANCA-associated vasculitides (AAV), which include granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome), are a group of multisystem autoimmune diseases characterized by necrotizing small- to medium-vessel vasculitis and the presence of serologically detectable ANCA. In a study of prevalence of aCL antibodies in patients with various connective tissue diseases, 3.8% of patients with AAV were aCL-positive, a prevalence paralleling the healthy control population.
There are scattered case reports of APS occurring in the context of all of the subtypes of AAV. As in APS, patients with AAV can present with pulmonary capillaritis and DAH. There are 2 reports of pulmonary capillaritis occurring in GPA patients with concurrent APS and deep venous thrombosis. In both cases, the investigators causally attributed DAH to GPA but hypothesized that thrombosis was related to the presence of aPL interacting with damaged endothelium.
This relationship between aPL and AAV has been most extensively explored in GPA. GPA patients are at an increased risk of venous thromboembolism. The Wegener’s granulomatosis Clinical Occurrence of Thrombosis Study (WeCLOT), using a cohort of 180 GPA patients enrolled in a randomized clinical trial, calculated the incidence of venous thromboembolic events to be 7 per 100 person-years. This rate was 20-fold higher than that in the general population and 7-fold higher than that observed in SLE patients. Venous thromboembolic events were temporally associated with periods of active disease.
To further explore hypercoagulability in active GPA, aCL and aβ2GPI antibody titers in the WeCLOT cohort were ascertained. Although aCL were found in 12% of the GPA patients, almost all were IgM isotype and there were no high-titer antibodies. Five patients (3%) had aβ2GPI positivity; again, these antibodies were low titer and predominantly IgM. There were no differences in aPL positivity between patients who had experienced a venous thromboembolic event and those who had not; thus, presence of aPL cannot explain the high incidence of venous thromboembolism in GPA. A 10% to 25% prevalence of aPL positivity that does not correlate with thrombosis has been corroborated in other GPA cohorts. APL in GPA are generally low titer, sometimes with resolution of aPL positivity on repeat testing. In addition, other noncriteria APS manifestations such as thrombocytopenia are not associated with the presence of aPL in GPA patients. One series of 5 patients with GPA and EGPA, positive aPL, and uncontrolled hypertension reported renal artery stenosis in the absence of atheromata: the investigators speculated that the renal artery stenosis may have been partial thromboses related to aPL.
A related condition whereby ANCA and aPL coexist is the cutaneous vasculopathy associated with levamisole-adulterated cocaine use. Levamisole, an anthelminthic agent used as a cocaine additive, has been implicated as the pathogenic antigen in the development of a vasculitic syndrome that includes neutropenia, retiform purpura with cutaneous necrosis, and autoantibody production. Approximately 90% of patients with levamisole-induced vasculopathy have a detectable ANCA, usually perinuclear ANCAs directed against atypical antigens such as human neutrophil elastase. LAC and aCL are also frequently detected in this syndrome; a review of 61 patients with levamisole-associated vasculopathy noted LAC positivity in 50% and IgM aCL positivity in 65% of patients. Biopsy of the cutaneous lesions reveals concurrent small-vessel vasculitis and thrombosis in one-third of cases, suggesting that both the ANCA and the aPL may be mechanistically important in the development of the clinical phenotype.
Though rare, medication-induced syndromes are also described: propylthiouracil and the anti–tumor necrosis factor α drug infliximab have been reported to induce concurrent aPL and vasculitis.
Henoch-Schönlein purpura
Henoch-Schönlein purpura (HSP), or IgA vasculitis, is a small-vessel immune-complex–mediated vasculitis associated with leukocytoclasia and IgA deposition. HSP is the most common systemic vasculitis in the pediatric population, characterized by palpable purpura in conjunction with joint, gastrointestinal, or renal involvement.
Patients with acute HSP have an increased number of circulating IgA-producing cells, often with increased IgA levels during active disease. Investigators have found aCL IgA antibodies in 75% of adults and pediatric patients with acute HSP ; levels of aCL IgA correlate with C-reactive protein and interleukin-6 levels in adult HSP, with an association between IgA aCL and renal involvement in one report. However, thrombotic events were not detected in any of the patients with IgA aCL, and most patients had undetectable IgA aCL antibody titers on repeat convalescent testing. One group found an association between central nervous system involvement of HSP and aPL in the serum and cerebrospinal fluid of 46 affected children ; however, clinical information and details on aPL isotype and titer were not reported.
The etiology of HSP is unknown, although many experts believe there is an infectious trigger with an antigenic stimulus leading to increased IgA production. Infection is also a well-known stimulus for aPL production (most commonly non-IgG isotypes); in most cases the infection-induced aPL are not pathogenic. Thus, detection of IgA aPL in active HSP may be reflective of an infectious exposure, and may not have specific pathogenic or prognostic implications.
Medium-Vessel Vasculitis
Polyarteritis nodosa
Polyarteritis nodosa (PAN) is a necrotizing vasculitis of medium-sized muscular arteries, and skin, nervous system, gastrointestinal, and renal involvement are common. A focal, segmental vasculitis with fibrinoid necrosis is the characteristic pathologic lesion of PAN on biopsy. Angiographic demonstration of microaneurysms is an acceptable surrogate for histopathologic confirmation for the diagnosis of PAN. Unlike AAV, patients with PAN do not seem to be at an increased risk for thromboembolic events.
There are several case reports documenting coexistence of classic PAN and APS. In one small cohort of 13 patients with PAN, 30% were aPL positive but no patients had an aPL-associated thrombotic event. Several reports describing coexisting PAN and APS present histopathologic evidence of vasculitis, or angiographic demonstration of microaneurysms and frank thrombosis in the presence of serologically detected aPL; treatment with immunosuppression and anticoagulation were initiated simultaneously. Other cases, however, were treated successfully with immunosuppression alone, with disappearance of aPL on repeat testing. Primary APS may also present with visceral aneurysms as are seen in PAN, which further complicates the association between these 2 conditions, especially in the absence of histologic documentation of vasculitis or thrombosis. The distinction between PAN and APS in the presence of visceral aneurysms is not trivial, as anticoagulation in the presence of aneurysms may confer increased risk of bleeding from a ruptured aneurysm: every effort should be made to confirm the diagnosis of APS in these rare cases.
One group has suggested an association of antiphosphatidylserine-prothrombin complex antibodies (aPS/PT) with a mild variant of PAN, cutaneous PAN (CPN). Elevated levels of IgG and IgM aPS/PT were identified in a series of patients with CPN without evidence of thrombosis.
Large-Vessel Vasculitis
Giant-cell arteritis
Giant-cell arteritis (GCA) is a granulomatous inflammatory disorder of medium and large blood vessels affecting the aorta and its major branches that occurs in adults older than 50 years. With an annual incidence between 19 and 30 per 100,000 population, GCA is the most common systemic vasculitis in adults. The most feared complication of untreated GCA is visual loss from ischemic optic neuropathy. Approximately 20% of patients with GCA will develop either unilateral or bilateral blindness, which usually occurs early in the disease course.
The presence of aPL has been explored in GCA to a greater extent than any of the other systemic vasculitides. The relationship between GCA and aPL was initially described by Cid and colleagues in a patient with biopsy-proven GCA, elevated IgM aCL, and arteriogram suggestive of arterial thrombosis in the bilateral lower extremities. The same group subsequently reported aCL in 3 of 40 (7.5%) patients with biopsy-positive GCA. Other studies have reported higher incidences of aCL, with IgG and IgM isotypes detected in 20% to 50% of GCA patients. By contrast, in a cohort of 45 GCA patients, no patients had aβ2GPI despite aCL positivity in half. Detectable aPL have been described in patients with polymyalgia rheumatica (PMR) in association with GCA, although aPL are typically negative in patients with isolated PMR.
Despite the high prevalence of aCL in GCA, there does not appear to be an association between aCL and ischemic events. In a longitudinal study of serial aCL measurements in 58 GCA patients, aCL was initially positive in 27 patients but normalized with treatment in all but 1. An increase in aCL titer was documented in 20 of 27 (74%) disease flares and paralleled an increase in acute-phase reactants. Presence of aCL had no relationship with prognosis, treatment response, or presenting signs or symptoms in GCA, and has been hypothesized to be a marker of endothelial damage. Endothelial disruption may uncover immunologically active antigens and stimulate antiendothelial antibodies, which may include aPL. As such, most experts recommend against routine testing for aPL in GCA.
Takayasu arteritis
Takayasu arteritis (TAK) is a granulomatous, large-vessel vasculitis predominantly affecting the aorta and its branches. Unlike GCA, TAK is generally a disease of young women, with a female to male ratio of 8.5 to 1 and most cases presenting before age 40 years. The reported prevalence of aPL positivity in TAK patients is variable, ranging from 0% to 53%. As in other vasculitides such as GCA, the presence of aPL in TAK corresponds with antiendothelial cell antibodies and disease activity. When detected in TAK, aPL are most likely an epiphenomenon reflecting damage to the vascular endothelium; however, some investigators speculate that the presence of aPL may contribute to the obstructive vasculopathy of late TAK following the initial inflammatory phase.
There are few case reports in the literature of patients with APS presenting with large-vessel involvement in a TAK-like distribution. There is debate in the literature as to the significance of aortic occlusive disease in primary APS ; whether this lesion is thrombotic or inflammatory is not readily distinguishable with conventional imaging, and tissue is rarely accessible. However, in most case reports patients were successfully treated with corticosteroids, suggesting an inflammatory etiology. Use of PET imaging has been suggested as a modality to help distinguish between thrombosis and inflammation in APS with suspected large-vessel involvement.
Variable-Vessel Vasculitis
Behçet syndrome
Behçet syndrome is a systemic vasculitis that can involve small, medium, or large vessels in the arterial or venous system. Recurrent oral and genital ulcers are a hallmark of Behçet syndrome. Other manifestations can include skin lesions, arthritis, uveitis, gastrointestinal ulceration, and vascular involvement. Pulmonary artery aneurysm and/or thrombosis are severe manifestations of Behçet syndrome, and carry 25% to 30% mortality. Pulmonary arterial disease is also associated with peripheral vascular disease, typically presenting as thrombophlebitis with superficial or deep venous thrombosis. Thrombi in Behçet syndrome are usually surrounded by an inflammatory infiltrate. Management of venous thrombosis in Behçet syndrome is controversial, but most experts support treatment with immunosuppression rather than anticoagulation.
The frequency and clinical associations of aPL have been investigated in several cohorts of Behçet patients. APL were first detected in 13 of 70 Behçet patients from a mixed European and Middle Eastern cohort, with a statistically significant association between aCL and retinal vascular involvement. This association with ocular disease was confirmed in a second cohort of 20 patients, with aPL detectable in 35% and associated with presence of uveitis. Tokay and colleagues subsequently found a much lower frequency of aPL positivity (7%) in a large cohort of Turkish patients. In a pooled analysis of 23 studies looking at aCL in more than 900 Behçet patients, the overall frequency of aCL was 19.2%. Regional variation in aCL was reported with positivity in only 9.5% of Turkish patients with Behçet syndrome compared with 25% in other populations. Importantly an association between aPL and thrombotic events has not been well established in this disorder.
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