Asymptomatic avascular necrosis in patients with primary antiphospholipid syndrome in the absence of corticosteroid use: A prospective study by magnetic resonance imaging

Abstract

Objective

To evaluate the prevalence of avascular necrosis (AVN), using magnetic resonance imaging (MRI), in patients with primary antiphospholipid syndrome (APS) and in patients with systemic lupus erythematosus (SLE), with or without anticardiolipin antibodies (aCL), who are asymptomatic for AVN and have not taken corticosteroids.

Methods

Seventy-nine subjects who were asymptomatic for AVN were evaluated by MRI of the femoral heads: 30 patients with primary APS who had never received corticosteroids, 19 SLE patients who had never received steroids (divided into 2 groups, aCL positive and aCL negative, in order to examine any association between AVN and aCL), and 30 healthy subjects who were age- and sex-matched with patients with primary APS. Established MRI criteria were used for a diagnosis of AVN.

Results

Asymptomatic AVN was evident in 6 (20%) of 30 patients with primary APS: 3 of them (1 man, 2 women) had intermediate bilateral AVN, and 3 (all women) had early AVN (bilateral in 1 patient). Results of hip and pelvis radiography and dynamic scintigraphy were negative. Followup MRI 6 months later revealed no changes. At the time of the initial MRI examination, the mean (±SD) age of patients in whom AVN was identified was 31.2 ± 7.3 years, and that of patients without AVN was 42.4 ± 11.9 years (P = 0.036). Livedo reticularis occurred significantly more commonly in the group with AVN (P = 0.041). None of the healthy subjects and none of the patients with SLE demonstrated AVN on MRI.

Conclusion

AVN can be detected by MRI in 20% of patients with primary APS. Younger patients tend to develop AVN more frequently than do older patients, and the presence of livedo reticularis may identify individuals at risk for AVN. Clinicians should be aware of this possible clinical manifestation of primary APS, because early diagnosis can lead to early intervention.

Avascular necrosis (AVN) of the bone is a disease in which cell death in components of bone occurs as a result of interruption of the blood supply. The most common site of AVN is the femoral head, probably because of restricted perfusion. Clinical symptoms associated with AVN are nonspecific, and the patient often remains entirely asymptomatic. Magnetic resonance imaging (MRI) is the most accurate method for detecting AVN (1).

The pathogenetic mechanisms of AVN have been partially elucidated. Extravascular pressure and subsequent tamponade of the arterial vessels or an intravascular thrombosis has been involved (2). Intravascular thrombosis can be associated with various underlying diseases.

Antiphospholipid syndrome (APS) is characterized by venous and arterial thrombosis in the presence of anticardiolipin antibodies (aCL) and/or the lupus anticoagulant (LAC) (3). AVN in association with aCL was first reported in 1985 by Asherson et al (4), in 5 patients with systemic lupus erythematosus (SLE). However, this association is still controversial for several reasons. In almost all studies describing AVN in patients with SLE, patients had received corticosteroids, which is the major predisposing factor for AVN (4, 5). AVN in patients with primary APS, who rarely receive steroids, has been documented only in sporadic reports (6–8). In addition, most of the previous studies were retrospective, and AVN has been examined only in symptomatic patients, using mainly conventional radiographic techniques.

The purpose of this study was to investigate prospectively by MRI the prevalence of AVN of the femoral head in patients with primary APS and patients with SLE (with or without aCL) who were asymptomatic for AVN and had never received corticosteroids. Patients with SLE were classified as being either aCL positive or aCL negative, in order to evaluate any association between AVN and aCL.

PATIENTS AND METHODS

Patients.

Seventy-nine patients who were asymptomatic for AVN were evaluated by MRI of the femoral heads. The 3 groups of patients were as follows: 30 patients with primary APS (7 men, 23 women) who received followup care at our department and had never received corticosteroids, 19 patients with SLE who had not previously received steroids (5 men and 14 women, divided into 2 groups: those without aCL [n = 10] and those with aCL but not APS [n = 9]), and 30 healthy subjects matched for age and sex to the patients with primary APS.

Primary APS was diagnosed according to Sapporo criteria (3), and SLE was diagnosed according to American College of Rheumatology (formerly, the American Rheumatism Association) criteria (9). Exclusion criteria were trauma, alcoholism, sickle cell disease, pancreatitis, Gaucher's disease, and pregnancy. Informed consent and institutional review board approval were received.

Magnetic resonance imaging.

Examination protocol.

In this prospective study, both hips were imaged using a 1.5T superconducting magnet. Imaging was performed in 3 planes. In the coronal plane, T1-weighted spin-echo pulse sequences as well as T2/proton density–weighted spin-echo pulse sequences were obtained for a complete evaluation of the femoral head. The presence of bone marrow edema was evaluated in the coronal plane with a STIR sequence and in some cases with an additional T2-weighted turbo spin-echo pulse sequence for comparison. In the axial (transverse) plane, a T2-weighted turbo spin-echo pulse sequence was obtained for the evaluation of articular and periarticular soft tissues and for comparison with signal abnormalities depicted in coronal T2-weighted spin-echo sequences. T1-weighted spin-echo sequences were obtained in the sagittal plane on both sides for a more detailed evaluation of the subcortical area of the femoral head. Postcontrast evaluation was performed in the coronal plane. This was preceded by a dynamic postcontrast T1-weighted fat-saturated pulse sequence in the axial or coronal plane in order to depict abnormal enhancement during the early postinfusion phases.

Image evaluation.

Images were reviewed by 2 radiologists blinded to the clinical diagnosis. Established criteria for AVN (1) were used. Early uncomplicated AVN was defined as the presence of a low-intensity band or rim in the subchondral zone of the femoral head (band sign), intermediate AVN was defined as the presence of a geographic area of decreased signal intensity with slightly diffuse margins (with or without a double-line sign), and advanced AVN was defined by the combination of the above findings with collapse and joint congruity. The double-line sign is seen on T2-weighted MR images as a high signal intensity line in an inner zone combined with low signal intensity in an outer zone.

Bone marrow edema was seen as an ill-defined epiphyseal marrow area of low signal intensity on T1-weighted MR images and of intermediate to high signal intensity on T2-weighted images, remaining at high intensity on fat-suppressed T2-weighted images. Femoral head perfusion was assessed with gadolinium-enhanced T1-weighted MRI to confirm low perfusion in the cases positive for AVN. Conventional radiography and dynamic bone scintigraphy of the hips were performed in all patients in whom AVN was demonstrated by MRI.

Laboratory examinations.

The presence of IgG and IgM aCL and anti–β₂-glycoprotein I (anti-β₂GPI) antibodies was determined using an enzyme-linked immunosorbent assay, as previously described (10). LAC was assayed by standard activated partial thromboplastin time, kaolin clotting time, and dilute viper venom time.

Statistical analysis.

The 2 groups of patients with primary APS (patients with AVN and those without AVN) were compared using nonparametric analysis as follows: the Mann-Whitney test was used for continuous variables (age at the time of MRI examination, disease duration), and Fisher's exact test was used for the clinical and laboratory variables, measured on a binary scale (positive–negative).

RESULTS

Asymptomatic AVN was revealed in 6 (20%) of the 30 patients with primary APS: 3 of these patients (1 man, 2 women) had intermediate bilateral AVN with a double-line sign (Figure 1A), and the other 3 (all women) had early uncomplicated AVN (bilateral in 1 patient) (Figure 1B). No cases of advanced AVN were observed. Hip and pelvis radiography and dynamic scintigraphy were negative in all 6 of these patients. One of the patients experienced knee pain 3 months after the initial examination, and an additional MRI revealed AVN of both knees. The other 5 patients remained asymptomatic. Followup MRI 6 months after the initial examination revealed no changes.

Figure 1. Magnetic resonance images of the femoral head in patients with primary antiphospholipid syndrome. A, Intermediate avascular necrosis (AVN). The double-line sign is seen on T2-weighted magnetic resonance images as a high signal intensity line in an inner zone, combined with a low signal intensity line in the outer zone. B, Early AVN. The band sign is seen as a low-intensity band in the subchondral zone of the femoral head.

Bone marrow edema (unilateral) was demonstrated in 4 (13%) of the 30 patients with primary APS; in 2 of these patients (6.6%) it was the sole MRI abnormality and was not associated with any subchondral irregularities. In these 2 patients, followup MRI 6 months later showed complete resolution of the edema.

None of the 19 patients in the SLE group and none of the 30 healthy individuals had positive MRI findings for AVN. Unilateral bone marrow edema was demonstrated in 1 SLE patient who was aCL negative.

Demographic, clinical, and laboratory features of the patients.

At the time of the initial MRI examination, the mean (±SD) age of patients with primary APS in whom AVN was revealed was 31.2 ± 7.3 years, and that of patients with primary APS in whom AVN was not demonstrated was 42.4 ± 11.9 years (P = 0.036). The mean (±SD) disease duration in primary APS patients with AVN was 4.5 ± 4.6 years, and that in primary APS patients without AVN was 6.8 ± 4.1 years (P = 0.26).

Among aCL-negative SLE patients, the mean (±SD) age at the time of the initial MRI examination was 35.5 ± 8.5 years, and that in aCL-positive SLE patients was 41.7 ± 7.7 years. The mean (±SD) disease duration in aCL-negative SLE patients was 4.8 ± 1.8 years, and that in aCL-positive SLE patients was 4.7 ± 1.9 years.

The prevalence of clinical and laboratory characteristics in primary APS patients with AVN and those without AVN was compared in order to assess any relationship between those charactertistics and AVN. It was shown that livedo reticularis occurred significantly more commonly in the AVN group (P = 0.041). No associations with other clinical characteristics (venous or arterial thrombosis, thrombocytopenia, abortions, Raynaud's phenomenon) or with the aCL titer, the presence of LAC, or the presence of anti-β₂GPI could be identified. Other factors that were not different between the 2 groups included hypertension, serum cholesterol and triglyceride levels, cigarette smoking, and alcohol abuse (all P > 0.05). All patients with primary APS were receiving coumarin treatment at the time of MRI examination.

DISCUSSION

The results of this prospective study showed an increased incidence of asymptomatic AVN of the femoral head (20%), as detected by MRI, in patients with primary APS. None of the patients with SLE (with or without aCL) who had never received corticosteroids and none of the healthy controls had documented AVN.

Several hypotheses regarding the pathogenesis of AVN have been proposed (2). In patients with nontraumatic AVN, histopathologic examinations have revealed thrombosis of terminal arteries in subchondral areas. Idiopathic AVN has been associated with a thrombophilic (acquired or inherited) and/or hypofibrinolytic state (11). Antiphospholipid antibodies are associated with thromboses in vessels of all sizes and at multiple organ sites, but their role in the pathogenesis of AVN remains controversial. A recent study demonstrated an unexpectedly high occurrence of AVN of the hip in patients with human immunodeficiency virus infection, especially in those with detectable levels of aCL (12). An association between AVN and aCL or LAC was also demonstrated in several studies involving SLE patients (4, 5). However, this association was not confirmed by other studies, in which different risk factors, such as corticosteroids, were suggested (13, 14).

The relationship between corticosteroid use and AVN is well established in the literature. Corticosteroids are commonly administered to patients with SLE or secondary APS, but are used rarely in patients with primary APS. In a retrospective study, Asherson et al reported that symptomatic AVN developed in 2 of 70 patients with primary APS, and that it was the initial manifestation of the syndrome in one of these patients (6). Since then, there have been sporadic case reports of bilateral or unilateral AVN of the hips and knees in patients with primary APS who were not receiving corticosteroids (7, 8).

Prospective studies examining the prevalence of AVN (in the absence of corticosteroid use) in patients with SLE (with or without aCL) or primary APS are lacking. Furthermore, most of the previous studies have examined only symptomatic patients and have used only conventional radiographic techniques. MRI is more sensitive than computed tomography, scintigraphy, or conventional radiography for detection of clinically silent AVN (1).

In our study, asymptomatic AVN was found to be more prevalent in younger patients. A significant association between AVN and livedo reticularis (P = 0.041) was also observed. Livedo reticularis represents the most common skin manifestation in APS, characterized by diminished blood flow in arterioles and dilatation of venules and capillaries. This alteration in blood supply may represent an additional risk factor for AVN in patients with APS. Magnetic resonance imaging is the most accurate method for detecting early and asymptomatic AVN.

The presence of bone marrow edema was evaluated because of its well-known association with early AVN (15), and was documented in 13% of the patients with primary APS in our study. Vande Berg et al (15) showed that a lack of accompanying subchondral changes on T2-weighted or contrast-enhanced T1-weighted images had 100% positive predictive value for a transient phenomenon. In our series, neither of the 2 cases involving reversible edema was associated with subchondral irregularities.

The occurrence of AVN in patients with SLE was first reported in 1960 by Dubois and Cozen (16). Those authors suggested that SLE itself, or vasculitis in the context of SLE, was the main cause of AVN. In our study, no patient with SLE, with or without aCL and in the absence of steroid use, had AVN of the femoral head as demonstrated by MRI. The number of patients with SLE was small because of the difficulty in recruiting SLE patients who had never received corticosteroids. In our study, SLE patients were divided into those who were aCL positive and those who were aCL negative, in order to examine any relation between AVN and aCL, but no correlation was observed. Houssiau et al, in a prospective study using MRI, found no significant difference in the prevalence of AVN between aCL-positive and aCL-negative SLE patients who were receiving corticosteroids (14).

We hypothesize that AVN may be documented not only in patients who are positive for aCL, but also in those who already had thrombotic manifestations in the context of APS. In fact, AVN might represent an additional clinical feature of APS. AVN of the hips is associated with significant functional disability. A better understanding of the pathogenesis of AVN and earlier diagnosis can modify its management, in order to avoid a major surgery such as arthroplasty.

In conclusion, asymptomatic AVN can be detected by MRI in approximately one-fifth of patients with primary APS. Avascular necrosis tends to develop more frequently in younger patients than in older ones, and livedo reticularis may identify individuals at risk for AVN. Clinicians should be aware of this clinical manifestation of primary APS, because early diagnosis can lead to early intervention.