12 Osteoarticular Manifestations of Antiphospholipid Syndrome

(1)

Antiphospholipid Syndrome

Maria G. Tektonidou and Haralampos M. Moutsopoulos

Antiphospholipid syndrome (APS) is a multi-system disorder characterized by arterial or venous thrombosis, pregnancy morbidity, and the presence of aPL, namely anticardiolipin antibodies (aCL) and lupus anticoagulant (LA). The syndrome is classiﬁed as primary or as secondary when it occurs in the context of other autoimmune disorders, especially systemic lupus erythematosus (SLE). A plethora of clinical manifestations have been associated with APS, some well recognized and others less widely known. Osteoarticular manifestations have not been commonly reported in clinical studies with APS patients, probably because of their uncertain association with the syndrome. Arthralgias represent the most well-deﬁned osteoarticular features of primary and secondary APS, whereas arthritis is mainly described in SLE-related APS. Osteonecrosis has been documented in association with antiphospholipid antibodies (aPL) in SLE patients with or without APS, but usually in the presence of steroid treatment. The existence of osteonecrosis in patients with primary APS (PAPS), in the absence of steroid administration, suggests an association between this disorder and APS.

Osteonecrosis

Osteonecrosis, also known as avascular necrosis or aseptic necrosis, is a disease in which cell death occurs in the components of bone as a result of interruption of the blood supply. It is a multi-factorial disorder associated with various traumatic and non-traumatic conditions and clinical entities (Table 12.1). If the etiology of osteonecrosis can not be identiﬁed, the disease is classiﬁed as idiopathic. Despite new developments in its diagnosis and treatment, the pathogenetic mechanisms of osteonecrosis remain partially elucidated. The most predominant hypotheses include the presence of mechanical vascular interruption (caused by trauma, fractures), injury to or pressure on a vessel wall (associated with vasculitis, infection, radiation, Gaucher disease), vascular embolism (by fat, nitrogen bubbles, sickle cells), and thrombosis [1].

Osteonecrosis has been associated with autoimmune diseases, including rheumatoid arthritis, systemic sclerosis, systemic vasculitis, and, especially, SLE [2–4].

Small vessel vasculitis or thrombotic microvasculopathy associated with aPL have been suggested as the pathogenetic mechanisms in these disorders.

127

(2)

APL and Osteonecrosis

Ischemia has been postulated as the predominant mechanism resulting in osteonecrosis since the first description of the disease [5]. In 1974, Jones et al suggested that intravascular coagulation with fibrin thrombosis, activated by several factors, is the likely final pathway leading to bone necrosis [6]. The above hypothesis has gained support by numerous studies reporting diverse coagulation abnormalities in the patients with osteonecrosis. Idiopathic osteonecrosis of the femoral head in adults and Legg-Calve-Perthes disease in children has been associated with several thrombophilic factors including protein C, S, or antithrombin III deficiency, activated protein C resistance, factor V Leiden, homocysteinemia, and aPL, as well as with abnormal fibrinolysis [7–11].

aPL are associated with vessel thromboses of all sizes and at multiple organ sites [12–14]. Thus, these antibodies may play an important role in osteonecrosis development, promoting thrombotic vasculopathy in the intraosseous microcirculation.

In some patients with non-traumatic osteonecrosis, histopathologic examinations have revealed thrombosis of terminal arteries in the subchondral areas [15].

Table 12.1. Etiologic factors associated with osteonecrosis.

Trauma

Hematologic disorders Sickle cell disease Thalassemias

Disseminated intravascular coagulation Polycythemia

Hemophilia Clotting disorders Inherited thrombophilic factors

Protein C deficiency Protein S deficiency Antithrombin III deficiency Factor V Leiden Homocysteinemia Dysfibrinogenemia

Tissue plasminogen activator decrease Plasminogen activator inhibitor increase Acquired thrombophilic factors

APL

Nephrotic syndrome Smoking Alcohol Pregnancy Estrogens Obesity Diabetes mellitus Cushing syndrome Corticosteroids Malignancies Hepatic failure Hyperlipidemia

Connective tissue diseases Systemic lupus erythematosus Antiphospholipid syndrome Rheumatoid arthritis Systemic vasculitis Systemic sclerosis Cytotoxic agents

Vincristine Vinblastine Cisplatin Bleomycine Methotrexate Cyclophosphamide 5-fluorouracil Infections

Human immunodeficiency virus Meningococcemia

Metabolic conditions Gaucher disease Hyperparathyroidism Hyperlipidemia Hemodialysis Renal transplantation Diabetes

Gout

Gastrointestinal diseases Pancreatitis

Inflammatory bowel disease Others

Radiation therapy Legg-Calve-Perthes disease Dysbaric osteonecrosis Fabry disease

(3)

However, histologic studies of the bone necrotic areas in patients with idiopathic osteonecrosis or in patients with autoimmune disorders are limited.

The presence of aPL has been described in several cases with idiopathic osteonecrosis of the jaw and femoral head. In a study by Glueck et al, 43 of the 55 patients with idiopathic osteonecrosis had one or more tests positive for thrombophilia and/or hypoﬁbrinolysis; 8 out of those patients (33%) were aCL positive [16]. aPL were also detected in 3 of 16 patients with Kienbock’s disease (3 patients had aCL and 2 had LA) [17]. Gruppo et al found abnormal serum aCL titers in 18 (33%) of 55 patients with idiopathic alveolar osteonecrosis of the jaw [18].

Korompilias et al noted an increased prevalence of medium and high aCL titres (37.5%) among 40 patients with non-traumatic hip osteonecrosis (7 with idiopathic osteonecrosis). No difference was found in the frequency of aCL between patients with idiopathic osteonecrosis and those with known risk factors for osteonecrosis (28.5% vs. 39.4%; P = 0.4) [19]. Jones et al examined 40 patients with osteonecrosis who had several etiologic associations (SLE, steroid treatment, heavy alcohol or tobacco), and 5 patients with idiopathic osteonecrosis [20]. They found that 37 (82%) of the above 45 patients had at least one coagulation factor abnormality versus 30% of controls (P < 0.0001). Four (80%) of the 5 patients with idiopathic osteonecrosis had abnormal IgG aCL levels (> 22 GPL). The high frequency of aPL in all the above studies with idiopathic osteonecrosis suggests an important role for these antibodies in the pathogenesis of the osteonecrotic lesions.

In addition, an association between osteonecrosis and aPL has been observed in patients with human immunodeﬁciency virus (HIV) infection, in the absence of known risk factors for osteonecrosis. In 1991, Solomon et al published a series of 8 HIV-infected patients with osteonecrosis and they noted that all of 5 patients tested for aCL were positive [21]. Additional cases of osteonecrosis in association with aCL have been subsequently reported [22–25]. Olive and coworkers reported 4 cases with hip osteonecrosis in a cohort of 1920 patients with HIV syndrome; three of them (75%) had positive aCL [26]. Another study undertaken by Brown et al found a prevalence of 50% of aCL in a group of 6 patients with osteonecrosis and underly- ing HIV infection [27]. Recently, Calza et al described 7 HIV-infected persons with femoral head involvement. Among them, only 4 patients were on antiretroviral therapy, 1 had moderate hypertriglyceridemia, and 3 were aCL positive [28]. In another recent study, 339 asymptomatic HIV-infected adults were examined prospectively by magnetic resonance imaging (MRI) for osteonecrosis of the hip.

Fifteen (4.4%) of 339 participants had osteonecrosis, while 14 (93%) of the above 15 patients had detectable levels of aCL [29].

However, the overall signiﬁcance of these antibodies in the development of osteonecrosis in HIV-infected patients remains unknown. Some authors suggested that the high frequency of aCL in patients with HIV with osteonecrosis should be interpreted with caution because these antibodies have been detected at high frequency in many studies with HIV-infected patients [30, 31]. The reported prevalence for IgG aCL in HIV varied from 0% to 90%. Moreover, there have been several cases of osteonecrosis occurring in HIV individuals with negative aPL [32–34]. HIV itself and hypertriglyceridemia secondary to protease inhibitor treatment have also been implicated in the pathogenesis of osteonecrosis [35]. Nevertheless, the ﬁrst cases of osteonecrosis in HIV patients were reported before protease inhibitors became available [22, 32]. Hence, the presence of aPL may be an added risk factor

(4)

for the development of osteonecrosis in HIV-infected patients, but more studies are required in larger groups of patients.

SLE and osteonecrosis

Osteonecrosis is a well-known complication in patients with SLE, contributing to significant morbidity. The reported prevalence of osteonecrosis in SLE varies from 5% to 40% in different studies including symptomatic and asymptomatic patients [36–39]. It was first documented in 1960 by Dubois and Cozen, who suggested that SLE itself or vasculitis are the main causes of osteonecrosis [40]. Since then, a number of pathogenetic factors have been analyzed. Corticosteroid treatment has long been recognized as a major predisposing factor for osteonecrosis in SLE [41–44]. The duration of steroid therapy, the total cumulative dosage, and the highest daily dosage have been independently involved [6, 36, 45]. However, the role of corticosteroids was not confirmed by other authors [40, 46, 47] who suggested additional risk factors such as fat emboli [45], hyperlipidemia [7], leukopenia [47], young age at the disease onset [38, 48], and Raynaud’s phenomenon [44, 49]. Gladman et al demonstrated that corticosteroid treatment, the presence of arthritis, and the use of cytotoxic drugs were independent risk factors for the development of osteonecrosis in SLE patients [50]. Another study showed that patients with osteonecrosis had higher frequency of Cushingoid body habitus, throm- bophlebitis, vasculitis, cigarette smoking, and preeclampsia [51]. An association with SLE activity, hypertension, and lupus nephritis has also been proposed by some authors [46, 52], but not by others [48, 53]. aPL have been strongly implicated in the pathogenesis of osteonecrosis.

The association between osteonecrosis and aPL in patients with SLE was ﬁrst described in 1985 by Asherson et al [54]. One year later, Lavilla et al reported 2 other SLE patients with osteonecrosis and positive aCL [55]. Nagasawa et al noted that SLE features such as Raynaud’s phenomenon, hyperlipidemia, nephrotic syndrome, hypertension, and disease activity were not related to osteonecrosis in a study with 111 SLE patients. On the other hand, the percentage of patients who had LA was found to be greater in those with osteonecrosis than in those without [56].

Mok et al [57] showed also an increased risk for osteonecrosis in SLE patients who were positive for LA (P = 0.02). Abeles et al described a higher prevalence of aCL in SLE patients with osteonecrosis in comparison with those without osteonecrosis (35% vs. 4%; P = 0.008). In 1993, Asherson and coworkers found that 27 (73%) of 37 patients with SLE with symptomatic osteonecrosis had positive aPL [51]. In 1997, Mont et al documented an association between osteonecrosis and IgG aCL levels. In a European multi-center study including 1000 patients with primary and secondary APS, the prevalence of symptomatic osteonecrosis was 2.4% [13]. With regards to patients with catastrophic APS, Egan et al described a 25-year-old woman presenting with multiple sites of thrombosis and multiple sites of osteonecrosis [59]. In a series of 80 patients with catastrophic APS, symptomatic osteonecrosis was found in 7% of cases [60].

All the above studies stressed the importance of aPL in predisposition to osteonecrosis. However, some authors consider that aCL do not play a determinant role in the pathogenesis of osteonecrosis suggesting other risk factors. Alarcon- Segovia et al failed to detect any association between osteonecrosis and aCL in a study including 500 consecutive SLE patients [61]. In 1995, in the Hopkins Lupus

(5)

Cohort, daily corticosteroid dosage, Raynaud’s phenomenon, and vasculitis were considered important risk factors for osteonecrosis, while LA and aCL were not [62]. Pistiner et al reported the presence of osteonecrosis in 26 (5.3 %) of 488 studied SLE patients and noticed a lack of correlation between osteonecrosis and aCL [63]. In the study by Migliaresi and coworkers, osteonecrosis occurred in 7 (10%) of 69 unselected SLE patients and was related to continuous high-dose steroid treatment but not to detectable aCL levels [64]. Mok et al reported that no relationship could be found between aCL or LA and the development of osteonecrosis in a cohort of 265 SLE patients receiving long-term follow up from 1978 to 1998 [65]. In another series of 280 SLE patients followed for 10 years, no increased frequency of aPL, Raynaud’s phenomenon, leukopenia, or SLE activity was found in the patients with osteonecrosis (N = 7) compared to those without osteonecrosis [53]. In a study undertaken by Cozen and Wallace, 26 (5%) of 488 patients with SLE developed asymptomatic osteonecrosis; no association with aCL or thromboem- bolic disease was observed [33]. Houssiau and associates examined prospectively by MRI the prevalence of osteonecrosis in a group of 40 SLE patients. The prevalence of osteonecrosis was 37.5% and its presence was correlated strongly with corticosteroid treatment but not with aCL status [66].

Therefore, no deﬁnite conclusions regarding the association between osteonecrosis and aPL could be deduced from the above studies. This could be explained in several ways. In almost all the previous publications, osteonecrosis has been described in patients who had received corticosteroid therapy, which is one of the major predisposing factors for bone necrosis. Most of these studies were retrospective and examined only symptomatic patients. However, it is well known that osteonecrosis can be entirely asymptomatic, especially in the early stage of disease. The diagnosis of osteonecrosis has been made using mainly plain radiographs which can identify advanced disease but can not detect early stage osteonecrosis [67, 68]. In addition, the diagnostic method for aCL measurement, the upper limit of normal, and the aCL serum levels (low, medium, or high titers) have not been reported in all the above studies. It has not been clearly reported also if the aPL were detected positive once or on more occasions. In addition, in some studies the measurement of aPL was done in samples drawn at the time of osteonecrosis while in others at the time of ﬁrst observation or during the follow- up period.

PAPS and Osteonecrosis

Corticosteroid treatment is widely used in the patients with SLE or SLE-related APS, but rather rarely in the patients with PAPS. The existence of osteonecrosis in PAPS patients in the absence of steroid use was ﬁrst documented by Asherson et al, suggesting an association between osteonecrosis and APS. They found that 2 out of 70 studied patients with PAPS had symptomatic osteonecrosis, and that it was the initial manifestation of the syndrome in one of them [69]. Alijotas et al reported the presence of aPL in 3 of 16 patients with Kienbocks disease; 1 had a history of deep vein thrombosis and recurrent abortions in association with positive aCL and LA [17]. Vela et al described a patient with PAPS who suffered a previous deep vein thrombosis and who subsequently developed osteonecrosis of the hip [70].

Similarly, a patient who had a history of hemiplegic migraine, cerebrovascular infarcts, and osteonecrosis of the left hip and the right knee has been reported [71].

(6)

Dubost documented a case with fatal PAPS and multiple bone necrotic areas [72]. In a retrospective study, Weber and associates analyzed the data from 108 APS patients followed from 1987 to 1996. They reported that symptomatic osteonecrosis was found in 7 (10%) of 69 patients with secondary APS but in none of 22 patients with PAPS [73].

Until recently, no prospective studies examining the prevalence of osteonecrosis in symptomatic and asymptomatic patients with PAPS were found in the literature. In a prospective study from our department, we evaluated the prevalence of osteonecrosis in patients with PAPS who were asymptomatic for osteonecrosis and had not taken corticosteroids [74]. Thirty patients with PAPS who had never received corticosteroids, 19 patients with SLE (with and without aCL) who had not previously received steroids and 30 healthy individuals, were examined prospectively by MRI of the femoral heads. Established MRI criteria were used for a diagnosis of early, intermediate, and advanced osteonecrosis. In positive cases, radiographs and dynamic scintigraphy were also performed. Asymptomatic osteonecrosis was found in 6 (20%) of the 30 patients with PAPS: 3 of them had intermediate bilateral osteonecrosis with the characteristic double-line sign on MRI (Fig. 12.1) and the other 3 patients had early osteonecrosis ﬁndings (Fig.12.2). No cases with advanced osteonecrosis were observed. Hip and pelvis radiography and dynamic scintigraphy were negative in all of 6 patients. None of the SLE patients (with and without aCL) and none of the healthy controls had documented osteonecrosis. In the osteonecrosis-positive cases, follow-up MRI 6 months after the initial examination revealed no changes. One of the 3 patients

Figure 12.1. Early osteonecrosis on this T₂-weighted spin echo magnetic resonance is indicated by the low intensity band in the subchondral zone of the femoral head (band sign) – a feature that is characteristic of osteonecrosis. Asymptomatic patient with primary antiphospholipid syndrome.

(7)

with intermediate osteonecrosis suffered from knee pain 3 months after the initial examination, and an additional MRI showed avascular necrosis (AVN) of both knees. Osteonecrosis was found to be more prevalent in younger patients and in patients with livedo reticularis. No associations with other clinical characteristics (venous or arterial thrombosis, thrombocytopenia, abortions, Raynaud’s phenomenon), aCL titer, presence of LA or anti–β2-glycoprotein I antibodies could be identiﬁed.

The increased incidence of osteonecrosis in PAPS patients in the absence of other predisposing factors conﬁrms the association between osteonecrosis and aPL, and suggests that osteonecrosis may represent an additional clinical feature of APS.

Furthermore, all the above ﬁndings raise the possibility that a proportion of young patients with osteonecrosis with positive aPL, in the absence of other risk factors, may have a form of PAPS.

Clinical Manifestations and Diagnosis of Osteonecrosis

Osteonecrosis can be entirely asymptomatic or it can be associated with pain and/or limitation of the movement in the affected joints. The most susceptible sites for osteonecrosis are the bones with single blood terminal supply such as the femoral head, the talus, the humerus head, or the carpal bones. The femoral head appears to Figure 12.2. Osteonecrosis indicated by the presence of the double line sign (arrow) seen on T₂-weighted spin echo image.

(8)

be the most vulnerable site for the development of osteonecrosis. Atypical sites of osteonecrosis have also been described in patients with APS [75]. Involvement of multiple bones may occur, especially in patients with SLE [76], and the condition may be often bilateral as it was shown in our study [73].

Given the unpredictable natural history of osteonecrosis, it is conceivable that early diagnosis is crucial in selecting the appropriate treatment options [77, 78].

Radiographic findings in early stages are unremarkable. In advanced disease, flattening, subchondral radiolucent lines (crescent sign) and collapse may be present. MRI is recognized as the most sensitive tool for the early recognition of osteonecrosis, having more than 95% overall sensitivity. It is significantly more sensitive than radiographs, radionuclide bone scan, or computerized tomography [79, 80]. MRI findings in early osteonecrosis include the presence of a decreased signal intensity band or rim in the subchondral zone on both T1- and T2-weighted images (band sign). The characteristic appearance of osteonecrosis, the double-line sign occurs later in the disease process. The double-line sign is seen on T2-weighted images as a high signal intensity line in an inner zone combined with low-signal intensity in an outer zone. Advanced osteonecrosis is characterized by the combina- tion of the above findings plus collapse and joint congruity. MRI imaging detects also the bone marrow edema, which can be associated with early osteonecrosis.

Van de Berg et al showed that lack of accompanying subchondral changes on T2-weighted or contrast-enhanced T1-weighted images had 100% positive predictive value for a transient phenomenon [81].

Treatment of Osteonecrosis

Treatment strategies primarily depend on the location, size, and stage of the lesion. Conservative therapy, used in early stages, includes non-steroidal agents or other analgesics for pain relief, steroid tapering, weight-bearing avoidance, bed rest, or even immobilization for some cases. However, conservative therapies usually fall to inhibit the progression of osteonecrosis. It has been well documented that without speciﬁc treatment, approximately 70% to 80% of hips with clinically established osteonecrosis have radiologic and clinical progression leading to the femoral head collapse [82]. Thus, various prophylactic surgical procedures have been proposed in order to suppress the evolution of further degener- ative changes. The goals of these procedures are the reduction of intramedullary pressure, removal of the necrotic area from the weight-bearing zone, and restora- tion of the blood supply in the necrotic area. The surgical treatment of choice in early stages, especially in young active patients, is core decompression with or without bone grafting [83]. Osteotomy has also been used with variable success [84]. Total joint arthroplasty is recommended for the late stage which is characterized by necrotic subchondral bone, articular cartilage collapse, and secondary osteoarthrosis (19).

Because of the ambiguity concerning the pathogenesis of osteonecrosis, the treatment of this disabling disorder has not focused on mechanisms of the disease process, but rather on the management of the end-stage bone changes. However, in patients with osteonecrosis and positive aPL the use of anticoagulants might provide an effective therapy. This hypothesis should be investigated in large, prospective studies.

(9)

Arthralgias and Arthritis in APS

Arthralgias are rather common in PAPS and SLE-related APS [13, 73, 86]. In 1989, Mackworth-Young et al described the clinical and serological features of 20 patients with PAPS and they found that 3 (15 %) of them had recurrent attacks of arthralgias [87]. In the largest cohort of APS patients with 1000 cases, the presence of arthralgias was documented in 271 (38.7%) patients with a similar distribution among primary and secondary APS [13]. Weber et al reported that arthralgias or arthritis was documented in 83% of SLE-related APS patients and in 41% of PAPS patients [73]. They also noticed that it was difﬁcult to distinguish frank and sustained arthritis from arthralgias on the basis of patient history, because most patients reported their articular symptoms as arthralgias.

The existence of arthritis in APS has been almost exclusively reported in patients with APS secondary to SLE or in lupus-like syndrome [69, 86]. In a retrospective study, Asherson et al observed that arthritis as well as other characteristic features of SLE (serositis, vasculitic rash, renal disease) were absent in PAPS [69]. In 1992, Piette et al suggested that the American Rheumatism Association criteria for SLE were of limited value in classifying patients with APS into primary or SLE-related APS. One year later, the same authors proposed a set of empirical exclusion criteria to distinguish PAPS from SLE-related APS [88]. According to these criteria the presence of frank arthritis excluded the diagnosis of PAPS. However, in a letter to the editor, Querel et al reported 8 patients with PAPS who suffered from non-erosive polyarthritis [89]. They noted though that 3 patients had lupus-like syndrome before or after the diagnosis of PAPS. Replying to the above letter, Piette and Asherson suggested that patients with persistent “true” APS should be distin- guished from those who progressively develop clinical and serologic abnormalities associated with SLE, including arthritis [90]. In a cohort of 1000 APS individuals, episodes of arthritis were observed in 56% of the patients with SLE-related APS compared to only 3% of patients with PAPS [13]. According to the above, it seems that arthritis is a rare manifestation of well-deﬁned PAPS.

The management of arthralgias/arthritis includes the use of nonsteroidal antinﬂammatory agents or other analgesics but they should be used with caution in cases receiving chronic coumarin treatment. In SLE-related APS, treatment with hydroxychloroquine or corticosteroids can also be used according to the severity of the articular symptoms and lupus activity. Besides its effect on arthralgias or arthritis, the role of hydroxychloroquine on thrombosis and lipids should also be stressed in patients with PAPS and SLE-related APS [91].

Conclusion

Diverse conditions associated with thrombotic lesions either in large vessels or in the microvasculature may be part of the APS clinical spectrum. Besides the classic clinical manifestations, including arterial and venous thrombosis or recurrent fetal loss, a number of other clinical conditions characterized as microangiopathic syndromes have been associated with APS. These syndromes can affect several organs including skin, brain, heart, and kidneys. Osteonecrosis may be another distinct

(10)

clinical feature of APS associated with arterial or venous microthrombosis.

Clinicians should be aware of the possible association between APS and osteonecrosis because early diagnosis may lead to early and proper management of this disabling disease. Patients with persistent symptoms originating from sites most susceptible to osteonecrosis should undergo MRI evaluation. A systematic screen- ing for aPL in all cases with diagnosed osteonecrosis in the absence of precipitating factors should also be considered.

References

1. Mankin HJ. Nontraumatic necrosis of bone (osteonecrosis). N Engl J Med 1992;326:1473–1479.

2. Zabinski SJ, Sculco TP, Dicarlo EF, et al. Osteonecrosis in the rheumatoid femoral head. J Rheumatol 1998;25:1674–1680.

3. Chang HK, Choi YJ, Baek SK, et al. Osteonecrosis and bone infarction in association with Behcet’s disease: report of two cases. Clin Exp Rheumatol 2001;19(suppl 24):S51–S4.

4. Wilde AH, Mankin HJ, Rodman GP. Avascular necrosis of the femoral head in scleroderma. Arthritis Rheum 1970;13:445–447.

5. Phemister DB. Fractures of the neck of the femur, dislocation of hip and obscure vascular distur- bances producing aseptic necrosis of the head of the femur. Surg Gynec Obstet 1934;59:415.

6. Jones JP Jr, Sakovich L, Anderson CE. Experimentally produced osteonecrosis as a result of fat embolism. In: Beckman EL, Elliott DH, Smith EM, eds. Dysbarism-related osteonecrosis. HEW Publ (NIOSH) 75-153. Washington DC: U.S Government Printing Ofﬁce; 1974:117–132.

7. Boettcher WG, Bonﬁglio M, Hamilton HH, et al. Nontraumatic necrosis of the femoral head. Relation of altered hemostasis to etiology. J Bone Joint Surg Am 1970;52:312–313.

8. Glueck CJ, Freiberg R, Tracy T, et al. Thrombophilia and hypoﬁbrinolysis. Pathophysiologies of osteonecrosis. Clin Orthop 1997;334:43–56.

9. Glueck CJ, Glueck HI, Greenfield D, et al. Protein C and S deficiency, thrombophilia and hypofibrinolysis: pathophysiologic causes of Legg-Perthes disease. Pediat Res 1994;35:383–388.

10. Van Veldhuizen PJ, Neff J, Murphey M, et al. Decreased ﬁbrinolytic potential in patients with idiopathic avascular necrosis and transient osteoporosis of the hip. Am J Hematol 1993;44:243–248.

11. Glueck CJ, Crawford A, Roy D, et al. Association of antithrombotic factor deﬁciencies and hypoﬁbrinolysis with Legg-Perthes disease. J Bone Joint Surg 1996;78:3–13.

12. Hughes GR. The antiphospholipid syndrome: ten years on. Lancet 1993;342:341–344.

13. Cervera R, Piette JC, Font J, et al. Antiphospholipid syndrome: clinical and immunological manifestations and patterns of disease expression in a cohort of 1000 patients. Arthritis Rheum 2002;46:1019–1027.

14. Tektonidou MG, Ioannidis JP, Boki KA, et al. Prognostic factors and clustering of serious clinical outcomes in antiphospholipid syndrome. QJM 2000;93:523–530.

15. Jones JP Jr. Intravascular coagulation and osteonecrosis. Clin Orthop 1992;277:41–53.

16. Glueck CJ, McMahon RE, Bouquot JE, et al. The pathophysiology of idiopathic osteonecrosis of the jaws: thrombophilia and hypoﬁbrinolysis [abstract]. J Invest Med 1995;43(suppl 2):234.

17. Alijotas J, Argemi M, Barquinero J. Kienbock’s disease and aPL. Clin Exp Rheumatol 1990;

8:297–298.

18. Gruppo R, Glueck CJ, McMahon RE. The pathophysiology of alveolar osteonecrosis of the jaw: anticardiolipin antibodies, thrombophilia and hypoﬁbrinolysis. J Lab Clin Med 1996;127:481–488.

19. Korompilias AV, Gilkeson GS, Ortel TL, et al. Anticardiolipin antibodies and osteonecrosis of the femoral head. Clin Orthop 1997;345:174–180.

20. Jones LC, Mont MA, Le TB, et al. Procoagulants and osteonecrosis. J Rheumatol 2003;30:783–791.

21. Solomon G, Brancato L, Winchester R. An approach to the human immunodeﬁciency virus positive patient with a spondyloarthropathic disease. Rheum Dis Clin North Am 1991;17:43–58.

22. Chevalier X, Larget-Pier B, Hernigou P, et al. Avascular necrosis of the femoral head in HIV-infected patients. J Bone Joint Surg Br 1993;75:160.

23. Belmonte MA, Garcia-Portales R, Domenech I, et al. Avascular necrosis of bone in human immun- odeﬁciency virus infection and aPL. J Rheumatol 1993;20:1425–1428.

24. Molina JF, Citera G, Rosler D. Coexistence of human immunodeﬁciency virus infection and systemic lupus erythematosus. J Rheumatol 1995;22:347–350.

(11)

25. Koeger AC, Banneville B, Gerster JC, et al. Avascular osteonecrosis in HIV-infected patients: 10 cases [abstract 277]. Arthritis Rheum 1995;38(Suppl):S119.

26. Olive A, Queralt C, Sierra G, et al. Osteonecrosis and HIV-infection: 4 more cases. J Rheumatol 1998;25:1243–1244.

27. Brown P, Crane L. Avascular necrosis of bone in patients with human immunodeﬁciency virus infection: report of 6 cases and review of the literature. Clin Infect Dis 2001;32:1221–1226.

28. Calza L, Manfredi R, Chiodo F. Osteonecrosis in HIV-infected patients and its correlation with highly active antiretroviral therapy (HAART). Presse Med 2003;32:595–598.

29. Miller KD, Masur H, Jones E, et al. High prevalence of osteonecrosis of the femoral head in HIV- infected adults. Ann Intern Med 2002;137:17–25.

30. Stimmler MM, Quismorio FP, McGehee WG, et al. Anticardiolipin antibodies in acquired immun- odeﬁciency syndrome. Arch Intern Med 1989;149:1833–1835.

31. Coll Daroca J, Gutierrez-Cebollada J, Yazbeck H, et al. Anticardiolipin antibodies and acquired immunodeﬁciency syndrome: prognostic marker or association with HIV infection. Infection 1992;20:140–142.

32. Gerster JC, Camus JP, Chave JP, et al. Multiple site avascular necrosis in HIV infected patients. J Rheumatol 1991;18:300–302.

33. Llauger J, Palmer J, Roson N, et al. Osteonecrosis of the knee in an HIV-infected patient. AJR Am J Roentgenol 1998;171:987–988.

34. Johns DG, Gill MJ. Avascular necrosis in HIV infection. AIDS 1999;13:1997–1998.

35. Monier P, McKown K, Bronze MS. Osteonecrosis complicating highly active antiretroviral therapy in patients infected with human immunodeﬁciency virus. Clin Infect Dis 2000;31:1488–1492.

36. Goldie I, Tibblin G, Scheller S. Systemic lupus erythematosus and aseptic bone necrosis. Acta Med Scand 1967;182:55–63.

37. Hurley RM, Steinberg RH, Patriquin H, et al. Avascular necrosis of the femoral head in childhood systemic lupus erythematosus. Can Med Assoc J 1974;111:781–784.

38. Kalla AA, Learmonth ID, Klemp P. Early treatment of avascular necrosis in systemic lupus erythematosus. Ann Rheum Dis 1986;45:649–652.

39. Gladman DD, Chaudhry-Ahluwalia V, Ibanez D, et al. Outcomes of symptomatic osteonecrosis in 95 patients with systemic lupus erythematosus. J Rheumatol 2001;28:2226–2269.

40. Dubois EL, Cozen L. Avascular (aseptic) bone necrosis associated with systemic lupus erythematosus. JAMA 1960;174:966–971.

41. Fisher DE, Bickel WH. Corticosteroid-induced avascular necrosis. A clinical study of seventy-seven patients. J Bone Joint Surg Am 1971;53:859–873.

42. Felson DT, Anderson JJ. Across-study evaluation of association between steroid dose and bolus steroids and avascular necrosis of bone. Lancet 1987;i:902–906.

43. Abeles M, Urman JD, Rothﬁeld NF. Aseptic necrosis of bone in systemic lupus erythematosus.

Relation to corticosteroid therapy. Arch Intern Med 1978;138:750–754.

44. Zizic TM, Marcoux C, Hungerford DS, et al. Corticosteroid therapy associated with ischemic necrosis of bone in systemic lupus erythematosus. Am J Med 1985;79:596–604.

45. Jones JP Jr, Engelman EP, Steinbach HL, et al. Fat embolization as a possible mechanism producing avascular necrosis [abstract]. Arthritis Rheum 1965;8:449.

46. Nilsen KH. Systemic lupus erythematosus and avascular bone necrosis. N Z Med J 1977;85:472–475.

47. Klipper AR, Stevens MB, Zizic TM, et al. Ischemic necrosis of bone in systemic lupus erythematosus.

Medicine (Baltimore) 1976;55:251–257.

48. Smith FE, Sweet DE, Brunner CM, et al. Avascular necrosis in SLE. An apparent predilection for young patients. Ann Rheum Dis 1976;35:227–232.

49. Hungerford DS. Pathogenetic considerations in ischaemic necrosis of bone. Can J Surg 1981;24:583–587.

50. Gladman DD, Urowitz MB, Chaudry-Ahluwalia C, et al. Predictive factors for symptomatic osteonecrosis in patients with systemic lupus erythematosus. J Rheumatol 2001;28:761–765.

51. Mont MA, Glueck CJ, Pacheco IH, et al. Risk factors for osteonecrosis in systemic lupus erythematosus. J Rheumatol 1997;24:654–662.

52. Cozen L, Wallace DJ. Avascular necrosis in systemic lupus erythematosus: clinical associations and a 47-year perspective. Am J Orthop 1998;27:352–354.

53. Rascu A, Manger K, Kraetsch HG, et al. Osteonecrosis in systemic lupus erythematosus, steroid induced or a lupus-dependent manifestation? Lupus 1996;5:323–327.

54. Asherson RA, Jungers P, Liote F, et al. Ischaemic necrosis of bone associated with the “lupus anticoagulant” and antibodies to cardiolipin [abstract]. In: Proceedings of the XVIth International Congress of Rheumatology, Sydney (Australia), 1985:373.

(12)

55. Lavilla P, Gil A, Khamashta MA, et al. Avascular necrosis of the bone and systemic lupus erythematosus. Rev Clin Esp 1987;181:289–290.

56. Nagasawa K, Ishi Y, Mayumi T, et al. Avascular necrosis of bone in systemic lupus erythematosus:

possible role of haemostatic abnormalities. Ann Rheum Dis 1989;48:672–676.

57. Mok CC, Lau CS, Wong RW. Risk factors for avascular bone necrosis in systemic lupus erythematosus. Br J Rheumatol 1998;37:895–900.

58. Asherson RA, Liote F, Page B, et al. Avascular necrosis of bone and aPL in systemic lupus erythematosus. J Rheumatol 1993;20:284–288.

59. Egan RM, Munn RK. Catastrophic antiphospholipid antibody syndrome presenting with multiple thromboses and sites of avascular necrosis. J Rheumatol 1994;21:2376–2379.

60. Asherson RA, Cervera R, Piette JC, et al. Catastrophic antiphospholipid syndrome: clues to the pathogenesis from a series of 80 patients. Medicine (Baltimore) 2001;80:355–377.

61. Alarcon-Segovia D, Deleze M, Oria CV, et al. APL and the antiphospholipid syndrome in systemic lupus erythematosus. A prospective analysis of 500 consecutive patients. Medicine (Baltimore) 1989;68:353–365.

62. Petri M. Muscosceletal complications of systemic lupus erythematosus in the Hopkins Lupus Cohort:

an update. Arthritis Care Res 1995;8:137–145.

63. Pistiner M, Wallace DJ, Nessim S, et al. Lupus erythematosus in the 1980s: a survey of 570 patients.

Sem Arthritis Rheum 1991;21:55–64.

64. Migliaresi S, Picillo U, Ambrosone L, et al. Avascular osteonecrosis in patients with SLE: relation to corticosteroid therapy and anticardiolipin antibodies. Lupus 1994;3:37–41.

65. Mok MY, Farewell VT, Isenberg DA. Risk factors for avascular necrosis of bone in patients with systemic lupus erythematosus: is there a role for aPL? Ann Rheum Dis 2000;59:462–467.

66. Houssiau FA, N’ Zeusseu Toukap A, Depresseux G, et al. Magnetic resonance imaging-detected avascular osteonecrosis in systemic lupus erythematosus: lack of correlation with antiphospholid antibodies. Br J Rheumatol 1998;37:448–453.

67. Mitchell DG, Rao VM, Dalinka MK, et al. Femoral head avascular necrosis: correlation of MR imaging, radiographic staging, radionuclide imaging, and clinical ﬁndings. Radiology 1987;

162:709–715.

68. Fordyce MJ, Solomon L. Early detection of avascular necrosis of the femoral head by MRI. J Bone Joint Surg Br 1993;75:365–367.

69. Asherson RA, Khamashta MA, Ordi-Ros J, et al. The ‘primary’ antiphospholipid syndrome: major clinical and serological features. Medicine (Baltimore) 1989;68:366–374.

70. Vela P, Battle E, Salas E, et al. Primary antiphospholipid syndrome and osteonecrosis. Clin Exp Rheumatol 1991;9:545–546.

71. Seleznick MJ, Silveira LH, Espinosa LR. Avascular necrosis associated with anticardiolipin antibodies. J Rheumatol 1991;18:1416–1417.

72. Dubost JJ, Kemeny JL, Soubrier M, et al. Primary antiphospholipid syndrome of fatal course and osteoarticular cytosteatonecrosis. Rev Med Interne 1994;15:535–540.

73. Weber M, Hayem G, de Bandt M, et al. Classiﬁcation of an intermediate group of patients with antiphospholipid syndrome and lupus-like disease: primary or secondary antiphospholipid syndrome? J Rheumatol 1999;26:2131–2136.

74. Tektonidou MG, Malagari K, Vlachoyiannopoulos PG, et al. Asymptomatic avascular necrosis in patients with primary antiphospholipid syndrome in the absence of corticosteroid use: a prospective study by magnetic resonance imaging. Arthritis Rheum 2003;48:732–736.

75. Mok MY, Isenberg DA. Avascular necrosis of a single vertebral body, an atypical site of disease in secondary APLS. Ann Rheum Dis 2000;59:494–495.

76. Fishel B, Caspi D, Eventov I, et al. Multiple osteonecrotic lesions in systemic lupus erythematosus. J Rheumatol 1987;14:601–604.

77. Assouline-Dayan Y, Chang C, Greenspan A, et al. Pathogenesis and natural history of osteonecrosis.

Semin Arthritis Rheum 2002;32:94–124.

78. Ohzono K, Saito M, Takaoka K, et al. Natural history of nontraumatic avascular necrosis of the femoral head. J Bone Joint Surg Br 1991;73:68–72.

79. Tervonen O, Mueller DM, Matteson EL, et al. Clinically occult avascular necrosis of the hip: prevalence in an asymptomatic population at risk. Radiology 1992;182:845–847.

80. Coleman BG, Kressel HY, Dalinka MK, et al. Radiographically negative avascular necrosis: detection with MR imaging. Radiology 1998;168:525–528.

81. Vande Berg BC, Malghem JJ, Lecouvet FE, et al. Idiopathic bone marrow edema lesions of the femoral head: predictive value of MR Imaging ﬁndings. Radiology 1999;212:527–535.

(13)

82. Merle d’Aubigne R, Postel M, Mazabraud A, et al. Idiopathic necrosis of femoral head in adults.

J Bon Joint Surg Br 1965;47:612–633.

83. Mont MA, Carbone JJ, Fairbank AC. Core decompression versus nonoperative management for osteonecrosis of the hip. Clin Orthop 1996;324:169–178.

84. D’Souza SR, Sadiq S, New AM, et al. Proximal femoral osteotomy as the primary operation for young adults who have osteoarthritis of the hip. J Bone Joint Surg Am 1998;80:1428–1438.

85. Cornell CN, Salvati EA, Pelicci PM. Long term follow-up of total hip replacement in patients with osteonecrosis. Orthop Clin North Am 1985;16:757–769.

86. Vianna JL, Khamashta MA, Ordi-Ros J, et al. Comparison of the primary and secondary antiphospholipid syndrome: a European multicenter study of 114 patients. Am J Med 1994;96:3–9.

87. Mackworth-Young CG, Loizou S, Walport MJ. Primary antiphospholipid syndrome: features of patients with raised anticardiolipin antibodies and no other disorder. Ann Rheum Dis 1989;48:362–367.

88. Piette JC, Whechsler B, Frances C, et al. Exclusion criteria for primary antiphospholipid syndrome. J Rheumatol 1993;20:1802–1804.

89. Queyrel V, Hachulla E, Cardon T. Arthritis in primary antiphospholipid syndrome? J Rheumatol 1996;23:1305.

90. Piette JC, Asherson RA. Arthritis in primary antiphospholipid syndrome? Reply. J Rheumatol 1996;23:1305–1306.

91. Edwards MH, Pierangeli S, Liu X, et al. Hydroxychloroquine reverses thrombogenic properties of aPL in mice. Circulation 1997;96:4380–4384.

92. Arruda VR, Belangero WD, Ozelo MC, et al. Inherited risk factors for thrombophilia among children with Legg-Calve-Perthes disease. J Pediatr Orthop 1999;19:84–87.