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Prevalence and Prevention of

Avascular Necrosis of Bone


in SLE

H. Michael Belmont, M.D.


Director, Bellevue Hospital Lupus Clinic
Chief Medical Officer, Hospital for Joint Diseases
Associate Professor of Medicine
New York University School of Medicine
Etiology of Bone Infarct/AVN/Osteonecrosis

Traumatic

Idiopathic (e.g. Legg-Calve-Perthes, Kienbock’s, etc.)

Atraumatic
Vasculopathy
Fat embolism/Adipose expansion
PATHOBIOLOGY OF SLE

• Systemic lupus erythematosus (SLE) is characterized by


immune dysregulation that results in the production of
autoantibodies, generation of circulating immune complexes,
and activation of the complement system.

• A pathological hallmark of SLE is the recurrence of


widespread and diverse vascular lesions: inflammatory and
thrombotic.

• The endothelial injury typical of SLE flares may serve as an


inciting event, which predisposes to the accelerated
atherosclerosis that is associated with the disorder as well as
disrupt the microcirculation (e.g. end artery of the femoral
head) to predispose to AVN.
As a result, SLE patients exhibit rates of myocardial
infarction and cerebrovascular accident that are up to 50-fold
higher than age and gender matched controls.

The risk of developing avascular necrosis is 10-40 times


greater than other patients on corticosteroids.

The increased frequency of coronary artery disease (CAD)


and AVN observed in patients with SLE may be unified by
the underlying vascular injury that distinguishes the disease.
Pathologic and Clinical Spectrum of Vasculopathy in SLE

Pathology Pathogenesis Clinical Phenomenon

Capillaritis Immune complex deposition Glomerulonehpritis, pulmonary alveolar


Vasculitis Activation of complement, hemorrhage
neutrophils, and endothelium Cutaneous purpura, polyarteritis nodosa-like
Modeled by Arthus lesion systemic and cerebral vasculitis, AVN

Leukothrombosis Intravascular activation of complement, Widespread vascular injury, hypoxia, cerebral


neutrophils, and vascular endothelium cerebral dysfunction, SIRS, AVN
Absence of local immune complex
deposition
Modeled by Shwartzman lesion

Thrombosis Antibodies to anionic phospholipid-protein Arterial and venous thrombosis, fetal wastage,
complexes interact with endothelial cells, thrombocytopenia, pulmonary hypertension, AVN
platelets, or coagulation factors
Modeled by APS
Disseminated intravascular platelet TTP
aggregation

Atherosclerosis Activated endothelium, increased


endothelial cell adhesion molecules,
increased tissue factor, decreased MI, CVA
27-hydroxylase
Evidence for Shwartzman Phenomenon in SLE

Increased C3a, C5a

Increased neutrophil CD11b/CD18 (beta 2 integrin, CR3)

Increased endothelial cell adhesion molecules

Increased endothelial cell nitric oxide synthase

Increased circulating endothelial cells

Histologic evidence of leukoaggregates (CNS, mesentery)


Neutrophil activation

CR3
. .. ..
ICAM-1
Resting PMN C5a . . .. . . .. . .. . . ..
.. . IC
.. . .. . ... . .. .
Resting
EC

Endothelial cell activation (priming)


IL-1ß
TNFα
C1q .. . ... .. . ...

..
. . ...
C5a E-selectin . .
C5b-9
aEC
aPL

Leukothrombosis

.. .. . .
.... ... .
.
.
Vaso-occlusive plug .... ..
. . ... . .. . ... . . .. .. .. . ...
. . .
. . .. . .
.
Endothelial Cell Adhesion Molecule Expression
in Active versus Inactive SLE
co ntro l (n=16) inactive SLE (n = 5)active SLE (n =11)
2.5

*P <0.01 active vs. control


Immunohistochemical score

2
*
1.5
**P <0.025 active vs. inactive
1

0.5 *
**
0 *
ELAM -1 VCAM -1 ICAM -1

Belmont, Buyon, Giorno, Abramson: Arthritis Rheum, 1994


Increased NO Accompanied by the Upregulation of
iNOS in Vascular Endothelium of SLE Patients
cNOS iNOS
2.5

Immunohistochemical score
60
P <.05
active vs. inactive P <.01
2 active vs. inactive

Immunohistochemical score
Nitrite released (uM)

40 1.5

20
0.5

0
0

Control Inactive SLE Active SLE Control Inactive SLE Active SLE
(n=5) SLEDAI <5 SLEDAI >5 (n=11) SLEDAI <5 SLEDAI >5
(n=10) (n=9) (n=8) (n=17)

Belmont et al., Arthritis Rheum, 1997


Confirmation of Increased CEC in Peripheral Blood from
Patients with Active SLE
80 ( Positive Selection on P1H12 Magnetic Beads)
70
60
50
40 b

30 bb bb
CEC/ml

20
10
0
Healthy Inactive SLE Active SLE
Co ntrols (SL EDAI < = 4) (SL EDAI > 4)

N=8 N = 15 N=9
Healthy Controls vs. Active SLE, P = 0.008
Inactive SLE vs. Active SLE, P = 0.002
Healthy Controls vs. Inactive SLE, P = 0.14)
SLE and Bone Infarct/AVN

• AVN is a frequent morbidity in lupus.

• The incidence is estimated to be between 5%-80%.

• SLE patients have the highest rate of AVN as


compared to rheumatoid arthritis, pemphigoid, and
asthma.
Prevalence of AVN in SLE
• Two prospective studies of high dose corticosteroid treated SLE
patients report a prevalence of AVN between 19-80%
Aranow J. Rheumatology 1997:24
Nagasawa British Journal of Rheumatology 1994:33

• Aranow screened 62 SLE patients by MRI for AVN. 43 of 62 patients


took ≥ 30mg/day of prednisone and 9 (19%) had evidence of AVN.
Patients who had taken < 30mg/day had no evidence of AVN.

• Nagasawa studied 23 SLE patients treated with high dose


corticosteroids (≥ 20mg/day), 8 (30%) had evidence of AVN by MRI.
This cohort was followed prospectively for 3 years. Five of these
patients received ≥ 30mg/day and 4 (80%) newly developed AVN
Risk Factors for AVN in SLE
- Daily steroid dosage
- Cushingoid body habitus
- Age
- Ethnicity
- Vasculitis
- Raynauds
- Thrombophlebitis
- Presence of cardiolipin antibody
- Increased disease activity

Bergstein, J Paediatrics 174;85


Velayos, Ann Intern Med 1966;64
Klipper Medicine 1976; 55
Zizic Am J Med 1985; 79
Novel Paradigm

We propose the high prevalence and multifocal nature


of AVN in SLE patients during high dose steroid
treatment of disease exacerbation results from the co-
occurrence of two processes
1. Vascular Injury with widespread activation of
endothelium and inflammatory vasculopathy or
thrombosis disrupting the microcirculation
2. Lipid Deposition with interosseous fat accumulation,
secondary to glucocorticoid induced abnormal lipid
metabolism, increasing intramedullary pressure (i.e.
bony compartment syndrome) and decreasing
perfusion
Materials and Methods

• The ICD-9 code for SLE, 710.0, and for AVN 733.40-
44, 49 were cross-matched in a computer search of the
medical records departments of Bellevue Hospital,
Hospital for Joint Diseases (HJD), and the HJD faculty
practice for the 18-month period between 08/99 and
02/00.

• In addition 170 charts were reviewed of patients who


met ACR criteria for SLE

• 44 charts of patients with AVN and SLE were used to


generate the case report forms.
RESULTS

• 44 patients, 42 female, 2 male and mean age 38 (19-61)

• 18 Hispanic, 13 African American, 12 Caucasian, 1 Asian

• 33 ascertained by MRI and 11 established at joint replacement

• 42 ANA (+), 36 dsDNA(+), 22 nephritis, 4 cerebritis, 10 ACA(+), 5


history of thrombotic event

• 18 Hyperlipidemia, 1CAD, 24 HTN, 5 Postmenospausal, 1


Diabetes Mellitus, 4 cigarette smoking, 5 Family History CAD,
mean cholesterol 233+/-14 mg/dl
RESULTS

• 44 patients, 42 female, 2 male and mean age 38 (19-61)

• 18 Hispanic, 13 African American, 12 Caucasian, 1 Asian

• 33 ascertained by MRI and 11 established at joint replacement

• 42 ANA (+), 36 dsDNA(+), 22 nephritis, 4 cerebritis, 10 ACA(+), 5


history of thrombotic event

• 18 Hyperlipidemia, 1CAD, 24 HTN, 5 Postmenospausal, 1


Diabetes Mellitus, 4 cigarette smoking, 5 Family History CAD,
mean cholesterol 233+/-14
RESULTS

• 5 Unifocal AVN, 25 bifocal AVN, with 24/25


bilateral femoral head, 15 multifocal with 3 or
more joints affected

• 95% received prednisone ≥ 60 mg/day and


97% received ≥ 30 mg/day. 97% received high
dose prednisone for a SLEDAI ≥ 8
SUMMARY

• AVN in SLE is unifocal in only 9% (5/44)

• AVN in SLE affects more than one joint in 82% (39/44)

• AVN in SLE affects bilateral femoral head in 50%


(24/44)

• AVN in SLE is multifocal with ≥ 3 joints in 34%


(15/44)

• AVN in SLE is associated with high dose steroid


therapy for increased disease activity
CONCLUSION

The finding that AVN in steroid treated SLE patients is


most often multifocal is consistent with our hypothesis
that diffuse vascular injury during disease activity
conspires with steroid induced marrow lipocyte
accumulation to compress blood vessels and results in
ischemic bone necrosis. Clinical trials with statins,
which by preventing abnormal fat metabolism and
endothelial injury may reduce this morbidity, are
warranted.
Increased Adipogenesis and Abnormal Lipid Metabolism
is Associated with Corticosteroid-induced Osteonecrosis
of Bone in Animal Models

• Clofibrate, decreased the corticosteroid-induced changes on


marrow fat conversion and the increase in femoral head pressure

• In the group only treated with methylprednisilone, the percentage


of fatty marrow was increased by an average of 28%, and the
average intrafemoral head pressure increased from a baseline of
25 to 55.

• In the group treated with steroids and clofibrate there was almost
no change in the percentage of fatty marrow and there was no
increase in the intrafemoral head pressure.
•Cui showed that a lipid-clearing agent prevented osteonecrosis in a
chicken model

•25 chickens were injected with methylprednisolone and 10 received


methylprednisolone plus lovastatin.

•At autopsy 56% or 14/25 of the chickens only given corticosteroids


had some evidence of necrosis, with 4/25 demonstrating evidence of
sub-chondral death and resorption and new bone formation.

•In the group given lovastatin, there was a smaller conversion to


fatty marrow and 10/10 had no evidence of osteonecrosis.

•In the study, the authors were able to show that lovostatin
counteracted the effect of steroids on the differentiation of precursor
cells in bone marrow into adipocytes.
• 14 of 20 rabbits with induced hypersensitivity vasculitis
and high dose corticosteroid exposure developed evidence
of AVN in the femoral metaphysis.

• In the groups only given corticosteroids without induction


of hypersensitivity vasculitis, there was no evidence of
AVN.

• Animal experiments done by Matsui, showed a possible


synergy between vasculitis, high-dose cortocosteroids and
AVN.

• Motomura Steroid induced osteonecrosis on rabbits No rx


14/20 (70%), warfarin 7/21 (33%), probucol 11/29 (37%),
warfarin + probucol 1/21 (5%).
HUMAN STUDIES

• There is increasing evidence to suggest that relationship between fatty


marrow content and AVN applies to humans.

• Vande Berg showed this using MRI, that lupus patients with evidence
of AVN on high dose cortocosteroids have a greater increase in the
percentage of fatty marrow and in the index of marrow conversion
compared to both age matched controls and to lupus patients on
comparative doses of corticosteroids who did not develop AVN.

• These findings support the notion that fat accumulation within the
closed system of the bone marrow produces the increased medullary
pressure that can result in AVN.
The Presence of Inflammation is a Newly Identified Risk
Factor for Coronary Disease
• Increased C-reactive protein (CRP) significantly predicts myocardial
infarction in men and women who did not have clinical evidence of
atherosclerotic coronary disease.

• The risk reduction attributable to pravastatin was much larger among


those patients with evidence of inflammation.

• Laboratory studies and experiments in animal models of atherosclerosis


indicate that pravastatin may decrease inflammatory mediators.

• The inhibition of HMG-CoA reductase by statins also prevents the


generation of mevalonate, the precursor of a complex series of isoprenoids
that postranslationally modify certain proteins by isoprenylation with
farnesyl or geranylgeranyl.

• The in vitro effects on endothelium (e.g. inhibiting adhesion molecule and


iNOS expression) is consistent with the hypothesis that statin antagonism of
prenylated proteins interferes with the activation of cellular components
involved in the inflammatory process such as endothelial cells.
STATINS

• Inhibit HMGCo A reductase and both cholesterol and mevalonate


synthesis (intracellular signalling)

• Reduce serum lipids

• Reduce risk of CAD

• Reduce risk of AVN

• Reduce risk of osteoporosis

• Modify disease activity and organ damage by preventing


endothelial activation
APLLE Trial
Four month randomized double-blind placebo controlled study of atorvostatin 40
mg po qd vs placebo to prevent AVN in steroid treated patients with active SLE
(rolling enrollment of 30 patients per year for 3 years)

Active SLE
Steroid ≥ .75 mg./kg > 4 weeks
No current statin
LFT < 2x normal
Baseline MRI 10 testable sites (bilateral femoral head and chondyle, tibial plateau,
distal tibia and talus)
Randomized to atorvostatin (lipitor) 40 mg po qd vs placebo
Stratified by APS status
Follow-up MRI 10 testable sites at 4 months and greater than 6 months

Primary endpoint: New AVN at any of the 10 testable sites (i.e. 90% power to
observe 50% reduction in new AVN at any of the 10 testable sites per patient
with assumption that 50% will have at least 1 new site of AVN)

Secondary endpoints: Cholesterol, TG, HDL, LDL, SLEDAI, ESR, hsCRP,


dsDNA, C3, C4, activated CEC, soluble adhesion molecules
APLLE TRIAL
APLLETRIAL

Baseline
Patient Age E/G Stratum Clinical MRI F/UMRI F/UMRI #2

1 DB 35 WF I fever, jts, heme 2/10 * 2/10 * 2/10*

2 PB 29 BF I renal, GI, heme 0/10 0/10

3 IR 32 HF II renal 0/10 0/10

4 MC 43 AF II renal 0/10 0/10

5 AR 35 HF II ILD 0/10 0/10 0/10

6 WW 20 BF II renal 0/10 0/10

7 AF 35 WM II renal 0/10 0/10 0/10

8 RM 31 BF ll renal 2/10 *** 2/10 *** 3/10***

9 SR 52 HF ll renal/skin/ILD 4/10 ** 4/10** 6/10****

10 CM 45 BF II renal 0/10 E/W

11 AW 47 BM II renal/iritis 2/10 *** 2/10 ***

12 DR 20 BM I renal/heme 0/10 0/10

13 MC 22 HF II renal/vasculitis 0/10 0/10

14 JP 19 AF II renal 0/10 0/10

15 MR 57 BF II renal 4/10*** N/A

16 HD 45 WF ll renal 0/10 N/A

17 AH 36 BF ll renal 1/10*** N/A

18 JF 33 HM II renal 1/10*** N/A

19 DR 20 BM ll renal 0/10 N/A


Summary
• Enrollment n =20: 15 female, 5 male; 9 African-American, 6 Hispanic, 3 Caucasian, and
2 Asians

• 18/20 high dose steroids for renal flare

• 8/20 (40%) AVN on baseline MRI secondary to steroid treatment for prior disease
exacerbation

• MRI (4 month f/u) 13/13 no new AVN

• MRI (6 month f/u) 2/5 patients (40%) demonstrate new AVN; 1 patient with 1 new and 1
patient with 2 new sites of AVN

• Atorvostatin well tolerated in this cohort with no significant elevation of transaminases or


CPK
Conclusion
• Steroid treatment of SLE disease exacerbation is associated with high
prevalence of AVN (i.e. 40% (8/20) at baseline and 40% (2/5) at longer term
MRI follow-up

• Time to onset of AVN in steroid treated patients uncertain (Oinuma et al AVN


in patients with SLE develops very early after starting high dose steroid
treatment Ann Rheum Dis 2001;60:1145-1148) 72 steroid SLE patients with
MRI 1, 3, 6 and 12 months and 32/72 patients (44%) develop ON between 1-5
months after starting steroids and no new AVN from 6-12 month

• Benefit of statins, atorvostatin 40 mg po qd, in preventing incidence of AVN


and secondary outcomes (i.e. cholesterol, TG, LDL, HDL, ESR, hs-CRP, C4,
C4, dsDNA, SLEDAI, Circulating endothelial cells) to be determined