Prevalence of Skeletal Disease Neal J. Weinreb, M.D.
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Transcript of Prevalence of Skeletal Disease Neal J. Weinreb, M.D.
Prevalence of Skeletal DiseaseNeal J. Weinreb, M.D.
Impact of Skeletal Manifestations
• Impact QOL more than hematological and organ abnormalities.
• Bone disease is common even with normal hematology.
• Discomfort, pain, and disability occur in a majority of patients.
Mean Ages
On ERT
NotOn ERT
AgeMean (SD)
Range
(n=1601)37.1 (19.5)
1, 92
(n=518)39.3 (20.6)
0, 93
DiagnosisMean (SD)
Range
(n=1406)17.9 (17.4)
0, 82
(n=488)25.7 (19.4)
0, 91
First InfusionMean (SD)
Range
(n=1600)30.6 (19.2)
0, 84N/A
Patient Demographics - Type 1 Patients
2000 Gaucher Registry Aggregate Data Report
History of Bone Symptoms at Baseline Type 1 Patients
2000 Gaucher Registry Aggregate Data Report
Symptom On ERT Not on ERT
Bone Pain 66% (811/1232)
49% (147/299)
Bone Crisis 29% (336/1162)
5% (15/280)
History of Bone Disease at Baseline – Type 1 Patients
2000 Gaucher Registry Aggregate Data Report
On ERT Not on ERTRadiological
Bone Disease
94% (1201/1278) 76% (275/360)
Avascular Necrosis
34% (406/1201) 12% (32/275)
Erlenmeyer Flask Deformity
61% (733/1201) 56% (153/275)
Infarction 35% (424/1201) 16% (45/275)
Joint Replacement 14% (171/1201) 6% (16/275)
Lytic Lesions 18% (214/1201) 10% (28/275)
Marrow Infiltration
59% (708/1201) 53% (147/275)
New Fractures 26% (310/1201) 10% (28/275)
Osteopenia 50% (595/1201) 34% (94/275)
Gaucher Registry: Baseline Severe Bone Disease Inpatients on ERT
0102030405060
1992-94 1995-96 1997-98 1999-00
Year of 1st Infusion
Per
cen
t of
Pat
ien
ts
5549
34
45
N = 449 N = 196 N = 159 N = 61
Gaucher Registry: Mean Age at 1st Infusion
0
5
10
15
20
25
30
35
1992-94 1995-96 1997-98 1999-00
Year of 1st Infusion
Mea
n A
ge
(Yea
rs) 29.3
23.4
28.329.4
N = 810 N = 311 N = 237 N = 73
History of Bone Pain at Baseline - Type 1 PatientsBy Age Category
Gaucher Registry: April 2001
Per
cen
t o
f P
atie
nts
Patients on ERT Patients Not on ERT
48.1
69.1
76.5
58.9
38.8
50.8
60.3
41.7
51.9
30.9
23.5
41.1
62.3
49.2
39.7
58.3
0
10
20
30
40
50
60
70
80
90
0-18 Y 19-40 Y 41-60 Y 61+ Y 0-18 Y 19-40 Y 41-60 Y 61+ Y
Yes No
N=335 N=247 N=80 N=122N=362 N=90 N=73 N=36
History of Bone Crises at BaselineType 1 Patients By Age Category
Per
cen
t o
f P
atie
nts
Patients on ERT Patients Not on ERT
N=304 N=216 N=81 N=110N=312 N=81 N=67 N=34
31.6
38.1
29.6
20.0
7.45.5
3.0 2.9
78.3
61.9
70.4
80.0
92.694.5
97.0 97.1
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0
0-18 Y 19-40 Y 41-60 Y 61+ Y 0-18 Y 19-40 Y 41-60 Y 61+ Y
Yes No
History of Bone Disease at BaselineType 1 Patients By Age Category
Gaucher Registry: April 2001
Per
cen
t o
f P
atie
nts
Patients on ERT Patients Not on ERT
N=339 N=266 N=80 N=118N=360 N=81 N=72 N=39
93.296.7 98.1 97.5
82.5
73.776.4
87.2
6.83.3 1.9 2.5
17.5
26.323.6
12.8
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0
0-18 Y 19-40 Y41-60 Y 61+ Y 0-18 Y 19-40 Y41-60 Y 61+ Y
Yes No
Patient Genotypes - Type 1 Patients
2000 Gaucher Registry Aggregate Data Report
Sixty percent (1287/2129) of all Type 1 patients enrolled reported genotype.
29 (10%)118 (12%)All Others
4 (1%)13 (1%)?/?
4 (1%)28 (3%)N370S/IVS2+1
3 (1%)28 (3%)L444P/?
1 (<1%)26 (3%)L444P/L444P
12 (4%)144 (15%)N370S/84GG
31 (10%)164 (17%)N370S/L444P
169 (56%)275 (28%)N370S/N370S
48 (16%)190 (19%)N370S/?
Not On ERTOn ERTGenotype
History of Bone Pain at Baseline Type 1 Patients By Genotype
63.2 63.6
52.3 52.2
36.8 36.4
47.7 47.8
0
10
20
30
40
50
60
70
N370S/N370S All Others N370S/N370S All Others
Yes No
Per
cen
t o
f P
atie
nts
Patients on ERT Patients Not on ERT
N=209 N=472 N=130 N=92
History of Bone Crises at BaselineType 1 Patients By Genotype
Per
cen
t o
f P
atie
nts
Patients on ERT Patients Not on ERT
23.0
33.5
0.8
10.3
77.0
66.5
99.2
89.7
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0
N370S/N370S All Others N370S/N370S All Others
Yes No
N=196 N=454 N=129 N=87
History of Bone Disease at BaselineType 1 Patients By Genotype
Per
cen
t o
f P
atie
nts
Patients on ERT Patients Not on ERT
98.5
95.2
73.6
79.8
1.54.8
26.4
20.2
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0
N370S/N370S All Others N370S/N370S All Others
Yes No
N=194 N=501 N=125 N=99
Mobility History at Baseline – Type 1 Patients on ERT
Gaucher Registry: March 2001
Wheelchair: 1.2%
Bedridden: 0.5%
N=602Unrestricted: 79.2%
OrthopedicAid: 7.1%
Walks withDifficulty : 12.0%
Skeletal Manifestations in Elderly Gaucher Patients
Dx Onset Pt Age Age Presenting Sx Subsequent Sx________
• PL* 24 26 AVN hip THR (59)Fx distal femur (64)
• JW* 20 61 Multiple Fx’s None on ERT; less pain
• MA 75 75 AVN; THR Prosthesis failed (80) Wheelchair bound (82)
• RS 71 77 R hip pain R hip Fx (79)L hip Fx (84)
* Splenectomy
0
2
4
6
8
10
12
14
0 10 20 30 40 50 60 70 80 90
Age at Diagnosis
SS
I SSI
Poly. (SSI)
Age at Diagnosis and Severity Score Index (Weinreb)
Skeletal Response to ERTNeal J. Weinreb, M.D.
Problems in Assessing Skeletal Symptoms and Response to ERT
• Multiple etiologies
– Degenerative vertebral disk disease
– Concurrent “senile” osteoporosis
– Degenerative and other arthritis
– Increased incidence of myeloma
• Uncertain correlation between clinical and MRI status
Concurrent Illnesses in Patients > 65 Years Old
Gaucher Registry: March 2001
38.4%
24.5%
20.1%18.2% 17.6%
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
40.0%
45.0%
50.0%
Cardiovascular Musculoskeletal Gastrointestinal Renal/Urological Metabolic/Endocrine
Disease Category
Pe
rce
nt
of
Pa
tie
nts
N = 159
Osteoarthritis: Association of Knee Pain With Bone Marrow Lesions
Clinical Course of Gaucher Disease (Zimran et al, Medicine 1992)
• Evaluation: 20 years after initial diagnosis
• Mean age at evaluation: 33 years
• Splenectomy: 43%
• Chronic symptoms mainly skeletal
• N370S homozygotes: milder clinical course
• Progression: childhood to early adulthood
• Stable in adulthood, especially N370S/ N370S
The Clinical Course of Treated and Untreated Gaucher Disease
• 45 patients examined at least 3 times• Observation period greater than one year• Little progression in adults (Beutler E et. al.
Blood Cells Mol Dis 1995; 21(2):86-108)– Few changes in blood counts– No increase in liver and spleen sizes– Changes in bone lesions largely in
preexistent site
Clinical Course of Gaucher Disease: Non-Jewish Patients
• Neiderau: 51 German patients, ages 5-74 – Observed average 16 years from diagnosis– Progressive complications until ERT started
• Bleeding and/or anemia splenectomy• Increasing bone disease including fracture
• Giraldo: 48 Spanish patients: progression 81%• Goldblatt: 10 Afrikaner patients: rapid
progression• Hollak: 20 Dutch patients: progressive in most
children and adults
Response to ERT (Literature)
• Decreases in bone pain during first year
– Both frequency and intensity
• Radiological improvement rare
• Painful crises may persist more than 3 years
• New AVN and fractures may occur
History of Bone Pain 12 Months* 24 Months** Overall at 24 Months
N-64/76(84.2%)N-129/292(44.2%)
Y-12/76(15.8%)N-89/172(51.7%)
Y (n=620)Y-83/172(48.3%)
N-25/96(26.0%)Y-163/292(55.8%)
Y-71/96(74.0%)
N-106/111(95.5%)N-166/177(93.8%)
Y-5/111(4.5%)N-108/116(93.1%)
N (n=349)Y-8/116(6.9%)
N-2/5(40.0%)Y-11/177(6.2%)
Y-3/5(60.0%)
Y = yes or presentN = no or absent ** Last report of Bone Pain between 12 and 24 months among those
with data at 12 months.
* Last report of Bone Pain through 12 months.
History of Bone Crisis 12 Months* 24 Months** Overall at 24 Months
N-50/52(96.2%)N-87/107(81.3%)
Y-2/52(3.8%)
N-57/61(93.4%)Y (n=283)
Y-4/61(6.6%)N-7/9(77.8%)
Y-20/107(18.7%)Y-2/9(22.2%)
N-186/187(99.5%)N-297/300(99.0%)
Y-1/187(0.5%)N-187/188(99.5%)
N (n=597)Y-1/188(0.5%)
N-1/1(100.0%)Y-3/300(1.0%)
Y-0/1(0.0%)
* Last report of Bone Crisis through 12 months.
** Last report of Bone Crisis between 12 and 24 months among those with data at 12 months.
Y = yes or presentN = no or absent
Time (Months) Post 1st Infusion
41.3
17.4
32.3
64.7
2.9
26.3
73.7
0.0
40.0
55.0
5.0
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
12 Months 24 Months 36 Months 48 Months
Improved
Stable
Worse
N=46 N=34 N=19 N=20
Per
cen
t o
f P
atie
nts
Overall Bone Assessment: Response to ERT Type 1 Patients <18 Years Old
Natural History of Gaucher Disease in Untreated Patients: Growth in Childhood
• Zevin et al, 1993 (Shaare Zedek) N=34– Growth retardation (height and weight) prominent (30%)– Most marked ages 2-5
• Kaplan et al, 1996 (Gaucher Registry) N=99– Abnormal growth pattern relative to general population
and family in 50% at all ages to 15 years– Associated with degree of hepatomegaly
• Kauli et al, 2000 (Petah Tiqva) N=52– Growth retardation and delay in puberty are common– More frequent with severe disease– Spontaneous catch-up even in untreated patients
Time (Months) Post 1st Infusion
Overall Bone Assessment: Response to ERT Type 1 Patients > 18 Years Old
22.5
68.5
9.0
23.9
71.7
4.4
32.4
56.8
10.8
20.0
76.0
4.0
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
12 Months 24 Months 36 Months 48 Months
Per
cen
t o
f P
atie
nts
N=111 N=46 N=37 N=25
Unrestricted
Walks with Difficulty
Orthopedic Aid
Wheelchair
Bedridden
Mobility: Response to ERT - Type 1 Patients 12 Months Post 1st Infusion (N=188/602) (31.2%)
50
30.7
23.0
46.147.6
4.8
99.3
Unrestricted Walks withDifficulty Orthopedic
Aid Wheelchair Bedridden12 Months
47.6
50
0
10
20
30
40
50
60
70
80
90
Per
cen
t o
f P
atie
nts
UnrestrictedWalks with Difficulty
Orthopedic AidWheelchair
Bedridden
(N=152)
(N=21)(N=13)(N=2)(N=0)
BaselineStatus
Gaucher Registry Results• Bone pain resolves in 50% of
symptomatic patients within 1-2 years of starting ERT.
• New onset of bone pain in asymptomatic patients occurred in 4% on ERT for 2 years.
• 80-90% with prior bone crises had no recurrences during first 2 years of ERT.
• Incidence of de novo crises during first 2 years of ERT is less than 1%.
Gaucher Registry Results
• After 2-4 years of ERT, physician assessment of overall bone involvement (clinical and radiological) suggests:– Improvement in 30-40% in pediatric patients– Progression in <5% in pediatric patients– Improvement in 20-30% of adult patients– Progression in 5-10% of adult patients
Gaucher Registry Results• After 12 months of ERT, mobility status is often
improved:– 54% of patients requiring orthopedic aid at baseline
able to ambulate without assistance.– 48% of patients who walked only with difficulty at
baseline have unrestricted mobility.– Only 5% of patients who walked with difficulty at
baseline progressed to use an orthopedic aid. – Worsening mobility occurred in <5% of patients who
were unrestricted at baseline.
• After 2 years of ERT, patients with residual bone pain are significantly older than those whose pain resolved– Long-standing skeletal damage may
be irreversible.– ERT usually prevents symptomatic
progression and may forestall irreversible complications
– Early treatment for symptomatic or high risk patients is advisable.
Gaucher Registry Results
Natural History of Gaucher Disease in Untreated Patients: Gaucher Registry Goals
• Obtain missing data and retrieve retrospective data on current patients
• Accrual of appropriate new patients• Obtain data on untreated patients for
the existent sub-Registries:–Quality of Life Pregnancy–Bone Density (DEXA) Pulmonary