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