- Mastocytosis is a heterogeneous group of disorders involving infiltration of mast cells in tissues. The prevalence of indolent systemic mastocytosis is estimated to be at least 13.0 cases per 100,000 people aged 15 and older. - A study of 221 patients with indolent systemic mastocytosis found that 41% reported lifetime fragility fractures, with many fractures occurring before mastocytosis diagnosis. Fracture risk assessment tools had poor accuracy in predicting fracture risk in these patients. - A multivariate analysis identified male gender, elevated bone resorption, low hip bone mineral density, absence of urticaria pigmentosa rash, and alcohol use as independent risk factors associated with fragility fractures after mastocytosis diagnosis.

1. Dr.
E.
van
der
Veer
Zwolle,
28
november
2015
IWO
copyright
Dr. E. van der Veer

2.
• Wat
is
mastocytose
• PrevalenAe
mastocytose
• PrevalenAe
osteoporoAsche
fracturen
(laag
energeAsch
trauma)
• Fractuur
risico
inschaJng
voor
individuele
paAënt
copyright
Dr. E. van der Veer

3. • Heterogeneous group of disorders
• one or more organ systems are involved
WHO-classification:
– Indolent systemic mastocytosis
– Aggressive systemic mastocytosis
– Systemic mastocytosis with an associated clonal
haematological non-mast cell lineage disease
(SM-AHNMD)
– Mast cell leukaemia/sarcoma
URTICARIA PIGMENTOSA
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Dr. E. van der Veer

4. Release of biochemical
mediators from mast cells
Pathologic infiltration of
mast cells in tissues
Abnormal growth and accumulation of
Clinical symptomsClinical symptoms
• Histamin
• Heparin
• Tryptase
• Prostaglandins
• Cytokines
• Interleukins
• etc
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Dr. E. van der Veer

5. • In serum
tryptase > 10 ng/ml
• In 2de nuchtere urine histaminemetaboliet
methylimidazolazijnzuur (MIMA)
MIMA > 2,0 mmol/mol kreatinine
• Daarna volgt beenmergonderzoek met histologisch,
cytologisch en genetisch onderzoek en
immunofenotypering
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Dr. E. van der Veer

6. diagnostic WHO-criteria
• Diagnosis in bone marrow biopsy:
– 1 major + 1 minor
– 3 minor
• Major criterion
– ≥ 2 multifocal mast cell infiltrates of ≥ 15 mast cells
• Minor criteria
– Atypical morphology of ≥ 25 % mast cells in bone marrow
– Atypical imunophenotype (co-expression of CD117 with CD2
and/or CD25)
– Increased serum tryptase (> 20 ng/ml)
– Detection of KIT point mutation at codon 816
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Dr. E. van der Veer

7.
Heterogeen ziektebeeld
Klachten:
• Jeuk
• Flushing
• Diarree
• Invaliderende moeheid
• Recidiverende anafylaxie
• Osteoporose
• Fracturen
Gevolg van mestcelophoping
• Hepatosplenomegalie
• Vergrote lymfklieren
Sommige mastocytose patiënten hebben geheel geen klachten
Puntmutatie in de KIT-stamcelreceptor op de mestcellen (Asp-816-Val)
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Dr. E. van der Veer

8. • Wat is mastocytose
• Prevalentie mastocytose
• Prevalentie osteoporotische fracturen
(laag energetisch trauma)
• Fractuur risico inschatting voor individuele
patiënt
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Dr. E. van der Veer

9. UMCG & Martini Hospital:
42 Mastocytosis patients
age 55 yrs (19-75)
38% man
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Dr. E. van der Veer

10. The prevalence of ISM was
at least
13.0 cases per 100.000
inhabitants aged ≥15 years.
ISM prevalence increased
with age.
JJ. van Doormaal et al
JACI 2013
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Dr. E. van der Veer

11. • Wat is mastocytose
• Prevalentie mastocytose
• Prevalentie osteoporotische fracturen
(laag energetisch trauma)
• Fractuur risico inschatting voor individuele
patiënt
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Dr. E. van der Veer

12. • Data on lifetime fractures and trauma circumstances were collected
– vertebral morphometry,
– patients’ records,
– questionnaires.
• Lifetime fractures were categorized
– a) high vs low energy trauma circumstances
– b) before and after ISM diagnosis.
• Clinical, lifestyle, and bone characteristics were measured at time of
diagnosis.
E. van der Veer et al
JACI 2014
Median follow-up 5.4 years (range 0.4-15.3)
start
symptoms
visit
life
Ame
fracture
diagnosis
Mastocytosis
data
collecAon
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Dr. E. van der Veer

13. Median follow-up 5.4 years (range 0.4-15.3) 5.3 years; range 0.4-15.3
5-year fracture-free survival 77 ± 3% 78 ± 4%
10-year fracture-free survival 69 ± 4%, 71 ± 4%
E. van der Veer et l JCI
2014 online
Before ISM diagnosis:
139 FFx in 54 patients
Post-diagnosis:
125 FFx in 56 patients
Before ISM diagnosis:
40 FFx in 27 patients
Post-diagnosis:
88 FFx in 43 patients
Lifetime fragility fractures were
reported by 41% (90/221) of the
patients with indolent systemic
mastocytosis (ISM).
E. van der Veer et al
JACI 2014
copyright
Dr. E. van der Veer

14. • Wat is mastocytose
• Prevalentie mastocytose
• Prevalentie osteoporotische fracturen
(laag energetisch trauma)
• Fractuur risico inschatting voor individuele
patiënt
copyright
Dr. E. van der Veer

15. Aim:
• to determine the high/low risk of future fragility
fractures in patients presenting with indolent
systemic mastocytosis.
E. van der Veer et al
JACI 2014
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Dr. E. van der Veer

16. • Data on lifetime fractures and trauma circumstances were collected
– vertebral morphometry,
– patients’ records,
– questionnaires.
• Lifetime fractures were categorized
– a) high vs low energy trauma circumstances
– b) before and after ISM diagnosis.
• Clinical, lifestyle, and bone characteristics were measured at time of
diagnosis.
- 28 patients receiving treatment for osteoporosis before ISM diagnosis
- 9 patients with missing bone data (BTM and BMD)
- 2 patients with a recent fracture or operation
- 1 patient had gender change
were excluded from FFx risk assessment.
E. van der Veer et al
JACI 2014
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Dr. E. van der Veer

17. Median follow-up 5.4 years (range 0.4-15.3) 5.3 years; range 0.4-15.3
5-year fracture-free survival 77 ± 3% 78 ± 4%
10-year fracture-free survival 69 ± 4%, 71 ± 4%
E. van der Veer et l JCI
2014 online
Before ISM diagnosis:
139 FFx in 54 patients
Post-diagnosis:
125 FFx in 56 patients
Before ISM diagnosis:
40 FFx in 27 patients
Post-diagnosis:
88 FFx in 43 patients
E. van der Veer et al
JACI 2014
copyright
Dr. E. van der Veer

18. Low BMD T-score < -2.5 SD
High uCTX Above premenopausal
values (T-score > 2 SD)
Johnell et al Osteop.Int. 2002
of hip fracture
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Dr. E. van der Veer

19. Fracture Risk Assessment Tools
10-year probability of hip fracture
10-year probability of a major osteoporotic fracture
(clinical spine, forearm, hip or shoulder fracture).
The model accepts:
• FRAX age 40 - 90 years.
• Garvan age 50 years or more
• Qfracture age 30 – 99 years
181 Indolent Systemic Mastocytosis patients,
aged 19-77 years,
mean 46 ± 13 years
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Dr. E. van der Veer

20. Qfracture age 30 – 99 years
• The following factors are needed to calculate a QFracture score in men and women:
• Age
• Sex
• Ethnicity
• Smoking status (non smoker, ex smoker, light, moderate, heavy)
• Alcohol use
• Type 1 or Type 2 diabetes
• Parental history of hip fracture/osteoporosis
• Nursing or care home residence
• History of prior osteoporotic (wrist, spine, hip, or shoulder) fracture
• History of falls
• Dementia
• Cancer
• Asthma or COPD
• Cardiovascular disease
• Chronic liver disease
• Chronic kidney disease
• Parkinson's disease
• Rheumatoid arthritis or systemic lupus erythematosis (SLE)
• Gastrointestinal malabsorption (including Crohns disease, ulcerative colitis, celiac disease, steatorrhoea, blind loop
syndrome)
• Epilepsy or use of anticonvulsants
• Use of antidepressants (at least 2 scripts in last 6 months)
• Use of corticosteroids (at least 2 scripts in last 6 months)
• Body mass index
• Additional factors are used for women only: Use of oestrogen only Hormone Replacement Therapy
• Endocrine problems (thyrotoxicosis, primary or secondary hyperparathyroidism, Cushings syndrome)
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Dr. E. van der Veer

21. The risk scores had poor accuracy,
AUC 0.60 (95% CI: 0.50-0.71) for major osteoporotic fractures,
AUC 0.66 (95% CI: 0.56-0.75) for hip fractures.
0
5
10
15
10 20 30 40 50 60 70 80
percentage
Age (years)
10-years fragility fracture risk
FFx post-diagnosis
E. van der Veer et al
JACI 2014
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Dr. E. van der Veer

22. E. van der Veer et alE. van der Veer et al
JACI 2014
Patient characteristic
Age (yrs) 46 ± 13 Age ≥ 50 yrs 77 42%
Male gender (n, %) 74 41%
Length (cm) 174 ± 10
Weight (kg) 79 ± 15 Weight < 60 kg 14 8%
BMI (kg/m2) 26.3 ± 4.4 BMI < 19.0 3 1.6%
BMI ≥ 30.0 34 19%
Smoking (n, %) 82 46% Current smoker 53 30%
Stopped within last 10 years 29 16%
Alcohol use (n, %) 135 75% Adverse reactions 38 21%
Mastocytosis characteristic
Disease duration (yrs) 7.5 (0.1 to 58)
Urticaria pigmentosa (n, %) 138 76%
Anaphylactic shock (n, %) 77 43%
Tryptase (µg/L) 27 (4.1 to 296) Tryptase > 20 122 67%
MH (µmol/mol creat) 257 (70 to 2554) MH > 167 141 78%
MIMA (mmol/mol creat) 3.2 (0.5 to 21.6) MIMA > 1.9 148 82%
MH = methylhistamin; MIMA = methylimidazole acetic acid; BMI = body mass index;
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Dr. E. van der Veer

23. Bone characteristics at diagnosis n %
Patients with FFx n % 27 15%
Number of FFx n 40
Osteosclerosis n % 10 6%
Osteocalcin µg/L 12.3 (3.6 to 37.2)
Osteocalcin Z-score SD -0.12 (-2.66 to 4.15) Osteocalcin Z-score > +2.0 10 6%
BALP U/L 21.5 (4.6 to 62.1)
BALP Z-score SD 1.22 (-2.09 to 8.55) BALP Z-score > +2.0 57 32%
PINP µg/L 39.9 (15.9 to 135)
PINP Z-score SD -0.04 (-2.10 to 6.62) PINP Z-score > +2.0 12 7%
sCTx pg/mL 195 (10 to 797)
sCTX Z-score SD -0.42 (-2.03 to 6.35) sCTX Z-score > +2.0 14 8%
LS BMD g/cm2 0.96 ± 0.15
LS BMD T-score SD -0.97 ± 1.39 Osteoporosis LS 25 14%
Hip BMD g/cm2 0.93 ± 0.13
Hip BMD T-score SD -0.35 ± 0.99 Osteoporosis hip 1 0.6%
FFx = Fragility fractures;
BALP = bone specific alkaline phosphatase; PINP = procollagen type 1 N-terminal peptide;
sCTX = serum type I collagen C-telopeptide; LS = lumbar spine; BMD = bone mineral density;
E. van der Veer et alE. van der Veer et al
JACI 2014
copyright
Dr. E. van der Veer

24. • Multivariate Cox regression
HR
95% CI
P-value B
MastFx-
scoreLower Upper
Male gender 2,043 1,045 3,996 0,037 0,715 1
sCTX Z-score ≥ +1.0 2,632 1,278 5,424 0,009 0,968 1
Hip BMD T-score ≤ -1.0 2,187 1,128 4,240 0,021 0,782 1
UP absence 2,047 1,074 3,899 0,029 0,716 1
Alcohol use 3,445 1,016 11,688 0,047 1,237 1
HR: hazard ratio; CI: confidence interval; B: regression coefficient;
sCTX: serum type I collagen C-telopeptide;
BMD: bone mineral density; UP: urticaria pigmentosa
E. van der Veer et alE. van der Veer et al
JACI 2014
• Univariate Cox regression
Patients with fragility fractures post-ISM-diagnosis were:
older
more often male
more often anaphylactic reactions
less often UP
higher levels of MIMA, osteocalcin and sCTX
lower hip BMD scores
reported more often alcohol intake
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Dr. E. van der Veer

25. E. van der Veer et alE. van der Veer et al
JACI 2014
copyright
Dr. E. van der Veer

26. • Multivariate Cox regression
HR
95% CI
P-value B
MastFx-
scoreLower Upper
Male gender 2,043 1,045 3,996 0,037 0,715 1
sCTX Z-score ≥ +1.0 2,632 1,278 5,424 0,009 0,968 1
Hip BMD T-score ≤ -1.0 2,187 1,128 4,240 0,021 0,782 1
UP absence 2,047 1,074 3,899 0,029 0,716 1
Alcohol use 3,445 1,016 11,688 0,047 1,237 1
HR: hazard ratio
CI: confidence interval;
B: regression coefficient
sCTX: serum type I collagen C-telopeptide
BMD: bone mineral density
UP: urticaria pigmentosa
Accuracy of the MastFx-model:
AUC = 0.80 (95% CI 0.73–0.88)
AUC = 0.80 (95% CI 0.72–0.87)
E. van der Veer et alE. van der Veer et al
JACI 2014
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Dr. E. van der Veer

27. Male gender 1
sCTX Z-score ≥ +1.0 1
Hip BMD T-score ≤ -1.0 1
UP absence 1
Alcohol use 1
E. van der Veer et alE. van der Veer et al
JACI 2014
copyright
Dr. E. van der Veer

28. Prevalence Mastocytosis
• The prevalence of mastocytosis was at least
13.0 cases per 100.000 inhabitants aged ≥15 years.
• ISM prevalence increased with age.
Prevalence Mastocytosis
• Lifetime fragility fractures were reported by 41% (90/221) of the
patients with indolent systemic mastocytosis (ISM).
• Follow-up from ISM-diagnosis to Fx data collection:
– median 5.4 years (range 0.4-15.3)
– 5-year fracture-free survival 77 ± 3%
– 10-year fracture-free survival 69 ± 4%
E. van der Veer et alE. van der Veer et al
JACI 2014
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Dr. E. van der Veer

29. • Independent predictors for future fragility fractures
– Male gender
– high levels of bone resorption marker sCTX
– low hip BMD
– absence of urticaria pigmentosa
– alcohol intake
• The MastFx-score, a prediction model using five characteristics,
showed good accuracy to distinguishes ISM patients at high,
intermediate and low risk for new FFx.
– ISM patients with a MastFx-score of ≥2 have a high risk for fragility
fractures.
E. van der Veer et alE. van der Veer et al
JACI 2014
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Dr. E. van der Veer

30. • The calculation of the fragility fracture risk should be an
important component in the management of patients
presenting with ISM
• Efforts should be made by the caretakers to optimize bone
quality in all ISM patients
Lifestyle changes
– Do exercises
– Adequate vitamin D and calcium intake
– Alcohol cessation is highly recommended
(because drinking is a modifiable risk factor of FFx in ISM)
High-risk patients will probably benefit from an early start
of therapeutic intervention
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Dr. E. van der Veer

31. copyright
Dr. E. van der Veer

32. q University of Groningen
q University Medical Center Groningen
q Nederlands Mastocytose Centrum Groningen
• Eveline van der Veer
• Suzanne Arends
• Sjoukje van der Hoek
• Joris B Versluijs
• Jan GR de Monchy
• Joanne NG Oude Elberink
• Jasper J van Doormaal
Support your
bones
They support
you!
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Dr. E. van der Veer