Natural history of fibrodysplasia ossificans progressiva ...
Management of acute “flare up” of - kpos.or.kr · Management of acute “flare-up” of...
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Management of acute “flare-up” of
fibrodysplasia ossificans progressiva
with short-term use of high-dose
corticosteroids
Jung Yun Bae *, Tae-Joon Cho
Seoul National University Children’s Hospital *Pusan National University Yangsan Hospital
Fibrodysplasia Ossificans
Progressiva (FOP)
• A rare and disabling genetic condition characterized by congenital malformations of the great toes and progressive heterotopic endochondral ossification (HEO).
• A recurrent mutation in activin receptor IA/activin-like kinase-2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor, exists in all sporadic and familial cases of classic FOP.
• Mostly a spontaneous new mutation or autosomal dominant transmission.
Clinical features define classic FOP
• Malformations of the great toes and progressive heterotopic
endochondral ossification (HEO).
• Neck stiffness, spine anomaly.
• Hearing loss, sparse/thin scalp hair, mild cognitive impairment,
severe growth retardation, cataracts, retinal detachment…
• Flare-ups
Flare-ups ?
• During the first decade of life, most children with FOP develop
episodic, painful inflammatory soft tissue swellings
->”Flare-ups”.
• Flare-ups are episodic; immobility is cumulative.
• Aponeuroses, fascia, ligaments, tendons, and skeletal muscles
transform into mature heterotopic bone.
• Several skeletal muscles including the diaphragm, tongue, and
extra-ocular muscles are spared. Cardiac muscle and smooth
muscle are spared.
Triggers of Flare-ups
• Intramuscular injection.
• Mandibular blocks for dental work.
• muscle fatigue.
• blunt muscle trauma.
• Falls.
• influenza-like illnesses.
Radiologic findings
Radiologic findings
Treatment of FOP
• No definite treatment.
• Medical intervention is supportive.
• Surgical intervention is unsuccessful and risks new, trauma-
induced HO.
Purpose
• To analize the result of short-term use of high-dose cortico
steroids for management of acute “flare-up” of FOP.
Materials & Methods
• 7 cases
• Duration: 1997~2013
• F : M = 5 : 2
• Follow-up: Avg. 5 years (range, 0.25 - 16)
• Retrospective review of medical records and radiographs.
• Resimen: Prednisone – 2 mgs/kg once daily for four days
Patients Data Patient Gender Age Site Sx. Trauma Sx. onset
1 M 9 shoulder pain - 3DA
2 F 23 hip pain - 10 DA
3 M 16 Shoulder& neck pain
- 1DA
4 F 8 Submandibular area pain & stiffness + 5DA
5 F 9 Submandibular area pain - 14DA
6 F 13 Thigh Pain &
swelling
+ 1DA
7 F 25 Knee Pain &
swelling
- 1DA
Change in VAS score during steroid
injection
0
1
2
3
4
5
6
7
8
9
10
initial Steroid #1 Steroid #2 Steroid #3 Steroid #4
VA
S s
core
Case
high-dose
corticosteroids
F/ 13 years , Rt. Knee pain & swelling, onset :1DA
Classes of medication
Class Ⅰ
• Short-term use of high-dose corticosteroids, and use of non-steroidal anti-inflammatory drugs (NSAIDs) including the new anti-inflammatory and anti-angiogenic cox-2 inhibitors
Class Ⅱ
• Leukotriene inhibitors, mast cell stabilizers, and aminobisphosphonates (Pamidronate; Zoledronate)
Class Ⅲ
• Signal transduction inhibitors, monoclonal antibodies targeting ACVR1, and retinoic acid receptor gamma agonists (presently under development).
(FOP Rx Guideline 2011, Kaplan)
Use of Corticosteroids
• Brief 4-day course of high-dose corticosteroids
; within the first 24 hours of a flare-up
1. The extremely early symptomatic treatment of flare-ups that affect: Major joints, jaw, submandibular area.
2. The prevention of flare-ups following major soft tissue injury (severe trauma).
3. The prevention of flare-ups in emergent, elective, and minor surgeries such as dental surgery, hypospadias repair, appendectomies, etc. (peri-operative use).
(Glaser & Kaplan, 2005 )
Use of Corticosteroids • Prednisone is 2 mg/kg/day (up to 100 mg), administered as a
single daily dose for no more than 4 days.
• In order to have the least suppressive effect on the
hypothalamic-pituitary-adrenal axis, the medication should be
given in the morning.
• High dose intravenous corticosteroid pulse therapy may be
considered, but must be performed with an inpatient
hospitalization to monitor for potentially dangerous side-effects
of hypertension.
Use of Corticosteroids
• When prednisone is discontinued, a non-steroidal anti-
inflammatory medication or cox-2 may be used symptomatically
for the duration of the flare-up.
• If the flare-up responds to the medication but recurs when the
prednisone is discontinued, a repeat 4-day course with a
subsequent 10-day taper can be considered.
Summary (FOP Rx Guideline 2011) 1. Within 24 hours of the onset of a flare-up.
2. Use for flare-ups on the Jaw, submadibular area, major joints. Do not use for flare-ups involving chest or back.
3. Prophylactically following major soft tissue trauma.
4. Peri-operative use: In emergent, elective, and minor surgeries such as dental surgery, hypospadias repair, appendectomies, etc.
5. Prednisone 2 mg/kg/day (up to 100 mg), administered as a single daily dose for no more than 4 days.
Conclusion
• The clinical management of FOP is focused in the
prevention of flare-ups.
• High dose glucocorticoids should be considered in the very
early treatment of acute flare-ups(within 24 hours).