International Clinical Council on
Fibrodysplasia Ossificans Progressiva

THE MEDICAL MANAGEMENT OF FIBRODYSPLASIA OSSIFICANS PROGRESSIVA

CURRENT TREATMENT CONSIDERATIONS

The following information is provided as a summary for the emergency care of patients with FOP, and are excerpted from the Treatment Guidelines. Details about the management of FOP are found in the Treatment Guidelines.

Executive Summary of Key Practice Points

Methods

Twenty-one ICC members and five consultants from 14 countries, chosen for their clinical expertise in FOP, collabo­rated to develop this summary statement. Participants included anesthesiologists, endocrinologists, rheumatologists, orthopaedic surgeons, clinical geneticists, molecu­lar geneticists, neonatologists, pediatricians, internists, physiatrists, geriatricians, dermatologists, dentists, oral surgeons and a non-voting representative from a parent support group. All participants completed a conflict-of-interest declaration. The consensus was supported by academic funding, without pharmaceuti­cal support. A modified Delphi-like consensus methodology was adopted (Di Rocco et al., 2017). A comprehensive literature search was conducted using Pub Med and the search terms “fibrodysplasia ossificans progressiva.” Additional relevant articles on FOP were also identified by Pub Med searches when supplementary information was necessary. A comprehensive review of >2500 articles formed the basis of discussion by the Publications Committee of the ICC. Preparations for the consensus took place over 12 months, including two preparatory meetings and regular teleconference dis­cussions between the working group members. In addition, recommendations were incorporated for widespread consideration from         Di Rocco et al., 2017 and Hsiao et al., 2019. At the final consensus meeting, propositions and recommen­dations were considered by participants and discussed in plenary session enabling reformulation of the rec­ommendations, if necessary. As FOP is an ultra-rare condition, evidence-based statements are generally moderate to low. If published data were unavailable or insufficient, experts’ clinical experiences and opinions were considered. Finally, all clinical experts ratified the executive summary. All revisions were conducted with the same standards.

General Recommendations:

1. The diagnosis of FOP is clinical (skeletal malformations including malformed great toes; soft tissue swelling and progressive heterotopic ossification (HO), but requires genetic confirmation (ACVR1 gene mutation). If FOP is suspected, all elective procedures such as surgeries, biopsies, and immunizations should be deferred until a definitive diagnosis is made.
2. Each patient should have a primary physician who is willing to consult with an FOP expert and help coordinate a local care team.
3. Patients and their families should be informed about the International Clinical Council on FOP (ICC), the International FOP Association (IFOPA), and country-specific support groups at the time of diagnosis.

Activities: Activity is encouraged at all ages, but passive range of motion (motion performed by someone other than the patient) must be avoided. Singing, water exercises, and activities for respiratory health are encouraged.

Avoid soft tissue injuries, contact sports, overstretching of soft tissues, muscle fatigue, biopsies, removal of heterotopic bone and all non-emergent surgical procedures.

Anesthesia:  An expert anesthesiologist experienced in general anesthesia for FOP patients must be consulted pre-operatively in all cases. If general anesthesia is required, an awake intubation by nasotracheal fiber-optic technique should be performed because of the neck malformations, jaw motion limitations, sensitive airway and risk of an obstructing neck flare. Highly-skilled FOP-aware anesthesiologists should be present for all elective intubations.

Covid-19: Please see the ICC and IFOPA websites (www.iccfop.org & www.ifopa.org) for latest updates.

Falls:  Locked upper limbs may accentuate head and neck trauma from falls.  Epidural hematomas are common (surgical emergency).  Consider protective headgear in children who have upper limb involvement. All head and neck injuries should be evaluated immediately on an emergent basis.

Flare-up: (Back/chest): Consider non-steroidal anti-inflammatory medications or COX-2 inhibitors (oral or topical) with GI precautions.  Use analgesics, muscle relaxants, and local applications of ice packs, as needed. Avoid narcotic analgesia.

Flare-ups: (Limbs/throat/submandibular): Patients can present with inflammatory flare-ups with significant swelling and inflammation. These symptoms can be highly variable between patients and events. Prednisone – 2 mgs/kg once daily (up to 100 mgs daily) in AM (per oral) for four days (or equivalent corticosteroid); begin as early as possible after the onset of flare-up signs and symptoms.  Keep prednisone on-hand as “pill-in-pocket” approach for emergencies.  Alternatively, Pulse IV steroids may be used as directed. Avoid corticosteroids, if possible, for axial flares. Use oral and/or topical NSAID analgesics and/or muscle relaxants, as needed, with assiduous GI precautions.  Local application of cool packs may also be helpful. Avoid narcotic analgesia whenever possible. FOP experts should be consulted with all submandibular flare-ups and the detailed guidelines should be assiduously followed.

Flare-ups (Prophylaxis): Flare-ups often result from over-use and soft tissue injuries. Prednisone – 1-2 mgs/kg, (per oral) once daily for 3-4 days to prevent flare-up after severe soft-tissue injury.  Do not use after minor bumps or bruises. Use prednisone prophylactically as directed for dental or surgical procedures.

Fractures: Fractures can occur in both normotopic and heterotopic bone, and usually heal normally without much heterotopic bone if treated conservatively. An FOP expert in fracture management should be consulted in all cases.

Gastrointestinal Issues: Many patients with FOP report frequent nausea and vomiting. The cause and significance of this is unknown. Gastrointestinal complaints should be investigated to rule-out more serious conditions.

Hearing:  Conductive hearing impairment is common in FOP.  FOP patients should be screened in childhood by audiometry for hearing impairment. Hearing aids may improve severe conductive hearing loss.

Immunizations:  Immunization by subcutaneous administration is recommended for all vaccines that can be administered by that route. Avoid all intramuscular immunizations and intra-nasal influenza immunizations with live or attenuated viruses as they may precipitate flare-ups of FOP. There have been no reported cases of flare-ups following subcutaneous immunization with the MMR or MMRV vaccines despite the fact that they contain attenuated viruses. Immunizations should not be given during flare-ups and should be avoided until 6-8 weeks after flare-ups resolve. All household contacts should be immunized against pertussis and COVID-19. At this time, the ICC is unable to recommend for or against the COVID vaccine for patients with FOP. Consult detailed immunization guidelines and updates on the ICC and IFOPA websites (www.iccfop.org & www.ifopa.org).

Influenza:  Administer influenza vaccines subcutaneously, but never during flare-ups. Wait until 6-8 weeks after a flare-up has resolved before administering influenza vaccine. Avoid live attenuated flu vaccine as it may cause flu-like symptoms and precipitate flare-ups of FOP. Household contacts of FOP patients should

be immunized annually. Consider anti-viral therapy if flu symptoms occur. Consult detailed influenza immunization guidelines as recommendations may change annually.

Injuries:  The prevention of flare-ups and heterotopic bone formation involves multimodal approaches. This includes the recognition and avoidance of known causes of flare-ups (contact sports, soft tissue injuries, blunt muscle trauma, muscle fatigue, muscle stretching, intramuscular injections and immunizations, biopsies, removal of heterotopic bone, all non-emergent surgical procedures and viral illnesses).

IVs:  Patients with FOP can tolerate peripheral blood collection and IVs when performed by an experienced phlebotomist. It is critical that the procedure be performed in as gentle and minimally-invasive manner as possible. Tourniquet time should be minimized. Consultation with clinicians who are familiar with the care of FOP patients is essential. Superficial IV access and venipuncture is acceptable.  Traumatic IV’s must be avoided.  Central lines, PICC lines, and arterial punctures may cause HO and must be avoided unless critical for the patient’s medical management.

Kidney Stones: There is a three-fold greater risk of kidney stones in FOP. Encourage fluid intake (preferably water) of 1.5-2 liters/day, and avoidance of high protein and high salt diets. Age- and sex-based recommended daily allowances for calcium should be maintained.

Limb Swelling:  Lymphedema and transient neuropathy may occur with flare-ups of limbs. Elevate legs while sleeping and recumbent, whenever possible. Take one low-dose aspirin daily with food for DVT prophylaxis, if indicated.  Rule-out deep vein thrombosis with Doppler ultrasound. Use fitted support stockings for chronic lymphedema (but avoid traumatic compression). Lymphedema therapy may be helpful for chronic lymphedema.

Medications:

Corticosteroids

1. Steroid prophylaxis is recommended for significant blunt muscle trauma.
2. Steroid prophylaxis is recommended for dental and surgical procedures.
3. Steroid treatment should be considered for the symptomatic relief of emergent flare-ups of the limbs, jaw and submandibular area.

COX-2 Inhibitors & NSAIDs

There is no definitive evidence that chronic treatment with COX-2 inhibitors or NSAIDS prevents or ameliorates flare-ups in FOP. However, COX-2 inhibitors or oral/topical NSAIDS may be helpful for symptomatic management of flare-ups and chronic arthropathy when corticosteroids are not indicated.

Bisphosphonates

There is no definitive evidence that bisphosphonates prevent or ameliorate flare-ups in FOP. However, intravenous bisphosphonates may be considered for the prevention of steroid-associated bone loss. Dentists should be made aware of any prior bisphosphonate use.

Imatinib

There is no definitive evidence that imatinib prevents or ameliorates flare-ups in FOP. However, early clinical observations support the implementation of clinical trials of imatinib in children with uncontrolled FOP flare-ups.

Chemotherapy Agents & Radiation Therapy

There is no evidence of efficacy with these agents. The use of these approaches is contraindicated in the management of FOP.

Bone Marrow Transplantation

This approach is ineffective and contraindicated in the treatment of FOP.

Miscellaneous Agents in FOP

The chronic use of antiangiogenic agents, calcium binders, colchicine, fluoroquinolone antibiotics, propranolol, mineralization inhibitors, PPAR-gamma antagonists and TNF-α inhibitors currently have no role in the management of FOP.

Definitive Therapeutic Targets in FOP

Much of the worldwide collaborative research effort in FOP is focused here, and detailed accounts of the work and progress can be found on www.clinicaltrials.gov, in the Twenty-Seventh Annual Report of the FOP Collaborative Research Project (Kaplan, Al Mukaddam, Shore et al., 2018), as well as in recent reviews. Patients should be informed about ongoing clinical trials.

Mental Health: If clinical evaluation suggests depression, psychological support is recommended. Family therapy may be helpful.

Neurological Issues: Patients with FOP have reported a higher incidence of neurological symptoms including pain both during and remote from an FOP flare-up. The sources of pain should be carefully explored. Some individuals with FOP report chronic headaches. If headaches persist, patients should be referred to a neurologist, who can make recommendations for treatment.

Nutrition: In cases of ankylosis of the jaw, a dietician should be consulted to ensure adequate nutrition.

Occupational Therapy (OT):  Occupational therapy, focused on enhancing activities of daily living may be useful to improve the quality of life of FOP patients. Perform periodic OT evaluations for assistive devices as activities of daily living change.

Orthodontics: Routine orthodontic care has not been reported to cause flare-ups of FOP. However, all FOP patients seeking orthodontic care should consult with an FOP dental expert.

Physical Therapy (PT):  Passive range of motion is strictly prohibited.  Warm water hydrotherapy may be helpful.

Pregnancy: Although pregnancy with FOP is possible, FOP poses major life-threatening risks to mother and child as well as life altering consequences to the entire family if a child is born with this condition. Pregnancy in FOP should never be undertaken without serious consideration and family planning. Unwanted pregnancies should be assiduously avoided. Independent genetic counseling is available, if desired. Should a pregnancy occur, guidance and care at a high-risk pregnancy center are imperative.

Pressure Ulcers: In patients with limited motion prevention of pressure sores by appropriate methods or devices is recommended. A wound care team should be involved in the care.

Respiratory Health: Singing, swimming and incentive spirometry are encouraged to maintain lung function. Perform baseline pulmonary function tests (PFTs), echocardiogram, chest x-ray and pulse oximetry after four years of age. Repeat periodically. Pulmonary consultation and sleep studies may be helpful in directing specific respiratory therapies. Supplemental oxygen should not be used in an unmonitored setting. In patients with respiratory insufficiency, immunization for influenza and pneumococcal pneumonia should be considered. Please follow immunization guidelines above.

Scalp Nodules: Scalp nodules are common signs of flare-up, especially in children with FOP. Although they can be alarming in size, they often spontaneously regress and are of minimal clinical significance.

School:  Use school aides to protect and assist children. Parents can request a medical letter for assistance. Preschool evaluation is helpful. School nurses, staff, and teachers should be aware of the limitations of FOP, and protocols for managing injuries and flare-ups as well as special adaptive needs.

Spinal Deformity: Spinal deformity is common in FOP and can occur independently of flare-ups. Rapid progression of spinal deformity – especially in childhood – should be evaluated by an expert in FOP.

Surgery:  Avoid surgery, except in emergencies. Always avoid surgery to remove heterotopic bone.

Teeth: Preventative dental care is essential and should begin at an early age. Avoid sugary sweets and drinks. Avoid mandibular blocks, over-stretching of the jaw, and muscle fatigue. Consult FOP dental experts before any procedure.

References

Di Rocco M, Baujat G, Bertamino M, Brown M, De Cunto CL, Delai PLR, Eekhoff EMW, Haga N, Hsiao E, Keen R, Morhart R, Pignolo RJ, Kaplan FS. International physician survey on management of FOP: a modified Delphi study. Orphanet J Rare Dis.  Jun 12;12(1):110. doi: 10.1186/s13023-017-0659-4, 2017

Hsiao EC, Di Rocco M, Cali A, Zasloff M, Al Mukaddam M, Pignolo R, Grunwald Z, Netelenbos C, Keen R, Baujat G, Brown MA, Cho TJ, De Cunto C, Delai P, Haga N, Morhart R, Scott C, Zhang K, Diecidue RJ, Friedman CS, Kaplan FS, Eekhoff EMW. Special considerations for clinical trials in fibrodysplasia ossificans progressiva. Br J Clin Pharmacol.  85(6): 1199-1207, 2019