Activity Transcript

Robert J. Pignolo, MD, PhD : Hello, welcome to the Medscape educational activity entitled “Fibrodysplasia Ossificans Progressiva: On the Cusp of a Change in Management -- New Guidelines, New Care Pathways”. My name is Bob Pignolo, and I'll be the moderator for this activity. I'd like to welcome our expert panelists, Dr Patricia Delai and Dr Clive Friedman. Both of our panelists and I are members of the International Clinical Council on FOP, and we look forward to a very informative program.

So let's begin with the new 2021 FOP management guidelines. There are several new or updated sections in our guidelines, including an executive summary, emergency guidelines for first responders, physicians, and dentists, new sections on scalp nodules in FOP, cardiopulmonary function in FOP, some evolving guidelines on COVID-19 precautions and guidance, dermatology in FOP, nutrition, calcium, and vitamin D guidelines, preventative oral healthcare in FOP, acceptable- or low-risk procedures in FOP, gastrointestinal issues, and aids, assistive devices, and adaptations. The complete updated version of the guidelines is available at www.iccfop.org. So, let me hand this over to Dr Delai, who will tell us about how the diagnosis of FOP is made.

Patricia L.R. Delai, MD : Hi everyone. I'm going to tell you about the clinic diagnostic of FOP and how important it is to recognize the disease early in infants. Why is it so important? If you make the right diagnosis in time, you will avoid procedures that will make the disease worse. Children are going to be protected against falls and other muscle injuries. Unnecessary tests and treatments are going to be avoided, including visits to hospital and doctors. The children, for sure, are going to have a better life: the environment where they live is going to be adapted, and doctors, caregivers, and school are going to be educated.

So the clinical features of FOP are: malformed toes, soft tissue swellings, and progressive heterotopic ossification. Of course, if you find all these three items, you have to confirm with the genetic test of the ACVR1 mutation.

So let’s talk a little bit about the malformed big toes. In this child, you’ll see that the child is perfectly normal at birth, but has the small malformed big toes. That is just a detail. Both toes must be malformed. The toe deformity is present at birth. The big toes may be missing the middle joint. The big toes are often the deformed in such a way that the toe is turned inward, towards the other toes. So here you have the toes again, on a newborn and on an adult.

The other thing are the soft tissue swellings that we call flare-ups. The flare-ups can be episodic. They can appear suddenly overnight, and they can also disappear quickly or last for a long period of time. I'm saying not only days, but also weeks and sometimes even months. They can be spontaneous or appear after trauma like intramuscular injections including immunizations, mandibular block for dental work, muscle fatigue, blunt muscle trauma for bumps, bruises, falls, and influenza-like viral illnesses or surgeries. The swellings are painful. Sometimes the skin is red, warm to the touch, and sensitive to the touch also. Flare-ups can appear suddenly, or they can last a long period of time, as I said before, and they may go away without any bone being formed or they may leave a bone behind.

The third important feature of FOP is the progressive heterotopic ossification. FOP may progress in two ways: by genetic messaging or as a result of trauma. The heterotopic ossification has a very characteristic anatomic and temporal pattern, typically first occurring in the dorsal, axial, cranial, and proximal regions of the body and later in the ventral, appendicular, caudal, and distal regions. Heterotopic ossification in FOP is episodic, but the disability is cumulative.

Dr Pignolo: Okay. Thank you, Dr Delai. Even though the recommendations for flare-ups prevention, immunizations, and infection management has not changed significantly, it is the mainstay of our focus of treatment, and I will review that quickly. So, early flare-ups typically occur in the scalp, head, and back. Fortunately, in the case of scalp flares, these incorporate into the growing skull. In other locations, the swelling almost always develops into heterotopic ossification. These are some examples of swellings and also flare-ups in the back, which can often be migratory. And finally, an example of flare-ups in the hip. As you can see, there's a tremendous amount of edema, and flare-ups in the hip have the tendency of taking a long time to resolve on the order of months or even greater than a year.

In addition to corticosteroids, the mainstay of treatment is injury prevention in FOP. So, these are some examples here. So, it's safe to give subcutaneous injections; it's unsafe to give intramuscular injections. It's safe to give routine measles, mumps, rubella immunizations administered by a subcutaneous injection; it's unsafe to give routine diptheria, tetanus, pertussis immunizations administered by an intramuscular injection. Routine vein puncture is safe; arterial punctures are not. Precautiously administered dental care is safe; overstretching of the jaw and intramuscular injections of local anesthetic, as in the case of a mandibular block, is unsafe. And of course, biopsies are never safe.

We also like to focus on prevention of falls. You can imagine, if the shoulders and the elbows are locked, it would be very difficult to break a fall. So, we advocate for modification of activities, improvement in household safety, use of protective devices like headgear, redirection of activity to less physically interactive play, and other home renovations. However, we realize that complete avoidance of high-risk circumstances may also reduce falls, but equally likely is that they compromise the patient's functional level and independence, and may be unacceptable to many.

Pulmonary issues are also critically important because patients with FOP develop thoracic insufficiency syndrome (TIS) that can lead to life-threatening complications, including pneumonia and right-sided heart failure. So, we take prophylactic measures to maximize pulmonary function, minimize respiratory compromise, and prevent influenza and pneumonia.

In terms of immunizations, and particularly for influenza, we can give the immunization subcutaneously with the smallest possible needle, with ice intermittently for 24 hours afterward. We also recommend having some antiviral medication on hand with or without getting the immunization and, of course, vaccination of household contacts. Contraindications to the influenza vaccination include allergy to eggs, previous severe adverse reactions, active flare-up, or nasal administration of the live attenuated virus.

There are other immunizations that can be giving subcutaneously, such as the measles, mumps, rubella vaccination, meningococcal, pneumococcal, and the inactivated polio vaccine. However, there are other immunizations that can only effectively be given through an intramuscular route, and these we do not recommend. We just note that most individuals with FOP have already had the infant series of immunizations prior to their diagnosis.

Guidance regarding COVID-19 has been updated. By way of background, we believe that COVID-19 will continue to pose a significant risk to the worldwide population, especially with consideration for new variants. We're concerned with some reports on non-genetic heterotopic ossification developing in non-FOP patients with COVID-19, that patients with FOP may be even more susceptible to flare-ups and subsequent heterotopic bone formation. Recommendations are changing rapidly, are country specific, and of course are based on COVID-19 vaccine availability. So, the ICC, at this time is unable to recommend for or against COVID vaccination. We realize that the decision to take the vaccine is a personal one, and that we need to consider the balance of risks and benefits with the whole medical care team. The most common side effects in non-FOP patients include fever, chills, muscle aches and pains, and fatigue, and rare allergic reactions or anaphylaxis. So, our major consideration for whether or not to recommend vaccination is the risk of intramuscular injection causing flare-ups, which then leads to additional heterotopic bone formation.

So now I'm going to turn the presentation over to Dr Friedman, who will talk about the multidisciplinary approach to FOP care.

Clive S. Friedman, BDS (Diplomate AAPD): Thank you. So, as you can clearly see from both Dr Pignolo and Dr Delai's presentation, the impact of FOP actually impacts all body systems and, therefore, any treatment approach needs to include a multidisciplinary team. So, we need to include all stakeholders, including the parents, the families, and caregivers. What I've noticed in the last while: it's important as well to include a champion. That is an advocate who perhaps is not a parent who can be actually champion and navigate the complex systems for these families through the medical and dental environment. So, we need to have a primary care physician, that we can always respond to, and then any of the specialists that are important in the patient’s care. Dentists are really important in that the oral care is a continuum that can be impacted dramatically, and so having a dentist as part of the team is really essential.

Because it impacts all the specialties, we need to have access to any of the specialties, and we should not forget the importance of the adjunctive specialties as well, like speech therapy, psychology, occupational therapy, physiotherapy, nutritionists, because of the issues that they have. Oftentimes, diet can be a really important aspect for that team approach.

So, what is really a good idea is for any families with FOP, to be clear about who the team leader is with respect to who is going to be that person who's going to be able to direct primary care for that individual through their life. Then, gathering the team is the next big issue, depending on what is going to need to be done. If it's a surgical procedure that needs to be done, for example, dental surgery, then we're going to need specific individuals that will be able to be included in that care, so someone like an anesthesiologist or a surgeon becomes really important. So, the engagement of a local multidisciplinary team becomes an essential aspect of long-term care.

Dr Pignolo: Thank you, Dr Friedman. Now, let's move on to skincare, and Dr Delai will cover this topic.

Dr Delai: Okay. When you talk about FOP dermatology, you will say, "Wow. But FOP is such a complex disease, why care about the skin?" And I will tell you why. So, let's take a closer look at FOP and dermatology. When you see the skin problems in a person that has FOP, you can find skin problems that are possibly related to FOP itself, linked to the genetic mutation. Of course, this needs to be confirmed by detailed study, but we see in some patients always the same skin problems. Skin problems that are possibly related to a consequence of FOP, as immobility, position of the body and poor blood circulation, problems that are possibly related to drugs since they use a lot of drugs, not only steroids, but other anti-inflammatories that are usually the cause of so many skin diseases, and individual skin problems. Remember, not everything is FOP. FOP is very complex, but there are other skin problems that may be genetic, environmental, occupational, and so on.

So the ones possibly related to FOP, that we are seeing in many patients with FOP is, first, seborrheic dermatitis, that you can see also here on the skull and other areas of the body, the irregular intense pigmented moles that we usually see in people with FOP, hypersensitivity to insect bites, and rare skin tumors like Merkel cell carcinoma that is a rare, aggressive, malignant primary cutaneous neuroendocrine tumor. So, this all needs to be studied, but we have seen this in many patients with FOP.

These skin problems are possibly a consequence of FOP. So, here you see one that is the intertrigo. Since patients have a lot of folds in their bodies, because of the position of the body, you may have this kind of inflammation of the skin that usually affect folds and is induced by heat, moisture, maceration, friction, and lack of air circulation. So frequently you can have the intertrigo and infections like candida and other bacteria or viral or other fungal infections. Also, you have the fungals on the nails because of the blood circulation that is altered. It's so easy to affect. You have other fungal skin infections because you have humidity on the folds of the body and other fungal skin infections, like on the toe, on the feet, and on the nails, as I said before. Another one is the pressure sores. This is very common because if you can't move, you can't change the position. So, it's very frequent to see the pressure sores on patients with FOP.

That's why it's very important to identify purple spots on the legs because they can't move and the circulation also because of the extra bones is very poor. So, they develop those purple spots and sometimes also the blisters. Since you have a lot of edema and also extra bone, the cells sometimes lose the connection, and they start forming blisters and this is usually associated with lymphedema. If you have all these problems, it's not uncommon to have skin infections and sepsis.

The problems that are possibly related to drugs. So here you have dry lips, some drugs that are used to treat FOP and are in study, they can lead to dry lips. Dry skin, eczema, and itching. Remember that all dry skins, they itch a lot, and you can imagine having FOP, not being able to move, if you have a part of your body itching, this is a very big disaster.

The monomorphic acne eruption and loss of the eyebrows. These are things that we have been seeing with some drugs that are being studied now. And, of course, the cutaneous rashes and hives and other, many times related to the drugs used for inflammation and pain. So, it's very important to remember that drugs that we usually use for inflammation and pain can lead to this kind of situation. And individual scheme problems like vitiligo, occupational allergy and others, that can be just individual problems, not related to FOP.

Dr Pignolo: Thank you, Dr Delai. Now, we're going to move on to dental care, which will be covered by Dr Friedman.

Dr Friedman: Thank you. So oral health cannot be separated from a person's overall physical, emotional, and psychological wellbeing. So, we really need to not differentiate the mouth from the rest of the body, and especially with FOP, which is a continuum, so when you have a young child and the continuum of FOP becomes worse as they get older, managing the oral health of that individual becomes absolutely essential. So, I've given you here, the 10 commandments of oral health in a very short version. So above all, any time we are providing any kind of dental care, safety is the most important aspect. So, acknowledging some of the issues that you've already heard, we need to take those into consideration. So, we need to manage the risk of an individual from getting problems from a very young age, and the better we can minimize any kinds of dental issues from a young age, we're going to have less problems as they grow older.

So, the importance of daily oral care is essential, and I acknowledge that this can sometimes be very difficult when you have so many other things going on, like flares and heterotopic ossifications and skin issues. If you think of the mouth as an extension of the body, as an extension of skin, it really is important to try and minimize and to maintain daily care for those issues. Importance of good nutritional practices and, as you've already heard, the importance of hydration and really getting individuals to drink as much water as possible. The exercise of the body, the muscles, the lungs is essential. And anytime we do any kind of oral intervention, we need to, as Dr Pignolo already identified, be very aware of anatomical position and where that individual sits and provide appropriate support for that individual when you are providing the care.

Now, the baseline metrics that every dentist should evaluate for every child whenever they come in, because as dentists we are seeing individuals on a more regular basis than perhaps the primary care physician, sometimes we can actually determine if there are lung issues well before the primary care physician can, and we can evaluate oxygenation rates. So, we can do pCO₂ or blood oxygen levels, and if we do that every time and evaluate that, we can see if there's a decrease in it over time. We want to minimize mouth opening during treatment, and if there are mobility restrictions, provide the appropriate support for those individuals. We want to minimize, as much as possible, any triggers. So, keeping the mouth open for an extended length of time, not a good idea. So, we want to give individuals lots of time, resting, and as much as possible, decrease the stress of what is already often an invasive procedure.

As Dr Pignolo identified, it’s completely contraindicated to do mandibular blocks; there are other means of providing treatment with different kinds of anesthesia, but ultimately, we want to prevent the need for actually doing any care. And then if we are going to be doing an intensive, extensive dental treatment, it's important to do preoperative prednisone. So, this will be dependent on the procedure. So, for example, if you have just a simple cleaning, you do not need to give preoperative prednisone.

So, when we have a look at oral health, because it's a continuum and it's throughout life, the dental issues that are going to occur are going to be different from when you are very young to when you are older. So many individuals by the time they are older will have, for example, complete ankylosis of the jaw, where they have absolutely no opening of the mouth. And you want to evaluate how FOP is impacting the individual's body structure and function on a continual basis.

So here you see a number of different individuals and the kinds of issues that can occur. In the top right-hand slide, you can see an individual with fairly extensive oral disease in a 3-year-old boy. Ideally, we want to try and prevent that. So, to get back to Delai's message, with respect to early identification, early diagnosis, so that this kind of treatment can be prevented and we do not have to provide that care. The middle picture is a picture of the need for orthodontics. Can orthodontics be done? Yes, it can, but under specific conditions. And these are things that are important to be monitoring and to intervene at the appropriate time.

Another aspect of regular care is for the dentist to actually take regular measurements of maximum opening. So, because we, again, are following on a regular basis, the key issues of obtaining metrics that will tell us whether there has been advancement of the FOP at all, become essential. So, the oxygenation, the maximum opening that you have, are all key things that can be done very simply and recorded as a metric on an ongoing basis.

As Dr Delai identified, the issue of dryness is really important. Saliva is an important one. So, saliva is essential with respect to many aspects of what happens in the body and saliva can tell us a lot of things in terms of how the overall health of an individual is occurring. So, we want to monitor the saliva and really hydrate so that we have as much saliva as possible.

Then finally, as individuals grow and they have individual issues that they're unable to maintain their own oral hygiene, then you need to obviously introduce as many different assistive devices as possible, which helps, as we go into the next session with Dr Pignolo, but here's an individual whose father actually needed to design implements for him to be able to eat as he no longer had any function in his arms and he was unable to feed himself. So, there are a number of things that have an impact on long-term health. And this will introduce you into the next section, Dr Pignolo, which is assistive devices.

Dr Pignolo: Thank you, Dr Friedman. So, one of the updated sections that we have in our most recent FOP management guidelines is a section on aids, assistive devices, and adaptations, or AADAs. We work closely with the IFOPA and their global registry to better understand the use of AADAs. We know from this registry that AADA use increases with age, that there are some commonly used AADAs, including bathing attendants, straws for drinking, reaching sticks, and memory foam bed mattresses. Then in a published report, we actually were able to associate some AADAS with improvement in global health scores. So the assistive devices and aids were actually improving their health, and these include things like customized motorized wheelchairs, drinking straws, portable urinals, pill crushers, roll in showers, portable commodes, airflow mattresses, ramps for home entry, automatic lights, customized counters, durable flooring, remote control entry, adaptive keyboards, adaptive chairs, special electronics, adaptive vehicles for motorized wheelchairs, wide doorways, voice-activated computer software, typing sticks, on screen keyboards that are not normally part of devices.

Now we're going to have a brief discussion about some of the high-level points that I think our expert panelists have made, and I'll ask Dr Delai and Dr Friedman to chime in when they want to make additional comments.

So, our guidelines are continuously evolving. Much of this information is based on clinical experience and expert opinion. As new information is being collected as part of the IFOPA global registry, natural history studies, and clinical trials, we can evaluate that information for future guidelines. And many issues remain to be settled regarding whether a presentation is related to the FOP genetic mutation, secondary to this heterotopic ossification that forms and immobility, or are they just common problems that are manifesting in the setting of FOP. And finally, dental issues are extremely important, especially in the setting of essentially100% likelihood of jaw ankylosis, especially in those with the classic R206H mutation. I'd like to ask Dr Delai and Dr Friedman to share with us their major take-home from their presentations.

Dr Delai: Bob, from my perspective, I think that people should pay attention to the criteria for the diagnosis of FOP, because once you remember FOP when you see a baby that have the malformed big toes or having swellings and so on, you're going to think about FOP and you will change the life of this patient because it doesn't have to suffer. And us, as doctors, we need to pay attention to these things and make the right diagnostic early.

Dr Pignolo: And Clive?

Dr Friedman: Thank you. So I think an important aspect, as Dr Pignolo says, is the likelihood of 100% jaw ankylosis as individuals grow older. So any individual that is receiving care, to be aware of that fact, and to preempt issues that may occur with 100% jaw ankylosis, so one can go in and alleviate and do early extractions, if necessary, to make sure that you have some area where a patient or an individual could eat appropriately or take medications. So, to be aware that that is likely going to happen and to preempt some of those issues along the way.

Dr Pignolo: Okay, thank you for those comments. So, we're going to end this program with some concluding remarks. Hopefully, this will capture the major points made in this presentation. I just want to remind the audience that the new 2021 FOP management guidelines are available at www.iccfop.org.

FOP remains a clinical diagnosis with genetic confirmation where available. The symptomatic treatment of flares is unchanged and consists of high-dose corticosteroids for an initial 4-day course. Other standard of care is aimed at injury prevention, prophylactic pulmonary care, and safe vaccination by subcutaneous injection. Protection against COVID-19 infection involves masking, social distancing, hygiene measures, and shared decision making with the FOP medical care team for consideration of vaccination. A multidisciplinary approach should be taken for the management of FOP, with primary care physicians, FOP experts, medical specialists having familiarity with FOP, dentists, oral surgeons, anesthesiologists, physiotherapists, and caregivers composing a collaborative and supporting care team.

Skincare issues in FOP may be directly related to the causative gene mutation, secondary to immobility and positioning, due to drugs associated with treatment of FOP, or etiologies completely unrelated to FOP itself. Oral health in FOP should focus on preventative dental care, avoiding prolonged mouth opening and overstretching of the jaw, and when necessary, procedures performed by dentists, oral surgeons knowledgeable about FOP. The use of aids, assistive devices, and adaptations can improve independence and functioning and should be introduced early as part of an anticipatory guidance for future needs.

I'd like to thank the faculty once again and the audience and ask them to answer the evaluation questions that follow.

This is a verbatim transcript and has not been copyedited.