Overview 

In this article, Fibrodysplasia Ossificans Progressiva (FOP) and corticosteroid treatment will be explored. Furthermore, the mechanism behind how FOP works and how it comes about, along with the processes and genetic basis behind flare ups of this disorder will be explained. FOP’s treatment mechanism is also discussed, specifically, how corticosteroids can be used to reduce the inflammation and tissue edemas.

To offer some preliminary insights, FOP is a genetic condition that every one in two million people have.¹ Structures surrounding and supporting bones such as: ligaments, tendons, and muscles start to turn into bone as the main clinical symptom of this disorder. The symptom is seen as bone structures outside of the normal skeletal structure, this characteristic is heterotopic ossification (HO).

An FOP flare up is where soft tissue surrounding bone gets inflamed and swollen, slowly developing into HO. 

Understanding Fibrodysplasia Ossificans Progressiva (FOP) 

Etiology and Pathophysiology (causes and symptoms in the body)

In cells, there is genetic information in the form of DNA (deoxyribonucleic acid). Regions of DNA which can code for particular features and proteins that carry out processes are called genes. In FOP, it has been confirmed that the majority of cases have a mutation in the gene sequence of ACVR1 which makes a type of protein called: bone morphogenetic protein (BMP.) BMP can signal other proteins and create a signaling pathway that controls the location and possibility of bones to form, by mutating this, the pathway is unregulated and causes FOP.¹

Understanding the main symptom of FOP

As a result of ACVR1 mutation, a key characteristic of FOP is developed: ectopic bone formation, also known as heterotopic ossification (HO.) This is where bone tissue is formed outside of the normal skeletal in non bone tissue areas. Usually, this mutation is developed in the womb (in utero) and affects skeletal development from birth, making it a hereditary and genetic disorder. However, it can be acquired from damage to the central nervous system (CNS - brain and spinal cord). HO can be thought of how the body responds to the initial trauma if it is acquired in the patient.¹

Flare Ups in FOP

Causes of a flare up

Another clinical manifestation of FOP, other than HO, is something called a ‘Flare up.’ Interestingly enough, a flare up is a precursor HO and it comes about as the primary innate wound repair response to damage or trauma to the body. 

To simplify: it is the body's first line of defense, as an attempt to heal and prevent further damage from trauma. Possible flare up causes include:²

• Injections (usually quite deep muscular injections)
• Immunisation injections or allergen tests
• Viral or bacterial infections 
• Biopsies 
• Particular invasive dental procedures
• Invasive surgeries
• Over exertion 
• Muscles stretching out of the normal range of the individual 
• General injuries and accidents 

The flare up manifests as a large-scale inflammation in the localized area of trauma, however, sometimes, it is possible to have a flare up without any trigger (external trauma). The non-bone tissue surrounding the skeleton will swell and develop into early HO if it goes untreated.²

Symptoms of a flare up

There are a few symptoms of FOP flare ups:³

• New swelling 
• Pain or redness in areas 
• Fluctuating temperature (fevers)
• Low appetite and energy 
• Increased stiffness in muscles and bones 
• Behavioral and mood fluctuations/changes

Impact of flare ups on disorder progression

All of these symptoms align with the onset of a flare up and can progress from mild to very severe originating from the midline of the body and spreading outwards to the arms and legs. 

If it continues to progress untreated and unregulated, then the soft tissue that surrounds joints and bones can solidify into bone (ossify) and could cause the onset of more symptoms for other disorders such as:⁴

• Neuropathy
• Respiratory infections 
• Heart failure 
• Hearing and visual impairment 
• Decreased cognitive abilities
• Hair Loss 

Role of Corticosteroids in Managing FOP Flare Ups

Anti-inflammatory effect

Within the first day of the FOP flare up corticosteroids can be used for the following four days to mitigate and reduce inflammation and build up of fluid in tissue around the body (tissue edemas). Although corticosteroids are recommended for flare ups, they should only be used for a short period for time. Corticosteroids should be used only for major joints, the jaw or submandibular area (region under the jaw and above the length of the neck), not in any other area of the body.⁵

Immune system modulation/Mechanism of action 

The immune system in the body triggers inflammation in areas of damage. This is done by white blood cells (immune system cells), that produce chemicals like cytokines that increase inflammation.

Corticosteroids have strong anti-inflammatory properties, by turning off genes which code for inflammatory signals like cytokines. This decreases inflammation; cytokines are not the only inflammatory chemical that white blood cells can produce others including:⁶

• Chemokines 
• Adhesion molecules⁷
• Inflammation enzymes
• Other inflammatory proteins with complimentary receptors⁸

Efficacy of Corticosteroids in FOP Management

Outcomes of Corticosteroid Treatment

As mentioned earlier, corticosteroids are used to treat symptoms of FOP flare ups such as inflammation and tissue edemas, however, it is most effective if applied in the first 24 hours of the flare up. 

Corticosteroids relieve but do not cure FOP or its flare ups. They don't prevent the flare up either,  just mitigate some of the symptoms.

There is a clear reduction in inflammation and in pain when using corticosteroids, especially within the first 24 hours of a flare up, which is when it is most effective. Some patients have found that intravenous bisphosphonates injections or non-steroidal-anti-inflammatory-drugs (NSAID) are more effective than corticosteroids which did not appear to improve tissue edemas or inflammation.⁹

Combination therapies involving corticosteroids

A particular type of medication: retinoid agonists also block HO (which is a characteristic of FOP.) Along with corticosteroids, a research study found that Palovarotene (a type of retinoid agonist) could prevent HO from worsening. Furthermore, both drugs in combination could be used over a longer period of time with few side effects.

Side Effects and Risks

Common Side Effects

All medications, specifically corticosteroids (which is a strong type of medication) have side effects, some are short and some are long term side effects.¹¹

Short term side effects are usually mild and they include:

• Weight gain 
• Mood fluctuations 
• Hypertension (Increased blood pressure)
• Hyperglycemia (high blood sugar)
• Pancreatitis
• Electrolyte imbalances

Long term side effects are more serious, some examples include:

• Osteoporosis
• Adrenal and growth suppression 
• Joint necrosis¹⁰
• Gastrointestinal issues
• Ophthalmological effects
• Congenital malformations (if an individual is pregnant and continues to take corticosteroids can affect the baby post birth)

Summary

This article has covered the rare hereditary disorder FOP which is where non-bone tissue such as tendons, ligaments and muscle start to turn into bone via HO. Corticosteroids can mitigate symptoms of FOP flare ups most effectively if they are used within the first 24 hours of a flare up. Corticosteroids mainly target inflammation and tissue edemas, they do not cure FOP. 

Despite the fact that corticosteroids are an effective treatment strategy for some symptoms, there are some prominent side effects ranging from short term to long term. On top of this, corticosteroids have been found to be even more effective in part with other treatments such as retinoid agonists. This has shown to provide a helpful long term regulation of flare ups.