Introduction

Erdheim-Chester disease is a rare disease with only a few documented cases. It involves the infiltration of various organs of the body by lipid-laden histiocytes, a type of immune cell. This disease is also referred to as a type of non-Langerhans’ cell histiocytosis.¹ Histiocytosis refers to the abnormal division and proliferation of histiocytes, and in Erdheim-Chester disease, this uncontrolled division takes place outside of the Langerhans cells. A lot of organs can be targeted and infiltrated by histiocytes, but the common parts of the body involved are the central nervous system (CNS), heart, lungs and bones. The onset of Erdheim-Chester disease involves mutations in oncogenes, which contribute to the development of uncontrolled cell growth and its progression.

Understanding the disease, the prognosis, and long-term outcomes is important for people suffering from Erdheim-Chester disease to facilitate the best possible treatment early and efficiently. While the progression of disease can range from mild to life-threatening symptoms, there is still the risk of vital organs being damaged that could potentially lead to more serious complications.^1,2

Key prognostic factors

Multiple factors affect the onset of Erdheim-Chester disease, one of which is age. Out of the approximately 1000 cases of the disease which have been reported, most of them were in middle-aged males. This was also the case in a study conducted on 44 patients in Japan suffering from the disease, where the median age of onset was 51 years old.³ Additionally, this study also concluded that most of the patients suffering from the disease experienced complications mostly in the CNS and the cardiovascular disease, which highlights that these organs carry the worst outcomes.

While there are still uncertainties in the pathophysiology of Erdheim-Chester disease, there is a high occurrence of genetic mutations in certain genes that influence prognosis. Some of these genes mutated include BRAF, NRAS, V600E and other genes which are associated with the MAPK pathway.³ MAPK is a protein kinase that is involved in the cells and initiates a cascade of signals that controls a range of different functions. One of the most important processes is regulating cell proliferation, where activation of the MAPK pathway promotes cell proliferation.⁴ Therefore, a mutation in this signalling cascade can interfere with the way the body controls division of cells and cause dysregulation, resulting in more cells dividing uncontrollably. This is the case in Erdheim-Chester disease for histiocytes dividing.

Evolution of prognosis

Over the years, there has been an evolution in the prognosis of Erdheim-Chester disease. Historically, there has been a very poor survival rate with very limited therapy options. However, in recent years, there have been improved and modernised treatments developed that have increased the survival rate and life expectancy of people suffering from the disease. Before modernised therapy options, the mortality rate was around 60% after 3 years of time of diagnosis.⁵ Promising results, however, have started to show new potential treatment methods that directly target the factors involved in the signalling cascade involved in the proliferation of histiocytes. The drug vemurafenib is one such example because its mechanism of action directly targets BRAF and inhibits it. As mentioned previously, BRAF is one of the genes that, if mutated, it can contribute to the onset of Erdheim-Chester. Additionally, other drugs such as infliximab are showing optimistic results.¹

Long-term outcomes

In the long term, Erdheim-Chester disease can manifest itself in multiple ways due to the way in which there is histiocytosis in multiple organs. One of the key manifestations seen is in the bones, specifically osteosclerosis of the long bones. Although this is involved in most patients, only 38% have symptoms when it comes to osteosclerosis. Over time, there has also been an improvement in the scanning techniques used to detect this hallmark, developing from X-rays in the past to CT scans and MRI scans as of recent.⁶

Long-term cardiovascular complications are also seen in Erdheim-Chester disease. Similar to osteosclerosis, improvement in technology has allowed more precise screening of these complications that arise in the disease, giving people an opportunity to intervene early. This is the case when detecting sheathing of the aorta, caused by the infiltration of histiocytes around the aorta of the heart and is detected through CT scans. While this is asymptomatic, not intervening in the long term can lead to myocardial infarction.⁶

Another vital organ targeted by histiocytes in Erdheim-Chester disease is the lungs. Up to half of all people suffering from the disease are seen to have some lung involvement that causes multiple other complications, such as cysts or micronodules. Other areas, such as the endocrine system, can be severely affected and, in some patients, cause diabetes insipidus, a condition where the balance of water in the kidneys is dysfunctional, leading to frequent urination and higher levels of thirst.⁶

The neurological long-term outcomes of Erdheim-Chester are one of the most important and highlight how targeted the CNS is in people suffering from the disease. Some of the complications that arise may include cognitive difficulty, cerebellar ataxia or cranial neuropathy, as well as many others. Through the discovery of cognitive dysfunction caused by Erdheim-Chester, it was also confirmed that the disease reduces brain volume, which is seen when comparing the affected brains with the healthy ones. ⁷

These organ damages can be very dangerous and leave lasting disability, leading patients to seek treatment. However, as previously mentioned, the recent advancement in technology has improved diagnosis techniques, making them more accurate. The recent discovery of mutated genes and the development of drugs that target these have also been found to increase the survival of people suffering from Erdheim-Chester disease.

Summary

Although Erdheim-Chester disease has a range of long-term negative outcomes, the advancement in technology has shifted the prognosis. New ways to scan the body, as well as improved treatment options, as of recent, have been shown to increase survival and also increase early intervention and efficient therapy. The long-term outcomes vary and depend on the organs which are targeted by histiocytes, at which point they infiltrate and divide uncontrollably. 

The recent discovery of the genes involved in the onset of Erdheim-Chester has led to more targeted drugs and therapies. As mentioned above, targeting and maintaining the MAPK signalling pathway is important to reduce uncontrolled cell division. However, the genetic profile of each individual is also different and therefore contributes to the long-term outcomes of the disease. Looking ahead in the future, focusing on improved targeted therapies may be beneficial to best treat the disease. While there haven’t been many cases in history of this disease, the recent rise of awareness has increased how many of documented cases there are and a higher focus on this topic overall.