Despite being a busy practicing hematologist-oncologist, I was able to retain my interest and involvement in GD developments. When enzyme replacement therapy for GD was approved in 1991, I became a founding member of the International Collaborative Gaucher Group (ICGG) Scientific Advisory Board and a regional coordinator for the newly organized ICGG Registry. In this capacity, I functioned as an educator and advisor for physicians who were interested in caring for GD patients and had the opportunity to collaborate in clinical research with remarkable GD expert scientists and physicians from all over the world. During my career, I have cared for about 250 GD patients and I have been privileged to participate as an investigator in many of the key clinical trials and studies that have greatly advanced our knowledge of the natural history and management of patients with this rare disorder.

Q. What are some of the unmet needs and challenges when treating Gaucher disease?

We still do not fully understand why the manifestations of Gaucher disease are so variable and the course is so unpredictable. The most common type of GD in the Western world (type 1) rarely affects the brain except in a small number of patients who develop GD-associated Parkinson disease later in life. However, other GD variants (types 2 and 3) are associated with brain damage that begins early in life and with death at a young age. Current treatments are largely ineffective for the neurological manifestations. However, there are some promising new treatment approaches under investigation. Because early diagnosis of these variants may be crucial for treatments to be effective, it is important to develop programmes for newborn screening or even prenatal screening in both developed and developing countries.

One of the triumphs of ERT is that splenectomy is now very uncommon and we rarely see young wheelchair-bound GD patients.

Regarding type 1 GD, it is challenging to treat older individuals who suffered irreversible bone or liver damage before effective treatment became available. Such patients require intensive palliative care and multifaceted interventions to minimise pain and disability. We also know that medical practices such as removal of the spleen that were unavoidable before the advent of modern treatments likely contributed to disabling skeletal disease. One of the triumphs of ERT is that splenectomy is now very uncommon and we rarely see young wheelchair-bound GD patients. Nevertheless, it is frustrating that some patients continue to suffer bone pain and disability either because they are not diagnosed sufficiently early or because initiation of treatment is delayed. Finally, ERT may not prevent all bone complications. Hence, new treatments with different mechanisms of action continue to be investigated and introduced.

Q. Can you tell us a little bit about how our bones work in general and what causes the bone complications in the case of Gaucher? 

Bones are made up of two compartments, the external calcified bony framework and the internal bone marrow. All the body’s blood cells and immune regulatory cells are made in the bone marrow. One type of bone marrow cell that can also travel throughout the body is called a macrophage. This type of cell grabs on to, internalises, and disposes of foreign substances like bacteria that get into the body. It also signals immune cells to make antibodies to fight the invader. Macrophages “eat” old blood cells that are ready for “retirement.” In GD, because of the deficient glucocerebrosidase enzyme that causes the disease, macrophages cannot digest everything that they eat and become engorged with glucocerebroside substrate. We call them Gaucher cells. Gaucher cells respond to “indigestion” by creating inflammation. We believe this at least partly explains some of the pathology of GD. 

The skeleton is a living tissue that constantly must be nourished and replenished. Without this process, bones would develop microfractures and become brittle and snap. 

The strength and integrity of the bony skeleton also depend on bone marrow cells. Osteoblasts deposit the calcified bone matrix and become the mature bone cells that keep the bone alive. Specialised macrophages called osteoclasts absorb and remodel the bones. The skeleton is a living tissue that constantly must be nourished and replenished. Without this process, bones would develop microfractures and become brittle and snap. Osteoblasts and osteoclasts normally operate in balance. The osteoclasts absorb the old bone matrix and the osteoblasts lay down new, fresh bone. In patients with GD, the osteoclasts are on overdrive and the osteoblasts are “poisoned” by a chemical product of GD called glucosylsphingosine and fail to do their job of creating new bone. Consequently, there is a net loss of bone substance, calcium crystals are not deposited normally, the bone becomes thinned out, weak, and brittle and prone to fracture even with minimal stress. 

Q. What is a bone crisis?

 Inflammatory cells rush to the area to clean up the dead tissue and release chemicals that cause redness, swelling and intense pain. Hence, a bone “crisis.

As Gaucher cells fill up the bone marrow, they may increase fluid pressure around the blood vessels and cut off supply of oxygen causing bone death (necrosis). Inflammatory cells rush to the area to clean up the dead tissue and release chemicals that cause redness, swelling and intense pain. Hence, a bone “crisis.”  Inflammation associated with the bone crisis can lead to fever and mimic an infection of the bone (osteomyelitis). There is no need for antibiotics and biopsies are inadvisable as they may increase the risk for actual infection. Bed rest and pain medications are usually indicated until the acute symptoms subside. Subsequently, physical therapy can help restore the function of the bone. Sometimes, however, the bone and its joints may never get back to normal and eventual joint replacement may be necessary. Fortunately, we are seeing fewer bone crises now that earlier diagnosis and treatment are more common. 

Q. Is bone pain a red flag for Gaucher disease diagnosis? 

Absolutely, although GD is certainly not the most common cause of bone or joint pain. If an individual has a significant bone problem and other findings commonly associated with GD such as an enlarged spleen or a decreased platelet count for which there is no logical explanation, then Gaucher disease should be considered. In children, failure of bone growth (short stature) can also be associated with Gaucher disease. 

Q. What advice would you give to physicians in managing the bone care of their patients with Gaucher disease?

​Take a detailed history at every visit. Ask about episodes of pain including location, frequency, severity, and the nature of the pain. Review all medications. Check for range of motion and observe how the patient walks.

Ask about falls and functional disabilities. In patients older than age 50, screen for immunoglobulin abnormalities (monoclonal gammopathy) annually as GD patients, even those with clinically mild disease, have an increased risk for developing plasma cell malignancies. Bone mineral density testing (DEXA)should be done at initial evaluation (whole body DEXA in children) and serially every 2-3 years. X-rays are of limited utility for follow up but MRI examinations of the lower extremities and low back are useful for monitoring bone marrow infiltration with Gaucher cells and calculating the bone marrow burden score. 

Q. What pro-active steps can people with Gaucher and bone issues take in managing and tracking their symptoms?

Regular physical exercise, preferably supervised by a qualified instructor, is very important. However, high impact sports may not be advisable for patients with osteoporosis, an enlarged spleen or a bleeding tendency.  Unhealthy substances like excess alcohol and cigarettes should be avoided as these are deleterious for bone health as well as health in general. A nutritious diet is commendable. Many patients with GD, even those on treatment, suffer from fatigue. Evaluation for a sleep disorder may sometimes be warranted.

A supportive network of GD-affected friends and families who understand what you are going through is also especially important. 

Attention to mental wellbeing and freedom from anxiety is also important and should be openly discussed with your physician. Documentation of health-related quality of life scores can be useful in patient-physician communication. A survey instrument designed specifically for GD is currently in development. 

Continuing education about the disease is an exercise in personal responsibility. There are many reliable resources available online for keeping up to date with new developments in Gaucher disease. A supportive network of GD-affected friends and families who understand what you are going through is also especially important. This is where Gaucher advocate organisations can provide great support.