Treatment pathways for rare diseases, including activated PI3K delta syndrome (APDS) can be complex and often require a multi-disciplinary approach. Dr Nicholas Hartog and Dr Virgil Dalm explain the current options and the challenges in treating APDS.

What are PIs and APDS?

PIs are an expanding group of rare genetic disorders with many different clinical manifestations. The hallmark symptoms of PIs are recurrent and severe infections, autoimmune and autoinflammatory complications. APDS is a recently identified primary immunodeficiency caused by variants in the PIK3CD or PIK3R1 genes. It was first described in 2013 and is estimated to affect 1–2 per million individuals worldwide.

Q. What is your involvement in the treatment of PIs and, more specifically, APDS?

Dr Hartog: As the director of our adult and paediatric primary immunodeficiency clinic, I am in charge of the treatment of many individuals with PIs, including APDS, who register with us. I discuss their symptoms, assess their disease progression, and coordinate with other specialists to best manage their care. Another part of my role is to identify if individuals with a PI diagnosis, for example, common variable immunodeficiency (CVID), need further testing for a variety of immunologic conditions, including APDS.

What is CVID?

CVID is one of the most common PIs. Individuals with CVID have low levels of specific proteins called immunoglobulins or antibodies, which leads to a decreased ability to fight infection.¹ According to Dr Dalm, CVID is considered a primary antibody deficiency.

Dr Dalm: Within the Erasmus Medical Center, we have a primary immunodeficiency centre, where we treat many adults and children with various PIs. A multidisciplinary care team is responsible for follow-up and treatment of these patients. We have a research group on PIs that holds several research lines, from basic research to translational research and clinical trials. We focus on non-infectious complications of PIs, including endocrine, psychiatric, neurodevelopmental and autoinflammatory complications.

What is the endocrine system?

The endocrine system is made up of the glands and organs that make hormones and release them into the bloodstream so they can reach tissues and organs in the body. The hormones released control various functions in the body. This includes growth, development, metabolism and reproduction. Source: National Cancer Institute

Q. What are the current clinical management options for APDS?

Dr Hartog: There are many possible ways to manage the symptoms of patients with APDS, but it really depends on their individual manifestations and clinical presentation. Treatment needs to be individualised to the patient. There is no curative treatment that exists at this time. Many individuals need prophylactic antibiotics in addition to IgG replacement therapy in order to treat infectious complications.

“Individuals with APDS may develop lung disease, gastrointestinal disease, haematologic disease and endocrine disease, which need to be managed with additional treatments.” – Dr Hartog

Dr Dalm: APDS can result in lymphoproliferative disorders, as well as haematological malignancies, including lymphoma. These complications require additional or specific treatment regimens, including immunosuppressive therapies and chemotherapy. 

Q. What are the challenges and limitations of the current clinical management of APDS?

Dr Hartog: Although many of the current disease management treatments are providing individuals with APDS a better quality of life, they are not a cure. The development of new therapies that are directed at treating the disease, and not just the symptoms of the disease are critical. We need a targeted therapy that addresses the specific defect in individuals with APDS. We have seen an explosion in the immunology world of the identification of new genetic diseases that leads to an understanding of the basis of an individual’s disease. However, there has not been a concurrent explosion in drug development to address these needs. 

Dr Dalm: Current treatment options (used to manage symptoms related to APDS), include mTOR inhibitors or haematopoietic stem cell transplantation (HSCT), based on the symptoms and severity of clinical phenotype. However, these options lack effectiveness in a significant number of individuals with APDS. HSCT also risks morbidity and mortality. Novel therapies are therefore urgently needed.

“Targeted drugs would be of benefit to individuals in practice. Approval and access to these drugs could be life-changing for individuals with APDS.” – Dr Dalm

Q. What do you feel would make the biggest difference for people with APDS?

Dr Dalm: Clinicians need to be able to recognise the clinical picture of an individual with APDS and know how to order genetic testing to prove the diagnosis. A definitive diagnosis is essential to personalise treatment and gain insights in the prognosis of the individual, as well as which complications can or could be expected over time.

Dr Hartog: More awareness and identification of the disease in the healthcare community is imperative. Even if we have new treatments, we can’t use them if we don’t first identify individuals with the disease. As well as educating physicians, educating the general public helps to inform individuals that there may be a genetic cause of their diseases), which has the potential to change the treatment they are receiving. Through this education, we can empower individuals to be advocates for their health, and to drive genetic testing for themselves.

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Activated PI3K delta syndrome (APDS) is a primary immunodeficiency (PI). It may also be referred to as a primary immunodeficiency disorder (PID), primary immune regulatory disorder (PIRD), an inborn error of immunity (IEI) and was previously known as PASLI disease.

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Reference:

[1]  Nord. Common Variable Immune Deficiency. Website. https://rarediseases.org/rare-diseases/common-variable-immune-deficiency/. 8^th November 2021