APDS is a rare, primary immunodeficiency1,2,*
Timeline of the most common pathologies seen in APDS3-5
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Joenja is indicated for adults and pediatric patients 12 years of age and older.
APDS has often been diagnosed as another PI or condition, causing delays in diagnosis4,†
*PI is also known as IEI.6
†This analysis of 39 patients with APDS revealed initial diagnoses of a range of other conditions.4
ALPS, autoimmune lymphoproliferative syndrome; CID, combined immunodeficiency; CVID, common variable immunodeficiency; IEI, inborn error of immunity; PI, primary immunodeficiency; XLA, X-linked agammaglobulinemia.
Adapted from Jamee M, Moniri S, Zaki Dizaji M, et al. Clinical, immunological, and genetic features in patients with activated PI3Kδ syndrome (APDS): a systematic review. Clin Rev Allergy Immunol. 2020;59(3):323-333.
Improved identification of symptoms and increased genetic testing are needed for earlier diagnosis1,2,7-9
- APDS, characterized in 2013, is caused by variants of the genes encoding PI3Kδ
- Genetic testing for APDS became available in 2017
- Pathogenic PI3Kδ variants have autosomal dominant inheritance patterns
Signs and symptoms of APDS vary widely4,8-10
APDS signs and symptoms are heterogeneous, even among family members with the same genetic variant9,11,12
Range and frequency of APDS symptoms
People with APDS usually experience 1 or more of the following symptoms3-5,13-15:
Immune imbalance is primarily responsible for APDS disease progression9,12
In APDS, hyperactivity along the PI3Kδ signaling pathway disrupts immune cell balance2
Scroll left to view cell table
In patients with APDS who experience disease progression2:
- Inadequate control of immune deficiency can lead to infections, end-organ lung damage such as bronchiectasis, and lymphoma
- Uncontrolled immune dysregulation may lead to lymphoproliferation including lymphadenopathy, splenomegaly, and potentially lymphoma
- End-organ damage has frequently preceded a confirmed diagnosis of APDS13,16 CMV, cytomegalovirus; EBV, Epstein-Barr virus; IgA, immunoglobulin A.
Recent studies have shown PI3Kδ to be a key factor in APDS progression3,9,15
APDS is caused by hyperactivity of the PI3Kδ enzyme, early in the complex PI3Kδ pathway2,17-19
- The diverse manifestations of APDS are caused by the multiple downstream effects of a hyperactive PI3Kδ enzyme
- Balanced activity of this signaling pathway is critical to normal immune cell development
The PI3Kδ enzyme is at the beginning of a complex signaling pathway
Note: Illustration does not include all steps in the signaling pathway.
Adapted from Rao VK, Webster S, Šedivá A, et al. Blood. 2023;141(9):971-983. doi:10.1182/blood.2022018546
References: 1. Angulo I, Vadas O, Garçon F, et al. Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science. 2013;342(6160):866-871. doi:10.1126/ science.1243292 2. Rao VK, Webster S, Šedivá A, et al. A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome. Blood. 2023;141(9):971-983. doi:10.1182/blood.2022018546 3. Maccari ME, Abolhassani H, Aghamohammadi A, et al. Disease evolution and response to rapamycin in activated phosphoinositide 3-kinase δ syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry. Front Immunol. 2018;9:543. doi:10.3389/fimmu.2018.00543 4. Jamee M, Moniri S, Zaki-Dizaji M, et al. Clinical, immunological, and genetic features in patients with activated PI3Kδ syndrome (APDS): a systematic review. Clin Rev Allergy Immunol. 2020;59(3):323-333. doi:10.1007/s12016-019-08738-9 5. Elkaim E, Neven B, Bruneau J, et al. Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2: a cohort study. J Allergy Clin Immunol. 2016;138(1):210-218.e9. doi:10.1016/j.jaci.2016.03.022 6. Tangye SG, Al-Herz W, Bousfiha A, et al. Human inborn errors of immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2020;40(1):24-64. doi:10.1007/s10875-019-00737-x 7. Anderson JT, Cowan J, Condino-Neto A, Levy D, Prusty S. Health-related quality of life in primary immunodeficiencies: impact of delayed diagnosis and treatment burden. Clin Immunol. 2022;236:108931. doi:10.1016/j.clim.2022.108931 8. Deau M-C, Heurtier L, Frange P, et al. A human immunodeficiency caused by mutations in the PIK3R1 gene. J Clin Invest. 2014;124(9):3923- 3928. 9. Data on file. Pharming Healthcare, Inc. 10. Lucas CL, Chandra A, Nejentsev S, Condliffe AM, Okkenhaug K. PI3Kδ and primary immunodeficiencies. Nat Rev Immunol. 2016;16(11):702-714. doi:10.1038/nri.2016.93 11. Genetic Alliance; The New York-Mid-Atlantic Consortium for Genetic and Newborn Screening Services. Understanding Genetics: A New York, Mid-Atlantic Guide for Patients and Health Professionals. Washington, DC: Genetic Alliance; July 8, 2009. 12. Nunes-Santos CJ, Uzel G, Rosenzweig SD. PI3K pathway defects leading to immunodeficiency and immune dysregulation. J Allergy Clin Immunol. 2019;143(5):1676-1687. 13. Coulter TI, Chandra A, Bacon CM, et al. Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: a large patient cohort study. J Allergy Clin Immunol. 2017;139(2):597-606.e4. doi:10.1016/j.jaci.2016.06.021 14. Carpier J-M, Lucas CL. Epstein-Barr virus susceptibility in activated PI3Kδ syndrome (APDS) immunodeficiency. Front Immunol. 2018;8:2005. doi:10.3389/fimmu.2017.02005 15. Rao VK, Webster S, Dalm VASH, et al. Effective “activated PI3Kδ syndrome”—targeted therapy with the PI3Kδ inhibitor leniolisib. Blood. 2017;130(21):2307-2316. doi:10.1182/blood-2017-08-801191 16. Bloomfield M, Klocperk A, Zachova R, Milota T, Kanderova V, Sediva A. Natural course of activated phosphoinositide 3-kinase delta syndrome in childhood and adolescence. Front Pediatr. 2021;9:697-706. 17. Okkenhaug K. Signalling by the phosphoinositide 3-kinase family in immune cells. Annu Rev Immunol. 2013;31:675-704. 18. Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3K pathway in human disease. Cell. 2017;170(4):605-635. doi:10.1016/j.cell.2017.07.029 19. Okkenhaug K, Vanhaesebroeck B. PI3K in lymphocyte development, differentiation and activation. Nat Rev Immunol. 2003;3(4):317-330. doi:10.1038/nri1056
