In the EU, a disease is defined as rare if it affects no more than 1 in 2,000 people and similarly in the US it is defined as a condition that affects less than 200,000 people.1 Despite being referred to as ‘rare’, collectively, there are 6,000 to 8,000 known rare diseases2 and more than 300 million people around the world are living with one.3 For these people, living with a rare disease can mean a long wait to receive an accurate diagnosis, less options in terms of care, and many unanswered questions. In order to address this current unmet need, we must bring a new focus to the challenges faced by those with rare diseases.
The challenges of a rare disease: Castleman disease
One such rare disease is Castleman disease (CD) – a group of unusual and life-threatening lymphoproliferative disorders that affect the lymph nodes and related tissues.4,5 Multicentric Castleman disease (MCD) is one of two main subtypes of CD, along with Unicentric Castleman disease (UCD). UCD only affects a single group of lymph nodes, whereas MCD is systemic and affects multiple regions, such as the chest and abdomen. MCD can be further divided into three categories – human herpesvirus-8 (HHV-8) associated MCD, MCD associated with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) syndrome and idiopathic MCD (iMCD).5
iMCD affects lymph nodes and related tissues5 but unlike other subtypes of MCD, as the name suggests, the cause of the disease is relatively unknown. Approximately 540-960 people in the US are affected each year, with a similar number estimated in Europe5 but because of its many unknowns and the fact that it presents differently from other subtypes of the disease, iMCD patients have the worst prognosis among those diagnosed with CD.5
With so few cases presenting, physicians are often unfamiliar with iMCD and very few have first-hand experience of treating it, making it difficult for physicians to diagnose the condition confidently and accurately. It has only been since 2017 that diagnostic criteria to support the identification of iMCD has been in place.5
In fact, the disease was only brought into focus recently after Physician-Scientist, Dr David Fajgenbaum - whom himself fell ill with iMCD - penned his memoir “Chasing My Cure: A Doctors Race to Turn Hope into Action”. It is this book that is often attributed to putting the disease on the map, highlighting the unique research approach Dr Fajgenbaum took to identify the disease and unlock effective treatment options. He also established the Castleman Disease Collaborative Network (CDCN), as a way to accelerate research into CD and support better patient outcomes. A lot of resulting progress has been made, but more challenges remain.
Beyond limited first-hand experience, iMCD is frequently misdiagnosed because symptoms are non-specific and overlap with several more well-known conditions such as human immunodeficiency viruses (HIV), rheumatoid arthritis and some blood cancers like lymphoma and multiple myeloma.5 These must first be ruled out,6 creating further diagnosis delays.
For some, symptoms may include enlarged lymph nodes, weight loss, fatigue, and fever.7 In more severe cases, an uncontrolled release of pro-inflammatory cytokines, known as a cytokine storm, may occur. This, along with a subsequent overproduction of immune cells, can lead to organ failure.8 At this stage, it is often too late for intervention and historically, we have seen patients die within two and a half years of diagnosis and less than 30% surviving beyond five years from diagnosis9 – a mortality rate that is amongst or higher than those of progressive non-Hodgkin’s lymphoma, stage II colon cancer and stage III breast cancer.10
What’s more, it was observed in a retrospective analysis of US real-world data claims that within the first year of diagnosis, iMCD patients had a 49.6% increase in inpatient hospitalisations and a 32.8% increase in emergency room visits. Within one-year of diagnosis, 27% of patients experienced malignancy, 12% suffered from renal failure, and 6.8% were affected by respiratory failure or Thrombus.9 Early diagnosis is therefore essential to reducing mortality in iMCD patients.5
These challenges have often left both patients and physicians with more questions than answers. It is not surprising therefore, that the initial relief that may be felt for people with iMCD when hearing they do not have cancer, may be short-lived, and instead replaced by newfound anxiety.
Finding a rainbow after the storm
Recently, the concept of the ‘cytokine storm’ has risen to notoriety because of the part it has been suggested to play in the development of severe symptoms in a number of COVID-19 patients.11 During this time, we have seen the scientific community come together rapidly to put this phenomenon under the microscope, to understand the complex interplay of numerous factors in this process and thereby identifying and trialling several promising treatments.
The uncertainty of COVID-19 brought with it a frightening new reality for all, but for many patients with a rare disease, worry and uncertainty is a reality that they live with daily. In just over a year, we have adapted and grown our knowledge of COVID-19 beyond expectation. Now that we have proven what is possible, and as we move towards vaccination and start to look forward with optimism, we must now take these learnings and translate them into the rare disease space.
An enormous amount of positive progress has been made in little more than 12 months with COVID-19, a resounding demonstration of the power of collaboration and what can be achieved with focused research and development. We now need to apply these efforts to the rare disease space, to overcome the uncertainty that patients still face and better support early diagnosis and treatment.
The future for rare disease
This year’s Rare Disease Day focus – rare is many, rare is strong, rare is proud – highlights a growing sentiment in the rare disease community, that people with rare disease do not receive the equal opportunity for diagnosis and care they deserve. By harnessing the learnings of the pandemic around collaboration and commitment to research and understanding, we can support better outcomes for patients. We have seen through the COVID-19 pandemic what can be achieved through true collaboration, dedication, and commitment to research. Moving forward, we need to come together and apply this approach, not only to Castleman disease, but to all rare diseases.
Around the world, important work is already being done to overcome the challenges faced by both patients and physicians alike, but we need to, and can, do more.
1 NIH.gov. FAQ about rare diseases. Available at: https://rarediseases.info.nih.gov/diseases/pages/31/faqs-about-rare-diseases. Accessed: February 2021.
2 European Commission. EU research on rare diseases. Available at: https://ec.europa.eu/info/research-and-innovation/research-area/health-research-and-innovation/rare-diseases_en. Accessed: February 2021.
3 Rare Disease Day. What is a Rare Disease? Available at: https://www.rarediseaseday.org/article/what-is-a-rare-disease. Accessed: February 2021.
5 Fajgenbaum, D.C. et al. International, evidence-based consensus diagnostic criteria for HHC-8 negative/idiopathic multicentric Castleman disease. Blood 2017;129(12):1646–1657.
6 Castleman Disease Collaborative Network. Diagnosis and treatment. Available at: https://cdcn.org/castleman-disease/diagnosis-treatment/. Accessed: February 2021.
7 NIH.gov. Multicentric Castleman Disease. Available: https://rarediseases.info.nih.gov/diseases/9644/multicentric-castleman-disease. Accessed: February 2021.
8 Fajgenbaum D.C. Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease. Blood 2018 Nov 29; 132(22): 2323–30.
9 Mukherjee S, et al. A Longitudinal Population Level Analysis of Healthcare Resource Utilization, Comorbidity, and Survival in Idiopathic Multicentric Castleman Disease Patients. 62nd ASH 2020. Available at: https://ash.confex.com/ash/2020/webprogram/Paper140449.html. Accessed: February 2021.
10 Sitenga, J. et al. Impact of siltuximab on patient-related outcomes in multicentric Castleman’s disease. Patient Relat Outcome Meas 2018; 9: 35–41.
11 Castelli V, Cimini A and Ferri C (2020) Cytokine Storm in COVID-19: “When You Come Out of the Storm, You Won’t Be the Same Person Who Walked in”. Front. Immunol. 11:2132. doi: 10.3389/fimmu.2020.02132