If you have ever seen a child during a sickle cell disease pain crisis, you have experienced something that is difficult to put into words. Hearing a child’s unrelenting scream from pain that is hard enough to describe, let alone live through, can make your blood run cold. No child should know what 11 on a pain scale of 1 to 10 feels like.
Asking an adult what a sickle cell pain crisis feels like usually yields a mix of graphic metaphors like having shards of glass in your blood shredding you from the inside out or breaking a bone over and over again. If you don’t have sickle cell disease (SCD), it is unlikely you will ever understand the agony of a pain crisis–it must be left for interpretation in the darkest corner of your imagination.
An instinct we share in the field of health care is the need to help those in despair. Well, what do we do here? Hydration, hydroxyurea, morphine, and monitoring. Check back in a few hours.
As a physician, why can’t I do more in 2021? It’s just an amino acid that’s out of place. Surely, by now, someone has figured out how to help, right?
Why Are We So Behind in SCD?
It’s worth comparing the advancements in other areas of medicine to gain a bit of perspective here. There are therapies for other diseases that have been approved relatively recently that are nothing short of miraculous.
For example, cystic fibrosis (CF) affects about 30,000 people in the United States1 and is the most common genetic disease in Caucasians.2 Like SCD, it is autosomal recessive. The most common cause boils down to a single amino acid substitution which alters the function of the cystic fibrosis transmembrane conductance regulator (CFTR) channel. The defect results in abnormal chloride transport across mucus membranes, leading to thick, viscous mucus which plugs up various ducts and results in a myriad of problems and a shortened lifespan.3
After years of research, lumacaftor-ivacaftor was approved by the US Food and Drug Administration (FDA) in 2015 and later granted approval for use in children as young as 2 years old.4,5 Fascinatingly, this wonder drug is capable of chaperoning the defective CFTR protein from the endoplasmic reticulum, sparing ubiquitination, and opening the channel upon integration with the cell membrane.6
The sophistication of this drug seemingly mocks the progress made in SCD, a fatal genetic disease that primarily affects African Americans. Until very recently, SCD research has not received the attention it deserves, and many sufferers say not enough is being done. Let’s further compare.
Read more about SCD epidemiology
The Journal of the American Medical Association (JAMA) published an eye-opening study in 2020 which brought to light the disparities between SCD funding and CF funding. The study points out that National Institutes of Health funding is allocated in accordance with disease burden, which explains why heart disease and cancer receive the largest amount of funding. CF and SCD received similar funding between 2008 and 2018, but this is not proportional to the respective disease burdens.
The prevalence of SCD is 3 times higher than CF. One in 365 black Americans is born with the disease, compared with 1 in 2500 white Americans. Moreover, the authors reported:7
- The mean NIH funding per person with CF was $2807, vs $812 per person with SCD.
- Mean philanthropic expenditure was $7690 per person with CF versus $102 for SCD.
- The number of publications on each disease between 2008 and 2018 was 1594 versus 926 in favor of CF.
- CF trials were more likely to receive industry funding.
The clinical trials arena for CF during this time was also more productive, receiving 4 drug approvals. SCD research was largely silent and uneventful during this period.7
In 2017, Endari™ (L-glutamine oral powder) broke the silence and became the first drug to be approved by the FDA for the treatment of SCD in almost 20 years.8 It is basically a purified nutritional supplement with minimal efficacy.
The company attempted to file for approval in Europe under the name Xyndari however, the European Medicines Agency (EMA) said “the main study did not show that Xyndari was effective at reducing the number of sickle cell crises or hospital visits.” Following this negative sentiment, Emmaus Medical Europe Ltd. withdrew its application for EMA approval.9
Strong evidence exists for the use of hydroxyurea in patients with SCD. It is effective in reducing pain crises, hospitalizations, blood transfusions, and possibly mortality. Despite the body of work in favor of hydroxyurea, a 2015 study in JAMA reported that more than 3 out of 4 patients with SCD who are eligible for hydroxyurea therapy are not on this medication. The authors cite various barriers to treatment, including lack of clinician training and failure to engage in shared decision making, as reasons for suboptimal management.10
The Frustration Continues
As mentioned above, lack of clinical training is an alarming hurdle SCD patients in the United States face for a disease that affects approximately 100,000 Americans.11 The reality is that only 20% of family physicians in the country are comfortable with treating the disease.12
It is estimated that the annual financial burden for patients was $10,000 for children and $30,000 for adults in 2016; these numbers are likely much higher today. As a result, a troubling number of patients do not receive adequate care and their main interaction with a medical team is in the emergency room.12
The frustration continues as patients with SCD are less likely to receive adequate analgesia despite higher overall pain scores when visiting an emergency room.12 Despite being in true, excruciating pain, SCD patients are disproportionately characterized as drug seekers.
An article in The New England Journal of Medicine (appropriately named, might I add, “When Actions Speak Louder Than Words—Racism and Sickle Cell Disease”) describes institutional racism as an undeniable reason for inadequate care for SCD patients and a factor in the lower funding SCD research has traditionally received.13 It’s a great read. Accounts of black patients who dress themselves nicely before going to the hospital for a pain crisis to avoid judgment and receive better care is a scene that personally breaks my heart. This indifference is experienced daily by patients. We must outgrow it.
It is easy to be outraged at the overt neglect for SCD on home soil but the situation in the US is envied by some nations. The mortality rate for children under 5 years of age for some African countries where newborn screening is not practiced is difficult to stomach. Rates reach an appalling 90% for these babies.12 Despite this, SCD remains globally invisible.
A Brighter Future
The future for SCD is not as grim as the past. Funding for clinical trials and drug development has steadily increased and groundbreaking research is being conducted in the realm of gene therapy.
In 2019, Victoria Gray, 34 years old, became the first person to be treated for SCD using clustered regularly interspaced short palindromic repeats, also known as CRISPR.14 One year later, she is functioning as someone who does not have SCD.
Helen Obando, a 16-year-old girl, became the youngest patient to receive gene therapy for SCD in 2020. She is receiving a treatment that suppresses the BCL11A gene in hematopoietic stem cells using a lentiviral vector. Upon follow-up, Obando is by all accounts symptom-free and enjoying a normal life in Arizona.15
Read more about experimental therapies for SCD
Gene therapy appears to be the haystack holding the cure for SCD and numerous clinical trials are underway to find it. This is a big change in philosophy, as for decades the goal of therapy was to manage symptoms, not to cure. The year 2021 saw a 32% increase in the number of clinical trials for SCD, despite a raging pandemic.16
The Centers for Disease Control (CDC), Centers for Medicare and Medicaid Services (CMS), and the US Department of Health and Human Services have all released guidelines on the management of pain and the use of opioids in patients with SCD. The CMS recommends that beneficiaries with SCD be excluded from opioid safety edits.
In November 2019, the American Society of Hematology (ASH) held its first annual SCD Adult Care Centers Workshop to train healthcare professionals how to start a clinical center focusing on the needs of adults with SCD. Also in 2019, 2 new therapies, voxeltor (Oxbryta) and crizanlizumab (Adakveo), were approved for treatment of the disease.17
It appears that SCD is finally exiting the shadows.