global burden of pain in sickle cell disease · thalassemia-0) 2% moderate-severe moderately...

Global Burden of Pain in Sickle Cell Disease

Andrew Campbell MDDirector, Comprehensive Sickle Cell Program

Children’s National Health SystemAssoc Professor of Pediatrics, George Washington University

School of Medicine

ARISE Virtual Training Programme LectureMay 14, 2020

1

1) Understand the Epidemiology of Pain Globally in SCD

2) Understand the Pathophysiology of SCD and it’s relationship to pain crisis

3) Understand the treatment options for SCD Pain Crises.

Learning Objectives

2

Melanie is 19 year old female with severe sickle cell disease (SCD) presents to her hematologist with severe pain. Prior to age 16, she reported four hospitalizations and two emergency department visits for acute pain management.

Brandow AM, Zappia KJ, Stucky CL. Sickle cell disease: a natural model of acute and chronic pain. Pain. 2017;158 Suppl 1(Suppl 1):S79-S84.

CASE : Pain Crisis

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Her pain significantly increased in frequency and severity between ages 16–19 with 10 hospitalizations and she reported almost daily pain. Her pain descriptors included radiating, burning, tingling, electric shocks, numbness and she reported cutaneous pain with slight skin pressure and with cold temperatures. Pain locations included chest, lower back, knees, feet and “all over.”

What can we offer Melanie for her Pain? Why is her pain worsening with age?What are the pathophysiologic mechanisms of her pain?


CASE : Pain Crisis

4

Sickle Cell in the blood vessels leads to

• Pain

• Vasculopathy

• Organ damage

Background

5

Types of Sickle Cell DiseaseApprox.

% of U.S. Patients Anemia MCV Hemoglobin

SCD-SS 65% Moderate-Severe

Normocytic 80-95

6-9 gm/dl

SCD-SC 25% Mild-Moderate

Mildly microcytic

66-72

9-12 gm/dl

SCD-Sβ+( Sickle Beta Thalassemia+)

8% Mild-Moderate

-Mild-Moderately microcytic

60-70

9-12 gm/dl

SCD-Sβ0(Sickle Beta Thalassemia-0)

2% Moderate-Severe

Moderately Microctyic

58-72

7-10 gm/dl

Hemoglobin ElectrophoresisExamples SCD and SCTrait

HGBE Hgb S Hbg C Hbg F Hgb A2 Hgb A1

SCD-AS (Trait)

Hgb S 35% Hgb F 2% Hgb A2 1% Hgb A1 60%

SCD-SS Hgb S 92% Hgb F 5% Hgb A2 2% Hgb A1 0%

SCD-SC Hgb S 50% Hgb C 47%

Hgb F 3% Hgb A2 N/A* Hgb A1 0%

SCD-Sβ+ Hgb S 65% Hgb F 9% Hgb A2 6% Hgb A1 20%

SCD-Sβ0 Hgb S 88% Hgb F 6% Hgb A2 6% Hgb A1 0%

7

Disease distribution

Piel et al (2013) The Lancet

Piel et al Oxford Univ

Estimates of SCA births

Summary of regional annual predicted estimates of HbS newborns affected (5x5km).HbSS newborns/year

Population0 CBR1 Mean Median IQR2 % WHO3

WHO regions

AFRO 888,817 0.0357 239,547 238,083 224,003 253,047 75.6 184,812AMRO 939,833 0.0162 13,708 13,104 11,126 15,610 4.6 4,432EMRO 560,803 0.0249 10,007 8,239 6,012 11,950 3.6 7,389EURO 893,002 0.0123 3,653 3,271 2,408 4,370 1.3 376

SEARO 1,789,082 0.0200 44,132 42,597 35,022 50,750 15.1 25,768WPRO 1,840,667 0.0128 4 9 2 3 0.0 9

0 In thousands 3 HbSS newborn estimates from Modell and Darlison, 20081 Crude birth rate

Piel et al (2013) The Lancet

SCD Clinical Severityà Pain Severity

Factors that decreases the severity of disease•Hbg F levels

•Co-inheritance of Alpha-Thalassemia Trait (sickle cell disease-Alpha Thal Trait)

•Hb-SC or Hb-Sβ+ Thalassemia

•Younger age

SCD Clinical ManifestationsSickled cells block the flow of blood

Increased bacterial infections.

Vaso-occlusive Crisis

• Jfield et al Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks−American Pain Society−American Academy of Pain Medicine Pain Taxonomy Diagnostic Criteria for AcuteSickle Cell Disease Pain, The Journal of Pain, Vol 00, No 00 (), 2019: pp 1−14 • Ballas, et al Definitions of the phenotypic manifestations of sickle cell disease. American journal of hematology, 85, 6–13 • Gupta et al Mechanisms of pain in SCD • Darbari et al The Vaso-Occlusive Pain Crisis in Sickle Cell Disease: Definition, Pathophysiology, and Management EJH

2020May 14, 2020

• #1 number one cause of hospital admissions worldwide for SCD

• Releases numerous inflammatory mediators that initiate the transmission of painful stimuli and the perception of pain

• Hospital readmission within 1 week occurs in about 16% of discharged patients

• In adults, 50% are re-admitted within 1 month in US


May 14, 2020

Acute pain (painful crises) can last for hours to days (or rarely weeks) begin early in childhood and often becoming more frequent in adolescents and adults

Patients may display variable degrees of persistent pain related to chronic bone and joint damage( .i.e à AVN)

Neurological changes in response to persistent pain can lead to an enhanced sensitivity to pain and psychosocial sequelae can increase subsequent suffering

The Journal of Pain, Vol 00, No 00 (), 2019: pp 1−14 Jfield et al Definitions of the phenotypic manifestations of sickle cell disease. American journal of hematology, 85, 6–13 Ballas, et al .

http://paperpile.com/b/SpImVm/cgeM

Current Issues in Sickle Cell Pain and Its Management Samir K. Ballas, MD, ASH Educational Book, 2007Cardeza Foundation for Hematologic Research, Department of Medicine, Thomas Jefferson University,

Philadelphia, PA

• Four distinct phases coupled with changes in certain markers of the disease

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Vaso-occlusive Crisis-> Where

May 14, 2020

A Variety of Vascular Beds:

• deep muscle• periosteum• bone/bone marrow*

Common Characteristics of these areas:

• richly innervated by nocioceptors activated by a variety of inflammatory mediators

• Jfield et al Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks−American Pain Society−American Academy of Pain Medicine Pain Taxonomy Diagnostic Criteria for AcuteSickle Cell Disease Pain, The Journal of Pain, Vol 00, No 00 (), 2019: pp 1−14 • Ballas, et al Definitions of the phenotypic manifestations of sickle cell disease. American journal of hematology, 85, 6–13 • Gupta et al Mechanisms of pain in SCD • Darbari et al The Vaso-Occlusive Pain Crisis in Sickle Cell Disease: Definition, Pathophysiology, and Management EJH 2020

Vaso-occlusive Crisis-> How

May 14, 2020

Vaso-occlusive Crisis: Why is it important

May 14, 2020

VOC are in part a reflection of disease activity:

• Pain crisis frequency varies widely between patients and is directly related to disease severity and increased mortality (O Platt et al).

• A better understanding of disease pathogenesis is an important aspect of sickle pain management.

• Pain is not entirely explained by specific physical examination findings (leg ulcers, priapism, edema) or imaging abnormalities (bone infarction,AVNosteomyelitis)


• Precipitated by temperature changes, stress, infection, dehydration and unknown factors

• Spine, pelvis, long and flat bones are commonly involved

• Treatment: Hydration, analgesia, rest, other supportive therapies( massage, heating pads, meditation, distraction,etc)

May 14, 2020

Dactylitis

Physical illustration of dactylitis in an infant

19

Image retrieve from Sickle Cell Research for Treatment and Cure. U.S. Department of Health and Human Services. National Institutes of Health, 2002, p. 10.

Dactylitis

• 50% of SCD patients <2 y/o present with dactylitis as first symptom

Treatment• Increase fluids, Tylenol/Motrin, massage; heating

pad; consider small amounts of opioid if severe in older children. In severe cases, may need IV opioids(i.e morphine) in older children

20

Incidence of First Vaso-occlusive Crisis

Gill FM, Sleeper LA, Weiner SJ, Brown AK, Bellevue R, Grover R, Pegelow CH, Vichinsky E.

Clinical Events in the first decade in a cohort of infants with sickle cell disease, CSSCD Group Study. Blood. 1995.86(2):776-783.

Presentation of Acute VOC

21

6%

32%

61%

92%96%

0%

20%

40%

60%

80%

100%

120%

6 months 12 months 2 y/o 6y/o 8 y/o

Incidence of 1st pain crisis in SCD Children

Vaso-occlusive Crisis-> How

May 14, 2020

Ware et al SCD Lancet Journal 2017

Vaso-occlusive CrisisàWhat factors may contribute to variability in sickle cell pain phenotype seen not only locally but globally??

• Genetic, ethnic, environmental factors, such as diet and nutritional status, cultural and national factors including health care delivery systems and norms of disease self-management, could play different roles in different settings, thereby explaining some of the differences in disease phenotype--> or pain crises patterns

• What are the Different patterns of pain around the world?

May 14, 2020

AN ANALYSIS OF PAIN CRISIS PATTERNS IN DIFFERENT GEOGRAPHIC REGIONS OF THE WORLD: ANALYSIS FROM THE CASIRE STUDY

• We investigated the sickle cell disease pain crisis patterns in three geographic regions of the world (USA, Europe [Italy, United Kingdom], and Africa (Ghana); N=868 PATIENTS

• Secondary data analyses of crises per year requiring ER/day hospital clinic visit (PC-ER/DH) or requiring hospitalization (PC-Hosp) were performed within each geographic region to assess PC frequency and care utilization variability.

May 14, 2020

1.51

0.81 0.9

1.27

2.35

1.65

0

0.5

1

1.5

2

2.5

Ghana N=57 UK/Italy N=200 U.S. N=94

Pediatrics (<18 y/o) Pain Crisis /year: Severe Genotype( SS, Sbeta Thal Zero)

Pediatrics( <18y/o).E.R./DH PC/year.

ap=0.313

ap=0.028**

ap=0.153

ap=0.114

ap=0.036**

ap=0.318

aOne Way Anova: PC per year: Index Countries (i.e. Ghana) compared to all other countries combined (i.e.: UK/Italy and U.S.); **p= <0.05

1.56

0.56

0.37

1.47

1.68

0.77

00.20.40.60.8

11.21.41.61.8


Pediatrics( <18y/o) Pain Crisis/year) Mild Genotype( SC, SBeta Thal+)

Pediatrics( <18y/o).E.R./DH PC/year.

Pediatrics( <18y/o). Hosp PC /year.

ap=0.153

ap<.0001**

ap=0.239

ap=0.534ap=0.293

ap=0.036**


2.15

0.65

2.3

1.2

1.97

2.54

0

0.5

1

1.5

2

2.5

3


Adults(>18 y/o) Pain Crisis /year: Severe Genotype( SS, SBeta Zero)

Adults >18y/o).E.R./DH PC/year. Adults >18y/o) Hosps PC/year.

ap=0.403

ap=0.017**

ap=0.509

ap=<0.001**

ap<0.001**

ap=0.525


2.15 2.17

0.91

2.04

0

0.5

1

1.5

2

2.5

Ghana N=72 U.S. N=23

Adults(>18 y/o) Pain Crisis /year: Mild Genotype( SC, Sbeta Thal+)

Adults >18y/o).E.R./DH PC/year.

Adults >18y/o).E.R./DH PC/year.

ap=0.868 ap=0.913

ap=0.064

ap=0.031**

Adults> 18y/o) Hosps PC/year.


AN ANALYSIS OF PAIN CRISIS PATTERNS IN DIFFERENT GEOGRAPHIC REGIONS OF THE WORLD: ANALYSIS FROM THE CASIRE STUDY

CONCLUSIONS:

• A different pattern of admission to ER and inpatient servicesseem to be present in the various regions: Children in Europepresented more hospitalizations for SCD related painful crisiswhile adults in the USA seem to present more ER and hospitaladmissions compared to other areas.

• Whether this is related to disease phenotype, geneticmodifying factors, environment characteristics ororganization of health care needs to be investigated.

May 14, 2020

Geographic Differences in Phenotype and Treatmentof Children with Sickle Cell Anemia from theMultinational DOVE Study( Inusa et al 2019 JCM)

May 14, 2020

• A total of 341 children, aged 2 to <18 years, with SCA, who had at least two documented VOCs in the previous year, were randomized.

• VOC was the composite endpoint of painful crisis or acutechest syndrome (ACS, Beijing, China).

• HU therapy was allowed if subjects were on a stable dose forat least 60 days prior to randomization.

May 14, 2020

Geographic Differences in Phenotype and Treatmentof Children with Sickle Cell Anemia from theMultinational DOVE (Determining Effects of Platelet Inhibition on Vaso-Occlusive Events)Study( Inusa et al 2019 JCM)

Geographic Differences in Phenotype and Treatmentof Children with Sickle Cell Anemia from theMultinational DOVE (Determining Effects of Platelet Inhibition on Vaso-Occlusive Events)Study( Inusa et al 2019 JCM)

May 14, 2020

FINDINGS AND CONCLUSIONS:

• VOC rate and percentage of VOC hospitalizations were highest inEurope.

• Regardless of region, most VOCs were treated with analgesics; approximately half were treated with intravenous fluids. T

• The proportion of VOC-related transfusions was greatest in Europe.

• Lengths of hospital stay were similar across regions.

• Conclusions: Overall differences in SAEs and hospitalization for VOCs may be due to cultural diversities, resource utilization, disease severity, or a combination of factors.

Vaso-occlusive Crisis: Common Approaches Acute Home management:

• Mild Pain( i.e. Home Pain Plan)

• Acetaminophen or Ibuprofen, Fluids, Rest, Heat therapy(heating pad, warm bath/shower)

• Moderate/ Severe Pain: ( i.e. escalated Home Pain Plan)

• Opioids( i.e. oral morphine, oxycodone, hydromophone, hydrocodone)

+• NSAID( i.e. ibuprofen , naproxen, advil, )

+• Oral hydration( avoid caffeinated products)

May 14, 2020


Pain Crisis: Home Treatment

If these methods are not effective in controlling the pain, recommend referral to ER or Day hospital for

further management.

May 14, 2020

Vaso-occlusive Crisis: ER/Day Hosp. ManagementER/Day Hospital pain management:

• Hydration– Oral or IV hydration( depending on hydration status)– Preferred Chioice of IV Fluids—recommend hypotonic fluids( ½

NS) vs. Normal Saline based on Emory’s Study of NS vs hypotonic fluids in ER fluid management in SCD patients

• Opioids– Parental(IV) Opioid vs Oral Opioids( increased from home dose)

treatment with repeated dosing ( 2-4 doses) – IV choices– morphine, hydromorphone; – Fentanyl—intranasal can be used as an up front opioid prior to IV

access at some centers– Consider Oral Opioids 1st if patient have not tried home oral opioids.

May 14, 2020

Vaso-occlusive Crisis: ER/Day Hosp. Management

ER/Day Hospital pain management:• NSAIDs:

– Ketorolac (Toradol) IV x1 dose– Oral Ibuprofen if not tried at home

• Other methods– Distraction, heating pad, massage, acupuncture

Admission Decision:

If pain score/level is stabilized or improvesà d/c home on oral pain regimen.If pain score/level worsens or is poorly controlled-àAdmit to hospital for pain management

May 14, 2020

Vaso-occlusive Crisis: Inpatient Hosp. Management

• Hydration– Oral or IV hydration( depending on hydration status)@ 1x maintenance; Avoid

hyperhydration( i.e. > 1.5x M)

• Opioids– Non Patient Controlled Anesthesia(PCA) Pain Management

• Around the Clock(ATC) Dosing scheduled Oral or Parental Opioids ( Preferred) every 2-4 hours

• Short acting breakthrough medication ( oral or Parental)• IV choices– morphine, hydromorphone; Fentanyl, not used as often

recently

• PCA Management• Morphine or Hydromorphone• Demand dosing; Continuous + Demand dosing • IV choices– morphine, hydromorphone; Fentanyl, not often used;

May 14, 2020

Sickle Cell Treatment:2 Main Goals

• Treat Acute Complications

• Prevention of Complications

Blood transfusions

• Mechanisms:

– Replace Sickle ”S” Blood with Normal “A” “Blood

– Increase the overall hemoglobin to improve anemia

– Goal: Lower the Hemoglobin ”S” % , in some cases< 30-40%

Post transfusion

Pre transfusion

–Mainstay for sickle cell acutecomplications including:

• Acute Syndrome• Splenic Sequestration• Severe Anemia( i.e. Aplatic Crisis-

Parvovirus)• Stroke• Hepatic Crisis

Blood transfusions

–Used for prevention of sickle cell complications:

• Primary and Secondary Stroke Prevention • Recurrent Acute Syndrome Prevention• Secondary Splenic Sequestration

Prevention• Advanced Stage Kidney Disease with

severe anemia• Worsening Pulmonary Hypertension• Secondary Priapism

Blood transfusions

Sicklingà End Organ Damage

Hemolysis

Adhesion

Inflammation

Coagulation

End Organ Damage

There are 4 FDA( US) approved drugs for Sickle Cell Disease

• 3( Adakveo/Crizanlizumab, hydroxyurea/hydroxycarbamide, Endari/L-Glutamine) are for prevention of pain;

• 1 (Oxbryta/voxelotor)to improve anemia/increase Hgb

• 1 Prevention of Complications and improve morbidity(hydroxyurea/hydroxycarbamide)

May 14, 2020

Hydroxyurea

(1) Fetal hemoglobin Induction

(2) lower neutrophil and reticulocyte counts

(3) decreased adhesiveness and improved rheology of circulating neutrophils and reticulocytes;

(4) reduced hemolysis throughimproved erythrocyte hydration, macrocytosis, and reduced intracellular sickling;

(5) Nitric oxide (NO) release with potential local vasodilatation and improved vascularresponse.

Hydroxyurea

• MSH( Adults) : HU reduced frequency of pain crisis, hospitalization, acute chest syndrome to by 50%

• Baby HUG: safety and efficacy in infants with SCA 2

• Adverse Effects: myelosuppression, long term effects unknown

• Dose 20 – 30 mg/kg/day• Visits q 3 months or more frequent with any dose

change/toxicity

May 14, 2020 Charache 1995;Thornberg 2012

NHLBI guidelines for SCD 2014

Objectives:This Phase III double-blinded placebo-controlled trial was designed to determine if HU treatment is safe, protects spleen and kidney function, and improves clinical and laboratory findings.

Design/Method: Subjects with Hb-SS or Hb-Sβ+ Thalassemia age 9-17 months at entry received liquid HU;

20 mg/kg/day

or

placebo for 2 years.

Baby HUG Study Results

Thornburg C. et al. Effects of Hydroxyurea on pain, dactylitis, acute chest syndrome and hospitalization in sickle cell anemia (SCA): results from the baby hug trial. American Society of Pediatric Hematology Oncology Conference. May2010.

Baby HUG Study Results

Thornburg C. et al. Effects of Hydroxyurea on pain, dactylitis, acute chest syndrome and hospitalization in sickle cell anemia (SCA): results from the baby hug trial. American Society of Pediatric Hematology Oncology Conference.

May2010.

Hydroxyurea- How does it work

Thornburg C. et al. Effects of Hydroxyurea on pain, dactylitis, acute chest syndrome and hospitalization in sickle cell anemia (SCA): results from the baby hug trial. American Society of Pediatric Hematology Oncology Conference. May2010.

Red Blood Cell Changes

How does hydroxyurea work?Hydroxyurea makes red blood cells bigger and less likely to sickle.

Figure 1

Nancy S. Green(2014) 75, 196-204. doi:10.1038/pr.2013.227

NHLBI SCD Guidelines: Hydroxyurea treatment recommendations

1. Educate all patients with SCA and their family members about hydroxyurea therapy.

2. In adults with SCA who have three or more sickle cell-associated moderate to severe pain crises in a 12-month period, treat with hydroxyurea. (Strong Recommendation, High-Quality Evidence)

3. In adults with SCA who have a history of severe and/or recurrent ACS, treat with hydroxyurea.* (Strong Recommendation, Moderate-Quality Evidence)

NHLBI SCD Guidelines: Hydroxyurea treatment recommendations

¡ In infants 9 months of age and older, children, and adolescents with SCA, offer treatment with hydroxyurea regardless of clinical severity to reduce SCD-related complications (e.g., pain, dactylitis, ACS, anemia).

¡ Strong Recommendation, High-Quality Evidence for ages 9–42 months;

Her pain significantly increased in frequency and severity between ages 16–19 with 10 hospitalizations and she reported almost daily pain. Her pain descriptors included radiating, burning, tingling, electric shocks, numbness and she reported cutaneous pain with slight skin pressure and with cold temperatures. Pain locations included chest, lower back, knees, feet and “all over.”

What can we offer Melanie for her Pain? Why is her pain worsening with age?What are the pathophysiologic mechanisms of her pain?


CASE : Pain Crisis

57

• At age 18, she started hydroxyurea which induces the production of fetal hemoglobin and ameliorates some SCD complications, including acute pain.


CASE : Pain Crisis

58

Time course of clinical pain expression over the lifespan of patients with sickle cell disease

May 14, 2020

Infancy(0-23mo) Toddler (2-5 y/o) Childhood( 5-12 y/o)

Clinical Pain Expression

HbF elevated•Minimal pain•Acute intermittent pain and dactylitis(“hand-foot syndrome”)•Splenic sequestration

HbF reaches nadir•Acute, intermittent pain events resulting in emergency department visits and hospitalizations

Continued acute, intermittent pain events resulting in emergency department visits and hospitalizations

PotentialPathophysiology

HbF protective against effects of HbS•Acute vascular occlusion and tissue ischemia by sickled cells

Decrease in HbF accompanied by increased HbS•Acute vascular occlusion and tissue ischemia by sickled cells•Chronic inflammation

Continued acute vascular occlusion and tissue ischemia by sickled cells•Chronic inflammation


• Despite a positive hematological response, significant pain persisted, severely impacting her quality of life. Her pain regimen included almost daily oxycodone, tramadol and ibuprofen.

• Questions raised by this common case include: • What is the underlying mechanism(s) causing the pain?• Why did her pain transition from acute and intermittent as a

young child to chronic, almost daily pain as an adolescent?• What alternative pain treatments can be used?


CASE : Pain Crisis

61

CHRONIC ORGAN Damage :Bone

CHILDHOOD ADOLESCENCE ADULT

NEUROPATHIC PAIN

PAIN FREQUENCY

PAIN( SICKLE)

SYSTEMIC INFLAM/ TISSUE DAMAGESICKLING/HYPOXIA

Time course of clinical pain expression over the lifespan of patients with sickle cell disease

May 14, 2020

Adolescence(13–18 yrs) Adulthood(≥19 yrs)

Clinical Pain Expression

Acute pain events increase in frequency•Length of hospital stay becomes longer•Chronic pain starts•Pain affects school attendance

Chronic daily pain is the norm•Acute intermittent pain crises continue, superimposed on chronic pain•Pain affects work attendance and employment•Higher rate of pain associated with increased mortality

PotentialPathophysiology

Continued acute vascular occlusion and tissue ischemia by sickled cells• Chronic inflammation• Sensitization of peripheral and central nervous system develops

Continued acute vascular occlusion and tissue ischemia by sickled cells•Chronic inflammation•Continued Sensitization of peripheral and central nervous system


Chronic Pain- A Global Problem

• Chronic pain transpires with increasing age as illustrated in the patient case above and in the Table

• Chronic, almost daily pain occurs irrespective of an acute vaso-occlusive crisis in 29.3% of adults.

• 40% of children and adolescents (ages 8–18 yrs) have chronic pain with 35% reporting daily pain

• Chronic SCD pain is also associated with more functional and psychosocial morbidity, unemploymentand school and work absenteeism


Chronic Pain SCD patients report:

• Nociceptive (i.e., throbbing, wrenching, tearing, pulsing, piercing, crushing, cramping) Pain

• Neuropathic descriptors (i.e., aching, cold, hot, penetrating, shooting, and stabbing)

• Thus, SCD pain is multifaceted in etiology

• Neuropathic pain questionnaires demonstrate that 30% of adult patients have neuropathic pain.


Chronic Pain SCD- Global Problem

• Complex etiology to SCD pain including – ischemic, inflammatory and neuropathic components

– the tissue sources of pain range from cutaneous to deep foci.

– Although tissue sources can include bony infarcts, avascular necrosis of the femoral/humoral heads and leg ulcers, most SCD patients with chronic pain do not have an obvious anatomic source making the etiology of chronic pain even more challenging to identify.


Novel Therapeutics for SCD

• Traditional Approaches to SCD Treatment was primarily targeted the Sickle Red Blood Cell

– Inside the Red Blood Cell• Drugs that improved RBC cellular hydration• Increase Hemoglobin F( Fetal) ( Hydroxyurea, Butyrate,• Blood Transfusions to reduce the % of Sickle RBCs• Cure with standard Bone Marrow Transplantation with high dose

chemotherapy


• New Approaches to SCD Therapies have shifted in many ways in the past 5-10 years.

• 1) Renewed Focus on what’s Outside the RBC


• New Approaches to SCD Therapies have shifted in many ways in the past 5-10 years.

• 2) What’s really happening inside the Sickle Red Blood Cell? Other mechanisms that trigger sickling?

Inflammation in SCD. SCD has been recognized as a chronic inflammatory disease.

Dachuan Zhang et al. Blood 2016;127:801-809

©2016 by American Society of Hematology


• Traditional Approaches to SCD Treatment was primarily targeted the Sickle Red Blood Cell

– Inside the Red Blood Cell• Drugs that improved RBC cellular hydration• Increase Hemoglobin F( Fetal) ( Hydroxyurea, Butyrate,• Blood Transfusions to reduce the % of Sickle RBCs• Cure with standard Bone Marrow Transplantation with high dose

chemotherapy

OXBRYTA

May 14, 2020

Increases Hgb by 1 gm in 59% of treated SCD patients( NEJM)

OXBRYTA is a prescription medicine used for the treatment of sickle cell disease in adults and children 12 years of age and older.

It is not known if OXBRYTA is safe and effective in children below 12 years of age.

This indication is approved under accelerated approval based on increase in hemoglobin (Hb).

OXBRYTA

May 14, 2020

Sickle cell VOC. SS-RBCs and other inflammatory mediators induce the activation of the endothelium.

Deepa Manwani, and Paul S. Frenette Hematology2013;2013:362-369

Anti- P Selectin Antibody( PSLG-1)

CONCLUSIONS

In patients with sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell–related pain crises than placebo and was associated with a low incidence of adverse events.


Adakveo

• ADAKVEO attaches to P-selectin, a sticky factor that plays a key role in blockages, also known as vaso-occlusion

• By attaching to P-selectin, ADAKVEO blocks connections between certain cells such as red blood cells, white blood cells, and platelets

May 14, 2020

https://www.youtube.com/watch?v=CWTW5pDPPDQ

https://www.youtube.com/watch%3Fv=CWTW5pDPPDQ

Adakveo

May 14, 2020

https://www.youtube.com/watch?v=CWTW5pDPPDQ

https://www.youtube.com/watch%3Fv=CWTW5pDPPDQ

Evaluation of Purified Poloxamer 188 in Children in Crisis (EPIC): A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial of ANX-188 (Purified Poloxamer 188) Injection in Children With Sickle Cell Disease Experiencing VasoOcclusive Crisis

300+ Patients Enrolled( Controls and Treatment Arms Combined)

The study did not meet its primary efficacy endpoint of demonstrating a statistically significant reduction in the mean duration of VOC (82 hours in the vepoloxamer group compared to 78 hours in the placebo group in the intent-to-treat population (p=0.09)).

Endari( L-Glutamine) : Improves Oxidative stress in SCD

Oxidative stress contributes to the pathophysiology of sickle cell disease.

Nicotinamide adenine dinucleotide (NAD+) is a ubiquitous oxidation–reduction (redox) cofactor in red cells and its reduced form, NADH, play major roles in maintaining redox balance.

Sickle red cells have a lower redox ratio ([NADH]:[NAD++NADH]) than normal red cells.

Endari( L-Glutamine) :

Essential amino acid

Increased levels are needed in certain conditions, such as stress)

Required to synthesize NAD.

Uptake of L-glutamine is several times greater in sickle red cells than in normal red cells primarily to increase the total intracellular NAD level

Endari( L-Glutamine) :

Endari( L-Glutamine) : Reduces Time to 1st and 2nd PC

• Based on our case presentation, do you think she should consider alternative treatments presented above if she has access to these new therapies?


CASE : Pain Crisis

90

global burden of pain in sickle cell disease · thalassemia-0) 2% moderate-severe moderately...

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