Sickle Cell Disease: A National Tragedy James G. Taylor VI, M.D. - PowerPoint PPT Presentation

Sickle Cell Disease: A National Tragedy James G. Taylor VI, M.D. Director, Howard University Center for Sickle Cell Disease Professor , Department of Medicine EMPAA Annual Meeting Baltimore, MD August 19, 2019 Center for Sickle Cell Disease

Disclosures • I receive research funding from the following sources: – NHLBI/NIH – NCATS/NIH – Pfizer – Howard University College of Medicine • Consultant: – Pfizer – GBT

Learning Objectives • Understand the basic pathophysiology of SCD. • Recognize that there are 3 available treatments for SCD. • Understand the unique challenges faced by adults with SCD. • Develop an appreciation for why fragmentation of care for adults has developed over the last 47 years

PATHOPHYSIOLOGY OF SCD

DISEASE OF HEMOGLOBIN Heme + Fe 2+ β • 4 Globin sub-units β 2 α -type (i.e. ζ or α ) • 2 β -type (i.e. ε or γ or β ) • α • 4 Heme groups / 1 per globin α • Reversible O 2 binding • Function: gas transport (O 2 , CO 2 , NO) • Mutated β subunit

GENETICS: GENOTYPES • Sickle Cell Disease: autosomal recessive inheritance • Either homozygous SS or compound heterozygosity • S trait – heterozygote (not affected) Genotype Partner Mutation Prevlence Glu6Val (GAG→GTG) - SS (sickle cell anemia) 75% Glu6Lys (GAG→AAG) SC (hb SC disease) C 17% S β + thalassemia β + thal Various 6% S β 0 thalassemia β 0 thal Various 2%

Pathophysiology: Sickle Hb Polymer Formation + O 2 Homogeneous Heterogeneous Growth & Growth nucleation nucleation alignment Polymerized hemoglobin Promotes: Vaso-occlusion (clogs vessels) ↓ O 2 Hemolysis (early rbc destruction)

HbS Polymer Formation: Contact Sites Lateral contacts Axial contacts Bunn HF. N Engl J Med. 1997

Sickle Hb Polymerization • Sickle hemoglobin polymerization • High [deoxy HbS] • Dehydration of red cell • HbS ↓ O 2 affinity to promote O 2 delivery to tissues in anemia • Factors inhibiting polymerization • Fetal hb inhibits HbS polymer formation • ↑ HbF = longer survival • Low [HbS] (as in sickle cell trait) Platt et al. NEJM 1991; Platt et al. NEJM 1994

Sickle Cell Vaso-Occlusion • Red cells release O 2 in capillaries. • Deoxy hemoglobin S forms sickle polymers. • Polymers deform cells into rigid sickled red cells. • Sickled RBCs obstruct post-capillary venules (vaso-occlusion). Steinberg; NEJM 340:1021, 1999.

Sickle Red Cell Hemolysis • Red hemolysis is the 2 nd feature of SCD. • Rigid sickled RBCs are fragile + reduced survival. • Reduced survival of red cells results in ANEMIA • Less blood means less O 2 carrying capacity • Less O 2 promotes sickling

Hemolysis Produces Inflammation • Inflammation is the 3 nd feature of SCD. • Hemolysis (rbc destruction) in the blood vessels releases Heme (reacts with oxygen). • Oxidative stress attracts white cells which can participate in vaso-occlusion Fe 2+ + H 2 O + O 2 = rust (oxidation) Inflammatory white blood cells Steinberg; NEJM 340:1021, 1999.

SYMPTOMS / COMPLICATIONS

Acute Chest Syndrome Multi-organ Failure Syndrome

Pain in SCD • Severe sudden onset pain • Vaso-occlusion • Most common manifestation • Most pain outpatient at home • 40% No symptoms during a year • 25% Hospitalized >5 times/year • Treatment is supportive care • Oral or IV opioids • 75% hospitalizations are adults with pain

Pain in SCD • Uncomplicated Pain in Hospital • Red cell transfusion does not help • RBC transfusion cost ~$5000 • Complications include iron overload • Hospitalization is Main Driver of Cost • 90% of hospitalizations are for pain

JAMA. 2010;303(13):1288-1294 • Acute care encounters highest for 18-30-year-olds • Rate higher for public vs. private payer • 30 day rehospitalization rate highest for 18-30-year- olds, with 41.1% (95% CI, 40.5%-41.7%)

Other Acute Complications • Pneumonia/Acute Chest Syndrome • Treatment: red cell transfusion, specific antibiotics, oxygen • Requires specialty care • Stroke • Mostly children • Acute event requires rapid exchange transfusion • Requires specialty care

Chronic Complications • Chronic Kidney Disease (CKD) • Major risk factor for mortality • Results in hypoplastic anemia (↓ Epo) • Requires specialist care • Chronic Pain • Defined as >50% of days for >6 months • Often chronic opioid therapy • Mental Health

Chronic Complications • Mental Health • Associated with frequent pain • Associated with sleep disturbance Depression Sleep Disturbance Wallen et al. BMC Psychiatry2014,14:207

TREATMENT

Therapy • FDA approved: – Hydroxyurea – L-glutamine • Opioids • Transfusion Therapy (q month) ↓ % HbS <50% • Marrow Transplantation (experimental) • Clinical Trials (experimental)

Hydroxyurea for SCD • Dosing: 15-35 mg/kg/day – Goal >20% HbF • Poor implementation – 30-40% adults prescribed at best • FDA Indications (SS only) Stettler et al. JAMA 2015; 313:1671. • >3 pain events/year • Recurrent Chest Syndrome • Severe anemia • >6 months of age (child)

Hydroxyurea Benefits: Pain Crisis Rate and Mortality 24 month RCT: 17 year follow-up: Steinberg MH et al. Am J Hematol 2010; 85:403. Charache S et al. NEJM 1995; 332:1317. 50% ↓ in pain crises Apparent prolonged survival with HU 50% ↓ in ACS Fitzhugh et al. PLOS One 2015, 10:e0141706. Decreased transfusions

L-Glutamine Reduces SCD Pain N=78 25% ↓ Pain 25% reduction, P=0.005 Hospitalizations, p=0.005 ↓ Acute Chest Syndromes, N=152 p=0.003 L-glut alone or with hydroxyurea Dose: 5-15 gm twice daily Niihara Y et al. N Engl J Med 2018;379:226-235

NAD Metabolism and Glutamine NAD Metabolism* NADH and Redox Potential* * Total NADH Redox Potential GLN Nmol/ml RBC % Redox Potential PRPP PPI GLU 120 90 NA NAD ATP AMP + PPI NA: nicotinic acid 80 60 PPI: pyrophosphate PRPP: phosphoribosylpyrophosphate GLN: glutamine GLU: glutamate • Oxidation plays an important part in pathophysiology of SCD 40 30 • NAD is an important physiological antioxidant in RBC • In sickle RBC NAD, redox potential is significantly compromised • Glutamine, a precursor for NAD, can 0 0 w/o w/ L-glutamine w/o w/ L-glutamine improve NAD redox potential P = <0.01 P = <0.01 Fe 2+ + H 2 O + O 2 = rust (oxidation) Niihara Y, et al. J Lab Clin Med. 1997 Jul;130(1):83-90. Niihara Y, et al. Am J Hematol. 1998 Jun;58(2):117-21.

L-Glutamine for SCD • Dosing: 5-15 grams BID • Dissolve in water • Side Effects • Typically GI: bloating, stomach upset, diarrhea • Barrier to Care • Many authorizations denied (esp. Medicaid MCOs )

Transfusion Therapy • Chronic transfusion indications • Frequent VOCs • High flow transcranial Doppler study (stroke risk) • Post stroke (duration undefined) • Pre-operative transfusion • ↑ peri-operative complications: chest syndrome, death • RBC transfusion decreases complications

Monthly Transfusion Therapy • Chronic transfusions • ~ monthly via exchange or simple tx (2 units) • Actual interval is every 3 - 4 weeks (individualized) • Treatment Goals Depend on Indication • HbS <50% for pain/ACS reduction Hb 9-10 avoid Hb > 12 if %S >30% (hyperviscosity) • HbS <30% for stroke prevention • Hemoglobin SC requires exchange transfusions

TIMELINE SICKLE CELL DISEASE RESEARCH #CureSickleCellNow

1910 First description of disease in a Chicago dental student

1949 Discovery of Sickle Hemoglobin and the Molecular Basis of the Disease. The 1 st Molecular Disease.

1949 - 1972 Molecular Medicine Refined – Great Science Lauded to Explain Disease Pathophysiology Few to No NIH Research Grants from to Study Natural History and Treatment of Patients with SCD

1972 National SCA Control Act Roland B. Scott, M.D. 1972: Start of NIH sickle cell research Bill (S. 2676) was signed as Public Law 92-294 (86 Stat. 136) on May 16, 1972. “This disease is especially pernicious…No cure has yet been found. An estimated 25,000 to 50,000 individuals are currently afflicted with the disease. Many … are crippled long before death, and some die from it prematurely.“

1972 HU Center for Sickle Cell Disease Founded and Newborn Screening Initiated Roland B. Scott, M.D.

1998 Hydroxyurea FDA Approved

O O 2017 OH H 2 N NH 2 L-Glutamine FDA Approved RBC redox potential GLN PRPP PPI GLU NA NAD ATP AMP + PPI NA: nicotinic acid PPI: pyrophosphate PRPP: phosphoribosylpyrophosphate GLN: glutamine GLU: glutamate

TREATMENT DISPARITY #CureSickleCellNow

Treatment Disparity And Cost • Hydroxyurea and L-Glutamine prevent painful episodes + hospitalizations • Washington DC, only 16% of adults are on Hydroxyurea (DC Medicaid, personal communication, N~600 adults) • Annual DC Medicaid cost (adults only) N~600 = $71 million = ~$120,000 per pt.