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

• 4 Globin sub-units
• 2 α-type (i.e. ζ or α)
• 2 β-type (i.e. ε or γ or β)
• 4 Heme groups / 1 per globin
• Reversible O2 binding
• Function: gas transport (O2, CO2, NO)
• Mutated β subunit

Heme + Fe2+ β β α α

GENETICS: GENOTYPES

Genotype Partner Mutation Prevlence SS (sickle cell anemia) SC (hb SC disease) Sβ+ thalassemia Sβ0 thalassemia

• C

β+ thal β0 thal Glu6Val (GAG→GTG) Glu6Lys (GAG→AAG) Various Various 75% 17% 6% 2%

• Sickle Cell Disease: autosomal recessive inheritance
• Either homozygous SS or compound heterozygosity
• S trait – heterozygote (not affected)

Pathophysiology: Sickle Hb Polymer Formation

Polymerized hemoglobin

Homogeneous nucleation Growth Heterogeneous nucleation Growth & alignment

+ O2 ↓ O2

Promotes: Vaso-occlusion (clogs vessels) Hemolysis (early rbc destruction)

HbS Polymer Formation: Contact Sites

Lateral contacts Axial contacts

Bunn HF. N Engl J Med. 1997

• Sickle hemoglobin polymerization
• High [deoxy HbS]
• Dehydration of red cell
• HbS ↓O2 affinity to promote O2 delivery to

tissues in anemia

• Factors inhibiting polymerization
• Fetal hb inhibits HbS polymer

formation

• ↑ HbF = longer survival
• Low [HbS] (as in sickle cell trait)

Sickle Hb Polymerization

Platt et al. NEJM 1991; Platt et al. NEJM 1994

Steinberg; NEJM 340:1021, 1999.

• Red cells release O2 in capillaries.
• Deoxy hemoglobin S forms sickle polymers.
• Polymers deform cells into rigid sickled red cells.
• Sickled RBCs obstruct post-capillary venules

(vaso-occlusion).

Sickle Cell Vaso-Occlusion

• Red hemolysis is the 2nd feature of SCD.
• Rigid sickled RBCs are fragile + reduced

survival.

• Reduced survival of red cells results in ANEMIA
• Less blood means less O2 carrying capacity
• Less O2 promotes sickling

Sickle Red Cell Hemolysis

• Inflammation is the 3nd 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

Hemolysis Produces Inflammation

Steinberg; NEJM 340:1021, 1999.

Fe2+ + H2O + O2 = rust (oxidation) Inflammatory white blood cells

SYMPTOMS / COMPLICATIONS

Multi-organ Failure Syndrome Acute Chest 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

• 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-
• lds, with 41.1% (95% CI, 40.5%-41.7%)
• JAMA. 2010;303(13):1288-1294

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

• FDA approved:

– Hydroxyurea – L-glutamine

• Opioids
• Transfusion Therapy (q month)

↓ % HbS <50%

• Marrow Transplantation (experimental)
• Clinical Trials (experimental)

Therapy

Hydroxyurea for SCD

• Dosing: 15-35 mg/kg/day

– Goal >20% HbF

• Poor implementation

– 30-40% adults prescribed at best

• FDA Indications (SS only)
• >3 pain events/year
• Recurrent Chest Syndrome
• Severe anemia
• >6 months of age (child)

Stettler et al. JAMA 2015; 313:1671.

Hydroxyurea Benefits: Pain Crisis Rate and Mortality

Charache S et al. NEJM 1995; 332:1317. Steinberg MH et al. Am J Hematol 2010; 85:403.

24 month RCT: 17 year follow-up: 50% ↓ in pain crises 50% ↓ in ACS Decreased transfusions Apparent prolonged survival with HU

Fitzhugh et al. PLOS One 2015, 10:e0141706.

N=152 N=78 25% reduction, P=0.005

25% ↓ Pain Hospitalizations, p=0.005 ↓ Acute Chest Syndromes, 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

L-Glutamine Reduces SCD Pain

30 60 90 w/o w/ L-glutamine

NA PRPP PPI GLU GLN ATP AMP + PPI NAD

NA: nicotinic acid PPI: pyrophosphate PRPP: phosphoribosylpyrophosphate GLN: glutamine GLU: glutamate

NADH and Redox Potential* *

• Oxidation plays an important part in

pathophysiology of SCD

• NAD is an important physiological

antioxidant in RBC

• In sickle RBC NAD, redox potential is

significantly compromised

• Glutamine, a precursor for NAD, can

improve NAD redox potential

NAD Metabolism*

40 80 120 w/o w/ L-glutamine

Total NADH Redox Potential

Nmol/ml RBC % Redox Potential P = <0.01 P = <0.01

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.

NAD Metabolism and Glutamine

Fe2+ + H2O + O2 = rust (oxidation)

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)

• 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

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

Monthly Transfusion Therapy

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 1st 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.

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: Start of NIH sickle cell research

1972

HU Center for Sickle Cell Disease Founded and Newborn Screening Initiated

Roland B. Scott, M.D.

1998

Hydroxyurea FDA Approved

2017

L-Glutamine FDA Approved

O O H2N OH NH2

NA PRPP PPI GLU GLN ATP AMP + PPI NAD

NA: nicotinic acid PPI: pyrophosphate PRPP: phosphoribosylpyrophosphate GLN: glutamine GLU: glutamate

RBC redox potential

TREATMENT DISPARITY

#CureSickleCellNow

• Hydroxyurea and L-Glutamine prevent

painful episodes + hospitalizations

• Washington DC, only 16% of adults are
• n Hydroxyurea

(DC Medicaid, personal communication, N~600 adults)

• Annual DC Medicaid cost (adults only)

N~600 = $71 million = ~$120,000 per pt.

Treatment Disparity And Cost

• Abstracted from DC Medicaid

Expenditures – Adults Only

• 100,000 SCD Patients
• ~60% adults = 60,000 patients
• 75% SS = 45,000 patients
• DC Medicaid = ~$120,000 / pt. / year
• 45,000 x $120,000 = $5.4 Billion Annually

Estimated Annual Healthcare Costs: National

• Children’s Hospitals!

– A true success for SCD – Newborn screening, hydroxyurea, stroke treatment

• What Happens When You Turn 18?

– Adult care – No central location – Patients have hard time finding good care

Where Do Patients Receive Care?

See Washington Post “Our Healthcare System Abandons Adult Sickle Cell Patients” March 21, 2016

Transition to Adult Care

• SCD complications ↑ after 16
• 18+ (after transition):
• Fewer transfusions and less chelation
• Less Hydroxyurea

Poor Incentives for Adult Sickle Cell Care

• Medicaid/Medicare population

– Severely affected patients do not work – Reimbursement $0.45 collected on each $1.00 billed by hospitals

• 40% Thirty Day Re-admission Rate

– No payment to hospitals for this care

• Hospitals do not want to treat these patients

due to poor re-imbursement

• End up with uncoordinated care in ER/hosp.

Barriers to Adult Care

• Medicaid for non-working young adults
• State programs limit sites of care
• The best care might be across a state line
• Examples
• Augusta, GA (Aiken, SC is adjacent city)
• DC metropolitan area
• PG county, MD (kids go to CNMC; adults go to

private practices in MD)

• Specialty care is really available in Baltimore

Todd RF et al. Blood 2004, 103:4383-4388

No Physicians for Adult Care

Problems with Adult Care

• Few dedicated adult care programs
• Run at a financial loss
• Few Day Hospital alternatives to ER
• Fragmented care (hospital based care)
• Ambulance – closest hospital
• Patients seek anonymity (stigma)
• Lack of Mental Health Care
• Anyone will prescribe opioids for SCD
• Few use PDMP (even when mandated)

Problems with Adult Care

• “We have a 19th century healthcare

delivery system while we are attempting to implement 21st century treatments.”

– CMO Jefferson Health, Philadelphia, PA

• SCD care concentrated at safetynet

hospitals

Case Study – Not SCD

Case Diagnosis SCD Opioid Rx Prescribers Pharm # Disposition 1 Sickle Korle Bu No 22 13 5 Left practice 2 Sickle cell trait No 12 2

• Left practice

3 C trait No 24 7

• On suboxone
• Importance of establishing a diagnosis

– Case 1: required DNA sequencing, not a sickling diagnosis – Case 2: 6 hospitalizations at Howard Hospital without a diagnostic test

Case Study 2 – Excessive Care

• 25 year old SS. Frequent ER/hospital

care since transition at age 18.

• Prescribed 25 MME/day over the last 7 years

at hospital discharge without supervision.

• 7 month delay in Psychiatric eval

Age 18 19 20 21 22 23 24 25 Admit 4 18 28 24 17 30 35* ER 1 4 27 30 27 61 322* Clinic 3 3 1 22

Case Study 3 – Chaos + OUD

• 35 year old SS. Complex sickle cell
• care. Recurrent priapism.

– Admit 4 times to HUH for acute priapism (3 positive urines for cocaine) – In clinic – Family member shows video suggesting opioid abuse. Methadone only. – Discharged next times by hospitalists with Dilaudid, Oxycontin and MS Contin. – Then received prescription at another DC hospital.

Case Study 4 – No Transition

• 21 yo SS. Present to ER with pain

(chest, legs), SOB, palpitations. Only history of SS.

– In ER, unstable, tachycardia. ECG LV strain. – CXR – – Patient expired in transit to MICU – Blood Bank: Last transfused 4 units at outside hospital for myocarditis admitting diagnosis

Case Study 4 – Continued

• Hospital Death Certificate
• Cardiac Arrest
• Acute Chest Syndrome
• Sickle Cell Anemia (no diagnostic proof)
• Center Director’s Review
• Cardiac Arrest
• Uncompensated Heart Failure
• Myocarditis
• Heart Failure precipitating Pain Crisis
• Sickle Cell Anemia

Case Study 5 – Famous

• Miles Davis (1926-1991)
• Diagnosed 1950 sickle cell anemia
• Heroin addiction, but sickle cell anemia
• No care available until 1970s
• Obituary: Stroke after pneumonia and history
• f hip replacements for sickle cell disease

Photo Tom Palumbo c. 1955

Jazz Musician and Composer

WHAT HAS RESEARCH ACCOMPLISHED?

50 40 30 20 10 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000

Year Life Expectancy (Years)

National Sickle Cell Act Transfusion for Stroke Prevention Hydroxyurea Preventive Penicillin

REALITY OF SCD 2019

An optimistic perspective on SCD: Living longer since 1972

American Journal of Preventive Medicine 2010 38, S512-S521DOI: (10.1016/j.amepre.2009.12.022)

REALITY OF SCD 2019

A Deeper Look: The only change in mortality is due to fewer deaths in children with SCD.

1000 2000 3000 4000

01 (A)02 (A)03 (A)04 (A)05 (A)06 (A)07 (A)08 (A)09 (A)10 (A)11 (A)12 (A)13 (A)14 (A)15 (A)16 (E)17 (E)

Research $ Per Patient Fiscal Year

RESEARCH DIRECTLY RELATED TO FUNDING

SCD CF Hemophilia

Patients in USA SCD 100,000 CF 33,000 H 20,000 Research further undermines clinical care – NIH researchers cannot care for patients.

BAD REALITY OF SCD RESEARCH 2019

1939 1943 1947 1951 1955 1959 1963 1967 1971 1975 1979 1983 1987 1991 1995 1999 2003 2007 2011 2015 Hemopilia SCD CF

8000 5000 1000

Research publications per year Year

FDA Approved Drugs Hemophilia 36 SCD 2 Cystic Fibrosis 8 HIV 39

RE: NATIONAL SICKLE CELL CONTROL ACT of 1972

• Funded 10 Centers for care and

research (NIH).

– 1975 – Expand to 15 Centers (3,333 pts./site)

• Re-authorization: Sickle Cell Treatment

Act 2004

– Authorized but no funding for 40 FQHCs (2500 pts./FQHC)

• 2007: NIH restructures SCD – no

centers, only research

– Funded academic center/10 adult SCD pts.

BAD REALITY OF SCD 2019

Restating the 1972 White House press release in 2017: “This disease is especially pernicious…No cure has yet been found. An estimated 75,000 to 100,000 individuals are currently afflicted with the disease. Many … are crippled long before death, and some die from it prematurely.“ Update: “We have 2 available treatments, but only ~16% of adults get either medication. We have too few doctors to care for patients, and if we had a cure today, it is unlikely that we could get it to patients.”

Why Is Care Better for Hemophilia?

• Another comparable blood disease
• Late 1990’s: Primary Prophylaxis – Prevents

Complications

– Nearly All Patients Receive this Treatment! – Care in Specialized Treatment Centers only!

• Financial Incentive: Hospitals Sell Factor to

Patients

– Hospitals want to care for these patients

Hemophilia

1973: the National Hemophilia Foundation launched a campaign to establish a nationwide network of treatment centers. Goal to provide comprehensive services in 1 facility. There are about 147 federally funded treatment centers across the country authorized under section 501(a)(2) of the Social Security Act.

20,000 affected in USA (2013 est.) Average 136 Hemophilia patients / center Howard follows 350 SCD patients!

EXECUTIVE SUMMARY

Sickle Cell Disease

• Only 2 FDA approved drugs

– (36 for hemophilia; 39 for HIV; 8 for cystic fibrosis)

• 90% of SCD hospitalizations for pain

– 100,000 patients in USA – 40% re-hospitalized within 30 days – >$1billion annual healthcare costs

• Sub-Optimal Adult Care

– No change in mortality for adults – Poor access to care – too few physicians; few incentives for hospitals to invest in care

Sickle Cell Disease

• No Treatment Available for 20% of

Patients

– 20% have SC or Sβ+ thalassemia – no FDA approved treatments

• Poor Implementation of Curative

Therapy

– Only 1% of SCD patients receive marrow transplants

• No Consolidated Effort for a Cure

– “Even if we had the cure today, we do not have the physicians to implement curative treatments.”