REVIEW

Clinical and Economic Evaluation of RepositoryCorticotropin Injection: A Narrative Literature Reviewof Treatment Efficacy and Healthcare ResourceUtilization for Seven Key Indications

Michael Philbin . John Niewoehner . George J. Wan

Received: May 1, 2017 / Published online: June 28, 2017� The Author(s) 2017. This article is an open access publication

ABSTRACT

Introduction: Repository corticotropin injec-tion (RCI; H.P. Acthar� Gel; MallinckrodtPharmaceuticals Inc., Hampton, NJ) is a highlypurified, prolonged-release porcine preparationof adrenocorticotropic hormone (ACTH) ana-logue that is FDA-approved for treatment of 19autoimmune and inflammatory disorders. Thediverse physiological actions of RCI at themelanocortin receptors (MCRs) affect processesinvolved in inflammation, pigmentation,steroidogenesis, and immunomodulation.Although RCI has been approved to treatinflammatory and autoimmune diseases formore than 60 years, recent progress in under-standing both MCRs and the effects of RCI inmodulating immune responses has led toincreased interest in RCI as a therapeutic choice.The objective of this narrative literature reviewis to summarize key clinical and economic data

on RCI treatment of seven disorders: infantilespasms (IS), multiple sclerosis (MS) relapses,proteinuria in nephrotic syndrome, rheumatoidarthritis (RA), dermatomyositis/polymyositis(DM/PM), systemic lupus erythematosus (SLE),and symptomatic sarcoidosis based on pub-lished literature and product information. Anextended report is available as the Academy ofManaged Care Pharmacy (AMCP) Formularydossier for H.P. Acthar� Gel.Methods: Key studies of clinical efficacy andhealthcare utilization and cost from 1956 to2016 are summarized.Results: The evidence supports the efficacy ofRCI across the seven indications. RCI is effectiveas a first-line therapy for IS. For the other sixconditions, RCI may improve clinical outcomesduring exacerbations or when the condition isresistant to conventional treatments. Use of RCIis associated with reduced use of biologics, cor-ticosteroids, and disease-modifying antirheu-matic drugs. Initiation of RCI therapy inpatients with IS, MS, RA, SLE, or DM/PM hasbeen associated with lower post-therapyhealthcare utilization and medical costs,including decreases in hospitalizations, hospitallength of stay, outpatient visits, and emergencydepartment visits.Conclusion: The evidence suggests that RCImay improve inflammatory and autoimmunedisease control and patient quality of life, par-ticularly in complex patients, and yield

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Electronic supplementary material The onlineversion of this article (doi:10.1007/s12325-017-0569-9)contains supplementary material, which is available toauthorized users.

M. Philbin � J. Niewoehner � G. J. Wan (&)Mallinckrodt Pharmaceuticals Inc., Hampton, NJ,USAe-mail: george.wan@mallinckrodt.com

Adv Ther (2017) 34:1775–1790

DOI 10.1007/s12325-017-0569-9

healthcare cost savings that demonstrate themedicine’s value.Funding: Mallinckrodt Pharmaceuticals Inc.

Keywords: ACTH; H.P. Acthar� Gel;Dermatomyositis; Healthcare utilization;Infantile spasms; Multiple sclerosis relapse;Nephrotic syndrome; Rheumatoid arthritis;Sarcoidosis; Systemic lupus erythematosus

INTRODUCTION

Autoimmune diseases have wide-ranging effectsin the body, including neurologic, renal, mus-culoskeletal, dermatologic, and pulmonaryeffects, and can lead to dysfunction of multipleorgans and tissues. These autoimmune diseasescan be associated with substantial patient mor-bidity, disability, and impaired quality of lifeand they may impose significant long-termhumanistic and economic burdens on families,healthcare systems, and society.

Autoimmunediseasesare treatedwithavarietyof therapeutic agents, including corticosteroids,immunosuppressants, immunomodulators, dis-ease-modifying antirheumatic drugs (DMARDs),biologics, and nonsteroidal anti-inflammatoryagents. Repository corticotropin injection (RCI;H.P. Acthar� Gel; Mallinckrodt PharmaceuticalsInc., Hampton, NJ, USA) is a highly purified,prolonged-release preparation of adrenocorti-cotropic hormone (ACTH) in a 16% gelatin for-mulation that is administered via intramuscularor subcutaneous injection. It has been in clinicaluse formore than 60 years. RCI was first approvedby theUS Food andDrugAdministration (FDA) in1952, before the 1962 enactment of the Kefau-ver-Harris Amendment to the Federal Food, Drugand Cosmetic Act, an amendment that requiresdrug manufacturers to provide proof of effective-ness and safety before approval. For this reason,much of the available research on RCI consists ofcase series, uncontrolled or small randomizedclinical trials, and retrospective analyses. Underthe FDA’s Drug Efficacy Study Implementation(DESI) program that was initiated following theKefauver-Harris Amendment, RCI has beenreviewed three times (in 1977, 1979, and 2010).With the most recent label update in 2015, RCI is

currently approved for 19 indications (Table S1)(supplementary table is available online) [1]. RCIis the only naturally sourced form of ACTHapproved for use in the USA.

RCI binds to melanocortin receptors (MCRs)and may have a diverse range of actions,including effects on inflammation, pigmenta-tion, steroidogenesis, and immunomodulation[1, 2]. Current understanding of the melano-cortin system points to a set of signaling path-ways that play a role in inflammation controland immunomodulation [3]. In recent years,progress in understanding both MCRs and theeffects of RCI in modulating immune responseshas led to a renewed interest in RCI as a thera-peutic choice [2].

The objective of this narrative literaturereview is to summarize the key clinical andeconomic data contained in the Academy ofManaged Care Pharmacy (AMCP) Formularydossier for H.P. Acthar� Gel for seven key indi-cations: infantile spasms (IS), multiple sclerosis(MS) relapses, proteinuria in nephrotic syn-drome, rheumatoid arthritis (RA), dermato-myositis/polymyositis (DM/PM), systemic lupuserythematosus (SLE), and symptomatic sar-coidosis [1, 4].

This article is based on previously conductedstudies and does not involve any new studies ofhuman or animal subjects performed by any ofthe authors.

CLINICAL VALUE OF REPOSITORYCORTICOTROPIN INJECTION

A number of studies in different therapeuticareas have assessed the clinical efficacy of RCIbefore and after treatment or compared RCIwith placebo or other common therapies. Theseare described below and summarized in Table 1.

Infantile Spasms

IS, also known as West syndrome, refers to aunique epilepsy syndrome of early infancy(\2 years of age) in which patients present witha distinct seizure type [5–7]. Untreated IS is

1776 Adv Ther (2017) 34:1775–1790

Table1

Clin

icalandhealthcare

utilization

studiesof

adrenocorticotropichorm

oneandrepository

corticotropininjection

Citations

Objective,design,andendp

oints

Key

inclusion/exclusioncriteria

Results

Clin

icalstudies

Infantile

spasms

Baram

etal.

[12]

Objective:Tocompare

theefficacyof

2-weekcoursesof

high-dose

ACTH

vs.p

redn

isoneforIS

treatm

ent

Studydesign:Randomized,single-blindtrial

Treatmentgroups:A

CTH

for2weeks

(150

U/m

2 /dayin

2divided

doses)or

oralprednisone

(2mg/kg/day

in2divideddoses)

Samplesize:29

Outcomes:Resolutionof

clinicalsignsandsymptom

s

Inclusioncriteria:InfantswithclinicalIS

Exclusion

criteria:Previous

steroidor

ACTH

treatm

ent

ResultsfavoredACTH;86.6%

ofinfantstreatedwithACTH

and

28.6%

ofinfantstreatedwithprednisone

hadcessationof

spasms

andresolution

ofhypsarrhythm

ia(p

=0.002)

Knu

ppet

al.

[13]

Objective:Toevaluate

earlyandsustainedresponse

toinitial

treatm

entof

IS

Studydesign:Prospective,observational,multisite

study

Treatmentgroups:ACTH,p

redn

isolone,vigabatrin,and

other

(nonstandard)therapy(various

dosing

regimens)

Samplesize:230

Outcomes:ISresponserate;resolutionof

hypsarrhythm

iaon

EEGat

2weeks

and3months

Inclusioncriteria:ChildrenwithnewonsetIS

between2months

and2yearsof

age

Exclusion

criteria:Earlyinfantile

epilepticencephalopathy;missing

treatm

ent,response,o

rfollow-updata

At2weeks,6

8%(66/97)of

thosewho

werereceivingACTH

and

56%

(30/54)of

thosewho

werereceivingprednisolone

had

responded(p

=0.13);theACTH

responseratewassignificantly

higher

than

inthosereceivingvigabatrin

(49%

,23/47;

p=

0.027)

ornonstand

ardtreatm

ent(22%

,7/32;

p\

0.001).

At3months,55%

(53/97)of

infantsreceivingACTH

had

responded,

comparedwith39%

(21/54)forprednisolone,3

6%(17/47)forvigabatrin,and

9%(3/32)

forothertherapies(overall

p\

0.001).T

heresponse

rate

intheACTH

groupwas

significantlyhigherthan

inthevigabatrin

group(p

=0.038)

and

marginally

higher

than

intheprednisolone

group(p

=0.06).Of

childrenwho

received

high-doseACTH,58%

(46/80)responded,

comparedwith38%

(6/16)

ofthosewho

received

low/

interm

ediate-doseACTH

Multiplesclerosisrelapse

Roseet

al.

[20]

Objective:ToinvestigateACTH

gelin

thetreatm

entof

patients

withacuteMSrelapses

Studydesign:Randomized,d

ouble-blind,

placebo-controlled,

multisite

trial

Treatmentgroups:40

URCIor

placebogelIM

twicedaily

for

7days,2

0U

twicedaily

for4days,and

20U

daily

for3days

Samplesize:197patients

Outcomes:Disability

Status

Scaleadministeredweeklyfor4weeks

Inclusioncriteria:Neurologicsignsof

dissem

inated

CNSdisease

withclearlydefin

edperiod

ofworsening

(bout)withinprevious

8weeks

Exclusion

criteria:AdvancedCNSdiseaseor

complicatingdisease

processesin

theirfirstbout,recentsteroidor

RCItherapy

Improvem

entin

Disability

Status

Scalewas

seen

in65%

ofACTH

gelp

atientscomparedwith48%

ofpatientsin

theplacebogroup

(n=

94);between-groupdifferencesweresignificant

atweeks

2and4.

There

was

a43%

greaterresponderrate

atweek1with

ACTH

relative

toplacebo(70%

vs.4

9%;p\

0.01)anda30%

greaterresponderrate

atweek3(86%

vs.6

6%;p\

0.01).The

averagenu

mberof

improved

standard

neurologicalexam

ination

item

swas

greaterforACTH

than

placeboforeach

ofthe4

weeklyintervals(allp\

0.01)

Proteinu

riain

nephroticsynd

rome

Bom

back

etal.[27]

Objective:T

ocollectprospectivestudydataon

ACTH

treatm

entin

resistantglom

erular

disease

Studydesign:Prospective,nonblin

ded,

open-labeltrial

Treatment:ACTH

gel(40U

SCtwiceweeklyfor2weeks,then

80U

twiceweeklySC

for22

weeks)

Samplesize:1

5(5

withresistantMN,5

withMCD

orFSGS,and5

withresistantIgA

nephropathy)

Outcomes:Proteinu

riafullor

partialremission

Inclusioncriteria:MN

orMCD/FSG

Swithat

least2previous

immun

osuppressive

therapiesor

IgA

nephropathyandreceiving

maxim

allytoleratedrenin–

angiotensin–

aldosteronesystem

blockage

Exclusion

criteria:Age

18yearsor

youn

ger,estimated

glom

erular

filtrationrate\30

mL/m

in/1.73m

2 ,useof

amonoclonal

antibody

withinprevious

6months,or

cyclophosphamidewithin

previous

3months,andothers

Proteinu

riawasreducedin

8of

15patients.T

woMN,1

MCD,and

1FSGSpatientachieved

partialrem

ission.T

wopatientsachieved

completeremission

Adv Ther (2017) 34:1775–1790 1777

Table1

continued

Citations

Objective,design,andendp

oints

Key

inclusion/exclusioncriteria

Results

Bom

back

etal.[28]

Objective:Toevaluate

theinitialuseof

RCIin

patientswith

refractory

nephroticsynd

rome

Studydesign:Retrospective

case

series

Treatment:RCI

Samplesize:21

Outcomes:Com

pleteremission,p

artialremission,lim

ited

response,

orno

response

Inclusioncriteria:Diagnosisof

idiopathicnond

iabeticnephrotic

synd

rometreatedwithRCI;at

least6monthsof

fulldata

available

Exclusion

criteria:N/A

Of21

patientswho

completed

RCItreatm

ent,7achieved

partial

remission

and4achieved

completeremission.O

f11patientswith

idiopathicMN,3

achieved

completeremission

and6achieved

partialremission

despitehaving

previouslyfailedameanof

2.4

therapies.Of10

patientswithnephroticsynd

romeof

other

etiologies,1

withIgA

nephropathyachieved

completeremission,

1withFSGSachieved

partialrem

ission,and

1withMPG

Nhada

limited

response

totherapy

Hogan

etal.

[29]

Objective:Toassesstheuseof

ACTH

inpatientswithproteinu

ria

dueto

FSGSpreviouslytreatedwithothertherapies

Studydesign:Nonrand

omized,two-site

trial

Treatmentgroups:(1)

40U

SCweeklyfor2weeks,80U

SCtwice

weeklyfor2weeks,then80

USC

twiceweeklyfor10

weeks

(n=

12)or

(2)40

USC

twiceweeklyfor2weeks,then80

USC

twiceweeklyforatarget

duration

of24

weeks

(n=

7)or

(3)

heterogeneoustreatm

entregimens(n

=5)

Samplesize:24

Outcomes:Com

pleteremission

ofproteinu

ria

Inclusioncriteria:Proteinu

riadueto

biopsy-provenFSGSand

evidence

ofnephroticsynd

rome

Exclusion

criteria:Being

ofchildbearingageandnotusingbirth

control,recent

active

immun

etherapy,pregnancy,decreasedrenal

function,k

nowncontraindicationsto

RCItherapy

Sevenpatientsachieved

remission

(2completeand5partial

responses).F

ivepatientshadasustainedremission

and2

experiencedproteinu

riarelapse(m

edianfollow-upof

90weeks)

Hladunewich

etal.[30]

Objective:Toassessthesafety

andefficacyof

RCIin

adultswith

biopsy-provenidiopathicMN

andproteinu

riadueto

nephrotic

synd

rome

Studydesign:Randomized,n

onblinded,

dose-find

ingphase1b/2

pilotstudy

Treatmentgroups:40

Uor

80U

RCIonce

ortwiceaweekfor

12weeks

(1dose

perweekfor4weeks,then2dosesperweek)

Samplesize:20

Prim

aryoutcom

es:Changes

inmeasuresof

nephroticsynd

rome

(improvem

entsin

proteinu

ria,serum

albumin,and

cholesterol

profile),documentedside

effects,andtoxicity

Second

aryoutcom

es:Com

pleteremission

(proteinuria\0.3g/day),

partialremission

(reduction

inproteinu

riaby

[50%

withafin

alurineprotein\3.5and[0.3g/day),and

noresponse

(reduction

inproteinu

riaby

\50%

orworsening

ofproteinu

ria)

Inclusioncriteria:Biopsy-proven

idiopathicMN,age[18

years

Exclusion

criteria:Docum

entedresistance

toim

mun

osuppressive

routines

used

inidiopathicMN;recent

useof

glucocorticoids,

calcineurininhibitors,m

ycophenolic

mofetilor

alkylating

agents;

active

infection;

second

arycauseof

mem

branousnephropathy,

diabetes

mellitus;acutethrombosisrequiringanticoagulation

therapy;pregnant

ornu

rsing

A[50%

decrease

inproteinu

riawas

notedin

50%

ofpatientsat

completionof

treatm

entandin

65%

ofpatientsat

12months.

Proteinu

riadecreasedfrom

amean(±

SD)of

9.1±

3.4g/dayat

baselin

eto

6.2±

4.8g/dayat

treatm

entcompletionand

3.9±

4.2g/dayat

12months(p\

0.001),w

ithsignificant

improvem

entsin

serum

albumin

andtotalandLDLcholesterol

(allp\

0.001).O

f4patientsreceiving40

URCI,1(25%

)achieved

partialrem

ission.O

f16

patientsreceiving80

URCI,2

(12.5%

)achieved

partialremission

and9(56.3%

)achieved

full

remission

Madan

etal.

[31]

Objective:Toexam

inetheefficacyandsafety

ofRCItreatm

entin

patientswithnephroticsynd

rome

Studydesign:Retrospective

multicenter

case

series

Treatment:RCI

Samplesize:44

Outcomes:Typeof

nephroticsynd

rome,response

totreatm

ent

Inclusioncriteria:Biopsy-confi

rmed

nephroticsynd

rome,24-h

proteinu

rialevelorurineprotein:

creatinine

ratiobeforeandafter

C6monthsof

RCItreatm

ent

Exclusion

criteria:N/A

Thirty-sevenpatientscompleted

treatm

ent.Aproteinu

riareduction

C30%

occurred

in81.1%

(30/37)of

patients.A

proteinu

ria

reductionC50%

occurred

in62.2%

(23/37).Meanreductionin

proteinu

riapost-treatmentwas

3984.8

±4069.1

mg/day

(p\

0.0001).Totalcholesteroldeclined

andserum

albumin

increased.Rem

ission

ofproteinu

riaoccurred

in56.8%(21/37)of

patients,eitherpartial(17/37,45.9%)or

complete(4/37,10.8%)

1778 Adv Ther (2017) 34:1775–1790

Table1

continued

Citations

Objective,design,andendp

oints

Key

inclusion/exclusioncriteria

Results

Rheum

atoidarthritis

Gaylis

etal.

[34]

Objective:Toassesseffectsof

RCIon

clinicalandstructural

endpointsin

patientswithearlyRA

Studydesign:Prospective,observational,open-labeltrial

Treatment:MTX15

mgweeklyplus

RCI80

Uweeklyor

biweekly

for24

weeks

Samplesize:10

Outcomes:Clin

icalresponse,rem

ission

Inclusioncriteria:A

tleast6tend

erandswollenjoints;a

CDAIscore

[6.0;

andosteitis,synovitis,o

rerosions

onMRI

Exclusion

criteria:N/A

Eight

of10

patientsshow

edaclinicalresponse

asmeasuredby

improvem

entin

CDAIscore.Twopatientsachieved

clinical

remission,3

hadlowdiseaseactivity,3

hadmoderatedisease

activity,1

hadhigh

diseaseactivity,and

1patientterm

inated

treatm

entearlybecauseof

lack

ofefficacy.All5patientswho

received

biweeklydosesdemonstratedaclinicalresponse

and

show

edastructuralresponse

ofregression

ofsynovitisand

regression

ornominalchange

inosteitis

Gilliset

al.

[35]

Objective:Toassessefficacyandsafety

ofSC

injections

ofRCIas

adjunctive

therapyin

adultswithactive

RA

Studydesign:Prospective,nonrandomized,o

pen-label,single-center

trial

Treatment:RCI80

USC

every72

hfor12

weeks

Samplesize:6

Prim

aryoutcom

es:Tenderjointcoun

t,swollenjointcoun

t,change

in20-item

Health

Assessm

entQuestionn

aire

Second

aryoutcom

es:ESR

level,CRP,

andpatientandphysician

globalVAS,

change

inDisease

ActivityScore

Inclusioncriteria:ActiveRA,n

otresponding

sufficiently

toC2

biologicagentswithdifferentmodes

ofaction

Exclusion

criteria:N/A

At12

weeks,all6patientshadreducedtend

erandswollenjoint

coun

ts.T

hree

show

edim

provem

entin

Health

Assessm

ent

Questionn

aire

scoreand6show

edim

provem

entin

Disease

ActivityScore.Im

provem

entswereseen

inESR

(4/6),CRPlevel

(4/6),andpatient(5/6)andphysician(6/6)globalVAS.

Improvem

entsin

allmeasuresgenerally

receded4weeks

after

treatm

entended

Dermatom

yositis/polymyositis

Levine[39]

Objective:Toinvestigateefficacyandsafety

ofACTH

inwom

enwithrefractory

DM

orPM

Studydesign:Retrospective

observationalcase

series

Treatment:RCI80

USC

once

weeklyor

twiceweeklyfor12

weeks

asshort-term

adjunctive

treatm

ent

Samplesize:5

Outcomes:Musclestrength,p

ain,

andfunction

Inclusioncriteria:Female;refractory

DM

orPM

;disease

exacerbation;n

oresponseto

orinability

totolerateside

effectsof

corticosteroids,IV

immun

oglobulin

,orsteroid-sparingdrugsfor

atleast60

days

Exclusion

criteria:N/A

Musclestrength,pain,andfunction

improved

inall5

patients.T

hree

patientswithim

paired

ambulation

before

treatm

entreturned

toindepend

entam

bulation,and

1was

ableto

return

towork

Aggarwal

etal.[40]

Objective:Toevaluate

theefficacy,safety,tolerability,and

steroid-sparingeffect

ofRCIin

refractory

adultDM/PM

Studydesign:Prospective,un

controlled,

open-labeltrial

Treatment:80

URCItwiceweeklyfor6months

Samplesize:12

Outcomes:Improvem

entin

myositisasdefin

edby

theInternational

MyositisAssessm

entandClin

icalStudiesGroup

(IMACS);safety;

tolerability;steroid-sparingeffect;myositisresponse

criteria

Inclusioncriteria:N/A

Exclusion

criteria:N/A

10of

11patients(91%

)completingthestudyexperienced

improvem

entin

myositisat

2–3months;sustained

improvem

entoccurred

in8patients(73%

).One

patientstopped

treatm

entbecauseof

heartblock.

Steroiddose

decreasedfrom

amedian(IQR)of

15mgat

baselin

eto

1.25

mgat

lastvisit

Adv Ther (2017) 34:1775–1790 1779

Table1

continued

Citations

Objective,design,andendp

oints

Key

inclusion/exclusioncriteria

Results

System

iclupuserythematosus

Fiechtnerand

Montroy

[44]

Objective:Toassesstheefficacyandsafety

ofRCIin

reducing

the

intensityof

flaresin

patientswithSL

E

Studydesign:Prospectiveopen-labeltrial

Treatmentgroups:R

CI(80U/m

Lby

SCinjectionfor10

days,w

ith

anoptional5additionaldays)

Samplesize:10

Prim

aryoutcom

es:Reduction

inflare

intensitybasedon

SLEDAI-2K

scores

Second

aryoutcom

es:Ph

ysicianGlobalAssessm

ent;PatientGlobal

Assessm

ent;Lupus

Qualityof

Life

scale;Fu

nctionalAssessm

entof

ChronicIllnessTherapy-Fatigue

scale;British

IslesLupus

Assessm

entGroup

Indexscores;andmarkersof

inflammation,

includingESR

andCRP

Inclusioncriteria:Diagnosisof

SLEwithchronicdiseaseactivity

requiringongoingtreatm

entor

observationforC8weeks,

moderatelyto

severelyactive

disease,meetACRcriteriaforSL

Eflare,receipt

ofprednisone

B20

mg/dayor

equivalent

for

C4weeks

orim

mun

osuppressive

orantimalarialtreatm

entfor

SLEforC8weeks

Exclusion

criteria:A

nynewprednisone

therapyor

change

incurrent

oralprednisone

therapy,receiptof

C1prescribed

NSA

ID,o

rsurgerywithinpast4weeks;historyof

allergyor

reaction

toany

component

ofRCIor

liveor

attenu

ated

vaccine;andothers

Atday28

therewerestatistically

significant

reductions

inSL

EDAI-2K

scores

andim

provem

entsin

PhysicianGlobal

Assessm

ent,PatientGlobalA

ssessm

ent,Fu

nctionalAssessm

entof

ChronicIllnessTherapy-Fatigue,and

erythrocytesedimentation

rate

(allpB

0.5)

Furieet

al.

[45]

Objective:T

oevaluatetheefficacyof

RCIaddedto

standard

ofcare

inpatientsrequiringmoderate-dose

corticosteroidsfor

symptom

aticSL

E

Studydesign:Prospective,rand

omized,d

ouble-blind,

placebo-controlled,

phase4pilotstudy

Samplesize:38

Treatment:RCI40

Udaily

or80

Ueveryotherdayor

volume-matched

placebogelfor4weeks,thenRCItaperedto

twiceweeklyfor4weeks

Outcomes:Changein

composite

measure

ofhybrid

SLEDAI

(hSL

EDAI),B

ILAG,and

CLASI

scores,and

tend

erandswollen

jointcoun

t

Inclusioncriteria:Persistentlyactive

SLEand/or

cutaneous

involvem

ent(hSL

EDAIscore[

2),m

oderateto

severe

rash

with

arthritisand/or

skin

involvem

entandBILAG

scoreof

Aor

Bin

mucocutaneous

and/or

musculoskeletalsystem

sdespitea

stabledose

ofprednisone

forC4weeks

Exclusion

criteria:Initiation

ofcorticosteroid

treatm

entwithin

previous

2months;active

nephritisor

active

CNSlupusrequiring

treatm

entwithinprevious

3months,andothercriteria

Atweek8,

theproportion

ofresponderswas

higher

inRCIgroups

(RCI40

U,5

3.8%

;RCI80

U,3

3.3%

),butdifference

from

placebo(27.3%

)was

notstatistically

significant.S

tatistically

significant

improvem

entswereseen

intheRCIgroups

for

hSLEDAI,BILAG,and

CLASI

scores

Symptom

aticsarcoidosis

Salomon

etal.

[51]

Objective:Torecord

observations

oneffectsof

RCIandcortisone

therapyin

patientswithsystem

icsarcoidosisof

thelungs

Studydesign:Caseseries

Treatment:RCI80

UIM

each

day,withagradualtaper,for

atotal

dose

of1500–2

000U,ororalcortisonefor35–4

5days

(300

mg

daily

for3days,200

mgdaily

for5days,and

100mgdaily

forthe

remaining

34days,for

atotaldose

of5300

mg)

Samplesize:5

Outcomes:Lesions,lun

gvolume,vitalcapacity,residualvolume,

ratioof

residualvolumeto

totallun

gcapacity,dyspn

ea,cough,and

generalwell-b

eing

Inclusioncriteria:A

ctiveconfi

rmed

system

icsarcoidosisof

thelungs

Exclusion

criteria:N/A

RCIandcortisonemarkedlysuppressed

sarcoidosislesionsin

all5

patients.H

owever,n

opatientsexperiencedfullremission

1780 Adv Ther (2017) 34:1775–1790

Table1

continued

Citations

Objective,design,andendp

oints

Key

inclusion/exclusioncriteria

Results

Baughman

etal.[52]

Objective:Topresentexperience

withRCIto

treatsarcoidosis

Studydesign:Retrospective

observationalstudy

Treatment:RCI

Samplesize:47

Outcomes:Responseto

treatm

ent,basedon

theresponse

ofthe

target

organ,

asim

proved

disease,stabledisease,or

noresponse

totreatm

ent

Inclusioncriteria:AllpatientswithsarcoidosistreatedwithRCIat

twocentersandwithat

least6monthsof

follow-updata

Exclusion

criteria:N/A

Allpatientswereinitially

treatedwithRCI80

IU(IM

orSC

)twice

aweek.

Of47

casesreview

ed,1

8discontinu

eddrug

usewithin

6monthsbecauseof

cost,death,drugtoxicity,ornoncom

pliance.

Oftheremaining

29patients,1

1(38%

)hadobjective

improvem

entin

oneor

moreorgans

afterC3monthsof

RCI

treatm

ent.Of21

patientstreatedforC6months,11

had

improvem

entsin

C1organand10

hadstabledisease;2hada

relapse.Of19

patientsreceivingprednisone

atbaselin

e,17

were

ableto

reduce

prednisone

reduce

by[50%

Health

care

resource

utilization

studies

Infantile

spasms

Goldet

al.

[53]

Objective:Todescribe

healthcare

resource

utilization

andcosts

resulting

from

early(within30

days

ofdiagnosis)versus

late

(30days

afterdiagnosis)treatm

entwithRCIto

manageIS

Studydesign:Retrospective

observationalstudyof

healthcare

claims

data

Treatment:RCI

Samplesize:252

Outcomes:Adjusted12-m

onth

meannu

mberof

outpatient

and

inpatientservices,m

edications,and

costs

Inclusioncriteria:Age\2yearsat

timeof

ISdiagnosis

Exclusion

criteria:Not

continuouslyenrolledin

health

plan

for

C3monthsbefore

andC12

monthsafterindexdate;subsequent

diagnosisof

tuberous

sclerosiscomplex

Of252patients,191

(76%

)hadearlyRCItreatm

entand61

(24%

)hadlate

treatm

ent.EarlyRCItreatm

entwas

associated

with3.8

fewer

outpatient

services

(99%

CI,-6.7to

-0.7)

Multiplesclerosisrelapse

Goldet

al.

[54]

Objective:Todescribe

healthcare

resource

utilization

andcostsin

patientswithMSrelapsetreatedwithRCIvs.P

MPor

IVIG

Studydesign:Retrospective

observationalstudyof

healthcare

claims

data

Treatment:RCIvs.P

MPor

IVIG

Samplesize:439(12-month

analysis);228(24-month

analysis)

Outcomes:12-m

onth

and24-m

onth

meannu

mberandcostof

hospitalizations,o

utpatientservices,and

prescription

medications

Inclusioncriteria:Diagnosisof

MS;

C2relapses

withfirstrelapse

treatedwithIVMPandsecond

relapsetreatedwithRCI,PM

P,or

IVIG

within30

days

ofexacerbation

Exclusion

criteria:

Not

continuouslyenrolledin

health

plan

forC6monthsbeforeand

C12

months(for

12-m

onth

analysis)or

C24

months(for

24-m

onth

analysis)afterindexdate

Inthe12-m

onth

adjusted

analysis,com

paredwiththePM

P/IVIG

group(n

=226),the

RCIgroup(n

=213)

hadfewer

hospitalizations

(0.2vs.0.4;p

=0.01)andoutpatient

services(29

vs.4

3;p=

0.0001),moreprescription

medications

(36vs.3

0;p=

0.0001),lower

inpatientcosts(U

S$15,000

lower;

p=

0.001)

andlower

outpatient

costs(U

S$54,000

lower;

p=

0.0001),andsimilartotalcosts.Resultsweresimilarforthe

24-m

onth

analysis

Rheum

atoidarthritis

Wuetal.[55]

Objective:Todescribe

healthcare

resource

utilization

andcostsfor

managem

entof

RA

before

andaftertreatm

entwithRCI

Studydesign:Retrospective

observationalstudyof

healthcare

claims

data

Treatment:RCI

Samplesize:180

Outcomes:H

ealth

careutilization

ratesandcostsforhospitalizations,

ED

visits,outpatientservices,and

drugsbeforeandafterinitiation

oftreatm

entwithRCI

Inclusioncriteria:Age

C18

yearswithRA

Exclusion

criteria:N/A

Health

care

utilization

before

vs.after

treatm

ent:

Hospitalizations:All-cause,42

vs.2

5per1000

patient-years,

p\

0.01;RA-related,1

3vs.4

per1000

patient-years,p\

0.01

ED

visits:All-cause,43

vs.2

3per1000

patient-years,p=

0.04;

RA-related,8

vs.1

per1000

patient-years,p\

0.01

Outpatientservices:All-cause,56

vs.4

7perpatient-year,p

\0.01;

RA-related,1

0vs.5

perpatient-year,p

\0.01

Costsbefore

vs.after

treatm

ent:

Drugs:US$273vs.U

S$4379

PPPM

,p\

0.01

Medical:US$658vs.U

S$93

PPPM

,p\

0.01

Adv Ther (2017) 34:1775–1790 1781

Table1

continued

Citations

Objective,design,andendp

oints

Key

inclusion/exclusioncriteria

Results

Dermatom

yositis/polymyositis

Knightet

al.

[56]

Objective:T

ocomparereal-worldhealthcareresource

utilization

and

costsin

patientswithDM/PM

treatedwithRCIvs.IVIG

and/or

rituximab

Studydesign:Retrospective

observationalstudyof

commercial

healthcare

claimsdata;propensity

scorematching

Treatment:RCIvs.IVIG

and/or

rituximab

Samplesize:1134

Outcomes:Meannu

mberandcostsof

hospitalizations

and

outpatient

visits,m

eanhospitallength

ofstay,m

eanmedication

costs,meantotalnonm

edicalcosts

Inclusioncriteria:D

iagnosisof

DM/PM,treatmentwithRCI,IVIG

and/or

rituximab

Exclusion

criteria:N/A

Com

paredwithIVIG

,RCIhadfewer

hospitalizations

(0.09vs.0.17

PPPM

;p=

0.049),h

ospitaloutpatient

department(H

OPD

)visits(0.60vs.1.39PP

PM;p

\0.001),and

physicianofficevisits

(2.01vs.2.33PP

PM;p

=0.035)

andshortermeanlength

ofstay

(3.24days

vs.4

.55days;p=

0.004).C

omparedwithrituximab,

RCIhadfewer

HOPD

visits(0.56vs.0

.92;

p\

0.001).

Com

paredwithIVIG

?rituximab,R

CIhadshorterlength

ofstay

(2.18daysvs.5.15;p\

0.001)

andfewerHOPD

visits(0.53

vs.1

.26;

p\

0.001).T

otalmeannonm

edicationPP

PMcosts

werelower

forRCIcomparedwithIVIG

(US$2126

vs.

US$3964;p\

0.001),rituxim

ab

(US$2008

vs.U

S$2607;P=

0.018),and

IVIG

?rituximab

(US$1234

vs.U

S$4858;p\

0.001)

System

iclupuserythematosus

Wuetal.[57]

Objective:Todescribe

theprofileof

patientswithSL

Einitiating

RCItreatm

ent

Studydesign:Retrospective

observationalstudyof

healthcare

claims

data

Treatment:RCI

Samplesize:29

Outcomes:Hospitalizationandoutpatient

visitratesandcosts

before

andafterRCItreatm

ent

Inclusioncriteria:A

geC18

yearswithC2diagnosesof

SLEandRCI

treatm

ent

Com

paredwiththepreind

experiod,the

postindexperiod

hadfewer

hospitalizations

PPPM

(0.075

vs.0.061)andED

visits(0.081

vs.

0.046)

visitspostindexcomparedwithpreind

ex.T

otalmedical

costswerelower

postindex(U

S$5869

vs.U

S$3724)as

were

inpatientcosts(U

S$3192

vs.U

S$799)

andED

costs(U

S$163vs.

US$84).Totalpostindexcostswerehigher

(US$6774

vs.

US$11,167

PPPM

),largelydriven

byhigher

pharmacycosts

(US$905vs.U

S$7443)

Multiplerheumaticcond

itions

Myung

etal.

[58]

Objective:T

odescribe

theprofileof

patientswithRA,D

M/PM,or

SLEinitiating

RCItreatm

ent

Studydesign:Retrospective

observationalstudyof

healthcare

claims

data

Treatment:RCI

Samplesize:2749

Outcomes:Dem

ographiccharacteristics,patterns

ofRCI,and

concom

itantmedicationuse

Inclusioncriteria:C

1claim

withdiagnosiscode

forRA,D

M/PM,or

SLEandanyuseof

RCI

Exclusion

criteria:C

laim

fornonrheum

atologiccond

itionassociated

withRCIuse(m

ultiplesclerosis,proteinu

ria)

Mostpatientsreceived

80U

ofRCItwiceweekly.The

proportions

ofpatientswho

used

acorticosteroid

werelower

afterRCI

initiation

than

before

(RA,6

7%preind

exand54%

postindex;

SLE,7

3%preind

exand58%

postindex;DM/PM,7

6%preind

exand58%

postindex;allp\

0.05).In

RA

patientswho

had

consistentlytakencorticosteroidsfor24

weeks

before

RCI

initiation,the

postindexmeancorticosteroid

dose

(11.47

±1.63

mg/daysupply)was

28%

lower

than

inthe

preind

experiod

(15.86

±1.71

mg/daysupply).The

proportions

ofRAandSL

Epatientsreceivingbiologicsandof

RA,SLE,and

DM/PM

patientsreceivingDMARDswerelower

afterRCI

initiation

(allp\

0.05)

ACRAmerican

College

ofRheum

atology,ACTH

adrenocorticotropichorm

one,BILAGBritish

IslesLupus

Assessm

entGroup,C

DAIClin

icalDiseaseActivityIndex,CLASI

Cutaneous

Lupus

Erythem

atosus

DiseaseAreaandSeverity

Index,

CNScentralnervoussystem

,CRPC-reactiveprotein,

DMARD

disease-modifyingantirheumatic

drug,DM/PM

derm

atom

yositis/polymyositis,ED

emergencydepartment,ESR

erythrocytesedimentation

rate,FSGSfocal

segm

entalglomerulosclerosis,IM

intram

uscular,IQRinterquartile

range,IS

infantile

spasms,IVIG

intravenousim

mun

oglobulin

,IVMPintravenousmethylpredn

isolone,MCD

minim

alchange

disease,MN

mem

branousnephropathy,

MPG

Nmem

branoproliferativeglom

erulonephritis,M

RImagneticresonanceim

aging,MSmultiplesclerosis,MTXmethotrexate,N/A

notavailable/notapplicable,N

SAID

nonsteroidalantiinflammatorydrug,P

MPplasmapheresis,

PPPM

perpatientpermonth,R

Arheumatoidarthritis,RCIrepository

corticotropininjection,

SCsubcutaneous,SLEsystem

iclupuserythematosus,SLEDAISystem

icLupus

Erythem

atosus

DiseaseActivityIndex,Uun

it,V

ASvisual

analogue

scale

1782 Adv Ther (2017) 34:1775–1790

associated with developmental delay, autism,mental retardation, and an 11% mortality rateby age 2 years [5–8]. In a study of 244 infantsaged 0–18 months, a delay in time to diagnosisfollowing initial presentation was associatedwith cognitive abnormalities (median time todiagnosis, 18 vs. 6 days; p\0.001) and motorabnormalities (median time to diagnosis, 17.5vs. 6 days; p\0.001) [9]. Outcomes may there-fore be improved by early recognition of IS andimmediate, effective treatment [6, 8, 10].

Compared with prednisone and conven-tional antiepileptic drugs, RCI may be moreefficacious for the treatment of IS. RCI hasorphan drug designation in the USA for treat-ment of IS [11]. In a US randomized controlledtrial of 29 infants (median age, 6 months),86.6% of infants treated with RCI (150 U/m2/day) and 28.6% of infants treated withprednisone (2 mg/kg/day) (p = 0.002) had ces-sation of spasms and resolution of hypsar-rhythmia after 2 weeks of therapy [12]. Themost frequently reported adverse events inRCI-treated infants were irritability and vora-cious appetite.

More recently, a US study of 230 infants at 22centers participating in the National InfantileSpasms Consortium reported that 55% ofinfants receiving RCI as initial treatmentresponded to therapy, compared with 39% fororal corticosteroids, 36% for vigabatrin, and 9%for other therapies (p\ 0.001) [13].

The 2004 IS guideline of the AmericanAcademy of Neurology and Child NeurologySociety recommends ACTH for short-term con-trol of IS, supported by strong (level B) evidence[5]. Although the guideline refers to ACTH, RCIis the only form of ACTH approved for use inthe USA, as noted previously. Based on threestudies of RCI [14–16] and one study of syn-thetic ACTH [14–16], the 2012 guideline updaterecommends that low-dose ACTH be consideredas an alternative to high-dose ACTH for treat-ment of IS (level B evidence) [6].

Multiple Sclerosis Relapses

MS is a complex and chronic demyelinatingautoimmune neurological disorder. It is most

frequently diagnosed between 20 and 40 yearsof age and is a leading cause of disability in thisage group [17]. Acute relapses in MS may pre-sent with severe symptoms. To decreaseinflammation and hasten recovery, a shortcourse of corticosteroids (high-dose intravenous[IV] or oral) is often prescribed. However, if apatient does not respond or presents withbreakthrough disease, ACTH, IV immunoglob-ulin (IVIG), or plasma exchange (plasmaphere-sis; PMP) may be required [18]. In the USA, RCIwas first approved for treatment of MS exacer-bations in 1978 and is currently indicated fortreatment of acute exacerbations of MS in adults[1, 19]. Intravenous immunoglobulin and PMPare not FDA-approved therapies for relapses inMS.

The efficacy of RCI compared with placeboor other common therapies for the treatment ofMS relapses has been evaluated. A large ran-domized, controlled, double-blind, multicentertrial found that RCI was superior to placebo forreducing the duration of relapse [20]. In a smallstudy comparing routes of administration,intramuscular and subcutaneous administra-tion of a 5-day course of RCI produced a com-parable decrease in symptoms [21].

Both the National Multiple Sclerosis Societyand the American Academy of Neurology havenoted that alternative treatment options areneeded for patients who experience MS relapsebut do not respond to, cannot tolerate, or donot wish to take steroids [22, 23]. Thus, forpatients needing an alternative treatment, RCImay provide an option.

Proteinuria in Nephrotic Syndrome

Nephrotic syndrome is a constellation of renaland extrarenal signs and symptoms thatincludes edema, proteinuria, hypoalbumine-mia, lipiduria, hyperlipidemia, and hypercoag-ulability. It is caused by several systemicdiseases and by primary insult to the kidney.Primary renal causes of nephrotic syndromeinclude minimal change disease, focal segmen-tal glomerulosclerosis, membranous nephropa-thy, immunoglobulin A (IgA) nephropathy, andmembranoproliferative glomerulonephritis,

Adv Ther (2017) 34:1775–1790 1783

and nephrotic syndrome may occur secondaryto systemic diseases such as diabetes and sys-temic amyloidosis [24–26]. In patients withresistant glomerular disease, RCI is a treatmentoption, along with conventional therapy. It isindicated for inducing diuresis or remission ofproteinuria in nephrotic syndrome withouturemia of the idiopathic type and in nephroticsyndrome due to lupus erythematosus [1].

Several studies have shown that RCI reducesproteinuria in several subtypes of treatment-re-sistant nephrotic syndrome: idiopathic mem-branous nephropathy, focal segmentalglomerulosclerosis, minimal change disease,membranoproliferative glomerulonephritis,lupus nephritis, and IgA nephropathy [27–31].

Rheumatoid Arthritis

RA is an autoimmune disease that leads toprogressive destruction of the joints and asso-ciated cartilage [32]. It is associated with severalcomorbidities, including cardiovascular andpulmonary manifestations, skeletal disorders,cognitive effects, infection, and malignancies[33].

RCI is an FDA-approved adjunctive therapyfor short-term administration (to tide thepatient over an acute episode or exacerbation)and for use in ‘‘selected cases who may requirelow-dose maintenance therapy’’ [1]. It has beenshown to be effective in combination withmethotrexate in terms of clinical response,inducing remission and slowing structuralchanges, with few serious adverse eventsobserved [34, 35]. In an open-label study, 10patients with early RA and at least six tenderand swollen joints were treated withmethotrexate plus RCI either weekly (n = 5) orbiweekly (n = 5) [34]. An improved ClinicalDisease Activity Index (CDAI) score wasobserved in eight patients. In the five patientswho received RCI biweekly, both clinical andstructural improvements were seen. A secondopen-label study of RA patients with an inade-quate response to two or more biologic agentswith different modes of action (N = 6) foundthat treatment with RCI for 12 weeks led toreductions in tender and swollen joint counts

and improvements in Disease Activity Score forRA (DAS28), Patient Global Visual AnalogueScale (VAS), and Physician Global VAS in allpatients [35].

Dermatomyositis and Polymyositis

DM and PM are autoimmune connective tissuediseases that are characterized by chronicinflammation of proximal skeletal muscles. DMalso affects the skin and may affect the joints,esophagus, heart, and lungs. Patients with DMor PM typically present with slowly progressiveweakness and reduced endurance in the musclesof the neck, shoulders, and pelvis [36–38].

Patients with DM or PM may experienceclinical benefit from RCI therapy. In a case ser-ies study, five patients experiencing a diseaseexacerbation who had either failed or experi-enced adverse effects with conventional treat-ment were treated with RCI once or twiceweekly for 12 weeks [39]. All patients showedimprovement in manual muscle testing scoresat 12 weeks, and no patients experienced sig-nificant adverse events. In an open-labeluncontrolled study of RCI (80 U twice weeklyfor 6 months), 10 of 11 patients (91%) experi-enced improvement in myositis as defined bythe International Myositis Assessment andClinical Studies Group (IMACS) [40]. In addi-tion, RCI was found to be generally safe, welltolerated, and steroid sparing.

Other than corticosteroids, RCI is the onlyFDA-approved drug for the treatment of DM/PM. It is indicated for use during an exacerba-tion or as maintenance therapy in selected cases[1].

Systemic Lupus Erythematosus

SLE is a systemic illness characterized byimmune hyperactivity and the production ofantinuclear, anticytoplasmic, and antiphos-pholipid antibodies. Patients typically presentwith fatigue, malaise, fever, arthralgia, myalgia,headache, loss of appetite, weight loss, and rash.The disease may progress to multiple end-organinvolvement, resulting in photosensitivity,arthritis, and serositis as well as renal,

1784 Adv Ther (2017) 34:1775–1790

neurological, and other disorders [41–43]. Dur-ing the course of the disease, intermittent acuterelapses or flares may result in tissue damage.RCI is indicated during an exacerbation or asmaintenance therapy in selected cases of SLE[1].

In a single-arm, uncontrolled, open-labelstudy of 10 female patients with moder-ate-to-severe SLE who were receiving conven-tional therapy and experiencing a disease flare,adjunctive RCI treatment for 10 days, with anoptional five additional days, led to reductionin disease activity and to improvement infunctional status, quality of life, and erythro-cyte sedimentation rate at 28 days [44]. Notreatment-related serious or unexpected adverseevents were observed. In an 8-week randomizedcontrolled trial of RCI for the treatment of per-sistently active SLE, 38 participants received RCI80 U every other day (n = 13), RCI 40 U daily(n = 13), or placebo (n = 12) [45]. Diseaseactivity was reduced in the RCI groups com-pared with placebo, including statistically sig-nificant decreases in the Hybrid SLE DiseaseActivity Index and the British Isles LupusAssessment Group index in both treatmentgroups at 8 weeks and in tender swollen jointcount in the 80 U RCI group at 8 weeks.

Symptomatic Sarcoidosis

Sarcoidosis is a chronic inflammatory granulo-matous disease that primarily affects the lungs(90% of affected patients have pulmonaryinvolvement), although other organs such asthe skin and eyes may be involved [46–48]. Thedisease follows a variable natural course, rang-ing from asymptomatic to a progressive diseasethat may be life threatening [48, 49]. Patientsmay be asymptomatic or have signs and symp-toms such as cough, fever, weight loss, chestpain, painful ankle swelling, painful red nod-ules on the shins, eye pain, and blurred vision[50]. Treatment is generally reserved for symp-tomatic disease. RCI is an FDA-approved treat-ment for symptomatic sarcoidosis [1].

RCI was reported to be effective for symp-tomatic sarcoidosis as early as the 1950s. A caseseries study of patients receiving RCI (n = 4) or

cortisone (n = 1) reported that treatment withRCI led to improvements in lung function andregression of skin, peripheral lymph node, par-otid gland, and eye lesions [51]. In a recentretrospective chart review of patients withadvanced sarcoidosis, 27 of 29 patients whoreceived RCI (alone or in combination withsteroids) for 6 months or longer experienced animprovement in their disease and 11 experi-enced objective improvement in the health ofone or more affected organs. In addition, 17 of19 patients receiving concomitant prednisonewere able to reduce their prednisone dose bymore than 50% [52]. Further evaluation of RCItherapy for symptomatic sarcoidosis is war-ranted, and prospective studies are underway.

HEALTHCARE UTILIZATIONAND COSTS

Evidence in multiple therapeutic areas suggeststhat use of RCI decreases healthcare utilization,which may be associated with lower expendi-tures from a healthcare systems perspective. Keyoutcomes data are summarized in Table 1 andadditional data are available in the AMCP dos-sier [4]. In some instances, these reductions inresource use may mitigate or potentially negatethe increased medication costs through medicalcost offsets.

Infantile Spasms

A claims-based analysis of infants with IS whowere treated with RCI demonstrated a resourceuse benefit associated with early treatment(within 30 days of diagnosis) compared withlater treatment (C30 days after diagnosis) [53].In particular, early use of RCI led to 3.8 feweroutpatient visits (99% confidence interval [CI]-6.7 to -0.7; p = 0.002) and 4.2 fewer visits forall health services combined (99% CI -7.9 to-0.4; p = 0.005).

Multiple Sclerosis Relapses

An economic analysis of patients with MSrelapses who had received prior treatment with

Adv Ther (2017) 34:1775–1790 1785

IV methylprednisone demonstrated decreasedhealthcare utilization for RCI therapy comparedwith the two therapies that are used most oftenfor the treatment of MS relapse, IVIG and PMP[54]. Over a 12-month period, the RCI grouphad 0.2 fewer hospitalizations (95% CI -0.3 to-0.1; p = 0.01), 15 fewer outpatient services(95% CI -20 to -10; p\0.0001), 3.7 fewer daysin hospital (95% CI -4.8 to -1.1; p = 0.01), 0.19fewer rehabilitation and long-term care facilitiesservices (95% CI -0.26 to -0.12; p\0.001), and3.2 fewer overall healthcare services (95% CI-5.2 to -1.1; p = 0.003) while incurring similartotal healthcare costs (US$106,400 vs.US$109,400; p = 0.74). Favorable cost outcomesfor RCI compared with IVIG or PMP also wereobserved in a 24-month analysis (inpatientcosts US$17,400 lower, p = 0.03; outpatientcosts US$121,000 lower, p\0.0001; total costsUS$33,400 lower, p = 0.13). Although drugcosts for RCI treatment were greater than forIVIG or PMP, they were offset by decreases ininpatient and outpatient costs (93% medicationcost offset at 12 months; 132% offset at24 months).

Rheumatoid Arthritis

In patients with RA, treatment with RCI mayresult in reduced healthcare utilization anddecreased use of other RA medications. TheHealthCore Integrated Research Database, alarge healthcare claims database containingdata for 36.8 million commercial health planmembers, was used to retrospectively examinehealthcare utilization and costs in patients withRA before and after initiating treatment withRCI [55]. Of 6190 eligible RA patients, 180patients had received RCI. Treatment with RCIwas associated with substantial reductions inthe use of corticosteroids, biologics, and non-biologic DMARDs. The RCI cohort also hadlower rates of hospitalization after treatmentinitiation compared with before (all-cause hos-pitalizations: 42 preinitiation vs. 25 postinitia-tion per 1000 patient-years, p\0.01; RA-relatedhospitalizations: 13 vs. 4 per 1000 patient-years, p\0.01), emergency department visits(all-cause visits: 43 vs. 23 per 1000 patient-years,

p = 0.04; RA-related visits: 8 vs. 1 per 1000 pa-tient-years, p\0.01), and outpatient services(all-cause encounters: 56 vs. 47 per patient-year,p\0.01; RA-related encounters: 10 vs. 5 perpatient-year, p\0.01). Patients incurred higherRA-related drug costs after RCI initiation com-pared with before initiation (US$4379 vs.US$273 per patient per month [PPPM],p\0.01). However, RA-related medical costswere substantially lower after RCI initiationthan before (US$93 vs. US$658 PPPM, p\0.01)because of fewer inpatient, outpatient, andemergency department services. The reductionin medical costs offset RCI drug costs by14–30%.

Dermatomyositis and Polymyositis

An economic analysis of 2009–2014 US claimsdata for patients with DM/PM found a decreasein healthcare utilization in patients treated withRCI [56]. Patients treated with RCI (n = 132),IVIG (n = 1150), or rituximab (n = 562) werepropensity score-matched on demographic andclinical characteristics and prior medicalresource utilization. The RCI group had fewermean hospitalizations than the IVIG group(0.09 vs. 0.17 PPPM; p = 0.049), shorter meanlength of stay (3.24 vs. 4.55 days; p = 0.004),and fewer hospital outpatient department visits(0.60 vs. 1.39 PPPM; p\0.001) and physicianoffice visits (2.01 vs. 2.33 PPPM; p = 0.035), butsimilar numbers of emergency department visits(0.04 vs. 0.05 PPPM; p = 0.472). RCI patientsalso had fewer hospital department outpatientvisits than patients receiving rituximab orIVIG ? rituximab and shorter hospital length ofstay. Total mean nonmedication costs weresignificantly lower in the RCI group than in theIVIG group (US$2126 vs. US$3964; p\0.001),rituximab group (US$2008 vs. US$2607;p = 0.018), and IVIG ? rituximab group(US$1234 vs. US$4858; p\0.001).

Systemic Lupus Erythematosus

In an analysis of healthcare utilization inpatients with SLE, 9944 eligible patients (ageC18 years) were identified using US commercial

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claims data for 2006–2015 [57]. Of this group,29 patients had initiated RCI therapy, with thedrug initiated an average of 23 months afterdiagnosis of SLE. Healthcare utilization in theperiod before RCI initiation (average duration,23 months) and the period after initiation (av-erage follow-up, 24 months) was compared.Decreases in mean number of hospitalizationsand ED visits PPPM were observed postinitia-tion. Drug costs increased from US$905 PPPMto US$7743 PPPM postinitiation; however,SLE-related medical costs decreased fromUS$3301 PPPM to US$893 PPPM (p = 0.02),primarily owing to lower hospitalization costs,offsetting approximately one-third of theincrease in drug costs.

Multiple Rheumatologic Conditions

In an analysis of a pooled population of patientswith various rheumatologic conditions (RA,n = 1269; SLE, n = 874; DM/PM; n = 606), theproportions of patients who used corticosteroidtherapy were significantly lower after RCI initi-ation (reduced from 67% preindex to 54%postindex for RA, from 73% to 58% for SLE, andfrom 76% to 58% for DM/PM; p\0.05 for allcomparisons) [58]. Furthermore, the propor-tions of patients who were receiving biologicsand DMARDs were also significantly loweredafter initiation of RCI treatment.

General clinical practice is to use RCI as alate-line therapy in patients with autoimmuneflares or whose disease has been inadequatelycontrolled with first-line therapies. Taken toge-ther, these various retrospective analyses sug-gest that treatment with RCI is associated withreduced healthcare utilization in patients withmoderate to severe disease progression. Thelower healthcare utilization may reflect animprovement in disease control, correspondingto the improvements in clinical outcomesobserved in the studies summarized above, andwarrants additional research.

CONCLUSION

RCI is used to treat several serious and rareautoimmune conditions. There has been a

renewed interest in RCI, partly because of recentprogress in understanding the mechanisms bywhich RCI modulates immune responses. Cur-rently, RCI is considered first-line therapy for IS;for other autoimmune disorders reviewed hereit is used primarily as later-line therapy inpatients experiencing a disease exacerbation oras adjunctive or maintenance therapy in selec-ted patients who do not respond to or areintolerant of conventional treatment.

More than two dozen clinical trials of RCI inthe treatment of MS relapses, symptomatic sar-coidosis, SLE, RA, optic neuritis, proteinuria,DM, and other diseases and conditions are cur-rently registered in the National Institutes ofHealth clinical trials database (http://www.ClinicalTrials.gov); it is anticipated that thisresearch will greatly improve our understandingof the appropriate use of RCI. The large burdenthat autoimmune diseases impose on patients,families, healthcare systems, and society war-rants continued research to expand the knowl-edge base of effective therapeutic options forthese challenging disorders.

The studies summarized in this review sup-port the potential clinical efficacy of RCI acrossseveral autoimmune diseases and disorders. Inaddition, retrospective analyses suggest thattreatment with RCI for RA, SLE, and DM/PMwas associated with substantial reductions inthe use of corticosteroids, biologics, and non-biologic DMARDs. Furthermore, initiation ofRCI therapy may be associated with subsequentlower healthcare utilization, including decrea-ses in hospitalizations, hospital length of stay,and outpatient visits. The evidence suggeststhat RCI may improve inflammatory andautoimmune disease control and patient qualityof life, particularly in complex patients, andyield healthcare cost savings that demonstratethe medicine’s value.

ACKNOWLEDGEMENTS

Writing support was provided by Marcia L.Reinhart and Judith S. Hurley, and editorialsupport was provided by Helen Barham andEsther Tazartes of Global Outcomes Group. The

Adv Ther (2017) 34:1775–1790 1787

authors also recognize Tara Nazareth and Win-nie Nelson for their critical review of themanuscript. The study, article processing char-ges, editorial support, and Open Access fee werefunded by Mallinckrodt Pharmaceuticals Inc.(Hampton, NJ, USA). All authors had full accessto all of the data in this study and take completeresponsibility for the integrity of the data andaccuracy of the data analysis. All named authorsmeet the International Committee of MedicalJournal Editors (ICMJE) criteria for authorshipof this manuscript, take responsibility for theintegrity of the work as a whole, and have givenfinal approval for the version to be published.

Disclosures. The authors of this manuscriptdisclose the following possible financial or per-sonal relationships with commercial entitiesthat may have a direct or indirect interest in thesubject matter of this presentation: MichaelPhilbin was an employee of Mallinckrodt Phar-maceuticals Inc. at the time of the study. He isnow an employee of Teva Pharmaceuticals.John Niewoehner is an employee of Mallinck-rodt Pharmaceuticals Inc. George J. Wan is anemployee of Mallinckrodt Pharmaceuticals Inc.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not involve any new studies of humanor animal subjects performed by any of theauthors.

Data Availability. Data sharing is notapplicable to this article as no datasets weregenerated or analyzed during the current study.This article is based on previously conductedstudies and does not involve any new studies ofhuman or animal subjects performed by any ofthe authors.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any non-commercial use, distribution, and reproductionin any medium, provided you give appropriatecredit to the original author(s) and the source,

provide a link to the Creative Commons license,and indicate if changes were made.

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