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254
Clinica.lPracticeof AltemariveMcdicine
Volume2, Number4, Wintcr 2001
OruentntPprn
Use of [JndenaturedTypeII Collagen
in the Treatntentof RheumatoidArthritis
David E. Trentham, IvlD,Andrew D. Halpner, phD,RoselynA. Trentham, MS,Manashi
Bagchi, run, ShiI Kothari, tvrs,Harry G. Preuss,lvo,DebasisBagchiornn
ABSTMCT: Meumatoid arthritis is a debiiitating chronic diseasethat lacks an effective treatment It is the ieading cause of disability in the
United States.Rheumatoid arthritis is an inflarDmatoryresponsebeiievedto invoive T cells reacting to an antigen witbin the joints and articular cartilage. Over-tle-counter pain reiievers and anti-inflammatory medications, such as aspiriq acetaminophen,and ibuprofen, are commonly used for preventive measures,but theseproducts only teat the symptoms, not tbe cause,and may also produce serious side effects.
A growing body of evidence indicates that type tr collagen is a major structual protein responsiblefor tcnsile stength and toughless in the
cartilege and also a potential autoantigen in people who have rheumatoidartbritis. If the activity of T cells that releasejoint-destroying factors could be reduced, outcomes for patiens with rheumatoid arthritis could be improved. One metbod of achieving this is termed oral tolerarlce, a concept that is proving useful in the treaunent of autoimmunediseases.Oral tolerance describesa 6tate of tmune hyporesponsiveness following tbe oral ingestion of a protein. It is, thereforc, a method by wtrich a peripheral immune toleraoce (down regulation) to a
particular antigen may be induced by presenting specific amouutsof that antigen to the gastrointestinalsystem. Several clinical studies have
demonstrated the effectiveness and usefulnessof undenaturedcollagenII in auenuatingthe symptoms of rheumatoid arthritis with no serious adverse effects. Thus its adririnisration may demonstratetherapeuticefhcacy by inducing oral toierancefor tp reabnent of this disease.
lntroduction
kttritis is one of the rnost prevalentcbronichealth
problems in theUnited States,affectingnearly43 million
people.'Althoughit is often thoughtof as a diseasethat
predominantly affects the elderly, it is the number I
causeof disabilityaffectingthoseoverthe ageof 15.In
facl more than half of those affected by artbritis are
under the ageof 65, and almost300,000of thoseaffected are children.'Each yearartbritisis responsible
for 44
millibn outpatientvisits and almost I million hospitalizations,andit is secondonly to heartdiseasein termsof
its effect on dayslost from work.2As might be imagined
from thesestatistics,the toll that arthritis takeson the
,healthcareindustry is substantial,costing the United
States approximately$65 billion eachyear in healthreiated expenses.
Unforrunately,the incidenceof artbritis doesnot appearto be decreasing,
andby theyear2020
the Centersfor DiseaseControl (CDC) predictsthat
almost 60 million Americanswiil sufferfrom someform
of this disease.
While the termarthritis may bring to mind a simple
condition characterized
by painful joints and diffrculty
performing certaintasks,it actuallyencompasses
more
than 100 different diseases.Of thesedifferentforms of
All correspondence
concemingthis aniclc shouldbe addrcssedto: Debasis
Bagchi, rm, CreightonUniversity Scbool of PharmacyScienccsand Allied
Health Professions,2500 California Plaza. Omaha, NE 68178 (e-mail:
[email protected]).
arthdtis, osteoarthritis (OA) and rheumatoid arthritis
GA) arethe most common.
Osteoafthrttis, OA currently affects 20 million
joint diseasein which the
Americans.It is a degenerative
cartilagecoveringtheendsofbones deteriorates,resultThis forrt
ing in pain,stiffoess,andlossof movement.3r
generally
and
develafter
tbe
age
of
40
begins
of artlnitis
pain
yeaxs.s
usually
report
People
opsslowly over urany
conbeginninginjoints on only one side ofthe body, in
trast to RA. While inflammationmay be present,joint
pain in OA is typically not accompaniedby the amount
or severiryof inflammationobservedin thosewith RA.
joints suchasthekneeandhip tend to be
Weight-bearing
joints such as the
moreaffectedtlan non-weight-bearing
elbow or shoulder.The generalfeeling of sicknessthat
calraccompanyotherformsof arthritisdoesnot usually
accompany
O/..
"nsw" disease.
RheumaftidAnhitis, RA is not a
of a diseaseresemblingRA
Oneof the fiist descriptions
can be found in rhe CharakaSamhita,a medical text
from india that datesback as far as 500 BC. Another
ancientreferenceto ttre diseasedatesto 100 BC; the
RomanScriboniusLargusdescribeda polyarthritic condition occurringmainly in elderly women that closely
resembled what we now understand to be RA,
Rtre-umatoid
arthritis currentlyaffects approximately 2
world's populartiillion AmericansandaboutIVoof tJ;re
tion. However,the pathologyandprogressionof RA is
somewhatdifferentfrom that of 04.6' It often develops
VOLUME2, NUMBER4, WINTERZwt 255
suddenly,within weeksor months,andgenerallybegins help to providea matrix in which the collagenas well as
betweenthe ages of 25 and 50. Non-weight-bearing watercancoexist.Thereare a numberof different types
joints suchas the hands,shoulders,
and elbowsareusuof collagen,but typeII accountsfor themajorpart of carally affectedbiiaterally,and a significantamountof redtilage.It is composedof 3 identicalchains(termeda-I
ness,tenderness,
swelling,andinflammationis oftenprechains)that form a triple heiix.r3-t5
This interconnected
sent.RA oftenresultsin a feeling of sicknessandfatigue
networkof collagenandproteogiycans
is crucialin mainandmaybe accompanied
by weightlossaswell asfever.6 tainingjoint flexibiliry andresistanceto srressand fracMorning joint stiffnessiasting for an hour or longer is
ture. In RA, autoantigenicresponses,most likely trigrelativeiy common.Subcutaneous
noduiesthatform over
geredby rype II collagen,ultimarely result in the probonesmay alsobe present.Interestingly,3 timesasmany
gressiveinflammation,pain,and destructioncharacteriswomen as men are afflicted with rheumatoidarttriris.
tic of this disease.''
Somepatientswiil experiencea monocycliccourseof the
Regardiess
of the initial cause,a progressivedegendiseasethat may abatewithin 2 years,while otherswiII
eration of the structureand function of the joint takes
experiencea polycyclic,or progressive,course.Of ail the
place,makingnormai activitiesof life increasinglydiffiforms of arthritis,RA tendsto be one of the mostserious
cult. In the caseof RA, the body is unableto recognize
anddisabling;76Vo
of rhosewho havehadthe disease
for
its collagenas normalandin rum attacksit as if it were
1.2or more yearsbecomecompletelydisabled.Lifespan
a foreign invader.r0'r?
A novel approachto treatment,
hasbeenshownto be shortenedby approximately7 years
termedoral tolerance,in which smallamountsof rypeII
in men and 3 yearsin women,which is equivalentto the
collagenare presentedto the gastrointestinaltact, has
increasedmortality observedin thosewith diabetesand
beenthefocusof significantpositivescientificresearch.,s
Hodgkin'sdisease.
Whatis achievedis a downregulationof the body's abiliry to destroyits own coilagen,resultingin improvement
Etiology
in symptomsand.slowing
theprogression
of the disease.
While RA is classifiedas an autoimmunedisease, However,to fully appreciatethe use of oral tolerancein
the exact causesthat resultin its developmentremaina
thetreatmentof RA, it is importantto understandthetypmys0ery.What is known is that manydifferentandcomical treatmentoptionscurrentlyin use.re
plex factorsare involved. Wtrile somecasesof OA may
be the result of yearsof "wear and tear" on joint strucCurrent Treatment Options
tures,otherforms canbe tracedto an injury, infection,or
The featment options for those with rheumatoid
metaboiicdisorder.6rRA, however,doesnot resultfrom
arthritis are rypically nonsteroidalanti-inflammatory
overuseof a joint or from injury, but rather from an
drugs(NSAIDs), aloneor in combinationwith what are
autoimmuneproblemin which thebodyatracksanddamknown as disease-modifyingantirheumatic drugs
ages its own tissue. The damagethat occurs in RA
@MARDs). As is well known,chronicuse of NSAJDs,
appearsto be propagatedby cytokinessecretedby T cells
especiallyin the elderly, is linked to numerous side
in responseto certain autoantigenicstimuli within the
effects,includinggastrointestinal
bleedingandrenalmaljoint.e''oVarious immunological factors are involved,
function.il Even the newer generation of COX-II
including but not limited to CD4-inducerlymphocytes, inhibitors such as rofecoxib (a furanone derivative),,'
CD4 memorycells,macrophages,
neutrophils,andtumor
celecoxib(a 1,5-diarylsubstituted
pyr azole),nandinfl ixnecrosisfactor.rt'r2
One of the most likely candidatesfor
imab (a monoclonalantibody)are not without their own
tiis autoantigenicstimulusis the collagencomponentof
probiems.23pa
While thesedrugsdo reduceinflammation,
cartilage,specificallytype tr collagen.Someresearchers they do not addressthe underlyingcausesof the arthritis
beteve that an infection may trigger the initial inflamandthereforecannotaltertheprogressionof the disease.
mation in a joint through molecularmimicry or other
Furthermore,rofecoxib and celecobixhave been conmechanisms,which in turn initiates the autoimmune traindicatedfor useby patientssufferingfrom hypersenresponse.Geneticsmay also play a role, as may other
sitivity, asthm4 urticaria,or allergic reactions.All of
factors,includingstress.
them can causebleeding,ulceration,perforationof the
The cartilage in joints allows for flexibiliry and
stomachand intestines,and anaphylactoidreactions.In
motionandprovidesa cushionagainsttheimpactof varaddition,rofecoxibhasrecentlybeenassociated
with a
ious forceson the bone,'3The detailedstructureof cartipossible increasedrisk of heart attack and stroke.z0
Iageis complexbut canbe simplifiedinto 2 majorcomProlongeduseof thesenewerCOX-II inhibitorsin the
ponents:collagenand proteoglycans.
Proteoglycans
are
elderlycanresultin sideeffectssimilarto thoseseenwith
large protein molecuiesattachedto iarge carbohydrate traditionalNSAIDs. DMARDs attemprto addressthe
chainscalledglycosaminogiycans.rs
Theseproteoglycans underlyingpathologyof RA morethoroughlyby slowing
256
CUNICAL PMCTICE OF ALTERNATWEMEDICINE
the progressionof the pathology.Oneof the components
in additionto inflammation,is microvasof this disease,
cular injury coupledwith the formationof new capillaries. Many of the DMARDs attemptto inlibit the fonnation of new capiliariesas well as addressthe underlying
inflam:lation. This category of drugs includes azathio'
prine, corticosteroids, gold, hydroxychloroquine,
and a numberof newermedsulfasalaziae,
methotrexate,
Whiie these
icationssuchasieflunomideand etanercept.
medicationshavebeenshown to offer clinical improvement to thosewith rheumatoidarthritis,they canaisobe
associatedwith signifrcant toxicity and side effects,
lymphoproliferativedisoringtu.iing myelosuppression,
ders, maculardamage,thrompocytopenia,osteoporosis'
hyperglycemia,and hepatotoxicify.Another factor that
shouldbe takeninto accountis cost the monthlycostfor
eranerceptandinfliximab, both of which mustbe injected, can be morethan $1000.Also, accordingto a recent
reportby theFDA, Remicade(infliximab)hasbeenasso'
ciatedwith tuberculosisinfection,nervedamage,andrisk
of cancerlymphomain patients.In severecasesof joint
damage,surgeryis often necessary,but this is alsocostly andinvo]vesa lengthyrecoverytime.4
Methylsulfonylniethane, chondroitin, and glucosamine,widely usedfor treatmentof OA,5 areknown
to help rebuild proteogiycansand reduceinfla:nmation
but are unable to help in the processof inactivating
"kilIer" T cells to amelioraterheumatoidarthritis.
ing joint-destroyingfactors,theoutcomefor patientswith
RA canbeimproved,andonesuchmethodto achievethis
is oral tolerance,The conceptof oral tolerancehas existed since1911,and Eaditionalmedicalliteratureis filied
with papersdescribingthis mechanismandhow it might
diseases,'0
benefitthosewith autoimmune
Recentstudieshaveshownthat small dosesof type
II collagenderivedfrom chickencartilageproduceoral
toleranceand work with the immune systemto prevent
the bodyfrom aftackingits joints'8'r8
Oral tolerancecan be inducedby 2 major mechaald clonalanergy'dependnisms,bystandersuppression
Throughout
that
is presbnted.
of
antigen
ing on the dose
gut-associated
of
are
the smail intestine,there
Patches
lymphoid tissue(GALT). Within the GALT canbe found
that contissuethatconsistsof nodules@eyer'sPatches)
and
B
lymphocytes,
of T
tain organizedassemblages
macrophages,and dendritic celis and are the primary
area within the gastrointestinaltract where immune
This immunetissueis designed
aregenerated.
responses
aswell as to
to protectthehostfrom ingestingpathogens
prevent the host from reacting to ingestedproteins. In
fact, scientistshaveattemPtedto usethe GALT asa route
for administeringvaccinesbut havebeendelerredby systhe generation
Nonetheless,
temic hyporesponsiveness.
is
the primary
GALT
tle
within
of immune responses
proteins
can supingested
orally
mechanismby which
presssystemicimmuniry.
0ral Tolerance
BystanderSuppression
This form of oraltoleranceis achievedby presenting
small amountsof antigen to the GALT, which in turn
generatesa T-cell response.After the antigen (in this
case,type II collageri)is consumed,regulatoryTM and
Th3 cells migratefrom the GALT throughthe iymphatic
systemand then into peripheralcirculation.When they
encounteran antigensimilarto that which wasingested,
they secretecytokines,inciuding transforminggrowth
factor-bet4interleukin-4,andinterleukin-10, that result
in the downregulationof activatedhelpelThl cells. It is
theseactivatedhelperT cellstlat are,in Part,involved in
producingthe inflammationand destructionof collagen
in RA. If this activiry againsthealthy collagencan be
the progressionof the diseasecanbe altered.
decreased,
It shouldbe notedthat the oral antigendoesnot need to
enter the systemiccirculation in order to induce a
astheregulatoryT cellsareinducedas a result
response,
of the interactionbetweenthe antigenandtheGAI 'T'ro
''
Whentheimmunesystemis functioningpropedy,it
in orderto
recognizesand identifiesforeign substances
heip eliminate them from the body.lo'rtOne type of
immunecell thatis particularlyimportantin this process
is the T cell, which can be classifiedin a numberof dif"Helper" T
ferent categories,dependingon function.
cells have the function of releasingfactors that help
iacreaseor decreasethe immune response'Thesehave
beenfurther classifiedinto Th-l andTh-2 subsets.Th-I.
cells amplify proinflammatory responses;Th-2 cells
"Killer" T cells attackanddestroy
limit suchresponses,
antigens,The B cell is also crucial to the functioningof
the immunesystem,as it is responsiblefor the production of antibodies.In a normal individual, the immune
systemdoesnot seekout and destoy healthytissuedue
in part to the fact that T cel1sthat have specificityfor
antigens on normal tissue are either suppressedor
destroyedprior to being releasedinto circulation.In the
caseof rheumatoidarthritis,however,T cells with selfantigensfor type II collagenare not properlydestroyed
or suppressed,
resultingin the damagethat is a characteristic hallmarkof this disease.
By decreasing
the activiry of T cells that arereleas-
Clonal Anergy
Anothermechanismby which an orally administered
protein can induce a down reguiation of an immune
calledclonalanergy.'oThis
responseis via a mechanism
VOLUME2, NUMBER4, WINTER2OOI 257
300,000children.Tenpatientsbetweenthe agesof 8 and
14yearswho hadactiveRA weretreatedorally with rype
II collagenfor 3 months.Eight of the i0 patientshad a
reductionin both swollenand tenderjoints at the end of
3 months.One patientin this study also achievedcompleteremission.It wasconcludedthat oral lreatmentwith
nativetype II collagennay be a safeand effectiveform
of treatmentfor juveniie RA.'6
of native Epe tr coilagensuppleA fourth study2T
mentationin RA reportedsignificant improvementin
subjectswho met Pauluscriteria(morningstiffness,joint
joint swelling,and erythrocytesedimentation
tenderness,
of thosetaking type tr coliarate).After 24 weeks,39Vo
gen versusl9Vo toktngplaceboexperiencedsignificant
improvement.While l9%o may appear to be a iarge
responsein the placebo group, it is not unusual to
observethis type of responseia studiesof arthritis.The
impressivefinding wastle high degreeof improvement
type II collagenas
in the grouptreatedwith undenahued,
comparedto the grouptakingtheplacebo.An interesting
observationin this study was that subjectswith a presenceof serumIgA andIgG antibodiesto collagenat the
beginningof the studyhada significantlybefterresponse
to treatmentthanthoselacking suchantibodies.
srudyperIn a fiftLrdouble-blind,placebo-controlled
fomred in Germany,90 subjectswith early RA were
dividedinto groupsreceivingdaily dosesof 1 mg collagen, 10 mg collagen,or placebo.aAt the end of the
study,3 patiensin the 10mg group,I patientin the I mg
group,and no patientsin the placebogroup had experiencedmarkedimprovement.While theseresultsmay not
appearvery impressive,theauthorsweresurprisedby the
degreeof benefit given the small subsetof patients.In
anotherGermanstudy,t6
daily dosesof I mg or 10 mg of
undenatured
type tr collagenresultedin reducedtype II
collagen antibodytites in patientsshowing a clinical
response.This study also suggestedthat 10 mg was a
more effectivedosethan I mg.'6Thesestudiesprovide
the basisandrationalefor the useofnative type tr collagen as a safe and effective modaiity of treatmentfor
thosesufferingfrom RA.
situationresultsfrom the ingeition of high dosesof an
antigen,which in rurninducesa stateof unresponsiveness
from overactiveThl cells.Theseceilsarenot deletedbut
arerenderedincapableofrespondingto a specificantigen.
theyarenrrnedoff, or "anergized,"andwill no
In essence,
longerrecognizetheantigenas a targetfor destruction.'o
Clinical Studies
Via the mechanismof oral tolerance,type tr collagen hasbeenstudiedfor its ability to benefitthosewith
RA. This makessense,becausetype II collagenis the
most abundantstructuralprotein presentin cartiiage.
Numerousanimalmodelsof arttritis havedemonstated
significant benefit from orally administered,native
(undenatured)fype II collagen. Its administrationhas
almostall experimentallyinducible
beenableto supPress
animals,
forms of RA in
including antigen-induced
arthritis, adjuvant arthritis, Upe tr collagen-induced
arthritis, streptococcalcell-wall arthritis, and siliconeinduced arthritis. These impressiveresults led to the
investigationof nativetype tr collagensupplementation
in humanswith RA. In 1993,an open-labelpiiot tial and
a phasetr trid ia humans were conductedat Harvard
Medical School.8Iathe pilot tid, 10 patientsdiagnosed
anddisease-modwith RA had their immunosuppressive
ifying drugs discontinuedand were given 0.1 mg of
nativetypeII collagendaily for 1 month,followedby 0.5
mg of nativetype tr coilagenfor the next? months.Six
of ttre 10 subjectsexperienced
a significantimprovernent
(defined rc >50Vocomparedwith baseline)in swollen
and tenderjoint counts,as well asmorningstiffrtess,50foot walk time, grip strengthtime, and erythrocytesedimentationrate. One subject who had previously been
teated with methotrexateexperiencedcompleteremission.which continuedfor 26 months.No adverseeffects
a
werenoted.EBecauseof theseobservedirnprovements,
placebo-controlledphase II follow-up trial was performedconsistingof 60 subjectswith severe,activeRA.
Participantswere randomly assignedto groups taking
eithera placeboor a daily doseof 0.1 mg nativetype II
collagenfor I month,then0.5 mg for 2 months.At I,2,
significant
and 3 months,thecollagengroupexperienced
improvement(P < 0.05)in the numberof swollenjoints,
the number of painful and tenderjoints (P = 0.06 at 2
months),and 50-footwalk time. Four patientsin the coliagen group, comparedwith no patientsin the placebo
group,experienced
compieteremissionof the disease.
One of the most notablefindings was the lack of side
effects as a result of the teatment, an importantissue
given the side effectsthat can be presentwith various
DMARDs and NSAIDs. Importantly,a recentindepenof type
dent reporthas also confirmedthe effectiveness
II collagenin juvenile RA,26a diseaseaffectingalmost
The Importance of a Native (Undenatured)
Form of Collagen
To conferoral tolerance,lype II collagen must be
used in its undenatured,3-dimensional,triple-helical
structure.r0'2e
Unfortunately,mostproductson the market
containingtype tr collagendo not contain the undenafured form. In theseproductsit has undergoneharsh
manufacturingprocedures
chemicalor high+emperature
which denafureit, thus renderingit inactive and incapable of eliciting an immune responseonce adminisstudiesexist to support
tered.In fact, no peer-reviewed
258
:UNT:ALzMCTICE oF ALTEruNATryrE
MEDICINE
the use of denaturedfype tr collagenin RA, and one
study has showndenaturedrype tr coilagento have no
In orderto insure
impact on the severityof the disease,2e
rype II coliagenis present,highly senthat undenatured
sitive ELISA assaysmust be performedto confirrn that
the collagenis bioiogicallyactive.
Source of Undenatured Type II Collagen
It is well understoodthat type II collagencan be
obtainedfrom all typesof animais,inciudingmice,rats,
chickens, pigs, and dogs, as well as from humans.
However,anidealcommercialsourcewouldbe to obtain
it in a cost-effectiveway from animalshousedandmaintainedin a germ-freeenvironment.Chickensraisedin a
controlled environmentwith ambienttemperatureand
purified air, free from bacteria,viruses,fungi, and other
microorganisms,are currently the best sourceof comtype tr collagen.
mercialundenatured
Dose
Clinical studiessupportthe use of native,undenatured type II collagen and recommendthat it be taken
with waterat bedtime.Furthermore,studieshaveshown
that small doses(rypically 10 mg or less)derivedfrom
chickencartilagework with the humanimmunesystem
to promotehealthyjoints andimprovemobiiiry andflexibility, as well as attenuatingthe symptomsof RA. The
collagenII on an
ideal situationis to ingestundenatured
the
acid
content
in
the stomachis
stomach
wben
empty
protein
absorption
in
a
human
body may
low. Generally,
take from 4 to 8 hours.
Potential Useof Undenatured Type II
Collagenin Osteoarthritis
Therapeuticinterventionsthat work rapidly for RA,
such as NSAIDs or cortisoneinjections,are alsopalliative for OA. Unfortunately,druis that work rapidiy for
OA do not, in general,provide sufficient reductionof
inflammationor pain reiief on their own in rheumatoid
arthritis.OA therapiesin this categoryincludeNSAIDS,
hydrochlohylan g-f 20,andmostprobablyglucosamine
ride andchondroitinsulfate.Presumably,this dichotomy
reiatesto themuchmoresubstantialdegreeof inflammation presentin RA versusOA.
usuallyassociatOA is a wearandtearphenomenon
with rigorousexered with aging;the diseaseprogresses
cise whenmusclesand bonesare alreadyweakeneddue
to aging(exercise
alsocausesmuscleandbonedamagein
patients
by an
with
RA). It is also ch4racterized
aged
joint
to
wear
inflammatorysynovialresponsethat ieads
gradual
deterioraandtear,3o
As RA will effectivelycause
tion and inflammationof certainjoints due to immune
disorders.OA will causewearandteardueto the normal
agingprocessandanincreasein enzymaticactivity.In the
absenceof significant and disfiguring inflammation
(whichis characteristic
of rheumatoidarthritis),wearand
as OA ratherthan RA
tear activity may be misdiagnosed
andtreatedaccordingly.In somecases,OA is addedasan
additionaldiagnosissimply becausewear and tear and
aging persists and exists normally. The biochemical
witb OA inflammation,suchas varimarkersassociated
ous cytokines(interleukin- and interleukin-10),tumor
necrosisfactor-alpha,and interferonsare alsoassociated
Therefore,therapiesusedto
with RA inflammation.rrro'3r
treat RA inJlammationare also used to treat severeOA
that type II
inflarrmation.Earlierresearchdemonstrates
which
inJlammation,
T-cell-mediated
collagensuppresses
is characterizedby cytokines interleukin-4 and interleukin-lO and is seenin the synoviumsof both OA and
RA patients.Anotherbenefitof rypeII collagenis that it
containssmall amountsof glucosamineand chondroitin,
which aregoodfor joint mobility andflexibiiity. In light
of thesefacts,it may be postulatedthat undenatured
rype
II collagenmay alsoprovidebenefitto a significantpopulationof OA patientsas well asthosewith RA.
Conclusion
Finding an effective cure for RA is a major challenge for health professionals.Over-the-counterpain
relievers,NSAIDS and other anti-inJlammatorydrugs,
and mbnoclonalantibodyand COX-[ inhibitors have
major adverseside effects,including liver disease,gasdysfunctions,and, possi8itis, vomiting,cardiovascular
rofecoxib,and
infliximab,
Futhermore,
tuberculosis.
bly,
regular use.
drugs
for
expensive
are
very
celecoxib
which
involves
is
surgery,
Anotherexpensivealternative
have
trials
clinical
a long recoverytime. Severalhuman
undeand usefulnessof
the effectiveness
demonstrated
natured lype II collagenin significantly reducing the
painful symptomsof RA with no adverseside effects'
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