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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' References l. Helmick CG, LawrenccRC, PollardRA, Lloyd E, HeyseSP' Arlhtitis and other rhcumaticconditions:who is affectednow, will be affected later? l. 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