Genetics, autoantibodies and clinical features in understanding and predicting rheumatoid arthritis

Hele tekst

(1)Genetics, autoantibodies and clinical features in understanding and predicting rheumatoid arthritis Helm-van Mil, A.H.M. van der. Citation Helm-van Mil, A. H. M. van der. (2006, October 26). Genetics, autoantibodies and clinical features in understanding and predicting rheumatoid arthritis. Retrieved from https://hdl.handle.net/1887/4929 Version:. Corrected Publisher’s Version. License:. Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden. Downloaded from:. https://hdl.handle.net/1887/4929. Note: To cite this publication please use the final published version (if applicable)..

(2) #HAPTER¬. 'ENETICS¬AND¬CLINICAL¬CHARACTERISTICS¬TO PREDICT¬RHEUMATOID¬ARTHRITIS¬7HERE¬ARE WE¬NOW¬AND¬WHAT¬ARE¬THE¬PERSPECTIVES. !(-¬VAN¬DER¬(ELM¬ ¬VAN¬-IL 47*¬(UIZINGA &UTURE¬2HEUMATOLOGY¬ .

(3) !"342!#4. )N¬ MEDICINE

(4) ¬ THE¬ PERSPECTIVE¬ OF¬ PREDICTION¬ CONTAINS¬ THREE¬ MAJOR¬ ISSUES¬ THE¬ VARIABILITY¬ OF¬THE¬HOST

(5) ¬THE¬CHARACTERISTICS¬OF¬THE¬DISEASE CAUSING¬AGENT¬AND¬THE¬INTERACTION¬BETWEEN¬ THESE¬FACTORS¬THE¬DISEASE¬PROCESS¬ITSELF ¬4HE¬CURRENT¬REVIEW¬FOCUSES¬ON¬THE¬PREDICTION¬OF¬ 2!¬IN¬PATIENTS¬WITH¬UNDIFFERENTIATED¬ARTHRITIS¬$ATA¬FROM¬INCEPTION¬COHORTS¬HAVE¬REVEALED THAT¬IN¬ABOUT¬A¬THIRD¬OF¬THE¬PATIENTS¬PRESENTING¬WITH¬RECENT¬ONSET¬ARTHRITIS¬TO¬A¬RHEUMA TOLOGIST¬ NO¬ DIAGNOSIS¬ CAN¬ BE¬ MADE

(6) ¬ SO CALLED¬ UNDIFFERENTIATED¬ ARTHRITIS¬ )N¬ A¬ PORTION¬ OF¬ THESE¬PATIENTS¬2!¬DEVELOPS

(7) ¬WHEREAS¬A¬SUBSTANTIAL¬PORTION¬REMITS¬SPONTANEOUSLY¬#URRENT¬ EPIDEMIOLOGICAL¬DATA¬ON¬2!¬INCIDENCE¬RATES¬ARE¬COMPATIBLE¬WITH¬HOST¬GENETIC ¬FACTORS¬BE ING¬AN¬INDEPENDENT¬PREDICTOR¬OF¬SUSCEPTIBILITY¬TO¬2!¬4HE¬MAJORITY¬OF¬THE¬GENETIC¬FACTORS¬ HAVE¬STILL¬TO¬BE¬IDENTIl¬ED¬BUT¬(,! ALLELES¬AND¬040. ALLELES¬HAVE¬NOW¬BEEN¬IDENTIl¬ED¬AS¬ RISK¬FACTORS¬IN¬A¬NUMBER¬OF¬POPULATIONS¬$ISEASE¬CHARACTERISTICS¬SUCH¬AS¬ANTI ##0¬ANTIBOD IES¬AND¬EROSIONS¬ON¬8 RAYS¬ARE¬IDENTIl¬ED¬AS¬BEING¬OF¬HIGH¬PREDICTIVE¬VALUE¬)N¬THE¬FUTURE

(8) MODELS¬ THAT¬ TAKE¬ INTO¬ ACCOUNT¬ BOTH¬ GENETIC¬ AND¬ CLINICAL¬ CHARACTERISTICS¬ WILL¬ HAVE¬ TO¬ BE EVALUATED¬ IN¬ PATIENT¬ GROUPS¬ WITH¬ UNDIFFERENTIATED¬ ARTHRITIS¬ IN¬ ORDER¬ TO¬ ESTABLISH¬ THE¬ AC. #HAPTER¬. CURACY¬OF¬THESE¬MODELS¬IN¬PREDICTING¬WITH¬AN¬¬PROBABILITY¬THE¬CHANCE¬ON¬PROGRESSION¬. . TO¬2!¬3UCH¬PREDICTION¬MODELS¬WILL¬BE¬OF¬HELP¬IN¬TREATMENT¬DECISIONS¬IN¬THESE¬PATIENTS.

(9) 'ENETICS¬AND¬CLINICAL¬CHARACTERISTICS¬TO¬PREDICT¬2!. ).42/$5#4)/.. !¬NUMBER¬OF¬DIFFERENT¬ITEMS¬ARE¬USED¬IN¬CLINICAL¬PREDICTION¬MODELS¬4HESE¬ITEMS¬VARY¬FROM¬ VARIABILITY¬OF¬THE¬HOST

(10) ¬THE¬VARIABILITY¬OF¬THE¬CAUSING¬AGENT

(11) ¬AND¬VARIABILITY¬IN¬THE¬DISEASE PROCESS¬AND¬l¬NALLY¬THE¬DYNAMICS¬OF¬THE¬INTERACTION¬THAT¬TAKES¬TIME¬INTO¬ACCOUNT¬AS¬WELL¬ %XAMPLES¬OF¬THE¬RELEVANCE¬OF¬MEASURING¬PURE¬HOST¬CHARACTERISTICS¬ARE¬EG¬THE¬"2#! ¬ CARRIERSHIP¬IN¬FAMILIES¬WITH¬A¬HISTORY¬OF¬BREASTOVARIAN¬CANCER¬%XAMPLES¬OF¬THE¬RELEVANCE OF¬THE¬CHARACTERISTICS¬OF¬THE¬DISEASE CAUSING¬AGENT¬IN¬SENSU¬STRICTU¬ARE¬THE¬CAUSING¬MICRO OR GANISMS¬IN¬INFECTIOUS¬DISEASES¬SUCH¬AS¬IN¬COMMUNITY ACQUIRED¬PNEUMONIA¬!N¬EXAMPLE¬IN RHEUMATOLOGY¬WHEN¬BOTH¬HOST¬AND¬CAUSING¬AGENT¬DETERMINE¬SUSCEPTIBILITY¬IS¬THAT¬CERTAIN MICRO ORGANISMS¬ EG¬ #HLAMYDIA ¬ PARTICULARLY¬ CAUSE¬ DISEASE¬ REACTIVE¬ ARTHRITIS ¬ IN¬ HOSTS¬ THAT¬ARE¬(,! "¬POSITIVE¬%XAMPLES¬TO¬DETECT¬DIFFERENCES¬IN¬PROGNOSIS¬BY¬STUDYING¬THE MODE¬OF¬INTERACTION¬OF¬HOST¬AND¬DISEASE INDUCING¬PROCESS¬ARE¬THE¬STUDY¬OF¬CHARACTERISTICS¬ OF¬DISEASED¬TISSUE¬SUCH¬AS¬MICRO ARRAY¬STUDIES¬IN¬BREAST¬CANCER¬!N¬EXAMPLE¬WHEN¬THE¬EVO LUTION¬OF¬THE¬DISEASE¬OVER¬TIME¬IS¬INCLUDED¬IN¬THE¬DETERMINATION¬OF¬A¬RESPONSE¬PARAMETER¬ IS¬ CERVICAL¬ ABNORMALITIES¬ DETECTED¬ BY¬ A¬ SLIGHTLY¬ ABNORMAL¬ CERVICAL¬ SMEAR¬ TEST¬ 4HE¬ VALUE OF¬SUCH¬A¬TEST¬CAN¬BE¬THAT¬THE¬CERVICAL¬SMEAR¬TEST¬IS¬ADVISED¬TO¬BE¬REPEATED¬WITHIN¬THREE¬ MONTHS¬TO¬SEE¬WHETHER¬NATURAL¬REGRESSION¬OF¬THE¬ABNORMALITIES¬HAS¬OCCURED¬OR¬WHETHER PROGRESSION¬TO¬ABNORMALITIES¬INDICATIVE¬OF¬PRECANCEROUS¬CHARACTERISTICS¬HAS¬OCCURRED 4HE¬OUTCOME¬OF¬A¬PREDICTION¬MODEL¬CAN¬BE¬THE¬DEVELOPMENT¬OF¬A¬DISEASE¬OR¬DISEASE¬SEVER ITY¬)N¬RHEUMATOLOGY¬AND¬PARTICULARLY¬IN¬RHEUMATOID¬ARTHRITIS¬2!

(12) ¬PHYSICIANS¬GENERALLY WANT¬TO¬AVOID¬MORBIDITY¬AND¬DISABILITY¬%XISTING¬PREDICTION¬MODELS¬ARE¬THEREFORE¬BUILT¬TO PREDICT¬CHRONICITY¬AND¬EROSIVENESS¬0REDICTION¬MODELS¬ARE¬OF¬IMPORTANCE¬AS¬THEY¬MIGHT¬ HELP¬IN¬TREATMENT¬DECISIONS¬4HEY¬MAY¬GUIDE¬THE¬CHOICE¬IN¬TREATMENT¬OPTIONS¬BETWEEN WAIT¬ AND¬ SEE

(13) ¬ START¬ WITH¬ A¬ RELATIVE¬ MILD¬ TREATMENT¬ OR¬ INITIATE¬ AGGRESSIVE¬ TREATMENT¬ DI RECTLY¬ 4HE¬ CURRENT¬ EVIDENCE¬ ON¬ EARLY ¬ TREATMENT¬ OF¬ 2!¬ IS¬ BASED¬ ON¬ LARGE¬ TRIALS¬ WITH 2!¬ PATIENTS

(14) ¬ IN¬ WHICH¬ 2!¬ IS¬ DEl¬NED¬ ACCORDING¬ TO¬ THE¬ !#2¬ CRITERIA¬ )NCEPTION¬ COHORTS¬ INCLUDE¬PATIENTS¬IN¬WHO¬DURING¬THE¬l¬RST¬VISITS¬WITH¬THE¬CURRENT¬METHODOLOGY¬A¬DIAGNOSIS¬ CAN¬DIRECTLY¬BE¬MADE¬ABOUT¬¬OF¬PATIENTS ¬!BOUT¬FORTY¬PERCENT¬OF¬PATIENTS¬IN¬INCEP TION¬COHORTS¬HAVE¬A¬FORM¬OF¬ARTHRITIS¬IN¬WHICH¬NO¬DEl¬NITE¬DIAGNOSIS¬CAN¬BE¬MADE¬THESE¬ PATIENTS¬ARE¬IDENTIl¬ED¬AS¬UNDIFFERENTIATED¬ARTHRITIS¬5! ¬4HESE¬5!¬PATIENTS¬CAN¬GO¬INTO REMISSION

(15) ¬DEVELOP¬2!¬OR¬DEVELOP¬OTHER¬DIAGNOSIS¬SEE¬&IGURE¬ ¬!T¬PRESENT¬NO¬DATA¬ ON¬THE¬EFFECTS¬OF¬TREATMENT¬OF¬5!¬PATIENTS¬ARE¬AVAILABLE¬%ARLY¬TREATMENT¬OF¬THE¬PATIENTS WITH¬5!¬THAT¬WILL¬DEVELOP¬2!¬MIGHT¬BE¬BENEl¬CIAL

(16) ¬WHEREAS¬TREATMENT¬OF¬THE¬GROUP¬THAT¬ WILL¬REMIT¬SPONTANEOUSLY¬IS¬POTENTIALLY¬HARMFUL¬4HE¬SPONTANEOUS¬REMISSION¬RATE¬OF¬5!¬ PATIENTS¬ IS¬ ABOUT¬ ¬ ¬ !S¬ CURRENT¬ KNOWLEDGE¬ ON¬ THE¬ EFFECTS¬ OF¬ TREATMENT¬ IN¬ 2!¬ IS¬ BASED¬ON¬PATIENTS¬WITH¬2!¬CLASSIl¬CATION¬ACCORDING¬TO¬THE¬!#2 CRITERIA¬IT¬WILL¬BE¬HELPFUL¬ TO¬HAVE¬A¬MODEL¬TO¬PREDICT¬DEVELOPMENT¬OF¬2!¬IN¬5!¬PATIENTS¬4HE¬PREDICTION¬OF¬2!¬IS. .

(17) 'LDJQRVLVDWDQGRUZHHNV. ,QFHSWLRQ &RKRUW. 'LDJQRVLVDW\HDU. 5KHXPDWRLG $UWKULWLV. 5KHXPDWRLG $UWKULWLV. 8QGLIIHUHQWLDWHG $UWKULWLV. 8QGLIIHUHQWLDWHG $UWKULWLV. 2WKHUGLDJQRVLV. 2WKHUGLDJQRVLV. 5HPLVVLRQ &IGURE¬¬&LOW¬DIAGRAM¬OF¬INCEPTION¬COHORT. #HAPTER¬. IN¬MOST¬CASES¬SYNONYMOUS¬WITH¬PREDICTION¬OF¬DISEASE¬PERSISTENCY¬AS¬THE¬REMISSION¬RATE. . OF¬2!¬IS¬ABOUT¬ ¬

(18) 4HE¬ CURRENT¬ REVIEW¬ IS¬ FOCUSSED¬ ON¬ PREDICTION¬ OF¬ 2!¬ 4HE¬ FOLLOWING¬ SECTIONS¬ WILL¬ REVIEW¬ THE¬ EVIDENCE¬ THAT¬ PURE¬ HOST¬ CHARACTERISTICS¬ ARE¬ INFORMATIVE

(19) ¬ PURE¬ DISEASE¬ CHARACTERISTICS ARE¬RELEVANT¬AND¬WHICH¬EVIDENCE¬IS¬AVAILABLE¬THAT¬A¬COMBINATION¬OF¬DISEASE¬CHARACTERISTICS

(20) HOST¬CHARACTERISTICS¬AND¬NATURAL¬COURSE¬ALLOWS¬PREDICTION¬4HE¬APPLICABILITY¬OF¬PREDICTION¬ MODELS¬ IS¬ ALSO¬ DETERMINED¬ BY¬ BASIC¬ EPIDEMIOLOGICAL¬ RULES¬ AND¬ THE¬ PREDICTIVE¬ VALUE¬ OF¬ A TESTMODEL¬IS¬DEPENDENT¬ON¬THE¬PREVALENCE¬OF¬THE¬DISEASE¬IN¬A¬GIVEN¬POPULATION¬&OR¬THE¬ QUESTION¬ON¬GENETIC¬TESTING¬hWHERE¬WE¬ARE¬NOW¬AND¬WHAT¬ARE¬THE¬PERSPECTIVESv¬THIS¬IS¬REL EVANT¬BECAUSE¬MOST¬CURRENT¬DATA¬ON¬GENETIC¬FACTORS¬DESCRIBE¬THE¬COMPARISON¬BETWEEN¬CASES AND¬HEALTHY¬CONTROLS¬4HESE¬ARE¬RELEVANT¬DATA¬TO¬UNDRAPE¬PATHOGENESIS

(21) ¬BUT¬ARE¬DIFl¬CULT¬TO¬ BE¬INTERPRETED¬WITH¬REGARD¬TO¬RELEVANCE¬IN¬DIAGNOSTIC¬TESTING¬IN¬INDIVIDUAL¬PATIENTS. 6!2)!"),)49¬).¬4(%¬(/34¬$%4%2-).%3¬).#)$%.#%¬/&¬2!. 4HIS¬HYPOTHESIS¬HAS¬A¬NUMBER¬OF¬RELEVANT¬IMPLICATIONS¬FOR¬2!¬&IRST

(22) ¬IT¬ASSUMES¬THAT¬THE TRIGGER¬OR¬TRIGGERING¬EVENTS¬FOR¬2!¬ARE¬COMMON¬AND¬THEREFORE¬THE¬OPPORTUNITY¬TO¬ENCOUN TER¬THESE¬TRIGGERING¬EVENTS¬IS¬NOT¬THE¬LIMITING¬OR¬DETERMINING¬FACTOR¬3ECOND

(23) ¬IT¬HAS¬IMPLICA TIONS¬ON¬THE¬THOUGHTS¬WHETHER¬2!¬IS¬ONE¬DISEASE¬OR¬AN¬ASSEMBLY¬OF¬TRULY¬DIFFERENT¬DISEASES AND¬THIRD¬IT¬ASSUMES¬THAT¬A¬NUMBER¬OF¬$.!¬VARIANTS¬ARE¬ASSOCIATED¬WITH¬DISEASE¬AND¬THAT¬ A¬$.!¬l¬NGERPRINT¬MIGHT¬PREDICT¬DISEASE¬SUSCEPTIBILITY¬.

(24) 'ENETICS¬AND¬CLINICAL¬CHARACTERISTICS¬TO¬PREDICT¬2!. $OES¬2!¬HAVE¬A¬COMMON¬TRIGGER 4HE¬ASSUMPTION¬THAT¬2!¬HAS¬A¬COMMON¬OR¬A¬COMBINATION¬OF¬COMMONLY¬AVAILABLE¬TRIGGERS IMPLY¬THAT¬SUCH¬TRIGGERS¬CAN¬BE¬ENCOUNTERED¬IN¬MOST¬POPULATIONS¬!N¬ARGUMENT¬IN¬FAVOUR OF¬THIS¬ASSUMPTION¬IS¬THAT¬2!¬IS¬A¬WORLDWIDE¬CONDITION¬INDICATING¬THAT¬THE¬TRIGGERS¬LEAD ING¬TO¬2!¬ARE¬WORLDWIDE¬AVAILABLE¬4HE¬INCIDENCE¬OF¬2!¬IS¬AGE¬RELATED

(25) ¬WITH¬A¬HIGHER¬2! INCIDENCE¬WITH¬HIGHER¬AGE¬4HIS¬AGE RELATED¬INCIDENCE¬OF¬2!¬PROVIDES¬SOME¬EVIDENCE¬HOW MANY¬ TRIGGERS¬ ARE¬ NEEDED¬ TO¬ GET¬ 2!¬ 2OBERTS 4HOMPSON¬ ET¬ AL¬ STUDIED¬ POPULATION¬ DATA¬ OBTAINED¬FROM¬THE¬!USTRALIAN¬"UREAU¬OF¬3TATISTICS¬IN¬ORDER¬TO¬ASSESS¬THE¬NUMBER¬OF¬EVENTS¬ NECESSARY¬LEADING¬TO¬2!¬ ¬"Y¬COMPUTER¬MODELLING¬IN¬WHICH¬THE¬AGE SPECIl¬C¬INCIDENCE¬ RATES

(26) ¬THE¬PROPORTION¬OF¬POPULATION¬AT¬RISK¬AND¬THE¬AGE¬AT¬ONSET¬ARE¬INCLUDED

(27) ¬THE¬NUMBER¬ OF¬RANDOM¬EVENTS¬THAT¬MUST¬OCCUR¬FOR¬THE¬DISEASE¬TO¬MANIFEST¬GIVEN¬A¬STOCHASTIC¬MODEL ¬ WAS¬ CALCULATED¬ 4HIS¬ NUMBER¬ VARIED¬ SOMEWHERE¬ BETWEEN¬ ¬ AND¬ ¬ EVENTS¬ )N¬ INCEPTION¬ COHORTS

(28) ¬THE¬PATIENTS¬WITH¬5!¬AT¬INCLUSION¬THAT¬AFTER¬¬YEAR¬OF¬FOLLOW UP¬HAD¬PERSISTENT¬5! WERE¬SIGNIl¬CANTLY¬YOUNGER¬THAN¬THE¬5!¬PATIENTS¬THAT¬DURING¬THE¬l¬RST¬YEAR¬DEVELOPED¬2!¬ ¬4HE¬DIFFERENCE¬IN¬AGE¬BETWEEN¬THE¬GROUPS¬THAT¬DO¬AND¬DO¬NOT¬PROGRESS¬TO¬2!¬MIGHT¬ REVEAL¬A¬DIFFERENCE¬IN¬TIME¬PERIOD¬AND¬SUBSEQUENT¬CHANCE¬TO¬ACQUIRE¬SUFl¬CIENT¬NUMBERS¬ OF¬TRIGGERING¬EVENTS 2!¬HAS¬A¬VARIABLE¬INCIDENCE¬IN¬DIFFERENT¬POPULATIONS¬)N¬0IMA¬)NDIANS¬THE¬INCIDENCE¬RATES IN¬THE¬SAME¬TIME¬PERIODS¬WERE¬¬TIMES¬HIGHER¬THAN¬IN¬THE¬#AUCASIAN¬53¬POPULATION¬AND ¬TIMES¬HIGHER¬THAN¬IN¬THE¬*APANESE¬POPULATION¬ ¬4HIS¬IMPLIES¬THAT¬THE¬FREQUENCY¬OF¬THE¬ EVENTS¬LEADING¬TO¬2!¬IS¬DIFFERENT¬IN¬THE¬DIFFERENT¬POPULATIONS¬ANDOR¬THAT¬THE¬HOST¬FACTORS¬ IN¬THE¬DIFFERENT¬POPULATIONS¬DIFFER¬4HE¬RELATIVE¬CONTRIBUTION¬OF¬GENETIC¬OR¬ENVIRONMENTAL FACTORS¬IS¬DIFl¬CULT¬TO¬DETERMINE

(29) ¬BUT¬BASED¬ON¬STUDIES¬OF¬POPULATIONS¬THAT¬HAVE¬MIGRATED TO¬DIFFERENT¬ENVIRONMENTS

(30) ¬IT¬IS¬LIKELY¬THAT¬THE¬MAJORITY¬OF¬THE¬DIFFERENCE¬IN¬RATES¬OF¬2!¬IN DIFFERENT¬POPULATIONS¬CAN¬BE¬EXPLAINED¬BY¬GENETIC¬FACTORS¬ ¬-OREOVER

(31) ¬THE¬DIFFERENCES IN¬THE¬FREQUENCY¬OF¬THE¬IDENTIl¬ED¬GENETIC¬RISK¬FACTOR¬FOR¬2!

(32) ¬THE¬(,! ALLELES¬ENCODING¬THE¬ SHARED¬EPITOPE

(33) ¬ASSOCIATE¬WITH¬THE¬FREQUENCY¬OF¬2!¬IN¬THE¬RESPECTIVE¬POPULATIONS¬ ¬!N¬ ADDITIONAL¬ARGUMENT¬THAT¬2!¬IS¬CAUSED¬BY¬COMMONLY¬AVAILABLE¬TRIGGERS¬IS¬THE¬ABSENCE¬OF¬ GEOGRAPHICAL¬CLUSTERING¬OF¬2!¬INCIDENT¬CASES¬ ¬)N¬THE¬AGGREGATE

(34) ¬THESE¬DATA¬SUGGEST¬THAT IN¬MODERN¬LIFESTYLE¬A¬COMBINATION¬OF¬TRIGGERS¬IS¬COMMON¬IN¬A¬VARIETY¬OF¬CULTURES¬BUT¬THAT¬ HOST¬CHARACTERISTICS¬DETERMINE¬WHETHER¬THESE¬TRIGGERS¬CAN¬LEAD¬TO¬2! &URTHER¬UNDERSTANDING¬CAN¬BE¬ACHIEVED¬BY¬STUDYING¬POPULATIONS¬AMONG¬WHOM¬2!¬IS¬ NOT¬PREVALENT¬!¬STUDY¬IN¬INDIGENOUS¬PEOPLE¬!BORIGINALS ¬IN¬!USTRALIA¬FOUND¬NO¬PALEO PATHOLOGICAL¬ OR¬ ETHNOGRAPHICAL¬ EVIDENCE¬ TO¬ SUPPORT¬ THE¬ EXISTENCE¬ OF¬ 2!¬ BEFORE¬ WHITE¬ SETTLEMENT¬ 3IMILARLY¬IN¬A¬RURAL¬.IGERIAN¬POPULATION¬2!¬WAS¬NOT¬OBSERVED¬ ¬INDICAT ING¬THAT¬EITHER¬THE¬COMMON¬TRIGGER¬WAS¬NOT¬PRESENT¬AT¬THAT¬TIME¬OR¬THAT¬THESE¬POPULATIONS ARE¬GENETICALLY¬PROTECTED¬!RGUMENTS¬FOR¬THIS¬LAST¬STATEMENT¬ARE¬THE¬MUCH¬LOWER¬FREQUENCY OF¬(,! $2¬ALLELES¬ENCODING¬2!¬RISK¬ALLELES¬IN¬THESE¬POPULATIONS¬#AREFUL¬STUDIES¬HAVE¬NOW¬ IDENTIl¬ED¬2!¬IN¬!BORIGINALS¬(OWEVER

(35) ¬IN¬ALL¬THE¬!BORIGINAL¬2!¬PATIENTS¬SOME¬EVIDENCE¬OF¬. .

(36) PRIOR¬INTERRACIAL¬MARRIAGE¬WAS¬FOUND¬4HIS¬INDICATES¬THAT¬GENETIC¬ADMIXTURE¬IS¬NECESSARY¬FOR DEVELOPMENT¬OF¬2!¬9ET

(37) ¬A¬CONTRIBUTION¬OF¬CHANGING¬LIFESTYLES¬THAT¬IS¬CONCOMITANT¬TO¬RACIAL ADMIXTURES¬CANNOT¬BE¬EASILY¬EXCLUDED )N¬ A¬ STUDY¬ FROM¬ -INNESOTA¬ THAT¬ STUDIED¬ 2!¬ INCIDENCE¬ RATES¬ FROM¬ ¬ TO¬

(38) ¬ THE¬ INCIDENCE¬RATE¬FELL¬PROGRESSIVELY¬OVER¬THE¬¬DECADES¬OF¬STUDY

(39) ¬FROM¬

(40) ¬IN¬

(41) ¬ TO¬

(42) ¬ IN¬ ¬ ¬ !¬ *APANESE¬ STUDY¬ SHOWED¬ THAT¬ THE¬ INCIDENCE RATES¬FELL¬IN¬*APAN¬AS¬WELL¬AND¬THE¬FALLING¬INCIDENCE¬RATES¬OVER¬TIME¬HAVE¬OCCURRED¬IN¬DIVERSE POPULATIONS¬ SUCH¬ AS¬ )NDIANS¬ AND¬ &INNISH¬ ¬ 4HERE¬ ARE¬ SEVERAL¬ POSSIBLE¬ EXPLANATIONS FOR¬THE¬DECREASE¬IN¬2!¬INCIDENCE¬!S¬THIS¬DECREASE¬IS¬APPARENT¬IN¬VARIOUS¬POPULATIONS

(43) ¬AN¬ EXPLANATION¬IS¬LIKELY¬A¬FACTOR¬THAT¬HAS¬AN¬IDENTICAL¬EFFECT¬IN¬ALL¬POPULATIONS¬THROUGHOUT¬ THE¬WORLD¬IN¬THE¬BIRTH¬COHORTS¬FROM¬¬TO¬¬)T¬IS¬PROPOSED¬THAT¬THIS¬IS¬CAUSED¬BY¬A CHANGE¬IN¬THE¬POPULATION¬GENOME¬ ¬4HE¬EXPLANATION¬FOR¬THIS¬GENETIC¬DRIFT¬IS¬THAT¬IN PREVIOUS¬TIMES

(44) ¬HUMAN¬REPRODUCTIVE¬SUCCESS¬WAS¬VERY¬UNEVENLY¬DISTRIBUTED

(45) ¬WITH¬A¬MINOR ITY¬OF¬FERTILE¬WOMEN¬WHO¬GAVE¬BIRTH¬TO¬THE¬MAJORITY¬OF¬NEWBORNS¬&OR¬EXAMPLE

(46) ¬IN¬THE¬¬ !USTRALIAN¬CENSUS

(47) ¬¬OF¬THE¬CHILDREN¬WERE¬THE¬OFFSPRING¬OF¬¬IN¬¬OF¬THE¬WOMEN¬ (OWEVER

(48) ¬IN¬RECENT¬TIMES¬THIS¬PREDOMINANCE¬STEADILY¬DECREASED¬SINCE¬BOTH¬FERTILE¬AND¬LESS¬. #HAPTER¬. FERTILE¬WOMEN¬HAVE¬EQUALLY¬CONTRIBUTED¬TO¬THE¬NEXT¬GENERATION¬4HERE¬ARE¬ALSO¬OTHER¬EX. . PLANATIONS¬FOR¬THE¬DECREASE¬IN¬2!¬INCIDENCE¬RATES¬OVER¬TIME¬"ESIDES¬A¬REAL¬TIME¬DEPENDENT DECLINE¬ IN¬ 2!

(49) ¬ CHANGING¬ METHODOLOGY¬ IN¬ CLASSIl¬CATION¬ MAY¬ BE¬ ALSO¬ IMPORTANT¬ ¬ )N ADDITION¬TO¬A¬DECREASE¬IN¬2!¬INCIDENCE

(50) ¬A¬DECREASE¬IN¬2!¬SEVERITY¬OVER¬TIME¬IS¬ALSO¬REPORTED¬ 4HIS¬DECLINE¬SEEMS¬TO¬BE¬CONTRIBUTABLE¬TO¬EARLIER¬AND¬MORE¬AGGRESSIVE¬TREATMENT¬ )N¬SUMMARY

(51) ¬THE¬OVERVIEW¬OF¬THE¬STUDIES¬ON¬INCIDENCE¬RATES¬OF¬2!¬ARE¬COMPATIBLE¬WITH¬ THE¬NOTION¬THAT¬HOST¬CHARACTERISTICS¬ARE¬THE¬MAJOR¬FACTORS¬THAT¬DRIVE¬WHETHER¬A¬PATIENT¬WILL¬ DEVELOP¬ 2!¬ 7E¬ SUGGEST¬ THAT¬ MOST¬ PERSONS¬ NOWADAYS¬ WILL¬ ENCOUNTER¬ THOSE¬ ¬ TRIGGER ING¬EVENTS¬AND¬THAT¬HOST¬FACTORS¬ARE¬THE¬DRIVING¬FORCE¬TO¬EXPLAIN¬DIFFERENCES¬IN¬INCIDENCE RATES¬ 7HAT¬IS¬THE¬EVIDENCE¬IN¬SUPPORT¬OF¬THE¬ASSUMPTION¬THAT¬2!¬IS¬ONE DISEASE¬VERSUS¬AN¬ASSEMBLY¬OF¬DIFFERENT¬DISEASES !T¬PRESENT

(52) ¬2!¬IS¬FORMALLY¬DIAGNOSED¬WHEN¬PATIENTS¬FULl¬L¬THE¬CRITERIA¬THAT¬WERE¬FORMULATED¬ BY¬THE¬!#2¬IN¬¬7HETHER¬THE¬PATIENTS¬THAT¬HAVE¬2!¬ACCORDING¬TO¬THESE¬CRITERIA

(53) ¬ALL¬HAVE THE¬SAME¬DISEASE¬ CHARACTERISED¬BY¬AN¬IDENTICAL¬PATHOGENESIS

(54) ¬IS¬QUESTIONABLE¬2ECENTLY¬IT WAS¬ OBSERVED¬ IN¬ A¬ %UROPEAN¬ AND¬ !MERICAN¬ POPULATION¬ THAT¬ 2!¬ PATIENTS¬ CARRYING¬ ANTI BODIES¬TO¬CITRULLINATED¬PROTEINS¬ANTI ##0¬ANTIBODIES ¬HAVE¬AN¬ASSOCIATION¬WITH¬DIFFERENT¬ GENETIC¬RISK¬FACTORS¬THAN¬PATIENTS¬THAT¬LACK¬THESE¬ANTIBODIES¬4HE¬SHARED¬EPITOPE¬ENCODING (,! ALLELES¬ONLY¬CONFERRED¬RISK¬TO¬ANTI ##0¬POSITIVE¬2!¬AND¬NOT¬TO¬ANTI ##0¬NEGATIVE¬2!¬ ¬!NTI ##0¬ANTIBODIES¬ARE¬REPORTED¬TO¬HAVE¬HIGH¬DISEASE¬SPECIl¬CITY¬AND¬ARE¬OFTEN¬PRES ENT¬BEFORE¬THE¬CLINICAL¬PRESENTATION¬

(55) ¬ANTI ##0¬ANTIBODIES¬ARE¬THEREFORE¬THOUGHT¬TO¬ PLAY¬A¬ROLE¬IN¬2!¬PATHOGENESIS¬4HE¬l¬NDING¬THAT¬THE¬SHARED¬EPITOPE¬ALLELES¬ONLY¬CORRELATE¬.

(56) 'ENETICS¬AND¬CLINICAL¬CHARACTERISTICS¬TO¬PREDICT¬2!. WITH¬ANTI ##0¬POSITIVE¬DISEASE¬STRONGLY¬SUGGESTS¬THAT¬2!¬PATIENTS¬THAT¬HAVE¬ANTI ##0¬ANTI BODIES¬HAVE¬DIFFERENCES¬IN¬THE¬PATHOPHYSIOLOGICAL¬PATHWAY¬COMPARED¬TO¬2!¬PATIENTS¬THAT ARE¬ANTI ##0¬NEGATIVE¬4HIS¬CONSEQUENTLY¬INDUCES¬THE¬QUESTION¬WHETHER¬ANTI ##0¬POSITIVE¬ AND¬NEGATIVE¬2!¬ARE¬DIFFERENT¬DISEASE¬ENTITIES¬WITH¬DISTINCT¬CLINICAL¬CHARACTERISTICS¬)N¬A¬RE CENT¬STUDY¬2!¬PATIENTS¬WITH¬AND¬WITHOUT¬ANTI ##0¬ANTIBODIES¬WERE¬EXTENSIVELY¬COMPARED¬ WITH¬REGARD¬TO¬CLINICAL¬CHARACTERISTICS¬.O¬DIFFERENCES¬WERE¬FOUND¬IN¬THE¬CHARACTERISTICS¬ON¬ DISEASE¬PRESENTATION¬BETWEEN¬THESE¬TWO¬PATIENT¬GROUPS¬AMONG¬OTHERS¬THE¬AGE¬OF¬DISEASE¬ ONSET

(57) ¬ THE¬ TYPE¬ OF¬ INITIAL¬ SYMPTOMS

(58) ¬ THE¬ DISTRIBUTION¬ OF¬ INITIAL¬ SYMPTOMS

(59) ¬ THE¬ PRESENCE AND¬DURATION¬OF¬MORNING¬STIFFNESS

(60) ¬AND¬THE¬NUMBER¬AND¬DISTRIBUTION¬OF¬PAINFUL¬OR¬SWOLLEN¬ JOINTS¬WAS¬SIMILAR¬IN¬ANTI ##0¬POSITIVE¬AND¬NEGATIVE¬2!¬PATIENTS¬ ¬&ROM¬THESE¬DATA¬IT¬ CAN¬ BE¬ CONCLUDED¬ THAT¬ DIFFERENT¬ PATHOPHYSIOLOGICAL¬ PATHWAYS¬ END¬ IN¬ ONE¬ PHENOTYPICAL PRESENTATION¬ OF¬ THE¬ DISEASE¬ 3PECIl¬C¬ CHARACTERISTICS¬ OF¬ THE¬ HOST¬ SUCH¬ AS¬ THE¬ PRESENCE¬ OF¬ ANTI ##0¬ANTIBODIES¬SUBSEQUENTLY¬ASSOCIATE¬WITH¬THE¬COURSE¬OF¬THE¬DISEASE 7HICH¬POTENTIAL¬GENETIC¬RISK¬FACTORS¬FOR¬2!¬ARE¬KNOWN 4HE¬(,!¬#LASS¬))¬MOLECULES¬ARE¬THE¬MOST¬POWERFUL¬RECOGNIZED¬GENETIC¬FACTORS¬SO¬FAR¬FOR¬ 2!

(61) ¬CONTRIBUTING¬TO¬AT¬LEAST¬¬OF¬THE¬TOTAL¬GENETIC¬EFFECT¬4HE¬(,! $2"¬ALLELES¬

(62) ¬.

(63) ¬

(64) ¬

(65) ¬

(66) ¬

(67) ¬

(68) ¬ ¬SHARE¬A¬CONSERVED¬AMINO¬ACID¬SEQUENCE¬ AT¬ POSITION¬ ¬ IN¬ THE¬ THIRD¬ HYPERVARIABLE¬ REGION¬ OF¬ THE¬ $2`¬ CHAIN¬ 4HESE¬ RESIDUES¬ CONSTITUTE¬AN _ HELICAL¬DOMAIN¬FORMING¬ONE¬SIDE¬OF¬THE¬ANTIGEN¬PRESENTING¬BINDING¬SITE 4HE¬3HARED¬%PITOPE¬HYPOTHESIS¬POSTULATES¬THAT¬THE¬SHARED¬EPITOPE¬MOTIF¬ITSELF¬IS¬DIRECTLY¬ INVOLVED¬IN¬THE¬PATHOGENESIS¬OF¬2!¬BY¬ALLOWING¬THE¬PRESENTATION¬OF¬AN¬ARTHRITOGENIC¬PEP TIDE¬%XTENSIVE¬EVIDENCE¬EXISTS¬SHOWING¬ASSOCIATIONS¬BETWEEN¬THE¬SHARED¬EPITOPE¬ENCODING¬ ALLELES¬AND¬SUSCEPTIBILITY¬TO¬2!¬4HE¬PRESENCE¬OF¬SHARED¬EPITOPE¬ENCODING¬ALLELES¬IS¬ASSOCI ATED¬WITH¬ODDS¬OF¬ ¬TO¬DEVELOP¬2!¬

(69) 4HE¬SECOND¬GENETIC¬RISK¬FACTOR¬IS¬A¬RISK¬ALLELE¬OF¬A¬HAEMATOPOIETIC SPECIl¬C¬PROTEIN¬TYROSINE¬ PHOSPHATASE

(70) ¬040.¬4HIS¬ALLELE¬WAS¬IDENTIl¬ED¬IN¬¬OF¬THE¬.ORTH¬!MERICAN¬WHITE¬CON TROLS¬AND¬¬OF¬THE¬2!¬PATIENTS¬AND¬CONFERS¬ODDS¬OF¬ABOUT¬¬TO¬DEVELOP¬2!¬ ¬4HIS¬ ALLELE¬CHANGED¬THE¬FUNCTION¬OF¬THE¬PROTEIN¬THAT¬FUNCTIONS¬AS¬NEGATIVE¬REGULATOR¬OF¬4 CELL¬ ACTIVATION

(71) ¬LEADING¬TO¬4 CELLS¬WITH¬A¬LOWER¬THRESHOLD¬FOR¬4 CELL¬ACTIVATION¬4HIS¬MUTATION¬IS APPARENTLY¬LEADING¬TO¬SEVERAL¬AUTOIMMUNE¬DISEASES¬SINCE¬THIS¬MUTATION¬ALSO¬CONFERRED¬RISK¬ FOR¬3,%

(72) ¬TYPE¬¬DIABETES¬AND¬'RAVES¬DISEASE¬

(73) ¬4HE¬LAST¬YEARS¬AN¬INCREASING¬NUMBER¬OF¬ 3.0S¬ASSOCIATED¬WITH¬2!¬HAVE¬BEEN¬IDENTIl¬ED¬3OME¬OF¬THEM¬HAVE¬NOT¬BEEN¬REPLICATED¬AND SOME¬SHOW¬DIFFERENT¬RESULTS¬IN¬DIFFERENT¬POPULATIONS¬!¬GENETIC¬RISK¬FACTOR¬THAT¬IS¬CURRENTLY¬ UNDER¬INVESTIGATION¬AND¬SEEMS¬TO¬BE¬ASSOCIATED¬WITH¬2!

(74) ¬DIABETES¬AND¬MYOCARDIAL¬INFARC TION

(75) ¬IS¬-(#4!¬4HIS¬3.0¬ASSOCIATES¬WITH¬A¬LOWER¬EXPRESSION¬OF¬-(#¬MOLECULES¬AND¬IN¬A¬ 3WEDISH¬COHORT¬OF¬¬2!¬PATIENTS¬AND¬¬CONTROLS¬THIS¬3.0¬CONFERRED¬A¬¬HIGHER¬RISK¬ TO¬DEVELOP¬2!¬ ¬4HE¬l¬NDINGS¬ON¬THIS¬3.0¬AWAIT¬REPLICATION¬)N¬*APANESE¬PATIENTS¬AND CONTROLS¬AN¬ASSOCIATION¬BETWEEN¬HAPLOTYPES¬COMBINATIONS¬OF¬3.0S¬ON¬ONE¬CHROMOSOME. .

(76) THAT¬TEND¬TO¬INHERIT¬TOGETHER ¬OF¬THE¬GENE¬ENCODING¬0!$)¬WITH¬INCREASED¬SUSCEPTIBILITY TO¬2!¬WAS¬OBSERVED¬ ¬4HE¬2! SUSCEPTIBLE¬0!$)¬VARIANT¬WAS¬SHOWN¬TO¬PRODUCE¬A¬MORE¬ STABLE¬TRANSCRIPT¬THAN¬THE¬NON SUSCEPTIBLE¬VARIANT

(77) ¬IMPLYING¬AN¬INCREASED¬PRODUCTION¬OF¬ 0!$)¬AND¬THEREFORE¬HIGHER¬LEVEL¬OF¬CITRULLINATION¬BY¬THE¬2! SUSCEPTIBLE¬VARIANT¬5NLESS¬A HIGHER¬LEVEL¬OF¬CITRULLINATION

(78) ¬THE¬DESCRIBED¬0!$)¬HAPLOTYPES¬DID¬NOT¬CORRELATE¬WITH¬THE¬ LEVEL¬OF ¬ANTI ##0¬ANTIBODIES¬ ¬4HE¬ASSOCIATION¬OF¬0!$)¬WITH¬2!¬IS¬SHOWN¬IN¬THE¬*APA NESE¬POPULATION¬$ATA¬FROM¬#AUCASIANS¬FROM¬&RANCE¬AND¬THE¬5+¬SHOWED¬NO¬ASSOCIATION¬ WITH¬ 0!$)¬ HAPLOTYPES¬ AND¬ 2!¬

(79) ¬ 3USCEPTIBILITY¬ GENES¬ CAN¬ INTERACT¬ SUCH¬ THAT¬ THE RESULTING¬PREDISPOSITION¬OF¬CARRYING¬BOTH¬GENES¬IS¬LARGER¬THAN¬THE¬SUMMED¬ODDS¬RATIOS¬OF¬ THE¬INDIVIDUAL¬GENES¬4HE¬PRESENCE¬OF¬SUCH¬INTERACTION¬IS¬IMPORTANT¬WITH¬REGARD¬TO¬PREDIC TION¬)N¬¬*APANESE¬2!¬PATIENTS¬AND¬¬CONTROLS¬A¬RISK¬FOR¬2!¬OF¬¬WAS¬IDENTIl¬ED¬FOR¬A RISK¬ALLELE¬IN¬THE¬ORGANIC¬CATION¬TRANSPORTER¬GENE¬3,#!¬ ¬)NTRIGUINGLY

(80) ¬THE¬IDENTI l¬ED¬3.0¬AFFECTS¬THE¬TRANSCRIPTIONAL¬EFl¬CIENCY¬OF¬3,#!¬IN¬VITRO¬BY¬ALTERING¬THE¬BINDING¬ AFl¬NITY¬OF¬A¬HAEMATOPOIETIC¬TRANSCRIPTION¬FACTOR

(81) ¬CALLED¬25.8¬!¬SMALL¬BUT¬SIGNIl¬CANT¬ ASSOCIATION¬WAS¬OBSERVED¬WITH¬THE¬MINOR¬ALLELE¬IN¬THE¬25.8 GENE¬)MPORTANTLY¬HOMO ZYGOSITY¬FOR¬BOTH¬SUSCEPTIBILITY¬ALLELES¬3,#!¬AND¬25.8 ¬SHOWED¬A¬HIGH¬ODDS¬RATIO. #HAPTER¬. OF¬

(82) ¬INDICATIVE¬FOR¬A¬GENE GENE¬INTERACTION¬ ¬2ECENTLY¬THE¬EFFECTS¬OF¬THIS¬25.8 ¬3.0¬. . WAS¬NOT¬FOUND¬IN¬A¬#AUCASIAN¬POPULATION¬ ¬!¬3.0¬IN¬THE¬PROMOTER¬REGION¬OF¬&#2,¬IS¬ RECENTLY¬SHOWN¬TO¬BE¬ASSOCIATED¬WITH¬SUSCEPTIBILITY¬TO¬2!¬ ¬&OR¬A¬LARGE¬NUMBER¬OF¬OTHER¬ GENES¬SUGGESTED¬TO¬BE¬RELEVANT¬IN¬THE¬PATHOPHYSIOLOGY¬OF¬2!

(83) ¬ASSOCIATION¬WAS¬OBSERVED¬ IN¬ONLY¬ONE¬STUDY¬WITHOUT¬REPLICATION¬4HESE¬STUDIES¬CONCERNED¬"ETA ADRENERGIC¬RECEPTOR¬ GENE¬3.0S

(84) ¬2!.+,

(85) ¬)#!-

(86) ¬6%'&

(87) ¬0$#$ ¬AND¬), 2!¬GENE¬ "ESIDES¬GENETIC¬RISK¬FACTORS¬THAT¬CONFER¬A¬HIGHER¬RISK¬TO¬DEVELOP¬2!

(88) ¬THERE¬ALSO¬A¬GENETIC RISK¬FACTORS¬THAT¬PROTECTS¬TO¬2!¬4HIS¬CONCERNS¬PARTICULARLY¬THE¬(,! $2"¬ALLELES¬THAT¬EN CODES¬FOR¬THE¬AMINO¬ACIDS¬$%2!!¬$2"

(89) ¬

(90) ¬

(91) ¬

(92) ¬

(93) ¬

(94) ¬ ¬ )NTERESTINGLY

(95) ¬THE¬(,! $2"¬ALLELES¬CAN¬ENCODE¬FOR¬DIFFERENT¬ALLELES¬WITH¬AN¬OPPOSITE¬EFFECT ON¬DISEASE¬SUSCEPTIBILITY¬4HE¬PROTECTIVE¬EFFECT¬OF¬THE¬$%2!! ENCODING¬ALLELES¬IS¬INDEPEN DENT¬FROM¬THE¬SHARED¬EPITOPE¬ENCODING¬ALLELES¬WITH¬PREDISPOSING¬EFFECTS¬

(96)

(97) ¬"OTH¬ IN¬THE¬PRESENCE¬AND¬IN¬THE¬ABSENCE¬OF¬SHARED¬EPITOPE¬ENCODING¬ALLELES¬THE¬$%2!! ENCOD ING¬ALLELES¬CONFER¬SIGNIl¬CANT¬LOWER¬ODDS¬OF¬¬TO¬DEVELOP¬2!¬ ¬ )N¬SUMMARY

(98) ¬THE¬CURRENT¬KNOWLEDGE¬ON¬WELL VALIDATED¬GENETIC¬RISK¬FACTORS¬TO¬BE¬INCLUDED IN¬ A¬ $.!¬ l¬NGERPRINT¬ IS¬ LIMITED¬ TO¬ (,! $2"¬ AND¬ 040.¬ (,! $2"¬ IS¬ ESTIMATED¬ TO¬ ACCOUNT¬FOR¬^¬OF¬THE¬GENETIC¬COMPONENT¬OF¬THIS¬AUTOIMMUNE¬DISEASE¬ ¬WHILE¬THE CONTRIBUTION¬OF¬040.¬IS¬MUCH¬SMALLER¬4HIS¬IMPLIES¬THAT¬A¬SIGNIl¬CANT¬PART¬OF¬THE¬GENETIC¬ CONTRIBUTION¬IS¬STILL¬TO¬BE¬IDENTIl¬ED¬)N¬A¬NUMBER¬OF¬WHOLE¬GENOME¬SCANS¬ ¬A¬CONSIDER ABLE¬NUMBER¬OF¬PEAKS¬OF¬LINKAGE¬HAVE¬BEEN¬IDENTIl¬ED¬)N¬A¬STUDY¬TO¬ESTIMATE¬THE¬NUMBER¬ OF¬ TRUE¬ 2!¬ GENE¬ REGIONS¬ THAT¬ TOOK¬ INTO¬ ACCOUNT¬ BOTH¬ THE¬ HETEROGENEITY¬ OF¬ 2!¬ AND¬ THE¬ PERFORMANCE¬OF¬A¬DENSE¬GENOME¬SCAN

(99) ¬IT¬WAS¬FOUND¬THAT¬¬ ¬¬REGIONS¬MEAN¬ ¬3$ ¬WERE¬ TRUE POSITIVES¬ AND¬ EVIDENCE¬ FOR¬ ¬ ADDITIONAL¬ REGIONS¬ WAS¬ PROVIDED¬ FROM¬ COVARIATE BASED¬.

(100) 'ENETICS¬AND¬CLINICAL¬CHARACTERISTICS¬TO¬PREDICT¬2!. ANALYSIS¬ ¬/NE¬OF¬THOSE¬REGIONS¬IS¬THE¬(,! $2"¬LOCUS

(101) ¬MEANING¬THAT¬AT¬LEAST¬¬ ¬ ADDITIONAL¬GENES¬WILL¬BE¬IDENTIl¬ED¬WITH¬EACH¬QUITE¬MODEST¬EFFECT¬4ECHNICAL¬PROGRESS¬SUCH AS¬ 3.0 BASED¬ LINKAGE¬ ANALYSIS¬ HAS¬ BEEN¬ DEMONSTRATED¬ TO¬ ALLOW¬ LOCI¬ TO¬ BE¬ DEl¬NED¬ MORE PRECISELY¬ ¬4HE¬CHANCE¬THAT¬THIS¬WILL¬LEAD¬TO¬THE¬IDENTIl¬CATION¬OF¬THE¬MAJORITY¬OF¬THE GENETIC¬RISK¬FACTORS¬IS¬LARGER¬WHEN¬2!¬IS¬CAUSED¬BY¬A¬DOZEN¬COMMON¬GENETIC¬VARIANTS¬THAN WHEN¬ 2!¬ IS¬ THE¬ RESULT¬ OF¬ MANY¬ RARE¬ MUTATIONS¬ 'IVEN¬ THE¬ FACT¬ THAT¬ (,!¬ AND¬ 040. HAVE¬ALREADY¬BEEN¬IDENTIl¬ED

(102) ¬WE¬SPECULATE¬THAT¬2!¬IS¬CAUSED¬BY¬A¬DOZEN¬COMMON¬GENETIC¬ VARIANTS¬4HE¬STATISTICAL¬METHODS¬TO¬EVALUATE¬MANY¬GENE¬VARIANTS¬WITH¬DISEASE¬STATUS

(103) ¬AS¬IN CANDIDATE GENE¬CASE CONTROL¬STUDIES¬ARE¬STILL¬IN¬ITS¬INFANCY¬ESPECIALLY¬FOR¬THE¬LOW¬EFFECT¬SIZES¬ OF¬THE¬INDIVIDUAL¬DISEASE¬LOCI¬AND¬THE¬SOMETIMES¬LOW¬FREQUENCIES¬OF¬THE¬DISEASE¬ALLELES ¬ 4HE¬STANDARD¬METHODS¬TO¬EVALUATE¬THE¬ASSOCIATION¬OF¬MULTIPLE¬MARKERS¬WITH¬DISEASE¬STA TUS¬ ARE¬ BASED¬ ON¬ MULTIMARKER¬ MULTIVARIATE¬ ANALYSES¬ &OR¬ SUCH¬ MULTIMARKER¬ MULTIVARIATE ANALYSES

(104) ¬ONE¬TYPICALLY¬USES¬LOGISTIC¬REGRESSION¬TO¬TEST¬SIMULTANEOUSLY¬THE¬MAIN¬EFFECTS¬AND¬ POSSIBLY¬INTERACTIONS ¬OF¬MULTIPLE¬MARKERS¬&OR¬EACH¬MARKER

(105) ¬A¬COVARIATE¬CAN¬BE¬CREATED

(106) ¬ SUCH¬AS¬THE¬NUMBER¬OF¬RARE¬ALLELES¬AT¬EACH¬MARKER¬7HEN¬THIS¬TYPE¬OF¬CODING¬IS¬USED¬IN¬ LOGISTIC¬REGRESSION

(107) ¬THE¬RESULTING¬SCORE¬STATISTIC¬FOR¬EACH¬MARKER¬IMPLIES¬MANY¬DEGREES¬OF¬ FREEDOM

(108) ¬IMPLYING¬THAT¬THE¬OVERALL¬ MODEL¬ SUFFERS¬FROM¬ WEAK¬POWER¬ -OREOVER¬ COMPLEX MODELS¬TEND¬TO¬OVERl¬T¬THE¬DATA¬STRESSING¬THE¬NECESSITY¬FOR¬REPLICATION¬IN¬INDEPENDENT¬CO HORTS¬$ESPITE¬THESE¬DIFl¬CULTIES¬THE¬OUTLOOK¬IS¬THAT¬THE¬GENETIC¬CONTRIBUTION¬TO¬2!¬IS¬ABOUT¬ ¬ ¬4HIS¬NUMBER¬IS¬ESTIMATED¬BY¬THE¬COMPARISON¬BETWEEN¬THE¬CONCORDANCE¬RATES¬ IN¬MONOZYGOTIC¬TWINS¬AND¬THE¬PREVALENCE¬IN¬THE¬RESPECTIVE¬POPULATIONS¬ ¬4HIS¬HIGH¬ PERCENTAGE¬IMPLIES¬THAT¬MEASUREMENT¬OF¬GENETIC¬HOST¬CHARACTERISTICS¬IS¬LIKELY¬TO¬HAVE¬A¬ROLE IN¬A¬PREDICTIVE¬TEST 7HICH¬ENVIRONMENTAL¬RISK¬FACTORS¬FOR¬2!¬ARE¬KNOWN 3O¬FAR¬SMOKING¬HAS¬BEEN¬SHOWN¬THE¬ONLY¬PLAUSIBLE¬ENVIRONMENTAL¬RISK¬FACTOR¬FOR¬2!¬!N¬ ASSOCIATION¬WITH¬SMOKING¬IN¬2!¬IS¬PARTICULARLY¬FOUND¬FOR¬RHEUMATOID¬FACTOR¬POSITIVE¬2!¬ COMPARED¬ TO¬ RHEUMATOID¬ FACTOR¬ NEGATIVE¬ DISEASE¬

(109) ¬ #URRENT¬ OR¬ EX SMOKERS¬ HAVE¬ A RISK¬FOR¬AUTOANTIBODY¬POSITIVE¬2!¬WITH¬AN¬ODDS¬RATIO¬OF¬ ¬4HE¬RISK¬INCREASES¬WITH¬ CUMULATIVE¬DOSE¬OF¬SMOKING¬ ¬!¬RECENT¬REPORT¬INVESTIGATED¬WHETHER¬SMOKING¬IS¬PRIMAR ILY¬ ASSOCIATED¬ WITH¬ THE¬ DEVELOPMENT¬ OF¬ RHEUMATOID¬ FACTOR¬ OR¬ ANTI ##0¬ ANTIBODIES¬ 4HIS STUDY¬ NICELY¬ REVEALED¬ A¬ GENE ENVIRONMENT¬ INTERACTION¬ BY¬ SHOWING¬ THAT¬ IN¬ THE¬ PRESENCE OF¬ (,! SHARED¬ EPITOPE¬ ALLELES¬ SMOKING¬ SIGNIl¬CANTLY¬ CONTRIBUTES¬ TO¬ THE¬ DEVELOPMENT¬ OF¬ ANTI ##0¬ANTIBODIES¬ ¬ !¬PREDICTIVE¬EFFECT¬OF¬ORAL¬ANTICONCEPTIVES¬ON¬2!¬HAS¬BEEN¬CLAIMED¬ ¬4HIS¬l¬NDING¬HAS¬ HOWEVER¬NOT¬BEEN¬REPLICATED¬IN¬THE¬.URSES¬(EALTH¬STUDY¬ . .

(110) 0REDICTIVE¬VALUE¬OF¬A¬$.!¬l¬NGERPRINT TEST !¬LARGE¬PROBLEM¬IN¬TRANSFERRING¬THE¬DATA¬ON¬GENETIC¬RISK¬FACTORS¬TO¬PREDICTION¬MODELS¬IS THAT¬THE¬MOST¬CURRENT¬STUDIES¬COMPARED¬PATIENTS¬AND¬CONTROLS

(111) ¬REVEALING¬ODDS¬RATIOS¬THAT¬ ARE¬ DETERMINED¬ ON¬ GROUP¬ LEVELS¬ 4HE¬ VALUE¬ OF¬ THESE¬ GENETIC¬ RISK¬ FACTORS¬ FOR¬ INDIVIDUAL¬ PREDICTIVE¬TESTING¬MAY¬BE¬LIMITED¬#OMPARE¬FOR¬EXAMPLE¬THE¬STATISTICAL¬MODELS¬TO¬PREDICT¬ THE¬PRE TEST¬PROBABILITY¬ON¬"2#! ¬GENES¬"2#!¬OR¬¬CARRIERS¬HAVE¬A¬VERY¬STRONG¬RISK FOR¬OVARIANBREAST¬CANCER¬4HE¬STATISTICAL¬MODELS¬TO¬PREDICT¬THE¬PRESENCE¬OF¬A¬"2#!¬RISK ALLELE¬ARE¬ONLY¬INFORMATIVE¬IN¬A¬SELECTED¬POPULATION¬WITH¬AFFECTED¬FAMILY¬MEMBERS¬ 4HIS¬EXAMPLE¬UNDERLINES¬THAT¬l¬NDINGS¬FOR¬A¬WHOLE¬GROUP¬CANNOT¬BE¬AUTOMATICALLY¬USED¬FOR¬ PREDICTION¬IN¬SUBGROUPS¬OF¬PATIENTS¬OR¬FOR¬INDIVIDUALS¬'ENES¬MAY¬CONFER¬RISK¬TO¬SUBGROUPS¬ OF¬2!¬PATIENTS¬&OR¬EXAMPLE

(112) ¬THE¬WELL KNOWN¬(,! SHARED¬EPITOPE¬ALLELES¬PREDISPOSE¬PARTIC ULARLY¬TO¬ANTI ##0¬POSITIVE¬2!¬ ¬4HE¬"2#! ¬EXAMPLE¬ALSO¬ELUCIDATES¬THAT¬THE¬PREDICTIVE¬ VALUE¬OF¬A¬TEST¬DEPENDS¬ON¬THE¬PREVALENCE¬OF¬A¬DISEASE¬IN¬A¬POPULATION¬&OR¬5!

(113) ¬A¬NUMBER OF¬INCEPTION¬COHORTS¬OF¬PATIENTS¬WITH¬RECENT¬ONSET¬ARTHRITIS¬HAVE¬IDENTIl¬ED¬PATIENTS¬WITH A¬ FORM¬ OF¬ ARTHRITIS¬ THAT¬ HAS¬ THE¬ POTENTIAL¬ FOR¬ A¬ PERSISTENT¬ COURSE

(114) ¬ WITHOUT¬ FULl¬LLING¬ THE CLASSIl¬CATION¬CRITERIA¬OF¬OTHER¬RHEUMATIC¬DISORDERS¬ ¬)N¬NINE¬COHORTS

(115) ¬THE¬PROPORTION. #HAPTER¬. OF¬PATIENTS¬WITH¬5!¬THAT¬EVOLVED¬INTO¬2!¬WITHIN¬¬YEAR¬VARIED¬FROM¬¬TO¬¬4HUS

(116) IN¬THIS¬GROUP¬OF¬5!¬PATIENTS¬THE¬PRE TEST¬PROBABILITY¬OF¬DEVELOPING¬2!¬VARIES¬BETWEEN¬ ¬'IVEN¬THE¬DYNAMICS¬OF¬DEVELOPMENT¬OF¬5!¬TO¬EITHER¬REMISSION¬OR¬PROGRESSION¬TO¬2!

(117) THE¬EVALUATION¬OF¬PREDICTIVE¬MODELS¬FOR¬THIS¬PATIENT¬GROUP¬IS¬HIGHLY¬RELEVANT. . #(!2!#4%2)34)#3¬/&¬4(%¬$)3%!3%¬02/#%33¬!.$¬02%$)#4)/.. 4HE¬THEORETICAL¬BACKGROUND¬OF¬THIS¬SECTION¬IS¬THE¬ASSUMPTION¬THAT¬THE¬EXPRESSION¬OF¬THE DISEASE¬IN¬AN¬INITIAL¬PHASE¬ALLOWS¬PREDICTION¬OF¬THE¬OUTCOME¬4HE¬GENOMIC¬REVOLUTION¬HAS FUELLED¬MUCH¬OPTIMISM¬THAT¬GENE¬EXPRESSION¬PROl¬LES¬ALLOW¬SUCH¬OUTCOME¬MEASURES¬'ENE¬ EXPRESSION¬PROl¬LES¬ARE¬CURRENTLY¬USED¬IN¬BREAST¬CANCER¬TO¬SELECT¬THE¬PATIENTS¬THAT¬WOULD¬ BENEl¬T¬FROM¬ADJUVANT¬THERAPY¬ ¬(OWEVER

(118) ¬OTHERS¬WARNED¬THAT¬THE¬PROGNOSTIC¬VALUE¬OF¬ THE¬PUBLISHED¬MICRO ARRAY¬RESULTS¬IN¬CANCER¬STUDIES¬SHOULD¬BE¬CONSIDERED¬WITH¬CAUTION¬AS THE¬LIST¬OF¬GENES¬IDENTIl¬ED¬AS¬PREDICTORS¬OF¬PROGNOSIS¬WAS¬HIGHLY¬UNSTABLE¬AND¬THE¬MOLECU LAR¬SIGNATURES¬DEPENDED¬STRONGLY¬ON¬THE¬SELECTION¬OF¬PATIENTS¬ ¬4HE¬PROGNOSTIC¬VALUE¬OF¬ THE¬SEVERAL¬MICRO ARRAYS¬IN¬ONCOLOGY¬THEREFORE¬NEEDS¬REPLICATION $ISEASE¬CHARACTERISTICS¬PRESENT¬AT¬THE¬PRESENTATION¬OF¬5!¬THAT¬PREDICT¬ PROGRESSION¬TO¬2! 4HE¬MOST¬IMPORTANT¬AND¬BEST VALIDATED¬DISEASE¬CHARACTERISTICS¬WITH¬REGARD¬TO¬PREDICTION¬ ARE¬ AUTO ANTIBODIES¬ ANTI ##0¬ AND¬ RHEUMATOID¬ FACTOR

(119) ¬ 2& ¬ AND¬ THE¬ PRESENCE¬ OF¬ EROSIONS ON¬THE¬RADIOGRAPHS¬OF¬HANDS¬AND¬FEET¬AT¬INITIAL¬PRESENTATION¬)N¬UNIVARIATE¬ANALYSIS

(120) ¬THE¬.

(121) 'ENETICS¬AND¬CLINICAL¬CHARACTERISTICS¬TO¬PREDICT¬2!. PRESENCE¬OF¬ANTI ##0¬ANTIBODIES¬IN¬PATIENTS¬WITH¬A¬5!¬CONFERRED¬AN¬ODDS¬RATIO¬OF¬¬TO DEVELOP¬2!

(122) ¬COMPARED¬TO¬ANTI ##0¬NEGATIVE¬PATIENTS¬WITH¬5!¬ ¬!¬LOGISTIC¬REGRESSION¬ MODEL¬SHOWED¬ODDS¬OF¬¬FOR¬ANTI ##0¬ANTIBODIES¬IN¬THE¬PREDICTION¬OF¬2!¬ ¬2AZA¬ET AL¬FOLLOWED¬¬PATIENTS¬WITH¬SYNOVITIS¬FOR¬LESS¬THAN¬¬MONTHS¬FOR¬¬WEEKS¬AND¬ASSESSED THE¬PROGNOSTIC¬VALUE¬OF¬ANTI ##0¬ANTIBODIES¬AND¬2&¬ ¬)N¬THIS¬STUDY¬THE¬COMBINATION¬ OF¬ ANTI ##0¬ ANTIBODIES¬ AND¬ 2&¬ HAD¬ A¬ POSITIVE¬ PREDICTIVE¬ VALUE¬ OF¬ ¬ AND¬ A¬ NEGATIVE¬ PREDICTIVE¬VALUE¬OF¬¬FOR¬A¬DIAGNOSIS¬OF¬2!¬ #LINICAL¬ DISEASE¬ CHARACTERISTICS¬ OF¬ ¬ 5!¬ PATIENTS¬ THAT¬ PRESENTED¬ TO¬ THE¬ ,EIDEN¬ %ARLY¬ !RTHRITIS¬#LINIC¬DIFFERED¬BETWEEN¬THE¬5!¬PATIENTS¬THAT¬DEVELOPED¬2!¬VERSUS¬THOSE¬WHO¬DID¬ NOT¬DEVELOP¬2!¬$ISEASE¬CHARACTERISTICS¬ASSOCIATED¬WITH¬2!¬DEVELOPMENT¬WERE¬A¬HIGHER¬AGE ¬VERSUS¬

(123) ¬FEMALE¬SEX¬¬VERSUS¬

(124) ¬DURATION¬OF¬MORNING¬STIFFNESS¬¬MINUTES¬ VERSUS¬¬MINUTES

(125) ¬LONGER¬DURATION¬OF¬SYMPTOMS¬¬VERSUS¬¬DAYS ¬AND¬A¬HIGHER¬NUM BER¬OF¬SWOLLEN¬JOINTS¬¬VERSUS¬ 6ISSER¬ ET¬ AL¬ DEVELOPED¬ A¬ CLINICAL¬ MODEL¬ FOR¬ THE¬ PREDICTION¬ OF¬ THREE¬ FORMS¬ OF¬ ARTHRITIS¬ OUTCOME¬SELF LIMITING¬DISEASE

(126) ¬PERSISTENT¬NON EROSIVE¬DISEASE¬AND¬PERSISTENT¬EROSIVE¬DIS EASE¬ ¬&OR¬THE¬DEVELOPMENT¬OF¬THIS¬MODEL¬THE¬l¬RST¬¬CONSECUTIVE¬PATIENTS¬REFERRED TO¬THE¬,EIDEN¬%ARLY¬!RTHRITIS¬#LINIC¬WERE¬STUDIED¬AND¬THE¬ARTHRITIS¬OUTCOME¬WAS¬RECORDED AFTER¬ TWO¬ YEARS¬ OF¬ FOLLOW UP¬ 4HE¬ DEVELOPED¬ PREDICTION¬ MODEL¬ CONSISTED¬ OF¬ ¬ VARIABLES SYMPTOM¬ DURATION¬ AT¬ l¬RST¬ VISIT

(127) ¬ MORNING¬ STIFFNESS¬ FOR¬ *¬ ¬ HOUR

(128) ¬ ARTHRITIS¬ IN¬ *¬ ¬ JOINTS

(129) ¬ BILATERAL¬ COMPRESSION¬ PAIN¬ IN¬ THE¬ METATARSOPHALANGEAL¬ JOINTS

(130) ¬ 2&¬ POSITIVITY

(131) ¬ ANTI ##0¬ POSITIVITY¬AND¬THE¬PRESENCE¬OF¬EROSIONS¬AT¬STUDY¬ENTRY¬4HE¬2/#¬AREA¬UNDER¬THE¬CURVE¬FOR¬ DISCRIMINATION¬ BETWEEN¬ SELF LIMITING¬ AND¬ PERSISTENT¬ NON EROSIVE¬ ARTHRITIS¬ WAS¬ ¬ AND¬ FOR¬ DISCRIMINATION¬ BETWEEN¬ PERSISTENT¬ NONEROSIVE¬ AND¬ EROSIVE¬ ARTHRITIS¬ ¬ ¬ !FTER¬ THE¬ADDITION¬OF¬PREDISPOSING¬(,! #LASS¬))¬ALLELES

(132) ¬THE¬DISCRIMINATIVE¬ABILITY¬OF¬THE¬MODEL¬ WAS¬NOT¬SIGNIl¬CANTLY¬IMPROVED¬ ¬4HE¬MODEL¬DERIVED¬BY¬6ISSER¬USED¬ALL¬PATIENTS¬OF¬THE ,EIDEN¬%ARLY¬!RTHRITIS¬#LINIC¬INSTEAD¬OF¬ONLY¬THE¬PATIENTS¬WITH¬5!¬4HE¬ADVANTAGE¬OF¬THE MODEL¬OF¬6ISSER¬IS¬THAT¬IT¬CAN¬BE¬USED¬FOR¬A¬hRANDOMv¬PATIENT¬WITH¬ARTHRITIS¬THAT¬VISITED¬AN¬ OUTPATIENT¬CLINIC¬OF¬A¬RHEUMATOLOGIST

(133) ¬THE¬DISADVANTAGE¬IS¬THAT¬IT¬ALSO¬PREDICTS¬OCCURRENCE OF¬ 2!¬ IN¬ PATIENTS¬ THAT¬ ALREADY¬ FULl¬LLED¬ THE¬ CLASSIl¬CATION¬ CRITERIA¬ FOR¬ 2!¬ #URRENTLY¬ IT¬ IS¬ ANALYZED¬WHETHER¬THE¬CLINICAL¬CHARACTERISTICS¬USED¬IN¬THIS¬MODEL¬ALSO¬HAVE¬PREDICTIVE¬VALUE¬ IN¬PATIENTS¬WITH¬5! 4O¬WHAT¬EXTENT¬CAN¬CLINICAL¬OBSERVATION¬BE¬USED¬IN¬PREDICTION #LINICAL¬OBSERVATION¬OF¬THE¬NATURAL¬COURSE¬IS¬THE¬BEST¬WAY¬OF¬PREDICTING¬WHAT¬THE¬SUBSE QUENT¬COURSE¬WILL¬BE¬&ROM¬A¬RETROSPECTIVE¬VIEWPOINT

(134) ¬THE¬HISTORY¬OF¬THE¬PATIENTS¬CAN¬BE¬ USED¬AS¬ILLUSTRATED¬IN¬THE¬MODEL¬PROPOSED¬BY¬6ISSER¬IN¬WHICH¬A¬LONG¬DURATION¬OF¬COMPLAINTS¬ WAS¬ASSOCIATED¬WITH¬HIGHER¬ODDS¬FOR¬CHRONIC¬AND¬EROSIVE¬DISEASE¬ ¬4HE¬POLICY¬TO¬INCLUDE¬ A¬hWAIT¬AND¬SEEv¬POLICY¬CAN¬ONLY¬BE¬TAKEN¬IN¬THE¬CONTEXT¬WHEN¬THE¬POSSIBLE¬DISADVANTAGES ARE¬CONSIDERED¬4HE¬PROGRESS¬FORM¬5!¬TO¬2!¬IS¬CHARACTERIZED¬BY¬THE¬ACQUISITION¬OF¬CERTAIN¬. .

(135) PHENOTYPIC¬ CHARACTERISTICS¬ THAT¬ FORM¬ THE¬ !#2¬ CLASSIl¬CATION¬ CRITERIA

(136) ¬ INCLUDING¬ JOINT¬ DE STRUCTION¬WITH¬SUBSEQUENT¬DEFORMITIES

(137) ¬AND¬EXTRA ARTICULAR¬FEATURES¬SUCH¬AS¬NODULES¬'IVEN THE¬ACCUMULATING¬EVIDENCE¬THAT¬APPROPRIATE¬THERAPY¬MIGHT¬PREVENT¬THE¬DEVELOPMENT¬OF¬ A¬ DETRIMENTAL¬ 2!¬ PHENOTYPE

(138) ¬ OBSERVATION¬ WITHOUT¬ TREATMENT¬ IS¬ IN¬ OUR¬ VIEW¬ ONLY¬ JUSTI l¬ED¬WHEN¬THE¬PATIENTS¬DOESNOT¬FULLl¬LL¬THE¬!#2¬CRITERIA¬3PECIl¬C¬STUDIES¬THAT¬COMPARE¬THE¬ INITIATION¬OF¬TREATMENT¬AS¬A¬FUNCTION¬OF¬DISEASE¬DURATION¬ARE¬SCARCE¬6ALUABLE¬DATA¬WERE¬OB TAINED¬IN¬A¬ YEAR¬FOLLOW UP¬STUDY¬BY¬%GSMOSE¬ET¬AL IN¬WHICH¬EARLY¬TREATMENT¬WITH¬INTRA MUSCULAR¬GOLD¬WAS¬COMPARED¬WITH¬A¬DELAYED¬TREATMENT¬STRATEGY¬ ¬4HE¬EARLY¬TREATMENT GROUP¬SHOWED¬IMPROVEMENT¬WITH¬RESPECT¬TO¬SIGNS¬AND¬SYMPTOMS

(139) ¬PHYSICAL¬FUNCTION¬AND RADIOGRAPHIC¬PROGRESSION

(140) ¬THUS¬SUPPORTING¬THE¬HYPOTHESIS¬OF¬A¬THERAPEUTIC¬@WINDOW¬OF¬OP PORTUNITY¬)N¬ANOTHER¬TRIAL¬BY¬VAN¬DER¬(EIDE¬ET¬AL¬IMMEDIATE¬VERSUS¬DELAYED¬INTRODUCTION¬ OF¬DISEASE MODIFYING¬ANTI RHEUMATIC¬DRUG¬$-!2$ ¬THERAPY¬WERE¬COMPARED¬IN¬PATIENTS¬ WITH¬RECENTLY¬DIAGNOSED¬2!¬ ¬%ARLY¬INTRODUCTION¬OF¬$-!2$S¬SHOWED¬GREATER¬PATIENT¬ IMPROVEMENT¬WITH¬REGARDS¬TO¬SIGNS¬AND¬SYMPTOMS

(141) ¬PHYSICAL¬FUNCTION¬AND¬RADIOGRAPHIC¬ PROGRESSION¬6AN¬!KEN¬ET¬AL¬COMPARED¬THE¬CONVENTIONAL¬PYRAMID¬STRATEGY

(142) ¬CONSISTING¬OF¬ SEQUENTIAL¬INSTITUTION¬OF¬.3!)$S¬AND¬SUBSEQUENT¬$-!2$¬THERAPY

(143) ¬WITH¬IMMEDIATE¬INI. #HAPTER¬. TIATION¬ OF¬ $-!2$¬ THERAPY¬ IN¬ AN¬ OBSERVATIONAL¬ STUDY¬ AGAIN

(144) ¬ THE¬ EARLY¬ TREATMENT¬ GROUP¬. . SHOWED¬LESS¬RADIOGRAPHIC¬PROGRESSION¬ ¬&INALLY

(145) ¬AN¬OBSERVATIONAL¬STUDY¬PERFORMED¬AT THE¬.ORFOLK¬!RTHRITIS¬2EGISTER¬PROVIDED¬EVIDENCE¬THAT¬PATIENTS¬IN¬WHOM¬$-!2$¬THERAPY WAS¬INITIATED¬WITHIN¬¬MONTHS¬OF¬DIAGNOSIS¬OF¬2!¬HAD¬A¬BETTER¬ YEAR¬RADIOGRAPHIC¬OUT COME¬THAN¬PATIENTS¬STARTING¬$-!2$¬THERAPY¬¬MONTHS¬AFTER¬2!¬DIAGNOSIS¬ ¬!LL¬THE¬ AFOREMENTIONED¬ STUDIES¬ HAVE¬ INVESTIGATED¬ THE¬ IMPORTANCE¬ OF¬ TIMING¬ OF¬ TREATMENT¬ WITH¬ REGARD¬TO¬DIAGNOSIS )N¬CONCLUSION

(146) ¬A¬ROLE¬FOR¬CLINICAL¬OBSERVATION¬IN¬PREDICTION¬FOR¬DEVELOPMENT¬OF¬2!¬SEEMS¬ ONLY¬JUSTIl¬ED¬IN¬5!¬PATIENTS¬WITH¬A¬LOW¬PROBABILITY¬TO¬DEVELOP¬2!. #/.#,53)/.. )N¬ THE¬ SEARCH¬ TO¬ PREDICT¬ 2!

(147) ¬ CURRENT¬ DATA¬ INDICATE¬ THAT¬ HOST¬ CHARACTERISTICS¬ ARE¬ RELEVANT TO¬PREDICT¬2!¬4HE¬IDENTIl¬CATION¬OF¬THESE¬HOST¬CHARACTERISTICS¬HAVE¬YIELDED¬(,!¬ALLELES¬AS¬ RISK¬AND¬AS¬PROTECTIVE¬ALLELES¬AND¬IDENTIl¬ED¬040.¬AS¬THE¬SECOND¬RISK¬GENE¬0ROGRESS¬TO¬ IDENTIFY¬GENETIC¬RISK¬FACTORS¬IS¬SLOW¬DUE¬TO¬THE¬FACT¬THAT¬EACH¬GENE¬MOST¬LIKELY¬HAS¬A¬VERY¬ SMALL¬EFFECT¬AND¬THE¬LACK¬OF¬GOOD¬STATISTICAL¬MODELS¬TO¬ANALYSE¬COMBINATIONS¬OF¬GENETIC¬RISK¬ FACTORS¬#LINICAL¬FACTORS¬TO¬BE¬INCLUDED¬IN¬A¬PREDICTIVE¬MODEL¬ARE¬MOST¬LIKELY¬THE¬DURATION OF¬MORNING¬STIFFNESS

(148) ¬THE¬PRESENCE¬OF¬AN¬ANTI ##0¬RESPONSE¬AND¬THE¬PRESENCE¬OF¬EROSIVE¬ ABNORMALITIES¬ON¬8 RAYS¬OF¬HANDS¬AND¬FEET.

(149) 'ENETICS¬AND¬CLINICAL¬CHARACTERISTICS¬TO¬PREDICT¬2!. 35--!29¬!.$¬&5452%¬0%230%#4)6%. 0REDICTION¬OF¬THE¬FUTURE¬IS¬IMPOSSIBLE¬BUT¬A¬MODEL¬CAN¬PROVIDE¬A¬PROBABILITY¬TO¬AN¬INDI VIDUAL¬PATIENT¬3UCH¬A¬PREDICTION¬MODEL¬SHOULD¬GUARANTEE¬A¬CLINICIAN¬AND¬PATIENT¬ENOUGH CERTAINTY¬EG¬ ¬THAT¬A¬PATIENT¬IS¬ASSIGNED¬TO¬THE¬CORRECT¬CATEGORY¬)N¬THE¬CONTEXT¬OF¬ 5!¬WERE¬ABOUT¬A¬THIRD¬WILL¬DEVELOP¬2!¬AND¬TWO¬THIRD¬WILL¬NOT¬DEVELOP¬2!

(150) ¬IT¬IS¬NOT¬EXACTLY¬ KNOWN¬WHAT¬THE¬MINIMUM¬VALUE¬OF¬2 HAS¬TO¬BE¬TO¬GET¬A¬VALUABLE¬PREDICTION¬MODEL¬4HE 2

(151) ¬THE¬FRACTION¬OF¬EXPLAINED¬VARIATION

(152) ¬IS¬A¬MEASURE¬FOR¬THE¬MODELS¬ABILITY¬TO¬PREDICT¬)T COMPARES¬ THE¬ MEAN¬ SQUARED¬ ERROR¬ OF¬ THE¬ PROGNOSTIC¬ MODEL¬ TO¬ THE¬ MEAN¬ SQUARED¬ ERROR OF¬ THE¬ MODEL¬ WITHOUT¬ ANY¬ PROGNOSTIC¬ VARIABLES¬ AND¬ DOES¬ NOT¬ HAVE¬ A¬ DIMENSION¬ 3OME INDICATION¬FOR¬AN¬ACCEPTABLE¬2 CAN¬BE¬OBTAINED¬FROM¬A¬SIMILAR¬PROBLEM

(153) ¬THE¬PREDICTION¬OF¬ THE¬SEVERITY¬OF¬JOINT¬DESTRUCTION¬IN¬2!¬$E¬6RIES¬ET¬AL¬RECENTLY¬DETERMINED¬THE¬ADEQUACY¬ OF¬CLINICAL¬PARAMETERS¬IN¬THE¬PREDICTION¬OF¬JOINT¬DESTRUCTION¬ ¬4HIS¬MODEL¬HAD¬A¬2¬OF¬ ¬AND¬CORRECTLY¬CLASSIl¬ED¬¬OF¬PATIENTS¬&URTHERMORE¬IT¬WAS¬CALCULATED¬THAT¬TO¬GET¬A¬ CORRECT¬CLASSIl¬CATION¬OF¬¬OF¬THE¬PATIENTS

(154) ¬SUCH¬A¬HYPOTHETICAL¬MODEL¬SHOULD¬HAVE¬A¬2 OF¬¬ ¬!¬MODEL¬THAT¬PREDICTS¬JOINT¬DAMAGE¬SCORES¬GIVES¬AN¬ESTIMATE¬FOR¬A¬CONTINUOUS¬ VARIABLE¬ AND¬ IS¬ THEREFORE¬ DIFFERENT¬ FROM¬ A¬ MODEL¬ THAT¬ PREDICTS¬ THE¬ ABSENCE¬ OR¬ PRESENCE OF¬DEVELOPMENT¬OF¬2!¬.EVERTHELESS¬THE¬DATA¬AS¬PRESENTED¬BY¬$E¬6RIES¬ET¬AL¬INDICATE¬THE¬ REQUIREMENTS¬ FOR¬ A¬ MODEL¬ TO¬ ADEQUATELY¬ PREDICT¬ DISEASE¬ DEVELOPMENT¬ IN¬ PATIENTS¬ WITH¬ 5!¬#URRENTLY

(155) ¬TO¬OUR¬KNOWLEDGE¬THERE¬ARE¬NO¬PREDICTION¬MODELS¬ANALYSED¬THAT¬ARE¬ABLE TO¬DETERMINE¬WITH¬AT¬LEAST¬¬CERTAINTY¬WHETHER¬AN¬INDIVIDUAL¬PATIENT¬WILL¬OR¬WILL¬NOT DEVELOP¬2!¬(OWEVER

(156) ¬GIVEN¬THAT¬MORE¬GENETIC¬FACTORS¬THAT¬ASSOCIATE¬WITH¬SUSCEPTIBILITY¬ TO¬2!¬WILL¬MOST¬LIKELY¬BE¬IDENTIl¬ED¬IN¬THE¬NEXT¬DECADE

(157) ¬WE¬EXPECT¬THAT¬THE¬RESULTS¬OF¬THE¬ GENETIC¬ VARIANTS¬ WILL¬ BE¬ INCLUDED¬ IN¬ FUTURE¬ PREDICTION¬ MODELS¬ 4HE¬ PREDICTIVE¬ VALUE¬ OF¬ DISEASE¬CHARACTERISTICS¬SUCH¬AS¬ANTI ##0¬ANTIBODIES¬HAS¬ALREADY¬BEEN¬IDENTIl¬ED¬AND¬GIVEN¬ ITS¬VERY¬LARGE¬AND¬VERY¬SPECIl¬C¬EFFECT

(158) ¬THIS¬WILL¬BE¬INCLUDED¬IN¬PREDICTION¬MODELS¬#LINI CAL¬CHARACTERISTICS¬HAVE¬NOT¬YET¬BEEN¬DEl¬NED¬IN¬GREAT¬DETAIL¬BUT¬WE¬EXPECT¬THAT¬WITH¬THE¬ CURRENT¬INCLUSION¬OF¬MANY¬PATIENTS¬IN¬DIFFERENT¬EARLY¬ARTHRITIS¬INITIATIVES

(159) ¬THESE¬DATA¬WILL BECOME¬AVAILABLE¬IN¬THE¬NEXT¬DECADE¬'IVEN¬THE¬EXPECTATION¬THAT¬GENETIC

(160) ¬SEROLOGICAL¬AND¬ CLINICAL¬ DATA¬ EACH¬ CONTAIN¬ INDEPENDENT¬ INFORMATION

(161) ¬ IT¬ SHOULD¬ BE¬ POSSIBLE¬ TO¬ COMBINE¬ THESE¬DATASETS¬TO¬GAIN¬MORE¬ACCURATE¬PROGNOSTIC¬INFORMATION¬(OPEFULLY¬THE¬2 OF¬SUCH¬A¬ MODEL¬WILL¬BE¬SUFl¬CIENTLY¬LARGE¬TO¬ALLOW¬PREDICTION¬AT¬THE¬PATIENT¬LEVEL¬ 4HIS¬REVIEW¬IS¬FOCUSSED¬ON¬PREDICTION¬OF¬THE¬DIAGNOSIS¬OF¬2!¬BUT¬NOT¬ON¬PREDICTION¬OF¬ THE¬PROGNOSIS¬OF¬2!¬4HIS¬IS¬CAUSED¬BY¬THE¬LACK¬OF¬EPIDEMIOLOGICAL¬DATA¬WHETHER¬SEVERITY OF¬2!¬SUCH¬AS¬RATE¬OF¬JOINT¬DESTRUCTION¬IS¬CAUSED¬BY¬EG¬GENETIC¬FACTORS¬)N¬THE¬NEXT¬DECADE¬ WE¬EXPECT¬THAT¬THESE¬BASIC¬EPIDEMIOLOGICAL¬DATA¬WILL¬BECOME¬AVAILABLE¬LEADING¬TO¬DEVELOP MENT¬OF¬PREDICTIVE¬TESTS¬FOR¬OUTCOME¬OF¬2!¬AS¬WELL. .

(162) 2%&%2%.#%3 ¬ ¬. ¬ ¬. ¬ ¬. ¬ ¬ ¬ ¬ ¬ ¬ ¬ ¬. #HAPTER¬. ¬ ¬. . ¬ ¬ ¬ ¬ ¬ ¬. ¬ ¬. ¬ ¬ ¬ ¬ ¬ ¬ ¬ ¬. ¬ ¬. ¬ ¬. 6AN¬!KEN¬*

(163) ¬VAN¬$ONGEN¬(

(164) ¬,E#ESSIE¬3

(165) ¬!LLAART¬#&

(166) ¬"REEDVELD¬&#

(167) ¬(UIZINGA¬47*¬,ONG TERM¬ OUTCOME¬ OF¬ RHEUMATOID¬ ARTHRITIS¬ THAT¬ PRESENTED¬ WITH¬ UNDIFFERENTIATED¬ ARTHRITIS¬ COMPARED¬TO¬RHEUMATOID¬ARTHRITIS¬AT¬PRESENTATION¬ ¬AN¬OBSERVATIONAL¬COHORT¬STUDY¬!NN 2HEUM¬$IS¬ ,INN 2ASKER¬30

(168) ¬!LLAART¬#&

(169) ¬+LOPPENBURG¬-


(171) ¬(UIZINGA¬47*¬3USTAINED¬RE MISSION¬ IN¬ A¬ COHORT¬ OF¬ PATIENTS¬ WITH¬ 2!¬ ASSOCIATION¬ WITH¬ ABSENCE¬ OF¬ )G- RHEUMATOID FACTOR¬ AND¬ ABSENCE¬ OF¬ ANTI ##0¬ ANTIBODIES¬ )NT¬ *¬ !DVANCES¬ 2HEUMATOLOGY¬ ¬ VAN¬ DER¬ (ELM VAN¬ -IL¬ !(

(172) ¬ $IEUDE¬ 0

(173) ¬ 3CHONKEREN¬ **

(174) ¬ #ORNELIS¬ &

(175) ¬ (UIZINGA¬ 47¬ .O¬ AS SOCIATION¬BETWEEN¬TUMOUR¬NECROSIS¬FACTOR¬RECEPTOR¬TYPE¬¬GENE¬POLYMORPHISM¬AND¬RHEU MATOID¬ARTHRITIS¬SEVERITY¬A¬COMPARISON¬OF¬THE¬EXTREMES¬OF¬PHENOTYPES¬2HEUMATOLOGY¬ /XFORD ¬ 2OBERTS 4HOMSON¬0*

(176) ¬*ONES¬-%

(177) ¬7ALKER¬*'

(178) ¬-ACFARLANE¬*'

(179) ¬3MITH¬-$

(180) ¬!HERN¬-*¬3TOCHAS TIC¬PROCESSES¬IN¬THE¬CAUSATION¬OF¬RHEUMATIC¬DISEASE¬*¬2HEUMATOL¬ ¬ $EL¬0UENTE¬!

(181) ¬+NOWLER¬7#

(182) ¬0ETTITT¬$*

(183) ¬"ENNETT¬0(¬(IGH¬INCIDENCE¬AND¬PREVALENCE¬OF¬ RHEUMATOID¬ARTHRITIS¬IN¬0IMA¬)NDIANS¬!M¬*¬%PIDEMIOL¬ 3ILMAN¬!*

(184) ¬0EARSON¬*%¬%PIDEMIOLOGY¬AND¬GENETICS¬OF¬RHEUMATOID¬ARTHRITIS¬!RTHRITIS¬2ES¬ 3 &ERUCCI¬%$

(185) ¬4EMPLIN¬$7

(186) ¬,ANIER¬!02HEUMATOID¬ARTHRITIS¬IN¬!MERICAN¬)NDIANS¬AND¬!LASKA .ATIVES¬A¬REVIEW¬OF¬THE¬LITERATURE¬3EMIN¬!RTHRITIS¬2HEUM¬ 3ILMAN¬!

(187) ¬(ARRISON¬"

(188) ¬"ARRETT¬%

(189) ¬3YMMONS¬$¬4HE¬EXISTENCE¬OF¬GEOGRAPHICAL¬CLUSTERS¬OF¬ CASES¬ OF¬ INm¬AMMATORY¬ POLYARTHRITIS¬ IN¬ A¬ PRIMARY¬ CARE¬ BASED¬ REGISTER¬ !NN¬ 2HEUM¬ $IS 2ACHEL¬!¬2OBERTS 4HOMSON

(190) A 0¬*¬2OBERTS 4HOMSON¬2HEUMATIC¬DISEASE¬AND¬THE¬!USTRALIAN¬ ABORIGINE¬!NN¬2HEUM¬$IS¬ 3ILMAN¬!*

(191) ¬/LLIER¬7

(192) ¬(OLLIGAN¬3

(193) ¬"IRRELL¬&

(194) ¬!DEBAJO¬!

(195) ¬!SUZU¬-#

(196) ¬ET¬AL¬!BSENCE¬OF¬RHEU MATOID¬ARTHRITIS¬IN¬A¬RURAL¬.IGERIAN¬POPULATION¬*¬2HEUMATOL¬¬ $ORAN¬ -&

(197) ¬ #ROWSON¬ #3

(198) ¬ /&ALLON¬ 7-

(199) ¬ (UNDER¬ ''

(200) ¬ 'ABRIEL¬ 3%¬ 4RENDS¬ IN¬ INCIDENCE¬ AND¬MORTALITY¬IN¬RHEUMATOID¬ARTHRITIS¬IN¬2OCHESTER

(201) ¬-INNESOTA

(202) ¬OVER¬A¬FORTY YEAR¬PERIOD¬ !RTHRITIS¬2HEUM¬ 3HICHIKAWA¬+

(203) ¬ )NOUE¬ +

(204) ¬ (IROTA¬3

(205) ¬ -AEDA¬ !

(206) ¬ /TA¬(

(207) ¬ +IMURA¬ -

(208) ¬ 5SHIYAMA¬4

(209) ¬ 4SUJIMOTO -¬ #HANGES¬ IN¬ THE¬ INCIDENCE¬ AND¬ PREVALENCE¬ OF¬ RHEUMATOID¬ ARTHRITIS¬ IN¬ +AMITONDA

(210) 7AKAYAMA

(211) ¬*APAN

(212) ¬ ¬!NN¬2HEUM¬$IS¬ (UIZINGA¬47*

(213) ¬,INN 2ASKER¬3

(214) ¬,ARD¬2'

(215) ¬7ESTENDORP¬2'¬'ENETIC¬DRIFT¬AS¬AN¬EXPLANATION¬ FOR¬THE¬REDUCED¬INCIDENCE¬OF¬2!

(216) ¬!RTHRITIS¬2HEUM¬ #UMMINS¬*¬%VOLUTIONARY¬FORCES¬BEHIND¬HUMAN¬INFERTILITY¬.ATURE¬¬ ¬ 5HLIG¬ 4

(217) ¬ +VIEN¬ 4+¬ )S¬ RHEUMATOID¬ ARTHRITIS¬ DISAPPEARING¬ !NN¬ 2HEUM¬ $IS¬ ¬ 7ELSING¬0-*

(218) ¬&RANSEN¬*

(219) ¬6AN¬2IELS¬0,#-¬)S¬THE¬DISEASE¬COURSE¬OF¬RHEUMATOID¬ARTHRITIS¬ BECOMING¬MILDER¬4IME¬TRENDS¬SINCE¬¬IN¬AN¬INCEPTION¬COHORT¬OF¬EARLY¬RHEUMATOID¬ ARTHRITIS¬!RTHRITIS¬2HEUM¬ (UIZINGA¬47*

(220) ¬!MOS¬#)

(221) ¬6AN¬DER¬(ELM ¬VAN¬-IL¬!(

(222) ¬ET¬AL¬2El¬NING¬THE¬COMPLEX¬RHEU MATOID¬ ARTHRITIS¬ PHENOTYPE¬ BASED¬ ON¬ SPECIl¬CITY¬ OF¬ THE¬ (,! $2"¬ SHARED¬ EPITOPE¬ FOR ANTIBODIES¬TO¬CITRULLINATED¬PROTEINS

(223) ¬!RTHRITIS¬2HEUM¬ 2ANTAPAA $AHLQVIST¬3

(224) ¬DE¬*ONG¬"!

(225) ¬"ERGLIN¬%

(226) ¬ET¬AL¬!NTIBODIES¬AGAINST¬CYCLIC¬CITRULLINATED PEPTIDE¬ AND¬ )G!¬ RHEUMATOID¬ FACTOR¬ PREDICT¬ THE¬ DEVELOPMENT¬ OF¬ RHEUMATOID¬ ARTHRITIS¬ !RTHRITIS¬2HEUM¬ .

(227) 'ENETICS¬AND¬CLINICAL¬CHARACTERISTICS¬TO¬PREDICT¬2!. ¬ ¬. ¬ ¬. ¬ ¬. ¬ ¬. ¬ ¬. ¬ ¬. ¬ ¬. ¬ ¬. ¬ ¬ ¬ ¬. ¬ ¬. ¬ ¬. ¬ ¬. ¬ ¬. ¬ ¬. ¬ ¬. .IELEN¬--

(228) ¬VAN¬3CHAARDENBURG¬$

(229) ¬2EESINK¬(7

(230) ¬ET¬AL¬3PECIl¬C¬AUTOANTIBODIES¬PRECEDE THE¬SYMPTOMS¬OF¬RHEUMATOID¬ARTHRITIS¬A¬STUDY¬OF¬SERIAL¬MEASUREMENTS¬IN¬BLOOD¬DONORS !RTHRITIS¬2HEUM¬ 6AN¬DER¬(ELM VAN¬-IL¬!(

(231) ¬6ERPOORT¬+.


(233) ¬ET¬AL¬!NTIBODIES¬TO¬CITRULLINATED PROTEINS¬AND¬DIFFERENCES¬IN¬CLINICAL¬PROGRESSION¬OF¬RHEUMATOID¬ARTHRITIS¬!RTHRITIS¬2ES¬4HER¬ 2 -AC'REGOR¬!¬/LLIER¬7

(234) ¬4HOMSON¬7

(235) ¬ET¬AL¬(,! $2" ¬GENOTYPE¬AND¬RHEU MATOID¬ARTHRITIS¬INCREASED¬ASSOCIATION¬IN¬MEN

(236) ¬YOUNG¬AGE¬AT¬ONSET

(237) ¬AND¬DISEASE¬SEVERITY¬ *¬2HEUMATOL¬ 6AN¬DER¬(ELM VAN¬-IL¬!(

(238) ¬(UIZINGA¬47

(239) ¬3CHREUDER¬'-

(240) ¬ET¬AL¬!N¬INDEPENDENT¬ROLE¬FOR¬ PROTECTIVE¬(,!¬#LASS¬))¬ALLELES¬IN¬RHEUMATOID¬ARTHRITIS¬SEVERITY¬AND¬SUSCEPTIBILITY

(241) ¬!RTHRI TIS¬2HEUM¬ ¬ "EGOVICH¬!"

(242) ¬#ARLTON¬6%

(243) ¬(ONIGBERG¬,!

(244) ¬ET¬AL¬!¬-ISSENSE¬3INGLE .UCLEOTIDE¬0OLYMOR PHISM¬IN¬A¬'ENE¬%NCODING¬A¬0ROTEIN¬4YROSINE¬0HOSPHATASE¬040. ¬)S¬!SSOCIATED¬WITH¬ 2HEUMATOID¬!RTHRITIS¬!M¬*¬(UM¬'ENET¬ 6AN¬/ENE¬-

(245) ¬7INTLE¬2&

(246) ¬,IU¬8

(247) ¬ET¬AL¬!SSOCIATION¬OF¬THE¬LYMPHOID¬TYROSINE¬PHOSPHATASE¬ 27¬VARIANT¬WITH¬RHEUMATOID¬ARTHRITIS

(248) ¬BUT¬NOT¬#ROHNS¬DISEASE

(249) ¬IN¬#ANADIAN¬POPULA TIONS¬!RTHRITIS¬2HEUM¬ 3IMKINS¬(-

(250) ¬-ERRIMAN¬-%

(251) ¬(IGHTON¬*

(252) ¬ET¬AL¬!SSOCIATION¬OF¬THE¬040.¬LOCUS¬WITH¬RHEU MATOID¬ARTHRITIS¬IN¬A¬.EW¬:EALAND¬#AUCASIAN¬COHORT¬!RTHRITIS¬2HEUM¬ 7ESOLY¬ *

No results found