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

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(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¬. '%.%2!,¬).42/$5#4)/..

(3)

(4) )NTRODUCTION. 2(%5-!4/)$¬!24(2)4)3. 2HEUMATOID¬ARTHRITIS¬2! ¬IS¬A¬SYMMETRIC¬POLYARTICULAR¬ARTHRITIS¬THAT¬MOST¬COMMONLY¬AF FECTS¬ THE¬ SMALL¬ JOINTS¬ OF¬ THE¬ HANDS¬ AND¬ THE¬ FEET

(5) ¬ BUT¬ MAY¬ INVOLVE¬ EVERY¬ SYNOVIAL¬ JOINT )Nm¬AMMATION¬ OF¬ THE¬ SYNOVIAL¬ MEMBRANE¬ THE¬ JOINT¬ LINING ¬ AND¬ DESTRUCTION¬ OF¬ ARTICULAR STRUCTURES¬CHARACTERIZE¬THE¬DISEASE¬PROCESS¬THAT¬IS¬CONSIDERED¬TO¬HAVE¬AN¬AUTOIMMUNE¬NA TURE¬.ORMALLY

(6) ¬THE¬SYNOVIUM¬IS¬RELATIVE¬ACELLULAR¬AND¬HAS¬A¬DELICATE¬INTIMAL¬LINING¬)N¬2!

(7) THE¬ SYNOVIUM¬ IS¬ INVADED¬ BY¬ INm¬AMMATORY¬ AND¬ IMMUNE¬ CELLS¬ AS¬ MACROPHAGES

(8) ¬ #$ ¬ 4¬ CELLS¬AND¬"¬CELLS¬AN¬INCREASE¬IN¬MACROPHAGE LIKE¬SYNOVIOCYTES¬AND¬l¬BROBLAST LIKE¬SYNOVIO CYTES¬LEAD¬TO¬SYNOVIAL¬HYPERPLASIA¬0ANNUS¬TISSUE

(9) ¬FORMED¬BY¬HYPERTROPHIC¬SYNOVIAL¬TISSUE

(10) ¬ SUBSEQUENTLY¬CONTRIBUTES¬TO¬CARTILAGE¬DESTRUCTION¬BY¬THE¬FORMATION¬OF¬DEGRADING¬ENZYMES AND¬l¬NALLY¬THE¬UNDERLYING¬BONE¬OF¬THE¬JOINT¬IS¬ERODED. )-0!#4¬/&¬2(%5-!4/)$¬!24(2)4)3. 2!¬IS¬THE¬MOST¬COMMON¬CHRONIC¬INm¬AMMATORY¬ARTHRITIS¬THAT¬HAS¬A¬LARGE¬IMPACT¬ON¬PHYSI CAL

(11) ¬SOCIAL¬AND¬EMOTIONAL¬FUNCTIONING¬AND¬ALSO¬CREATES¬A¬LARGE¬BURDEN¬OF¬ECONOMIC¬COSTS¬ 2!¬AFFECTS¬ ¬OF¬THE¬ADULT¬POPULATION¬IN¬%UROPE¬AND¬.ORTH¬!MERICA¬

(12) ¬)N¬THE .ETHERLANDS¬THE¬@3TANDAARD¬$IAGNOSE REGISTRATIE¬VAN¬2EUMATISCHE¬ZIEKTEN¬OF¬4./¬REPORTS A¬PREVALENCE¬OF¬¬PER¬

(13) ¬MEN¬AND¬¬PER¬

(14) ¬WOMEN

(15) ¬STANDARDIZED¬FOR¬THE¬$UTCH POPULATION¬IN¬¬ ¬&ROM¬THE¬PATIENTS¬PERSPECTIVE¬2!¬IS¬CHARACTERISED¬BY¬PAIN

(16) ¬STIFF NESS¬AND¬FATIGUE¬ ¬AND¬AT¬EXAMINATION¬THE¬FEATURES¬ARE¬INm¬AMMATION¬AND¬DESTRUCTION¬OF¬ JOINTS¬!LTHOUGH¬THE¬COURSE¬OF¬2!¬IS¬HIGHLY¬VARIABLE¬AMONG¬PATIENTS

(17) ¬THE¬PHYSICAL¬SYMP TOMS¬OFTEN¬HAVE¬IMPORTANT¬FUNCTIONAL¬CONSEQUENCES¬4HE¬PREVALENCE¬OF¬WORK¬DISABILITY¬AS CRIBED¬TO¬2!¬IS¬IMPRESSIVE¬&OLLOW UP¬OF¬PATIENTS¬ENROLLED¬IN¬THE¬./!2¬COHORT¬5+ ¬FOUND¬ THAT¬ IN¬ THE¬ EARLY¬ YEARS¬ AFTER¬ DISEASE¬ ONSET¬ ABOUT¬ ¬ OF¬ PATIENTS¬ PERMANENTLY¬ STOPPED WORKING¬DUE¬TO¬2!

(18) ¬AND¬THAT¬PATIENTS¬WITH¬2!¬WERE¬¬TIMES¬MORE¬LIKELY¬TO¬STOP¬WORK¬ON¬ HEALTH¬GROUNDS¬COMPARED¬TO¬MATCHED¬CONTROLS¬ ¬!LBERS¬ET¬AL¬OBSERVED¬IN¬A¬$UTCH¬COHORT OF¬EARLY¬2!¬PATIENTS¬WORK¬DISABILITY¬IN¬¬ ¬4HEY¬ALSO¬STRESSED¬THE¬BROADER¬IMPACT¬OF¬ 2!¬ON¬DAILY¬LIFE¬AS¬OVER¬¬OF¬PATIENTS¬NEEDED¬EXTRA¬REST¬DURING¬DAY¬TIME¬AND¬ ¬ OF¬PATIENTS¬EXPERIENCED¬SIGNIl¬CANT¬IMPAIRMENT¬IN¬TRANSPORT¬MOBILITY¬AND¬LEISURE¬ACTIVI TIES¬ ¬4HE¬COSTS¬OF¬2!¬HAVE¬BEEN¬STUDIED¬IN¬DETAIL¬BUT¬ESTIMATES¬VARY¬LARGELY¬BETWEEN¬ COUNTRIES¬AND¬HEALTH¬SYSTEMS¬4HE¬DIRECT¬COSTS¬PER¬PATIENTS¬ARE¬ESTIMATED¬AT¬æ

(19)

(20) ¬ ANNUALLY¬AND¬INDIRECT¬COSTS¬AT¬æ

(21)

(22) ¬ANNUALLY¬ ¬4HE¬MENTIONED¬ESTIMATES¬ARE MEANS

(23) ¬WHICH¬MASK¬MAJOR¬INTER INDIVIDUAL¬DIFFERENCES¬BECAUSE¬THE¬DISTRIBUTION¬OF¬COSTS¬IS SKEWED¬WITH¬A¬SMALL¬MINORITY¬OF¬PATIENTS¬ACCOUNTING¬FOR¬A¬LARGE¬PROPORTION¬OF¬COSTS¬ ¬ )N¬A¬$UTCH¬STUDY¬THE¬MEAN¬ANNUAL¬DIRECT¬COSTS¬DUE¬TO¬2!¬WERE¬ESTIMATED¬TO¬BE¬æ

(24) ¬PER¬ PATIENT¬ ¬. .

(25) 4HE¬PREVALENCE¬AND¬THE¬HUGE¬SOCIAL¬CONSEQUENCES¬OF¬2!¬UNDERLINE¬THE¬IMPORTANCE¬OF¬THOR OUGH¬UNDERSTANDING¬OF¬THE¬PATHOGENESIS¬OF¬2!¬AND¬THE¬DEVELOPMENT¬OF¬EFFECTIVE¬THERAPEU TIC¬STRATEGIES¬4HE¬LAST¬DECADE¬IT¬HAS¬BEEN¬RECOGNISED¬THAT¬2!¬NEEDS¬TO¬BE¬DIAGNOSED¬EARLY¬ AND¬TREATED¬PROMPTLY¬WITH¬DISEASE¬MODIFYING¬ANTIRHEUMATIC¬DRUGS¬IN¬ORDER¬TO¬SUCCESSFULLY INTERFERE¬WITH¬THE¬DISEASE¬PROCESS¬AND¬WITH¬THE¬PROGRESSION¬TO¬JOINT¬DAMAGE¬AND¬DISABILITY 4HIS¬NEW¬TREATMENT¬PARADIGM¬IN¬COMBINATION¬WITH¬NEW¬TREATMENT¬OPTIONS

(26) ¬HAVE¬ALREADY IMPROVED¬THE¬PROSPECTS¬FOR¬PATIENTS¬WITH¬2!¬IN¬GENERAL

(27) ¬WITH¬IMPROVED¬GLOBAL¬DISEASE¬AC TIVITY

(28) ¬RETARDATION¬OF¬JOINT¬DESTRUCTION

(29) ¬PREVENTION¬OF¬DISABILITY¬AND¬REDUCTION¬OF¬MORTALITY ¬!T¬PRESENT

(30) ¬THE¬ULTIMATE¬AIM¬OF¬THERAPEUTIC¬INTERVENTIONS¬IN¬PATIENTS¬WITH¬A¬CHRONIC¬ ARTHRITIS¬IS¬REMISSION¬(OPEFULLY

(31) ¬IN¬THE¬FUTURE¬BETTER¬UNDERSTANDING¬OF¬THE¬DISEASE¬PROCESS¬ WILL¬RESULT¬IN¬A¬FURTHER¬SHIFT¬IN¬TREATMENT¬STRATEGIES¬)DEALLY

(32) ¬THE¬DEVELOPMENT¬OF¬2!¬CAN¬ BE¬RECOGNISED¬IN¬A¬VERY¬EARLY¬STAGE¬AND¬TREATMENT¬IN¬THIS¬PHASE¬IS¬ABLE¬TO¬HAMPER¬PROGRES SION¬TO¬THE¬CHRONIC¬DISORDER¬(OWEVER

(33) ¬CURRENTLY

(34) ¬PREVENTION¬OF¬2!¬IS¬MILES¬AWAY¬AND¬THE GENETIC¬AND¬ENVIRONMENT¬FACTORS¬THAT¬RESULT¬IN¬2!¬ARE¬FAR¬FROM¬COMPLETELY¬UNDERSTOOD. #HAPTER¬. 0!4(/0(93)/,/'9¬/&¬!.$¬2)3+¬&!#4/23¬&/2¬2(%5-!4/)$¬!24(2)4)3. . 'ENETIC¬FACTORS 4HE¬MOST¬IMPORTANT¬GENETIC¬RISK¬FACTOR¬FOR¬2!¬WAS¬DOCUMENTED¬ALMOST¬¬YEARS¬AGO¬BY¬ 3TASTNY¬BY¬THE¬RECOGNITION¬THAT¬(,! $2¬(,! $2" ¬IS¬ASSOCIATED¬WITH¬2!¬ ¬,ATER¬ STUDIES¬ SHOWED¬ THAT¬ ALSO¬ SEVERAL¬ OTHER ¬ (,! $2"¬ ALLELES¬

(35) ¬

(36) ¬

(37) ¬

(38) ¬.

(39) ¬

(40) ¬ ¬AND¬ ¬WERE¬ASSOCIATED¬WITH¬THE¬DISEASE¬ ¬4HE¬PRODUCTS OF¬THESE¬ALLELES¬APPEARED¬TO¬SHARE¬AN¬AMINO¬ACID¬SEQUENCE¬AT¬POSITION¬ ¬IN¬THE¬THIRD HYPERVARIABLE¬REGION¬OF¬THE¬$2`¬CHAIN¬OF¬THE¬(,! $2"¬MOLECULE¬1+2!!

(41) ¬122!!¬OR¬ 222!! ¬4HESE¬RESIDUES¬ARE¬PART¬OF¬ONE¬SIDE¬OF¬THE¬ANTIGEN¬PRESENTING¬BINDING¬SITE¬&IGURE ¬ 4HE¬ 3HARED¬ %PITOPE¬ HYPOTHESIS¬ POSTULATES¬ THAT¬ THE¬ SHARED¬ EPITOPE¬ MOTIF¬ ITSELF¬ IS¬ DI RECTLY¬INVOLVED¬IN¬THE¬PATHOGENESIS¬OF¬2!¬BY¬ALLOWING¬THE¬PRESENTATION¬OF¬AN¬ARTHRITOGENIC¬ PEPTIDE¬TO¬4¬CELLS¬ ¬5NFORTUNATELY

(42) ¬SPECIl¬C¬ARTHRITOGENIC¬PEPTIDES¬THAT¬BIND¬TO¬THE¬$2¬ PROTEINS¬IN¬2!¬HAVE¬NOT¬BEEN¬IDENTIl¬ED¬2El¬NEMENT¬OF¬THE¬3HARED¬%PITOPE¬HYPOTHESIS

(43) ¬ AS¬WELL¬AS¬ALTERNATIVE¬ROLES¬FOR¬THE¬SHARED¬EPITOPE¬MOTIF¬HAVE¬BEEN¬PROPOSED¬ ¬!L THOUGH¬THE¬EXACT¬ROLE¬OF¬THE¬SHARED¬EPITOPE¬IN¬THE¬PATHOPHYSIOLOGY¬OF¬2!¬IS¬STILL¬ELUSIVE

(44) THERE¬IS¬EXTENSIVE¬EVIDENCE¬SHOWING¬AN¬ASSOCIATION¬BETWEEN¬THE¬SHARED¬EPITOPE¬ENCODING ALLELES¬AND¬SUSCEPTIBILITY¬TO¬2!¬AS¬WELL¬AS¬SEVERITY¬OF¬2!¬ ¬4HE¬TOTAL¬GENETIC¬CONTRIBU TION¬TO¬2!¬HAS¬BEEN¬QUANTIl¬ED¬BY¬THE¬COMPARISON¬OF¬MONOZYGOTIC¬AND¬DIZYGOTIC¬TWINS¬ AND¬IS¬ESTIMATED¬TO¬BE¬ ¬ ¬4HE¬(,!¬CLASS¬))¬MOLECULES¬ARE¬SO¬FAR¬THE¬MOST¬POWER FUL¬GENETIC¬FACTOR¬THAT¬ACCOUNT¬FOR¬ABOUT¬¬OF¬THE¬TOTAL¬GENETIC¬EFFECT¬ .

(45) )NTRODUCTION. &IGURE¬ 3TRUCTURE¬OF¬THE¬(,! $2"¬MOLECULE 4HE¬(,! $2"¬MOLECULE¬IS¬COMPOSED¬OF¬AN _ CHAIN¬AND¬A¬HIGHLY¬POLYMORPHIC ` CHAIN¬4HE¬ANTIGEN PRESENTING¬BINDING¬SITE¬IS¬FORMED¬BY¬A ` SHEET¬m¬OOR ¬AND¬TWO¬HELICES¬AT¬BOTH¬SIDES¬4HE¬AMINO¬ACID¬RESIDUES¬AT¬POSITION¬ ¬ARE¬INDICATED¬ "ASED¬ON¬"ROWN¬*(¬ . !UTOANTIBODIES !N¬IMPORTANT¬REASON¬WHY¬2!¬IS¬CONSIDERED¬TO¬BE¬AN¬AUTOIMMUNE¬DISEASE¬IS¬THE¬PRESENCE¬OF¬ AUTOANTIBODIES¬4HE¬CLASSICAL¬AUTOANTIBODY¬ASSOCIATED¬WITH¬2!¬IS¬RHEUMATOID¬FACTOR¬2&

(46) ¬ AN¬AUTOANTIBODY¬THAT¬IS¬DIRECTED¬AT¬THE¬&C PART¬OF¬IMMUNOGLOBULIN¬'¬2&¬IS¬NOT¬UNIQUE¬ FOR¬2!

(47) ¬AND¬CAN¬BE¬FOUND¬IN¬OTHER¬AUTOIMMUNE¬DISEASES

(48) ¬INFECTIOUS¬DISEASES¬AND¬HEALTHY¬ ELDERLY ¬PERSONS¬4HE¬SENSITIVITY¬OF¬2&¬VARIES¬BETWEEN¬ ¬AND¬THE¬SPECIl¬CITY¬BETWEEN¬ ¬ 4HE¬ LATEST¬ YEARS

(49) ¬ THERE¬ HAS¬ BEEN¬ A¬ CONSIDERABLE¬ INTEREST¬ IN¬ THE¬ OBSERVATION¬ THAT¬ THE PRESENCE¬ OF¬ ANTIBODIES¬ TO¬ CITRULLINE CONTAINING¬ PROTEINS¬ IS¬ HIGHLY¬ SPECIl¬C¬ FOR¬ 2!¬ 4HE¬ OBSERVATION¬THAT¬THESE¬ANTIBODIES¬APPEAR¬EARLY¬IN¬2!¬AND¬CAN¬BE¬FOUND¬YEARS¬BEFORE¬THE¬ DISEASE¬ONSET¬

(50)

(51) ¬AS¬WELL¬AS¬THE¬l¬NDING¬THAT¬CITRULLINATED¬PROTEINS¬ARE¬EXPRESSED¬IN¬THE INm¬AMED¬JOINT¬

(52)

(53) ¬LEADS¬TO¬THE¬HYPOTHESIS¬THAT¬THE¬ANTI CYCLIC¬CITRULLINATED¬PEPTIDES¬ ANTI ##0 ¬ANTIBODIES¬ARE¬OF¬PATHOPHYSIOLOGICAL¬IMPORTANCE¬IN¬2!¬#ITRULLINATION¬IS¬THE¬ POSTTRANSLATIONAL¬MODIl¬CATION¬OF¬PROTEIN BOUND¬ARGININE¬INTO¬THE¬NON STANDARD¬AMINO ACID¬ CITRULLINE¬ 4HIS¬ PROCESS¬ IS¬ MEDIATED¬ BY¬ THE¬ ENZYM¬ PEPTIDYLARGININE¬ DEIMINASE¬ AND¬ RESULTS¬IN¬A¬SMALL¬CHANGE¬IN¬MOLECULAR¬MASS¬AND¬THE¬LOSS¬OF¬A¬POSITIVE¬CHARGE¬!LTHOUGH¬THE¬ ROLE¬OF¬CITRULLINATION¬REMAINS¬TO¬BE¬DETERMINED

(54) ¬IT¬HAS¬BEEN¬PROPOSED¬THAT¬CITRULLINATION¬ PLAYS¬A¬PIVOTAL¬ROLE¬IN¬PREPARING¬INTRACELLULAR¬PROTEINS¬FOR¬DEGRADATION¬DURING¬APOPTOSIS¬

(55) ¬AND¬IN¬THE¬REGULATION¬OF¬TRANSCRIPTION¬THROUGH¬CITRULLINATION¬OF¬HISTONES¬ ¬%VEN THOUGH¬CITRULLINATION¬SEEMS¬TO¬BE¬A¬NONSPECIl¬C¬FEATURE¬OF¬INm¬AMMATION

(56) ¬IT¬IS¬NOT¬YET¬CLEAR¬. .

(57) &IGURE¬¬#ONVERSION¬OF¬ARGININE¬TO¬CITRULLINE

(58) ¬MEDIATED¬BY¬THE¬ENZYM PEPTIDYLARGININE¬DEIMINASE¬0!$ . WHICH¬CIRCUMSTANCES¬LEAD¬TO¬BREAKING¬TOLERANCE¬TO¬CITRULLINATED¬PROTEINS¬AND¬THE¬DEVELOP #HAPTER¬. MENT¬OF¬ANTI ##0¬ANTIBODIES¬4HE¬SENSITIVITY¬OF¬ANTI ##0¬ANTIBODIES¬FOR¬2!¬IS¬ ¬AND¬. . THE¬SPECIl¬CITY¬IS¬ABOUT¬ ¬

(59) . 5.$)&&%2%.4)!4%$¬!24(2)4)3. )N¬ONLY¬A¬MINORITY¬OF¬THE¬PATIENTS¬THAT¬PRESENT¬WITH¬RECENT ONSET¬ARTHRITIS¬TO¬AN¬EARLY¬AR THRITIS¬CLINIC¬A¬DEl¬NITE¬DIAGNOSIS¬CAN¬BE¬MADE¬DIRECTLY¬/NLY¬¬OF¬THE¬PATIENTS¬THAT¬WERE INCLUDED¬IN¬THE¬,EIDEN¬%ARLY¬!RTHRITIS¬#LINIC¬WERE¬DIAGNOSED¬WITH¬2!¬AT¬THE¬TWO¬WEEKS VISIT¬ ¬AND¬IN¬A¬CONSIDERABLE¬NUMBER¬OF¬PATIENTS¬ABOUT¬ ¬NO¬DIAGNOSIS¬ACCORDING TO¬ONE¬OF¬THE¬!#2 CRITERIA¬COULD¬BE¬MADE¬ ¬THESE¬PATIENTS¬ARE¬IDENTIl¬ED¬AS¬UNDIFFER ENTIATED¬ARTHRITIS¬5! ¬4HE¬DISEASE¬COURSE¬OF¬THE¬PATIENTS¬WITH¬5!¬IS¬VARIABLE¬&IGURE¬ &ROM¬SEVERAL¬INCEPTION¬COHORT¬STUDIES¬IT¬IS¬KNOWN¬THAT¬ABOUT¬ ¬OF¬THE¬5! PATIENTS REMIT¬SPONTANEOUSLY

(60) ¬WHEREAS¬ONE THIRD¬DEVELOPS¬2!¬ ¬4HE¬ANALYSIS¬OF¬THE¬CLINICAL EVOLUTION¬OF¬PATIENTS¬WITH¬5!¬IS¬EXTREMELY¬INTERESTING¬AS¬THE¬ANALYSIS¬OF¬THE¬DISEASE¬COURSE¬ IN¬ COMBINATION¬ WITH¬ GENETICAL¬ AND¬ SEROLOGICAL¬ FACTORS¬ MAY¬ ALLOW¬ INSIGHT¬ IN¬ THE¬ FACTORS THAT¬ ARE¬ ASSOCIATE¬ WITH¬ PROGRESSION¬ TOWARDS¬ 2!¬ OR¬ TOWARDS¬ REMISSION¬ )NVESTIGATION¬ OF¬ 5! PATIENTS¬AND¬THE¬DISEASE¬COURSE¬IS¬NOT¬ONLY¬RELEVANT¬AS¬IT¬MAY¬REVEAL¬PATHOPHYSIOLOGI CAL¬ASPECTS¬OF¬2!

(61) ¬IT¬ALSO¬ALLOWS¬THE¬IDENTIl¬CATION¬OF¬PREDICTIVE¬FACTORS¬FOR¬PROGRESSION¬TO¬ 2!¬ 2ECOGNITION¬ OF¬ INDEPENDENT¬ PREDICTIVE¬ VARIABLES¬ AND¬ KNOWLEDGE¬ ON¬ THE¬ PREDICTIVE¬ POWER¬OF¬THESE¬VARIABLES¬ARE¬INGREDIENTS¬TO¬CREATE¬A¬PREDICTION¬MODEL¬THAT¬ESTIMATES¬THE CHANCE¬ON¬2! DEVELOPMENT¬IN¬INDIVIDUAL¬PATIENTS¬WITH¬5!¬2ECENT¬RESEARCH¬INDICATES¬THAT¬.

(62) )NTRODUCTION. 6ORZO\ SURJUHVVLYH *HQHUDO. 8QGLIIHUHQWLDWHG. &KURQLFGHVWUXFWLYH. 3RSXODWLRQ. $UWKULWLV. SRO\DUWKULWLV5KHXPDWRLG $UWKULWLV. 5DSLGO\ SURJUHVVLYH &IGURE¬ 6ARIABLE¬DISEASE¬COURSE¬OF¬PATIENTS¬WITH¬UNDIFFERENTIATED¬ARTHRITIS. TREATMENT¬WITH¬METHOTREXATE¬IN¬VERY¬EARLY¬DISEASE¬STAGES¬AS¬5!¬IS¬EFFECTIVE¬IN¬HAMPERING¬ PROGRESSION¬TO¬2!¬

(63) ¬PROVIDING¬EVIDENCE¬FOR¬THE¬USE¬OF¬DISEASE¬MODIFYING¬ANTIRHEUMATIC DRUGS¬IN¬5!¬#ONVERSELY

(64) ¬A¬CONSIDERABLE¬AMOUNT¬OF¬5! PATIENTS¬REMIT¬SPONTANEOUSLY¬AND¬ THESE¬PATIENTS¬SHOULD¬NOT¬BE¬TREATED¬WITH¬POTENTIAL¬TOXIC¬DRUGS¬4HESE¬DATA¬UNDERLINE¬THAT AT¬PRESENT¬SUPPORT¬FOR¬CLINICIANS¬IN¬TREATMENT¬DECISIONS¬IN¬PATIENTS¬WITH¬RECENT ONSET¬5!¬ IS¬URGENTLY¬NEEDED. !)-¬!.$¬/54,).%¬/&¬4(%¬4(%3)3. 4HE¬AIMS¬OF¬THIS¬THESIS¬WERE¬MAINLY¬THREE FOLD ¬ 4O¬INVESTIGATE¬THE¬ASSOCIATION¬OF¬SEVERAL¬GENETIC¬FACTORS¬WITH¬2! ¬ 4O¬ELUCIDATE¬THE¬ROLE¬OF¬THE¬(,!¬#LASS¬))¬ALLELES¬IN¬THE¬DEVELOPMENT¬OF¬BOTH¬ANTI ##0 ANTIBODIES¬AND¬2! ¬ 4O¬IDENTIFY¬PREDICTIVE¬FACTORS¬FOR¬THE¬DEVELOPMENT¬OF¬2!¬AND¬TO¬DEVELOP¬A¬PREDICTION MODEL¬THAT¬DETERMINES¬THE¬RISK¬TO¬PROGRESS¬FROM¬5!¬TO¬2!¬IN¬INDIVIDUAL¬PATIENTS 4HIS¬THESIS¬IS¬DEVIDED¬IN¬FOUR¬PARTS )N 0ART¬ THE¬ ASSOCIATION¬ BETWEEN¬ SEVERAL¬ GENETIC¬ FACTORS¬ AND¬ 2!¬ SUSCEPTIBILITY¬ AND¬ SEVERITY¬IS¬EXAMINED !LTHOUGH¬THE¬PREDISPOSING¬EFFECTS¬OF¬THE¬SHARED¬EPITOPE¬ENCODING¬(,! $2"¬ALLELES¬ARE GENERALLY¬ACCEPTED

(65) ¬CONTROVERSY¬EXISTED¬REGARDING¬THE¬POSSIBLE¬PROTECTIVE¬EFFECTS¬OF¬CERTAIN¬ (,! $2"¬ALLELES¬4HESE¬ALLELES¬CONTAIN¬INSTEAD¬OF¬THE¬SHARED¬EPITOPE¬ANOTHER¬COMMON ANCHOR¬REGION¬CONSISTING¬OF¬THE¬AMINO¬ACIDS¬$%2!!¬!LTHOUGH¬SOME¬EVIDENCE¬FOR¬THE¬PRO TECTIVE¬EFFECT¬OF¬THE¬PRESENCE¬OF¬$%2!! ENCODING¬ALLELES¬EXISTED

(66) ¬IT¬WAS¬NOT¬CLEAR¬WHETHER THE¬EFFECT¬OF¬$%2!!¬IS¬REALLY¬PROTECTIVE¬OR¬WHETHER¬THE¬PROTECTIVE¬EFFECT¬IS¬ATTRIBUTABLE¬TO THE¬CONCOMITANT¬ABSENCE¬OF¬PREDISPOSING¬SHARED¬EPITOPE¬ALLELES¬#HAPTER¬¬INVESTIGATED THE¬EFFECT¬OF¬THE¬$%2!! ENCODING¬(,! $2"¬ALLELES¬ON¬2!¬SUSCEPTIBILITY¬AND¬SEVERITY¬AND¬ DIFFERENTIATED¬THE¬PROTECTIVE¬EFFECT¬FROM¬NON PREDISPOSITION¬BY¬COMPARING¬SUBGROUPS¬OF¬ PATIENTS¬WITH¬AN¬EQUAL¬AMOUNT¬OF¬PREDISPOSING¬ALLELES. .

(67) 4UMOR¬NECROSIS¬FACTOR¬4.& ALPHA¬IS¬A¬PRO INm¬AMMATORY¬CYTOKINE¬THAT¬PLAYS¬A¬SIGNIl¬ CANT¬ROLE¬IN¬PROMOTING¬JOINT¬INm¬AMMATION¬IN¬2!¬AND¬4.& ALPHA¬BLOCKERS¬ARE¬THE¬MOST EFFECTIVE¬DRUGS¬IN¬THE¬TREATMENT¬OF¬2!¬)N¬¬AND¬¬TWO¬SEPARATE¬GROUPS¬REPORTED¬ON¬ THE¬ASSOCIATION¬OF¬A¬3INGLE¬.UCLEOTIDE¬0OLYMORPHISM¬3.0 ¬IN¬THE¬4.& RECEPTOR¬¬GENE¬IN¬ FAMILIAL¬2!¬#ONTROVERSY¬EXISTED¬ON¬THE¬ASSOCIATION¬OF¬THIS¬3.0¬WITH¬2!¬SEVERITY¬#HAPTER ¬ASSESSED¬THE¬EFFECT¬OF¬THE¬4.&2 ¬-2¬3.0¬ON¬2!¬SEVERITY¬BY¬TAKING¬ADVANTAGE¬OF¬THE EXTREMES¬OF¬THE¬PHENOTYPES¬THAT¬EXIST¬IN¬RHEUMATOID¬ARTHRITIS¬THE¬GENOTYPE¬FREQUENCIES OF¬THE¬PATIENTS¬THAT¬ACHIEVED¬REMISSION¬AND¬THE¬PATIENTS¬THAT¬DEVELOPED¬SEVERE¬DESTRUCTIVE¬ DISEASE¬WERE¬COMPARED #HAPTER¬¬INVESTIGATED¬THE¬ASSOCIATION¬BETWEEN¬THE¬#4¬3.0¬IN¬THE¬PROTEIN¬TYRO SINE¬PHOSPHATASE¬NON RECEPTOR¬¬040. ¬GENE¬AND¬2!¬SUSCEPTIBILITY

(68) ¬2!¬SEVERITY¬AND 5!¬4HIS¬040.¬GENE¬IS¬LOCATED¬AT¬CHROMOSOME¬¬AND¬ENCODES¬FOR¬A¬LYMPHOID¬TYROSINE¬ PHOSPHATASE¬THAT¬MEDIATES¬THE¬INHIBITION¬OF¬4 CELL RECEPTOR¬SIGNALING¬4HE¬#A4¬3.0¬ CHANGES¬ THE¬ AMINOACID¬ AT¬ POSITION¬ ¬ FROM¬ ARGININE¬ 2 ¬ TO¬ TRYPTOPHAN¬ 7 ¬ AND¬ HAS¬ RECENTLY¬BEEN¬IDENTIl¬ED¬AS¬A¬RISK¬FACTOR¬FOR¬2!¬ ¬4HE¬STUDY¬DESCRIBED¬IN¬CHAPTER¬¬AIMED¬ TO¬REPLICATE¬THE¬ASSOCIATION¬BETWEEN¬THIS¬3.0¬AND¬2!¬AND¬TO¬EXTEND¬THIS¬l¬NDING¬BY¬STUDY ING¬WHETHER¬THIS¬3.0¬IS¬ALSO¬CORRELATED¬WITH¬2!¬SEVERITY¬AND¬5! #HAPTER¬. )N #HAPTER¬ IT¬IS¬EXPLORED¬WHETHER¬THE¬RECEPTOR¬FOR¬ADVANCED¬GLYCATION¬END¬PRODUCTS¬. . 2!'% ¬'3¬POLYMORPHISM¬IS¬AN¬INDEPENDENT¬RISK¬FACTOR¬FOR¬2!¬4HERE¬ARE¬l¬NDINGS¬THAT¬ SUGGEST¬A¬ROLE¬FOR¬2!'%¬SIGNALING¬IN¬THE¬PATHOGENESIS¬OF¬2!¬2!'%¬SEEMS¬TO¬BE¬IMPORTANT¬ IN¬ITS¬ABILITY¬TO¬AMPLIFY¬PRO INm¬AMMATORY¬IMMUNE¬RESPONSES¬AND¬SEVERAL¬2!'%¬LIGANDS¬ DISPLAY¬INCREASED¬LEVELS¬IN¬SYNOVIAL¬TISSUE¬OR¬SYNOVIAL¬m¬UID¬IN¬PATIENTS¬WITH¬2!¬ ¬ )N¬ADDITION

(69) ¬THE¬'3¬3.0¬HAS¬BEEN¬FOUND¬TO¬BE¬MORE¬PREVALENT¬IN¬2!¬PATIENTS¬COMPARED¬ TO¬CONTROLS¬ ¬!S¬THIS¬3.0¬IS¬IN¬STRONG¬LINKAGE¬DISEQUILIBRIUM¬WITH¬THE¬(,! $2¬ALLELE

(70) ¬ CHAPTER¬¬EXAMINED¬WHETHER¬THE¬REPORTED¬ASSOCIATION¬CAN¬BE¬EXPLAINED¬THROUGH¬LINKAGE¬ WITH¬(,! $2 #HAPTER¬¬REVIEWED¬RECENTLY¬IDENTIl¬ED¬GENETIC¬FACTORS¬AND¬THEIR¬CONTRIBUTION¬TO¬2! )N¬ 0ART¬ ASSOCIATIONS¬ BETWEEN¬ THE¬ (,!¬ #LASS¬ ))¬ ALLELES¬ AND¬ AUTOANTIBODIES¬ ARE¬ DE SCRIBED #ONSIDERING¬ THE¬ HIGH¬ SPECIl¬CITY¬ OF¬ ANTI ##0¬ ANTIBODIES¬ FOR¬ 2!

(71) ¬ THE¬ l¬NDING¬ THAT¬ THE¬ PRESENCE¬ OF¬ SHARED¬ EPITOPE¬ ENCODING¬ (,! $2"¬ ALLELES¬ CORRELATE¬ WITH¬ THE¬ PRESENCE¬ OF¬ AUTOANTIBODIES¬ IN¬ 2!¬ AND¬ THE¬ ASSUMPTION¬ THAT¬ ANTI ##0¬ ANTIBODIES¬ ARE¬ OF¬ PATHOPHYSI OLOGICAL¬ IMPORTANCE¬ FOR¬ 2!

(72) ¬ THE¬ NATURE¬ OF¬ THE¬ ASSOCIATION¬ BETWEEN¬ (,!¬ AND¬ ANTI ##0¬ ANTIBODIES¬IS¬FURTHER¬EXPLORED #HAPTER¬ ¬ COMPARED¬THE¬SHARED¬EPITOPE¬FREQUENCIES¬OF¬ HEALTHY¬CONTROLS¬AND¬2!¬PATIENTS¬WITHOUT¬AND¬WITH¬ANTI ##0¬ANTIBODIES¬IN¬TWO¬INDEPEN DENT¬COHORTS¬USING¬TWO¬DIFFERENT¬METHODS¬ASSOCIATION¬AND¬LINKAGE )N CHAPTER¬ THE¬ ASSOCIATION¬ BETWEEN¬ THE¬ NON SHARED¬ EPITOPE¬ ENCODING¬ (,! $2"¬ ALLELES¬AND¬ANTI ##0¬ANTIBODY¬NEGATIVE¬2!¬IS¬INVESTIGATED.

(73) )NTRODUCTION. 4HE¬ MOST¬ PROMINENT¬ ENVIRONMENTAL¬ RISK¬ FOR¬ 2!¬ IS¬ SMOKING¬ SMOKERS¬ HAVE¬ INCREASED LEVELS¬OF¬2&¬ ¬AND¬ARE¬MORE¬PRONE¬TO¬DEVELOP¬2!¬ ¬2ECENTLY

(74) ¬A¬GENE ENVIRON MENTAL¬ INTERACTION¬ BETWEEN¬ SMOKING¬ AND¬ THE¬ SHARED¬ EPITOPE¬ WAS¬ DESCRIBED

(75) ¬ PROVIDING RISK¬FOR¬2& POSITIVE¬BUT¬NOT¬FOR¬2& NEGATIVE¬2!¬ ¬)N CHAPTER¬¬IT¬IS¬STUDIED¬WHETHER¬A GENE ENVIRONMENTAL¬INTERACTION¬IS¬PRESENT¬FOR¬THE¬ANTI ##0¬ANTIBODY¬RESPONSE¬3ECOND

(76) THIS¬STUDY¬INVESTIGATED¬WHETHER¬THE¬INTERACTION¬BETWEEN¬SMOKING¬AND¬THE¬SHARED¬EPITOPE¬ ALLELES¬IS¬UNIQUE¬FOR¬2!¬OR¬IS¬ALSO¬PRESENT¬IN¬5! )N¬CHAPTER¬¬IT¬IS¬SHOWN¬THAT¬THE¬SHARED¬EPITOPE¬ALLELES¬ARE¬ONLY¬A¬RISK¬FACTOR¬FOR¬ANTI ##0 POSITIVE¬ 2!¬ AND¬ NOT¬ ASSOCIATED¬ WITH¬ ANTI ##0¬ NEGATIVE¬ 2!¬ !S¬ THE¬ CONTRIBUTION¬ OF¬ THE SHARED¬EPITOPE¬CONTAINING¬(,! ALLELES¬TO¬THE¬PATHOGENESIS¬OF¬2!¬IS¬NOT¬WELL¬UNDERSTOOD

(77) THE¬l¬NDINGS¬OF¬CHAPTER¬¬LED¬US¬TO¬EVALUATE¬THE¬HYPOTHESIS¬THAT¬THE¬SHARED¬EPITOPE¬ALLELES¬ ARE¬MAINLY¬A¬RISK¬FACTOR¬FOR¬ANTI ##0¬ANTIBODIES¬RATHER¬THAN¬FOR¬ANTI ##0¬POSITIVE ¬2!¬4O THIS¬END

(78) ¬THE¬DISEASE¬COURSE¬OF¬PATIENTS¬PRESENTING¬WITH¬5!¬IN¬COMBINATION¬WITH¬THE¬(,! CLASS¬))¬ALLELES¬AND¬AUTOANTIBODIES¬WAS¬STUDIED¬4HE¬RESULTS¬ON¬THIS¬ANALYSIS

(79) ¬AS¬WELL¬AS¬DATA¬ ON¬THE¬ASSOCIATION¬BETWEEN¬THE¬SHARED¬EPITOPE¬ALLELES¬AND¬THE¬LEVEL¬OF¬ANTI ##0¬ANTIBODIES¬ ARE¬DESCRIBED¬IN CHAPTER¬ 4HE¬RESULTS¬DESCRIBED¬IN¬CHAPTERS¬ ¬STRONGLY¬SUGGEST¬THAT¬THE¬PATHOGENIC¬MECHANISMS¬ UNDERLYING¬ANTI ##0¬ANTIBODY¬POSITIVE¬AND¬NEGATIVE¬2!¬ARE¬DIFFERENT¬4HESE¬OBSERVATIONS INSPIRED¬SUBSEQUENT¬RESEARCH¬ADDRESSING¬THE¬QUESTION¬WHETHER¬ANTI ##0 POSITIVE¬2!¬AND ANTI ##0 NEGATIVE¬2!¬ARE¬DIFFERENT¬DISEASE¬ENTITIES¬OR¬HAVE¬DIFFERENT¬PHENOTYPICAL¬PROPER TIES¬4HEREFORE

(80) ¬IN¬CHAPTER¬ ANTI ##0¬ANTIBODY¬POSITIVE¬AND¬NEGATIVE¬2!¬PATIENTS¬ARE¬ COMPARED¬FOR¬SEVERAL¬ASPECTS¬OF¬THEIR¬PHENOTYPE¬INITIAL¬SYMPTOMS

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(83) ¬SO¬FAR¬THE¬CONTRIBUTION¬OF¬ GENETICS¬TO¬2!¬SEVERITY¬IS¬NOT¬KNOWN¬. .

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(86) ¬ CHAPTER¬ ¬ PRESENTS¬ THE¬ DEVELOPMENT¬ OF¬ A¬ PREDICTION¬ MODEL¬ FOR¬ THE¬ DISEASE¬ OUTCOME¬IN¬PATIENTS¬WITH¬RECENT ONSET¬5!¬AND¬THE¬VALIDATION¬OF¬THIS¬MODEL¬IN¬AN¬INDE PENDENT¬COHORT¬OF¬5! PATIENTS 4HE¬RESULTS¬OF¬THE¬STUDIES¬PERFORMED¬IN¬THIS¬THESIS¬ARE¬SUMMARIZED¬AND¬DISCUSSED¬IN¬CHAP. #HAPTER¬. TER¬. .

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