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¬. (,! $2¬IS¬ASSOCIATED¬WITH¬ANTI ##0 ANTIBODY¬NEGATIVE¬RHEUMATOID¬ARTHRITIS. +.¬6ERPOORT &!¬VAN¬'AALEN !(-¬VAN¬DER¬(ELM¬ ¬VAN¬-IL '-4¬3CHREUDER &#¬"REEDVELD 47*¬(UIZINGA 220¬DE¬6RIES 2%-¬4OES !RTHRITIS¬2HEUM¬ .

(3) !"342!#4. /BJECTIVES 2ECENT¬DATA¬HAVE¬SHOWN¬THAT¬THE¬MOST¬PROMINENT¬AND¬LONGEST¬KNOWN¬GE NETIC¬RISK¬FACTORS¬FOR¬RHEUMATOID¬ARTHRITIS¬2!

(4) ¬(,! $2"¬SHARED¬EPITOPE¬ALLELES

(5) ¬ARE¬ONLY¬ ASSOCIATED¬WITH¬2!¬THAT¬IS¬CHARACTERIZED¬BY¬THE¬PRESENCE¬OF¬ANTIBODIES¬AGAINST¬CYCLIC¬CITRUL LINATED¬PEPTIDE¬ANTI ##0¬ANTIBODIES ¬AND¬NOT¬WITH¬ANTI ##0 NEGATIVE¬2!¬7E¬UNDERTOOK¬ THIS¬ STUDY¬ TO¬ INVESTIGATE¬ WHETHER¬ ANTI ##0 NEGATIVE¬ 2!¬ IS¬ ASSOCIATED¬ WITH¬ OTHER¬ (,! $2"¬ALLELES¬ -ETHODS (,!¬ TYPING¬ WAS¬ PERFORMED¬ FOR¬ ¬ PATIENTS¬ FROM¬ THE¬ ,EIDEN¬ %ARLY¬ !RTHRITIS¬ #LINIC¬WHO¬WERE¬DIAGNOSED¬AS¬HAVING¬2!¬WITHIN¬THE¬l¬RST¬YEAR¬OF¬FOLLOWUP¬¬ANTI ##0 POSITIVE¬PATIENTS¬AND¬¬ANTI ##0 NEGATIVE¬PATIENTS

(6) ¬¬PATIENTS¬WHO

(7) ¬AFTER¬¬YEAR

(8) ¬HAD¬ UNDIFFERENTIATED¬ARTHRITIS¬5! ¬¬ANTI ##0 POSITIVE¬PATIENTS¬AND¬¬ANTI ##0 NEGATIVE¬ PATIENTS

(9) ¬AND¬¬HEALTHY¬CONTROL¬SUBJECTS¬/DDS¬RATIOS¬/2S ¬WITH¬¬CONl¬DENCE¬IN TERVALS¬¬#)S ¬FOR¬(,! $2"¬ALLELE¬FREQUENCIES¬WERE¬DETERMINED¬FOR¬ALL¬PATIENT¬GROUPS COMPARED¬WITH¬THE¬HEALTHY¬CONTROL¬GROUP 2ESULTS¬(,! $2¬WAS¬MORE¬FREQUENTLY¬PRESENT¬IN¬THE¬ANTI ##0 NEGATIVE¬2!¬GROUP¬THAN¬ IN¬ THE¬ CONTROL¬ GROUP¬ /2¬

(10) ¬ ¬ #)¬ ¬ 4HIS¬ WAS¬ NOT¬ THE¬ CASE¬ FOR¬ ANTI ##0 #HAPTER¬. POSITIVE¬2!¬/2¬

(11) ¬¬#)¬ ¬(,! $2¬WAS¬ALSO¬MORE¬FREQUENTLY¬PRESENT¬IN. . ANTI ##0 NEGATIVE¬5!¬PATIENTS¬/2¬

(12) ¬¬#)¬

(13) ¬BUT¬NOT¬IN¬ANTI ##0 POSITIVE¬ 5!¬PATIENTS¬/2¬

(14) ¬¬#)¬ #ONCLUSIONS¬(,! $2¬IS¬ASSOCIATED¬WITH¬ANTI ##0 NEGATIVE¬ARTHRITIS¬AND¬NOT¬WITH¬ANTI ##0 POSITIVE¬ ARTHRITIS¬ 4HESE¬ DATA¬ SHOW¬ THAT¬ DISTINCT¬ GENETIC¬ RISK¬ FACTORS¬ ARE¬ ASSOCIATED WITH¬THE¬PRESENCE¬OF¬ANTI ##0¬ANTIBODIES¬IN¬2!¬AND¬INDICATE¬THAT¬DIFFERENT¬PATHOGENETIC¬ MECHANISMS¬UNDERLIE¬ANTI ##0 POSITIVE¬AND¬ANTI ##0 NEGATIVE¬2!.

(15) !SSOCIATION¬BETWEEN¬(,! $2¬AND¬ANTI ##0¬NEGATIVE¬2!. ).42/$5#4)/.. 2HEUMATOID¬ARTHRITIS¬2! ¬IS¬A¬MULTIFACTORIAL¬AUTOIMMUNE¬DISEASE¬WITH¬A¬COMPLEX¬GENETIC¬ BACKGROUND¬!S¬IN¬OTHER¬AUTOIMMUNE¬DISEASES

(16) ¬AN¬ASSOCIATION¬BETWEEN¬2!¬AND¬THE¬(,!¬ COMPLEX¬HAS¬LONG¬BEEN¬OBSERVED¬IN¬MANY¬DIFFERENT¬POPULATIONS¬AND¬IS¬THOUGHT¬TO¬ACCOUNT FOR¬APPROXIMATELY¬ONE THIRD¬OF¬THE¬GENETIC¬COMPONENT¬OF¬2!¬SUSCEPTIBILITY¬ ¬4HERE¬IS¬ EXTENSIVE¬ EVIDENCE¬ FOR¬ THE¬ ASSOCIATION¬ BETWEEN¬ CERTAIN¬ FREQUENTLY¬ OCCURRING¬ (,! $2"¬ ALLELES

(17) ¬ THE¬ SO CALLED¬ hSHARED¬ EPITOPEv¬ 3% ENCODING¬ ALLELES¬ $2"

(18) ¬

(19) ¬

(20) ¬.

(21) ¬

(22) ¬

(23) ¬

(24) ¬

(25) ¬

(26) ¬AND¬

(27) ¬AND¬SUSCEPTIBILITY¬TO¬2!¬ ¬4HESE 3%¬ALLELES¬ENCODE¬FOR¬A¬COMMON¬AMINO¬ACID¬SEQUENCE¬IN¬THE¬THIRD¬HYPERVARIABLE¬REGION¬OF¬ THE¬$2"¬MOLECULE¬1+2!!

(28) ¬122!!

(29) ¬OR¬222!! )N¬RECENT¬YEARS

(30) ¬MANY¬STUDIES¬ON¬ANTIBODIES¬AGAINST¬CYCLIC¬CITRULLINATED¬PEPTIDE¬##0 SHOWED¬THAT¬THESE¬ANTIBODIES¬ARE¬HIGHLY¬SPECIl¬C¬AND¬PREDICTIVE¬FOR¬2!¬

(31) ¬THAT¬THEY¬CAN¬ BE¬ DETECTED¬ YEARS¬ BEFORE¬ ONSET¬

(32) ¬ AND¬ THAT¬ THEY¬ ARE¬ ASSOCIATED¬ WITH¬ JOINT¬ DESTRUCTION¬ ¬&URTHERMORE

(33) ¬THE¬PRESENCE¬OR¬ABSENCE¬OF¬THESE¬ANTIBODIES¬SEEMS¬TO¬BE¬A¬STABLE¬TRAIT¬ ¬!NTI ##0¬ANTIBODIES¬ARE¬DETECTED¬IN¬3% POSITIVE¬AS¬WELL¬AS¬IN¬3% NEGATIVE¬2!¬PATIENTS¬ #ARRIERSHIP¬OF¬3%¬ALLELES¬IN¬2!¬IS¬ASSOCIATED¬WITH¬THE¬PRESENCE¬OF¬ANTI ##0¬ANTIBODIES¬ ¬ )NTERESTINGLY

(34) ¬ WHEN¬ WE¬ RECENTLY¬ COMPARED¬ ANTI ##0 POSITIVE¬ AND¬ ANTI ##0 NEGATIVE¬ 2!¬ PATIENTS¬ WITH¬ HEALTHY¬ CONTROLS

(35) ¬ WE¬ FOUND¬ THAT¬ (,! $2"¬ ALLELES¬ ENCODING¬ THE¬ 3%¬ WERE ONLY¬ASSOCIATED¬WITH¬2!¬IN¬THE¬PRESENCE¬OF¬ANTI ##0¬ANTIBODIES¬AND¬WERE¬NOT¬ASSOCIATED WITH¬ANTI ##0 NEGATIVE¬2!¬ ¬4HESE¬DATA¬INDICATE¬THAT¬THE¬3% ENCODING¬ALLELES¬ARE¬NOT¬ ASSOCIATED¬ WITH¬ 2!¬ AS¬ SUCH

(36) ¬ BUT¬ RATHER¬ WITH¬ ANTI ##0 POSITIVE¬ 2!¬ 4HESE¬ OBSERVATIONS INDICATE¬THAT¬DISTINCT¬PHENOTYPIC¬MANIFESTATIONS¬OF¬THE¬DISEASE¬ARE¬ASSOCIATED¬WITH¬DISTINCT GENETIC¬RISK¬FACTORS¬4HEY¬ALSO¬RAISE¬THE¬QUESTION¬OF¬WHETHER¬ANTI ##0 NEGATIVE¬2!¬IS¬AS SOCIATED¬WITH¬(,! $2"¬ALLELES¬OTHER¬THAN¬3% ENCODING¬ALLELES¬7E¬THEREFORE¬INVESTIGATED¬ THE¬ POSSIBLE¬ASSOCIATIONS¬OF¬PARTICULAR¬ (,! $2"¬ ALLELES¬ WITH¬ ANTI ##0 POSITIVE¬ 2!¬ AND ANTI ##0 NEGATIVE¬2!¬4O¬VERIFY¬THE¬RESULTS¬AND¬TO¬STUDY¬WHETHER¬THE¬RESULTS¬WERE¬SPECIl¬C¬ FOR¬2!

(37) ¬WE¬ALSO¬PERFORMED¬THE¬SAME¬ANALYSIS¬IN¬A¬GROUP¬OF¬PATIENTS¬WITH¬UNDIFFERENTIATED¬ ARTHRITIS¬5! . 0!4)%.43¬!.$¬-%4(/$3. 3TUDY¬POPULATION )N¬¬AN¬%ARLY¬!RTHRITIS¬#LINIC¬%!# ¬WAS¬STARTED¬AT¬THE¬$EPARTMENT¬OF¬2HEUMATOLOGY¬OF¬ THE¬,EIDEN¬5NIVERSITY¬-EDICAL¬#ENTER

(38) ¬AS¬DESCRIBED¬PREVIOUSLY¬ ¬4HE¬POPULATION¬STUDIED¬ HERE¬CONSISTED¬OF¬¬PATIENTS¬WHO

(39) ¬WITHIN¬THE¬l¬RST¬YEAR¬OF¬FOLLOW UP

(40) ¬FULl¬LLED¬THE¬!MERI CAN¬ #OLLEGE¬ OF¬ 2HEUMATOLOGY¬ !#2¬ FORMERLY

(41) ¬ THE¬ !MERICAN¬ 2HEUMATISM¬ !SSOCIATION ¬ ¬REVISED¬CRITERIA¬FOR¬2!¬ ¬AND¬¬PATIENTS¬WHO

(42) ¬AFTER¬¬YEAR¬OF¬FOLLOW UP

(43) ¬COULD. .

(44) NOT¬BE¬PROPERLY¬CLASSIl¬ED¬ACCORDING¬TO¬ONE¬OF¬THE¬!#2¬CRITERIA¬SETS¬AND¬WERE¬THEREFORE¬CAT EGORIZED¬AS¬HAVING¬5!¬&OR¬EVERY¬PATIENT¬WITHIN¬THE¬COHORT

(45) ¬ROUTINE¬DIAGNOSTIC¬LABORATORY SCREENING¬ WAS¬ PERFORMED

(46) ¬ INCLUDING¬ MEASUREMENTS¬ OF¬ )G- RHEUMATOID¬ FACTOR¬ )G- 2& ¬ )NFORMED¬PATIENT¬CONSENT¬WAS¬OBTAINED

(47) ¬AND¬THE¬STUDY¬WAS¬APPROVED¬BY¬THE¬LOCAL¬MEDICAL ETHICS¬COMMITTEE¬&OUR¬HUNDRED¬TWENTY THREE¬HEALTHY¬$UTCH¬INDIVIDUALS¬SERVED¬AS¬CON TROLS¬4HE¬CONTROL¬SUBJECTS¬WERE¬NORMAL¬HEALTHY¬DONORS¬OF¬BOTH¬SEXES¬WHO¬WERE¬RANDOMLY SELECTED¬AND¬WERE¬AGES¬¬YEARS¬AND¬YOUNGER (,!¬GENOTYPING (,!¬CLASS¬))¬ALLELES¬WERE¬DETERMINED¬IN¬ALL¬PATIENTS¬AND¬CONTROLS¬4HE¬(,! $2"¬SUB TYPING WAS¬ PERFORMED¬ BY¬ POLYMERASE¬ CHAIN¬ REACTION¬ USING¬ SPECIl¬C¬ PRIMERS¬ AND¬ HYBRIDIZATION WITH¬SEQUENCE SPECIl¬C¬OLIGONUCLEOTIDES !NTI ##0¬AUTOANTIBODIES 3ERUM¬ANTIBODIES¬DIRECTED¬AGAINST¬##0¬WERE¬ASSESSED¬WITH¬A¬COMMERCIAL¬ENZYME LINKED IMMUNOSORBENT¬ASSAY¬)MMUNOSCAN¬2!

(48) ¬-ARK¬¬%URO $IAGNOSTICA

(49) ¬!RNHEM

(50) ¬4HE¬.ETH ERLANDS ¬!NTI ##0¬ANTIBODIES¬WERE¬MEASURED¬IN¬SERUM¬COLLECTED¬WITHIN¬¬MONTHS¬AFTER #HAPTER¬. THE¬l¬RST¬VISIT¬ ¬OR

(51) ¬WHEN¬SERUM¬WAS¬NOT¬AVAILABLE¬WITHIN¬THIS¬TIME¬PERIOD

(52) ¬IN¬THE¬l¬RST. . STORED¬SERUM¬SAMPLE¬AVAILABLE¬THEREAFTER 3TATISTICAL¬ANALYSIS /DDS¬RATIOS¬/2S ¬WERE¬CALCULATED¬USING¬THE¬%PI¬)NFO¬3TATCALC¬COMPUTER¬PROGRAM¬#ENTERS¬ FOR¬$ISEASE¬#ONTROL¬AND¬0REVENTION

(53) ¬!TLANTA

(54) ¬'! ¬TO¬COMPARE¬(,! $2¬ALLELE¬FREQUENCIES¬ BETWEEN¬ THE¬ PATIENT¬ GROUPS¬ AND¬ THE¬ CONTROL¬ POPULATION¬ /2S¬ WERE¬ REPORTED¬ WITH¬ CONl¬DENCE¬INTERVALS¬¬#)S

(55) ¬WHICH¬EXCLUDED¬THE¬VALUE¬OF¬¬IN¬CASE¬OF¬STATISTICAL¬SIGNIl¬ CANCE¬%XACT¬CONl¬DENCE¬LIMITS¬WERE¬USED¬AS¬DESCRIBED¬BY¬-EHTA¬ET¬AL¬ ¬&OR¬(,! $2

(56) BOTH¬ ALLELE¬ FREQUENCIES¬ AND¬ GENOTYPE¬ FREQUENCIES¬ WERE¬ COMPARED¬ BETWEEN¬ THE¬ PATIENT¬ GROUPS¬AND¬THE¬CONTROL¬POPULATION¬USING¬THE¬SAME¬METHODS¬DESCRIBED¬ABOVE. 2%35,43. 4O¬ l¬ND¬ POSSIBLE¬ ASSOCIATIONS¬ OF¬ (,! $2"¬ ALLELES¬ WITH¬ ANTI ##0 POSITIVE¬ OR¬ ANTI ##0 NEGATIVE¬ 2!

(57) ¬ WE¬ ANALYZED¬ (,! $2"¬ ALLELE¬ FREQUENCIES¬ AND¬ THE¬ PRESENCE¬ OF¬ ANTI ##0 ANTIBODIES¬ IN¬ ¬ 2!¬ PATIENTS¬ OF¬ THE¬ ,EIDEN¬ %!#¬ 4WO¬ HUNDRED¬ SIX¬ OF¬ THE¬ 2!¬ PATIENTS HAD¬ANTI ##0¬ANTIBODIES¬AND¬¬WERE¬ANTI ##0¬NEGATIVE¬/THER¬PATIENT¬CHARACTERISTICS¬ ARE¬PRESENTED¬IN 4ABLE¬¬!FTER¬WE¬DETERMINED¬(,! $2"¬ALLELE¬FREQUENCIES

(58) ¬WE¬CALCULATED /2S¬AND¬¬#)S¬FOR¬BOTH¬PATIENT¬GROUPS¬COMPARED¬WITH¬A¬CONTROL¬GROUP¬OF¬¬HEALTHY¬ INDIVIDUALS¬SEE¬4ABLE¬ ¬.

(59) !SSOCIATION¬BETWEEN¬(,! $2¬AND¬ANTI ##0¬NEGATIVE¬2!. 4ABLE¬ "ASELINE¬CHARACTERISTICS¬OF¬THE¬¬RHEUMATOID¬ARTHRITIS¬2! ¬PATIENTS¬AND¬ UNDIFFERENTIATED¬ARTHRITIS¬5! ¬PATIENTS¬WITHIN¬THE¬STUDY. 2!. 5!. !GE

(60) ¬MEAN¬RANGE ¬YEARS. ¬ . ¬ . &EMALE

(61) ¬. . . )G-¬RHEUMATOID¬FACTOR¬POSITIVE

(62) ¬. . . !NTI ##0 ¬ANTIBODY¬POSITIVE

(63) ¬. . . 0RESENCE¬OF¬EROSIONS¬ON¬RADIOGRAPHS¬OF¬HANDS¬AND¬FEET.

(64) ¬. . . $URATION¬OF¬SYMPTOMS

(65) ¬MEDIAN¬RANGE ¬WEEKS. ¬n. ¬ . ¬##0¬¬CYCLIC¬CITRULLINATED¬PEPTIDE. ¬ RADIOLOGICAL¬ DATA¬ WERE¬ AVAILABLE¬ FOR¬ ¬ OF¬ THE¬ ¬ 2!¬ PATIENTS¬ AND¬ FOR¬ ¬ OF¬ THE¬ ¬ 5!¬ PATIENTS 4ABLE¬ !SSOCIATION¬OF¬(,! $2¬ALLELES¬WITH¬ANTI ##0¬POSITIVE¬OR¬NEGATIVE¬RHEUMATOID¬ARTHRITIS 2! ¬AND¬UNDIFFERENTIATED¬ARTHRITIS¬5! $2. ANTI ##0 ¬2! .. ANTI ##0 ¬2! .. ANTI ##0 ¬5! .. ANTI ##0 ¬5! .. #O .. .¬. /2 ¬#). .¬. /2 ¬#). .¬. /2 ¬#). .¬. /2 ¬#). .¬. 'ENOTYPE¬FREQUENCY $2$2. . ¬ . ¬ . . . . . $2X. . . . . . . . . . XX. ¬ . . . . . . ¬ . . ¬ . $2$2¬ OR¬$2X. . ¬ . . ¬ . . . . . ¬. !LLELE¬ FREQUENCY. ¬ . ¬ . . ¬ . . ¬ . . . . 2!¬ RHEUMATOID¬ ARTHRITIS¬ 5!¬ UNDIFFERENTIATED¬ ARTHRITIS¬ #OCONTROLS¬ ##0¬ CYCLIC¬ CITRULLINATED PEPTIDE¬/2¬ODDS¬RATIO¬¬#)¬¬CONl¬DENCE¬INTERVAL /2S¬WERE¬CALCULATED¬COMPARING¬DOUBLE DOSE¬$2¬CARRIERS¬$2$2

(66) ¬SINGLE DOSE¬$2¬CARRIERS¬$2X OR¬AT¬LEAST¬SINGLE DOSE¬$2¬CARRIERS¬WITH¬CARRIERS¬OF¬NO¬$2¬ALLELES¬XX ¬IN¬PATIENTS¬VERSUS¬CONTROLS¬AND¬ COMPARING¬ALLELE¬FREQUENCIES¬IN¬ALL¬GROUPS¬VERSUS¬CONTROLS. !S¬DESCRIBED¬PREVIOUSLY

(67) ¬THE¬3%¬ALLELES¬$2"

(68) ¬

(69) ¬

(70) ¬AND¬ ¬WERE¬ASSOCI ATED¬WITH¬PREDISPOSITION¬FOR¬ANTI ##0 POSITIVE¬2!

(71) ¬AS¬WERE¬$2¬AND¬$2¬)NTERESTINGLY

(72) ¬ (,! $2¬ WAS¬ ASSOCIATED¬ ONLY¬ WITH¬ PREDISPOSITION¬ FOR¬ ANTI ##0 NEGATIVE¬ 2!¬ /2¬

(73) ¬#)¬ ¬4ABLE¬ ¬4HIS¬ASSOCIATION¬WAS¬NOT¬FOUND¬FOR¬ANTI ##0 POSITIVE¬2!

(74) ¬IN DICATING¬THAT¬(,! $2¬IS¬ONLY¬ASSOCIATED¬WITH¬2!¬IN¬THE¬ABSENCE¬OF¬ANTI ##0¬ANTIBODIES 4O¬CONl¬RM¬THESE¬l¬NDINGS¬IN¬ANOTHER¬GROUP¬OF¬PATIENTS¬AND¬TO¬ADDRESS¬THE¬QUESTION¬OF¬ WHETHER¬THE¬ASSOCIATION¬IS¬ONLY¬FOUND¬IN¬ANTI ##0 NEGATIVE¬2!¬OR¬WHETHER¬IT¬IS¬ALSO¬PRES ENT¬IN¬ANOTHER¬FORM¬OF¬ARTHRITIS

(75) ¬WE¬ALSO¬ANALYZED¬THE¬ASSOCIATION¬OF¬(,! $2¬WITH¬5!¬ )N¬A¬GROUP¬OF¬¬PATIENTS¬WHO

(76) ¬¬YEAR¬AFTER¬THEIR¬l¬RST¬VISIT

(77) ¬WERE¬CATEGORIZED¬AS¬HAVING. .

(78) 4ABLE¬ (,! $2¬ALLELE¬FREQUENCIES¬IN¬RHEUMATOID¬ARTHRITIS¬WITH¬AND¬WITHOUT¬ANTI ##0¬ANTIBODIES¬ AND¬)G- 2&. 0OPULATION. (,! $2¬ALLELE¬FREQUENCY . $2¬ALLELES¬TOTAL¬ALLELES. . /2¬¬#). ANTI ##0¬ ¬¬2&¬. ¬¬. . ¬ . ANTI ##0¬ ¬¬2&¬. ¬¬. . ¬ . ANTI ##0¬n¬¬2&¬. ¬¬. . ¬ . ANTI ##0¬n¬¬2&¬n. ¬¬. . ¬ . #ONTROLS. ¬¬. . . 2!. 2!¬RHEUMATOID¬ARTHRITIS¬##0¬CYCLIC¬CITRULLINATED¬PEPTIDE¬2&¬RHEUMATOID¬FACTOR¬/2¬ODDS¬RATIO¬ ¬#)¬¬CONl¬DENCE¬INTERVAL /2S¬WERE¬CALCULATED¬COMPARING¬ALLELE¬FREQUENCY¬OF¬THE¬DISEASED¬GROUP¬WITH¬ALLELE¬FREQUENCY¬IN¬THE¬ HEALTHY¬CONTROL¬GROUP. 5!¬4ABLE¬

(79) ¬(,! $2¬WAS¬MORE¬FREQUENTLY¬PRESENT¬IN¬ANTI ##0 NEGATIVE¬PATIENTS¬N¬¬ ¬THAN¬IN¬HEALTHY¬CONTROLS¬/2¬

(80) ¬¬#)¬

(81) ¬SUGGESTING¬THAT¬(,! $2¬IS¬ NOT¬SPECIl¬CALLY¬ASSOCIATED¬WITH¬ANTI ##0 NEGATIVE¬2!

(82) ¬BUT¬RATHER¬WITH¬ANTI ##0 NEGATIVE #HAPTER¬. ARTHRITIS¬.O¬ASSOCIATION¬WAS¬OBSERVED¬BETWEEN¬(,! $2¬AND¬ANTI ##0 POSITIVE¬5!¬N¬. . ¬/2¬

(83) ¬¬#)¬ ¬4ABLE¬ ¬!NALYSIS¬OF¬(,! $2¬ALLELE¬FREQUENCIES¬IN¬5! PATIENTS¬THUS¬CONl¬RMED¬THE¬RESULTS¬FOUND¬IN¬2!¬PATIENTS¬AND¬INDICATED¬THAT¬ASSOCIATION WITH¬(,! $2¬ALSO¬OCCURS¬IN¬ANTI ##0 NEGATIVE¬5!¬!NALYSIS¬OF¬WHETHER¬(,! $2¬IS¬ASSO CIATED¬WITH¬DEVELOPMENT¬OF¬2!¬IN¬PATIENTS¬WHO¬PRESENTED¬INITIALLY¬WITH¬ANTI ##0 NEGATIVE¬ 5!¬DID¬NOT¬SHOW¬THAT¬(,! $2¬INCREASED¬THE¬RISK¬FOR¬DEVELOPING¬2!¬DATA¬NOT¬SHOWN

(84) ¬ INDICATING¬THAT¬(,! $2¬IS¬NOT¬A¬PROGNOSTIC¬RISK¬FACTOR¬FOR¬THE¬DEVELOPMENT¬OF¬2!¬IN¬THIS GROUP¬OF¬PATIENTS 3INCE¬THE¬PRESENCE¬OF¬ANTI ##0¬ANTIBODIES¬IS¬LINKED¬TO¬THE¬PRESENCE¬OF¬2&¬AND¬SINCE¬2& IS¬ASSOCIATED¬WITH¬THE¬3%¬

(85) ¬WE¬NEXT¬COMPARED¬THE¬FREQUENCIES¬OF¬(,! $2¬IN¬)G- 2& POSITIVE¬AND¬)G- 2& NEGATIVE¬2!¬PATIENTS¬WITH¬THAT¬IN¬CONTROLS¬)NDEED

(86) ¬(,! $2¬WAS¬ALSO¬ ASSOCIATED¬WITH¬2& NEGATIVE¬2!¬/2¬

(87) ¬¬#)¬ ¬(OWEVER

(88) ¬AFTER¬DIVIDING¬THE¬ STUDY¬POPULATION¬INTO¬THOSE¬WITH¬AND¬WITHOUT¬ANTI ##0¬ANTIBODIES

(89) ¬THE¬ASSOCIATION¬WAS LOST¬FOR¬THE¬ANTI ##0 POSITIVE¬GROUP¬4ABLE¬ ¬!NTI ##0 NEGATIVE

(90) ¬2& POSITIVE¬2!¬PATIENTS AND¬ ANTI ##0 NEGATIVE

(91) ¬ 2& NEGATIVE¬ 2!¬ PATIENTS¬ BOTH¬ HARBOURED¬ (,! $2¬ SIGNIl¬CANTLY¬ MORE¬FREQUENTLY¬THAN¬DID¬CONTROL¬SUBJECTS¬/2¬

(92) ¬¬#)¬ ¬AND¬/2¬

(93) ¬ #)¬

(94) ¬ RESPECTIVELY ¬ )N¬ CONTRAST

(95) ¬ ANTI ##0 POSITIVE

(96) ¬ 2& POSITIVE¬ 2!¬ PATIENTS¬ AND ANTI ##0 POSITIVE

(97) ¬2& NEGATIVE¬2!¬PATIENTS¬DID¬NOT¬/2¬

(98) ¬¬#)¬ ¬AND¬/2¬

(99) ¬¬#)¬

(100) ¬RESPECTIVELY ¬4ABLE¬ ¬4HESE¬DATA¬INDICATE¬THAT¬ANTI ##0¬STATUS

(101) ¬ RATHER¬THAN¬2&¬STATUS

(102) ¬IS¬THE¬PREDOMINANT¬DISEASE¬TRAIT¬ASSOCIATED¬WITH¬(,! $2.

(103) !SSOCIATION¬BETWEEN¬(,! $2¬AND¬ANTI ##0¬NEGATIVE¬2!. 4ABLE¬ (,! $2"¬ALLELE¬FREQUENCIES¬IN¬¬ANTI ##0¬POSITIVE¬2!¬PATIENTS

(104) ¬¬ANTI ##0¬NEGATIVE¬ 2!¬PATIENTS¬AND¬¬HEALTHY¬CONTROLS. $2". ANTI ##0¬POSITIVE¬2!¬ . . /2¬¬#). ANTI ##0¬NEGATIVE¬2!¬ . . /2¬¬#). #ONTROLS . . . $2 4OTAL. . . ¬ . . . ¬ . . . $2 A B 4OTAL. . . ¬ . . . ¬ . . . $2 C D 4OTAL. . . ¬ . . . ¬ . . . $2 4OTAL. . . ¬ . . . ¬ . . . $2 4OTAL. . . ¬ . . . ¬ . . . $2 4OTAL. . . ¬ . . . ¬ . . . $2 4OTAL. . . ¬ . . . ¬ . . . ¬ . ¬ . ¬ ¬ . ¬ . ¬ . ¬ . .

(105) #HAPTER¬. $2". . ANTI ##0¬POSITIVE¬2!¬ . . /2¬¬#). ANTI ##0¬NEGATIVE¬2!¬ . . /2¬¬#). #ONTROLS . . . $2 E F 4OTAL. . . ¬ . . . ¬ . . . $2 4OTAL. . . ¬ . . . ¬ . . . $2 G 4OTAL. . . ¬ . . . ¬ . . . $2 4OTAL. . . ¬ . . . ¬ . . . $2 4OTAL. . . ¬ . . . ¬ . . . $2 4OTAL. . . ¬ . . . ¬ . . . . . . . . . 4OTAL ALLELES. ¬ . ¬ . ¬ . ¬ . 2!¬RHEUMATOID¬ARTHRITIS¬5!¬UNDIFFERENTIATED¬ARTHRITIS¬##0¬CYCLIC¬CITRULLINATED¬PEPTIDE¬/2¬ODDS¬ RATIO¬¬#)¬¬CONl¬DENCE¬INTERVAL /2S¬WERE¬CALCULATED¬COMPARING¬ALLELE¬FREQUENCIES¬OF¬THE¬DISEASED¬GROUP¬WITH¬ALLELE¬FREQUENCIES¬IN¬THE HEALTHY¬ CONTROL¬ GROUP¬ (,!¬ TYPINGS¬ WITHOUT¬ SUBTYPING¬ ARE¬ PRESENTED¬ AS¬ X ¬ 3UBTYPINGS¬ WITHOUT CONCLUSIVE¬RESULT¬ARE¬PRESENTED¬AS¬ A ¬ ¬ FOR¬ SUBTYPING¬ (,! $2"

(106) ¬ ¬ OR¬ ¬ B ¬ FOR¬ SUBTYPING¬ (,! $2"¬ ¬ OR¬. ¬OR¬ ¬ C¬¬FOR¬SUBTYPING¬(,! $2"

(107) ¬ ¬OR¬ ¬ D¬¬FOR¬SUBTYPING¬(,! $2"

(108) ¬ ¬OR¬ ¬ E¬¬FOR¬SUBTYPING¬(,! $2" ¬OR¬ ¬ F¬¬FOR¬SUBTYPING¬ (,! $2" ¬OR¬ ¬G¬¬FOR¬SUBTYPING¬(,! $2" ¬OR¬ .

(109) !SSOCIATION¬BETWEEN¬(,! $2¬AND¬ANTI ##0¬NEGATIVE¬2!. $)3#533)/.. 4HE¬ DATA¬ PRESENTED¬ HEREIN¬ SHOW¬ THAT¬ DISTINCT¬ GENETIC¬ RISK¬ FACTORS¬ ARE¬ ASSOCIATED¬ WITH¬ DISTINCT¬SUBTYPES¬OF¬2!¬AS¬DEl¬NED¬BY¬THE¬PRESENCE¬OF¬ANTI ##0¬ANTIBODIES¬3% ENCODING¬ ALLELES¬ARE¬ASSOCIATED¬WITH¬ANTI ##0 POSITIVE¬2!¬AND¬NOT¬WITH¬ANTI ##0 NEGATIVE¬DISEASE¬ )N¬ CONTRAST

(110) ¬ ANTI ##0 NEGATIVE¬ DISEASE¬ IS¬ ASSOCIATED¬ WITH¬ (,! $2

(111) ¬ WHILE¬ THIS¬ ASSOCIA TION¬ IS¬ NOT¬ FOUND¬ IN¬ ANTI ##0 POSITIVE¬ 2!¬ !LTHOUGH¬ (,! $2¬ OR¬ 3%¬ EXPRESSION¬ IS¬ NOT REQUIRED¬FOR¬THE¬DEVELOPMENT¬OF¬ANTI ##0 NEGATIVE¬OR¬ANTI ##0 POSITIVE¬2!

(112) ¬RESPECTIVELY

(113) OUR¬ l¬NDINGS¬ ARE¬ IMPORTANT¬ BECAUSE¬ THEY¬ INDICATE¬ THAT¬ DISTINCT¬ PATHOGENIC¬ MECHANISMS¬ MAY¬UNDERLIE¬ANTI ##0 POSITIVE¬AND¬ANTI ##0 NEGATIVE¬2! )N¬A¬PREVIOUS¬STUDY¬OF¬A¬RELATIVELY¬SMALL¬NUMBER¬OF¬PATIENTS¬N¬¬

(114) ¬IT¬WAS¬FOUND¬THAT (,! $2¬FREQUENCIES¬IN¬2!¬PATIENTS¬DIFFER¬FROM¬THE¬FREQUENCIES¬OBSERVED¬IN¬CONTROLS¬ ¬ ,IKEWISE

(115) ¬IN¬A¬GROUP¬OF¬¬!RAB¬2!¬PATIENTS

(116) ¬(,! $2¬CONFERRED¬A¬RISK¬FOR¬2!¬SUSCEPTIBILITY

(117) ¬AND¬A¬MORE¬RECENT¬STUDY¬SHOWED¬A¬SIGNIl¬CANTLY¬INCREASED¬FREQUENCY¬OF¬(,! $2¬IN PATIENTS¬WITH¬SYNOVITIS¬OF¬RECENT¬ONSET¬ ¬)N¬A¬#AUCASIAN¬POPULATION¬OF¬¬2!¬PATIENTS

(118) AN¬ASSOCIATION¬WITH¬(,! $2¬WAS¬OBSERVED¬AFTER¬EXCLUDING¬3%¬ALLELES¬FROM¬THE¬ANALYSIS¬ ¬ /UR¬ l¬NDINGS¬ REPRESENT¬ AN¬ EXTENSION¬ OF¬ THOSE¬ l¬NDINGS¬ BY¬ ESTABLISHING¬ THAT¬ (,! $2¬IS¬ASSOCIATED¬ONLY¬WITH¬A¬PARTICULAR¬SUBSET¬OF¬2!¬/UR¬ANALYSIS¬ALSO¬CONl¬RMED¬THAT¬ PARTICULAR¬(,! $2"¬ALLELES

(119) ¬SUCH¬AS¬$2

(120) ¬$2

(121) ¬AND¬$2

(122) ¬PROTECT¬AGAINST¬2!¬ ¬7E NOW¬SHOW¬THAT¬THESE¬ALLELES¬TEND¬TO¬BE¬ASSOCIATED¬WITH¬PROTECTION¬AGAINST¬BOTH¬ANTI ##0 POSITIVE¬AND¬ANTI ##0 NEGATIVE¬DISEASE¬4HEREFORE

(123) ¬OUR¬DATA¬INDICATE¬THAT¬THE¬(,!¬ALLELES CONFERRING¬PROTECTION¬DO¬SO¬INDEPENDENTLY¬OF¬THE¬ANTI ##0¬STATUS

(124) ¬WHILE¬THE¬ALLELES¬THAT PREDISPOSE¬TO¬2!¬ARE¬ASSOCIATED¬WITH¬DISTINCT¬2!¬PHENOTYPES¬ANTI ##0 POSITIVE¬OR¬ANTI ##0 NEGATIVE¬2! )T¬IS¬DEBATABLE

(125) ¬HOWEVER

(126) ¬WHETHER¬THE¬ASSOCIATION¬OF¬(,! $2¬WITH¬ANTI ##0 NEGATIVE 2!¬AND¬5! ¬IS¬ATTRIBUTABLE¬TO¬THE¬(,! $2¬GENE¬ITSELF¬/THER¬GENETIC¬FACTORS¬IN¬HIGH¬LINK AGE¬DISEQUILIBRIUM¬WITH¬(,! $2¬MAY¬ALSO¬UNDERLIE¬THE¬OBSERVED¬ASSOCIATION¬(,! $2¬IS¬ KNOWN¬TO¬BE¬PART¬OF¬A¬CONSERVED¬ANCESTRAL¬HAPLOTYPE¬!"$2"

(127) ¬ALSO¬KNOWN¬AS¬THE ¬HAPLOTYPE¬ ¬THAT¬OCCURS¬FREQUENTLY¬IN¬#AUCASIAN¬INDIVIDUALS¬AND¬HAS¬BEEN¬REPORTED¬ TO¬BE¬ASSOCIATED¬WITH¬2!¬ ¬*AWAHEER¬ET¬AL¬DESCRIBED¬AN¬ADDITIONAL¬GENETIC¬RISK¬FACTOR PRESENT¬WITHIN¬THE¬MAJOR¬HISTOCOMPATIBILITY¬COMPLEX¬-(# ¬THAT¬IS¬PART¬OF¬THIS¬CONSERVED¬ HAPLOTYPE¬ ¬4HEIR¬l¬NDING¬CONCERNED¬A¬CERTAIN¬ALLELIC¬COMBINATION¬OF¬TUMOR¬NECROSIS¬ FACTOR¬4.& ¬POLYMORPHISMS¬AND¬ANOTHER¬POLYMORPHISM¬ON¬THE¬(,!¬CLASS¬)))¬REGION¬OF¬ CHROMOSOME¬ ¬ ,IKEWISE

(128) ¬ THE¬ CLASS¬ )))¬ -(#¬ 4.& LYMPHOTOXIN¬ REGION¬ WAS¬ DESCRIBED¬ AS APPEARING¬TO¬INm¬UENCE¬SUSCEPTIBILITY¬TO¬2!¬SEPARATELY¬FROM¬THE¬(,! $2¬REGION¬

(129) ¬AND¬A MICROSATELLITE¬MARKER¬-)" ¬THAT¬IS¬ALSO¬PART¬OF¬AN¬ANCESTRAL¬HAPLOTYPE¬ASSOCIATED¬WITH $2" ¬WAS¬DESCRIBED¬AS¬A¬RISK¬FACTOR¬FOR¬2!¬INDEPENDENTLY¬OF¬$2" ¬ )N¬SUMMARY

(130) ¬(,! $2¬IS¬ASSOCIATED¬WITH¬ANTI ##0 NEGATIVE¬2!¬AND¬5!¬AND¬NOT¬WITH ANTI ##0 POSITIVE¬2!¬OR¬5!¬4HE¬DATA¬PRESENTED¬HEREIN¬INDICATE¬THAT¬SEPARATE¬GENETIC¬RISK. .

(131) FACTORS¬ARE¬ASSOCIATED¬WITH¬DIFFERENT¬PHENOTYPES

(132) ¬WHICH¬SUGGESTS¬THAT¬VARIOUS¬PATHOGENETIC¬. #HAPTER¬. MECHANISMS¬UNDERLIE¬ANTI ##0 POSITIVE¬AND¬ANTI ##0 NEGATIVE¬DISEASE. .

(133) !SSOCIATION¬BETWEEN¬(,! $2¬AND¬ANTI ##0¬NEGATIVE¬2!. 2%&%2%.#%3 ¬ ¬ ¬ ¬. ¬ ¬. ¬ ¬. ¬ ¬. ¬ ¬. ¬ ¬. ¬ ¬. ¬ ¬ ¬ ¬. ¬ ¬ ¬ ¬. ¬ ¬ ¬ ¬ ¬ ¬. ¬ ¬. $EIGHTON¬#-

(134) ¬7ALKER¬$*

(135) ¬'RIFl¬THS¬)$

(136) ¬2OBERTS¬$&¬4HE¬CONTRIBUTION¬OF¬(,!¬TO¬RHEUMA TOID¬ARTHRITIS¬#LIN¬'ENET¬¬¬ 'REGERSEN¬ 0+

(137) ¬ 3ILVER¬ *

(138) ¬ 7INCHESTER¬ 2*¬ 4HE¬ SHARED¬ EPITOPE¬ HYPOTHESIS¬ AN¬ APPROACH¬ TO UNDERSTANDING¬THE¬MOLECULAR¬GENETICS¬OF¬SUSCEPTIBILITY¬TO¬RHEUMATOID¬ARTHRITIS¬!RTHRITIS 2HEUM¬¬¬ ¬ 6AN¬'AALEN¬&!

(139) ¬,INN 2ASKER¬30

(140) ¬VAN¬6ENROOIJ¬7*

(141) ¬DE¬*ONG¬"!

(142) ¬"REEDVELD¬&#

(143) ¬6ERWEIJ¬#,

(144) ET¬AL¬!UTOANTIBODIES¬TO¬CYCLIC¬CITRULLINATED¬PEPTIDES¬PREDICT¬PROGRESSION¬TO¬RHEUMATOID ARTHRITIS¬IN¬PATIENTS¬WITH¬UNDIFFERENTIATED¬ARTHRITIS¬A¬PROSPECTIVE¬COHORT¬STUDY¬!RTHRITIS 2HEUM¬¬¬ 2ANTAPAA $AHLQVIST¬3

(145) ¬DE¬*ONG¬"!

(146) ¬"ERGLIN¬%

(147) ¬(ALLMANS¬'

(148) ¬7ADELL¬'

(149) ¬3TENLUND¬(

(150) ¬ET¬AL¬ !NTIBODIES¬ AGAINST¬ CYCLIC¬ CITRULLINATED¬ PEPTIDE¬ AND¬ )G!¬ RHEUMATOID¬ FACTOR¬ PREDICT¬ THE DEVELOPMENT¬OF¬RHEUMATOID¬ARTHRITIS¬!RTHRITIS¬2HEUM¬¬¬ -EYER¬/

(151) ¬,ABARRE¬#

(152) ¬$OUGADOS¬-

(153) ¬'OUPILLE¬0

(154) ¬#ANTAGREL¬!

(155) ¬$UBOIS¬!

(156) ¬ET¬AL¬!NTICITRUL LINATED¬PROTEINPEPTIDE¬ANTIBODY¬ASSAYS¬IN¬EARLY¬RHEUMATOID¬ARTHRITIS¬FOR¬PREDICTING¬l¬VE¬ YEAR¬RADIOGRAPHIC¬DAMAGE¬!NN¬2HEUM¬$IS¬¬¬ +ASTBOM¬ !

(157) ¬ 3TRANDBERG¬ '

(158) ¬ ,INDROOS¬ !

(159) ¬ 3KOGH¬ 4¬ !NTI ##0¬ ANTIBODY¬ TEST¬ PREDICTS¬ THE DISEASE¬COURSE¬DURING¬¬YEARS¬IN¬EARLY¬RHEUMATOID¬ARTHRITIS¬THE¬3WEDISH¬4)2!¬PROJECT ¬ !NN¬2HEUM¬$IS¬¬¬ 6AN¬ 'AALEN¬ &!

(160) ¬ VAN¬ !KEN¬ *

(161) ¬ (UIZINGA¬ 47

(162) ¬ 3CHREUDER¬ '-

(163) ¬ "REEDVELD¬ &#

(164) ¬ :ANELLI¬ %

(165) ¬ ET AL¬ !SSOCIATION¬ BETWEEN¬ (,!¬ CLASS¬ ))¬ GENES¬ AND¬ AUTOANTIBODIES¬ TO¬ CYCLIC¬ CITRULLINATED PEPTIDES¬##0S ¬INm¬UENCES¬THE¬SEVERITY¬OF¬RHEUMATOID¬ARTHRITIS¬!RTHRITIS¬2HEUM¬¬ ¬ ¬ (UIZINGA¬47

(166) ¬!MES¬#)

(167) ¬VAN¬DER¬(ELM VAN¬-IL¬!(

(168) ¬#HEN¬7

(169) ¬VAN¬'AALEN¬&!

(170) ¬*AWAHEER¬$

(171) ¬ ET¬AL¬2El¬NING¬THE¬COMPLEX¬RHEUMATOID¬ARTHRITIS¬PHENOTYPE¬BASED¬ON¬SPECIl¬CITY¬OF¬THE (,! $2"¬SHARED¬EPITOPE¬FOR¬ANTIBODIES¬TO¬CITRULLINATED¬PROTEINS¬!RTHRITIS¬2HEUM¬)N PRESS 6AN¬ !KEN¬ *

(172) ¬ VAN¬ "ILSEN¬ *(

(173) ¬ !LLAART¬ #&

(174) ¬ (UIZINGA¬ 47

(175) ¬ "REEDVELD¬ &#¬ 4HE¬ ,EIDEN¬ %ARLY¬ !RTHRITIS¬#LINIC¬#LIN¬%XP¬2HEUMATOL¬¬¬3UPPL¬¬3 !RNETT¬&#

(176) ¬%DWORTHY¬3-

(177) ¬"LOCH¬$!

(178) ¬-C3HANE¬$*

(179) ¬&RIES¬*&

(180) ¬#OOPER¬.3

(181) ¬ET¬AL¬4HE¬!MERICAN 2HEUMATISM¬!SSOCIATION¬¬REVISED¬CRITERIA¬FOR¬THE¬CLASSIl¬CATION¬OF¬RHEUMATOID¬ARTHRI TIS¬!RTHRITIS¬2HEUM¬¬¬ -EHTA¬#2

(182) ¬0ATEL¬.2

(183) ¬'RAY¬2¬/N¬COMPUTING¬AN¬EXACT¬CONl¬DENCE¬INTERVAL¬FOR¬THE¬COM MON¬ODDS¬RATIO¬IN¬SEVERAL¬¬X¬¬CONTINGENCY¬TABLES¬*¬!M¬3TAT¬!SSOC¬¬¬ /LSEN¬ .*

(184) ¬ #ALLAHAN¬ ,&

(185) ¬ "ROOKS¬ 2(

(186) ¬ .ANCE¬ %0

(187) ¬ +AYE¬ **

(188) ¬ 3TASTNY¬ 0

(189) ¬ ET¬ AL¬ !SSOCIATIONS¬ OF¬ (,! $2¬WITH¬RHEUMATOID¬FACTOR¬AND¬RADIOGRAPHIC¬SEVERITY¬IN¬RHEUMATOID¬ARTHRITIS¬!M¬ *¬-ED¬¬¬ ,EGRAND¬,

(190) ¬,ATHROP¬'-

(191) ¬-ARCELLI "ARGE¬!

(192) ¬$RYLL¬!

(193) ¬"ARDIN¬4

(194) ¬$EBEYRE¬.

(195) ¬ET¬AL¬(,! $2 GENOTYPE¬RISKS¬IN¬SEROPOSITIVE¬RHEUMATOID¬ARTHRITIS¬!M¬*¬(UM¬'ENET¬¬¬ 3ATTAR¬-!

(196) ¬AL¬3AFFAR¬-

(197) ¬'UINDI¬24

(198) ¬3UGATHAN¬4.

(199) ¬"EHBEHANI¬+¬!SSOCIATION¬BETWEEN¬(,! $2¬ANTIGENS¬AND¬RHEUMATOID¬ARTHRITIS¬IN¬!RABS¬!NN¬2HEUM¬$IS¬¬¬ %L¬ 'ABALAWY¬ (3

(200) ¬ 'OLDBACH -ANSKY¬ 2

(201) ¬ 3MITH¬ $

(202) ¬ !RAYSSI¬ 4

(203) ¬ "ALE¬ 3

(204) ¬ 'ULKO¬ 0

(205) ¬ ET¬ AL¬ !S SOCIATION¬OF¬(,!¬ALLELES¬AND¬CLINICAL¬FEATURES¬IN¬PATIENTS¬WITH¬SYNOVITIS¬OF¬RECENT¬ONSET !RTHRITIS¬2HEUM¬¬¬ $E¬6RIES¬.

(206) ¬4IJSSEN¬(

(207) ¬VAN¬2IEL¬0,

(208) ¬VAN¬DE¬0UTTE¬,"¬2ESHAPING¬THE¬SHARED¬EPITOPE¬HY POTHESIS¬(,! ASSOCIATED¬RISK¬FOR¬RHEUMATOID¬ARTHRITIS¬IS¬ENCODED¬BY¬AMINO¬ACID¬SUBSTITU TIONS¬AT¬POSITIONS¬ ¬OF¬THE¬(,! $2"¬MOLECULE¬!RTHRITIS¬2HEUM¬¬¬ . .

(209) ¬ ¬. ¬ ¬. ¬ ¬ ¬ ¬. ¬ ¬. #HAPTER¬. ¬ ¬. . 2EVIRON¬$

(210) ¬0ERDRIGER¬!

(211) ¬4OUSSIROT¬%

(212) ¬7ENDLING¬$

(213) ¬"ALANDRAUD¬.

(214) ¬'UIS¬3

(215) ¬ET¬AL¬)Nm¬UENCE¬ OF¬ SHARED¬ EPITOPE NEGATIVE¬ (,! $2"¬ ALLELES¬ ON¬ GENETIC¬ SUSCEPTIBILITY¬ TO¬ RHEUMATOID ARTHRITIS¬!RTHRITIS¬2HEUM¬¬¬ 0RICE¬0

(216) ¬7ITT¬#

(217) ¬!LLCOCK¬2

(218) ¬3AYER¬$

(219) ¬'ARLEPP¬-

(220) ¬+OK¬##

(221) ¬ET¬AL¬4HE¬GENETIC¬BASIS¬FOR¬THE ASSOCIATION¬OF¬THE¬¬ANCESTRAL¬HAPLOTYPE¬!

(222) ¬"

(223) ¬$2 ¬WITH¬MULTIPLE¬IMMUNOPATHO LOGICAL¬DISEASES¬)MMUNOL¬2EV¬¬¬ ,EGRAND¬,

(224) ¬,ATHROP¬'-

(225) ¬"ARDIN¬4

(226) ¬-ARCELLI "ARGE¬!

(227) ¬$RYLL¬!

(228) ¬$EBEYRE¬.

(229) ¬ET¬AL¬(,!¬HAP LOTYPES¬IN¬NON FAMILIAL¬RHEUMATOID¬ARTHRITIS¬!NN¬2HEUM¬$IS¬¬¬ *AWAHEER¬$

(230) ¬,I¬7

(231) ¬'RAHAM¬22

(232) ¬#HEN¬7

(233) ¬$AMLE¬!

(234) ¬8IAO¬8

(235) ¬ET¬AL¬$ISSECTING¬THE¬GENETIC¬ COMPLEXITY¬OF¬THE¬ASSOCIATION¬BETWEEN¬HUMAN¬LEUKOCYTE¬ANTIGENS¬AND¬RHEUMATOID¬AR THRITIS¬!M¬*¬(UM¬'ENET¬¬¬ -ULCAHY¬"

(236) ¬7ALDRON ,YNCH¬&

(237) ¬-C$ERMOTT¬-&

(238) ¬!DAMS¬#

(239) ¬!MOS¬#)

(240) ¬:HU¬$+

(241) ¬ET¬AL¬'ENETIC VARIABILITY¬IN¬THE¬TUMOR¬NECROSIS¬FACTOR LYMPHOTOXIN¬REGION¬INm¬UENCES¬SUSCEPTIBILITY¬TO¬ RHEUMATOID¬ARTHRITIS¬!M¬*¬(UM¬'ENET¬¬¬ :ANELLI¬ %

(242) ¬ *ONES¬ '

(243) ¬ 0ASCUAL¬ -

(244) ¬ %ERLIGH¬ 0

(245) ¬ VAN¬ DER¬ 3LIK¬ !2

(246) ¬ :WINDERMAN¬ !(

(247) ¬ ET¬ AL¬ 4HE TELOMERIC¬PART¬OF¬THE¬(,!¬REGION¬PREDISPOSES¬TO¬RHEUMATOID¬ARTHRITIS¬INDEPENDENTLY¬OF¬ THE¬CLASS¬))¬LOCI¬(UM¬)MMUNOL¬¬¬ .

(248)

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