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¬. 4HE¬(,! $2"¬SHARED¬EPITOPE¬ALLELES ARE¬PRIMARILY¬A¬RISK¬FACTOR¬FOR¬ANTI ##0 ANTIBODIES¬AND¬ARE¬NOT¬AN¬INDEPENDENT RISK¬FACTOR¬TO¬DEVELOP¬RHEUMATOID ARTHRITIS. !(-¬VAN¬DER¬(ELM¬ ¬VAN¬-IL +.¬6ERPOORT &#¬"REEDVELD 47*¬(UIZINGA 2%-¬4OES 220¬DE¬6RIES !RTHRITIS¬2HEUM¬ .

(3) !"342!#4. /BJECTIVES¬ 4HE¬ 3HARED %PITOPE¬ 3% CONTAINING¬ (,! $2" ALLELES¬ REPRESENT¬ THE¬ MOST SIGNIl¬CANT¬GENETIC¬RISK¬FACTOR¬FOR¬RHEUMATOID¬ARTHRITIS¬2! ¬2ECENT¬STUDIES¬SHOWED¬THAT¬ THE¬3% ALLELES¬ONLY¬ASSOCIATE¬WITH¬2!¬THAT¬IS¬CHARACTERIZED¬BY¬THE¬PRESENCE¬OF¬ANTI #YCLIC #ITRULLINATED¬0EPTIDE¬##0 ANTIBODIES

(4) ¬AND¬NOT¬WITH¬ANTI ##0 NEGATIVE¬DISEASE¬(ERE¬WE STUDIED¬ WHETHER¬ THE¬ 3% ALLELES¬ CONTRIBUTE¬ TO¬ THE¬ DEVELOPMENT¬ OF¬ ANTI ##0 POSITIVE¬ 2!

(5) ¬ OR¬RATHER¬ASSOCIATES¬WITH¬THE¬PRESENCE¬OF¬ANTI ##0 ANTIBODIES¬4HEREFORE¬THE¬INm¬UENCE¬OF¬ 3% ALLELES¬AND¬ANTI ##0 ANTIBODIES¬ON¬THE¬PROGRESSION¬FROM¬RECENT¬ONSET¬UNDIFFERENTIATED¬ ARTHRITIS¬5! ¬TO¬2!¬IS¬INVESTIGATED -ETHODS &ROM¬THE¬,EIDEN¬%ARLY¬!RTHRITIS¬#OHORT

(6) ¬AN¬INCEPTION¬COHORT¬OF¬PATIENTS¬WITH¬ RECENT¬ ONSET¬ ARTHRITIS

(7) ¬ THE¬ PATIENTS¬ WITH¬ 5!¬ AT¬ THE¬ WEEK¬ VISIT¬ WERE¬ SELECTED¬ N 3% ALLELES

(8) ¬RHEUMATOID¬FACTOR¬2& ¬AND¬ANTI ##0 ANTIBODY¬LEVELS¬WERE¬DETERMINED¬0ROGRES SION¬TO¬2!¬OR¬OTHER¬DIAGNOSES¬WAS¬MONITORED 2ESULTS¬¬5!¬PATIENTS¬DEVELOPED¬2!¬DURING¬ YEAR¬FOLLOW UP

(9) ¬WHEREAS¬¬PATIENTS¬RE MAINED¬UNCLASSIl¬ED¬OR¬DEVELOPED¬OTHER¬DIAGNOSES¬4HE¬3% ALLELES¬CORRELATED¬WITH¬THE¬PRES. #HAPTER¬. ENCE¬OF¬ANTI ##0 ANTIBODIES

(10) ¬BUT

(11) ¬AFTER¬STRATIl¬CATION¬FOR¬ANTI ##0 ANTIBODIES

(12) ¬NOT¬WITH¬THE¬. . PRESENCE¬OF¬2&¬"OTH¬IN¬3% POSITIVE¬AND¬3% NEGATIVE¬5! PATIENTS

(13) ¬THE¬PRESENCE¬OF¬ANTI ##0 ANTIBODIES¬ WAS¬ SIGNIl¬CANTLY¬ ASSOCIATED¬ WITH¬ THE¬ DEVELOPMENT¬ OF¬ 2!¬ -ORE¬ INTRIGUINGLY¬ HOWEVER

(14) ¬NO¬APPARENT¬CONTRIBUTION¬OF¬THE¬3% ALLELES¬WAS¬FOUND¬ON¬THE¬PROGRESSION¬TO¬2!¬ WHEN¬STRATIl¬ED¬FOR¬THE¬PRESENCE¬OF¬ANTI ##0 ANTIBODIES¬)N¬ANTI ##0 POSITIVE¬PATIENTS¬THE PRESENCE¬OF¬3% ALLELES¬WAS¬ASSOCIATED¬WITH¬SIGNIl¬CANTLY¬HIGHER¬LEVELS¬OF¬ANTI ##0 ANTIBOD IES

(15) ¬SUGGESTING¬THAT¬THE¬3% ALLELES¬ACT¬AS¬CLASSICAL¬IMMUNE¬RESPONSE¬GENES #ONCLUSIONS¬4HE¬3% ALLELES¬DO¬NOT¬INDEPENDENTLY¬CONTRIBUTE¬TO¬THE¬DEVELOPMENT¬OF¬2!¬ FROM¬5!

(16) ¬BUT¬RATHER¬TO¬THE¬DEVELOPMENT¬OF¬ANTI ##0 ANTIBODIES.

(17) (,! SHARED¬EPITOPE¬ALLELES¬RISK¬FACTOR¬FOR¬ANTI ##0¬ANTIBODIES. ).42/$5#4)/.. 4HE¬MOST¬IMPORTANT¬GENETIC¬RISK¬FACTOR¬FOR¬RHEUMATOID¬ARTHRITIS¬2! ¬ARE¬THE¬(,! #LASS¬ ))¬ALLELES¬%SPECIALLY¬THE¬(,! $2"¬ALLELES¬ENCODING¬FOR¬THE¬SHARED¬EPITOPE¬3% ¬CONFER¬A¬ HIGHER¬RISK¬TO¬DEVELOP¬2!¬ ¬4HE¬SHARED¬EPITOPE¬HYPOTHESIS¬POSTULATES¬THAT¬THE¬SHARED¬ EPITOPE¬ MOTIF¬ A¬ CONSERVED¬ AMINO¬ ACID¬ SEQUENCE¬ IN¬ THE¬ PEPTIDE¬ BINDING¬ POCKET¬ OF¬ THE $2"¬MOLECULE ¬IS¬DIRECTLY¬INVOLVED¬IN¬THE¬PATHOGENESIS¬OF¬2!¬BY¬ALLOWING¬THE¬PRESENTA TION¬OF¬AN¬ARTHRITOGENIC¬PEPTIDE¬TO¬4¬CELLS¬ ¬2ECENTLY

(18) ¬IT¬WAS¬OBSERVED¬BY¬TWO¬DIFFERENT¬ METHODS¬ LINKAGE¬ AND¬ ASSOCIATION¬ ANALYSIS ¬ THAT¬ THE¬ 3% ALLELES¬ ARE¬ ONLY¬ A¬ RISK¬ FACTOR¬ FOR¬ 2!¬ THAT¬ IS¬ CHARACTERISED¬ BY¬ THE¬ PRESENCE¬ OF¬ ANTI CYCLIC¬ CITRULLINATED¬ PEPTIDE¬ ANTI ##0 ANTIBODIES¬AND¬THAT¬THE¬3% ALLELES¬ARE¬NOT¬ASSOCIATED¬WITH¬ANTI ##0 NEGATIVE¬2!¬ ¬!NTI ##0¬ANTIBODIES¬ARE¬HIGHLY¬SPECIl¬C¬FOR¬2!

(19) ¬CAN¬BE¬DETECTED¬YEARS¬BEFORE¬THE¬l¬RST¬CLINICAL MANIFESTATION¬OF¬2!¬ ¬AND¬ARE¬REPORTED¬TO¬BE¬A¬GOOD¬PREDICTOR¬FOR¬THE¬DEVELOPMENT¬OF¬2!¬ ¬"ECAUSE¬THE¬CONTRIBUTION¬OF¬THE¬3% CONTAINING¬(,! ALLELES¬TO¬THE¬PATHOGENESIS¬OF¬2! IS¬NOT¬WELL¬UNDERSTOOD

(20) ¬THE¬NOVEL¬INFORMATION¬ON¬THE¬ASSOCIATION¬OF¬3% ALLELES¬WITH¬ANTI ##0 POSITIVE¬DISEASE¬ ¬LED¬US¬TO¬EVALUATE¬THE¬HYPOTHESIS¬THAT¬THE¬3% ALLELES¬ARE¬MAINLY¬ A¬RISK¬FACTOR¬FOR¬ANTI ##0 ANTIBODIES

(21) ¬RATHER¬THAN¬FOR¬ANTI ##0 POSITIVE ¬2!¬4O¬THIS¬END

(22) WE¬TOOK¬ADVANTAGE¬OF¬A¬WELL CHARACTERIZED¬INCEPTION¬COHORT¬AND¬STUDIED¬THE¬PATIENTS¬WITH AN¬EARLY¬ARTHRITIS¬THAT¬AT¬PRESENTATION¬COULD¬NOT¬BE¬CLASSIl¬ED¬ACCORDING¬TO¬THE¬!#2 CRITERIA UNDIFFERENTIATED¬ ARTHRITIS ¬ !NALYSIS¬ OF¬ THE¬ CLINICAL¬ EVOLUTION

(23) ¬ IN¬ COMBINATION¬ WITH¬ GE NETIC¬AND¬SEROLOGICAL¬RISK¬FACTORS

(24) ¬OF¬THESE¬PATIENTS¬PRONE¬TO¬DEVELOP¬2!¬ALLOWS¬INSIGHT¬IN THE¬FACTORS¬THAT¬ARE¬ASSOCIATED¬WITH¬PROGRESSION¬TOWARDS¬2!¬!CCORDINGLY¬THIS¬PERMITS¬THE ANALYSIS¬OF¬THE¬CONTRIBUTION¬OF¬THE¬3% ALLELES¬TO¬THE¬DEVELOPMENT¬OF¬2!¬AFTER¬STRATIl¬CATION¬ FOR¬ANTI ##0¬ANTIBODIES. 0!4)%.43¬!.$¬-%4(/$3. 3TUDY¬POPULATION &OR¬THIS¬STUDY

(25) ¬THE¬,EIDEN¬%ARLY¬!RTHRITIS¬#LINIC¬%!# ¬WAS¬USED¬SEE¬FOR¬DESCRIPTION¬REF¬ )N¬SHORT

(26) ¬THE¬%!#¬WAS¬STARTED¬IN¬¬0ATIENTS¬WERE¬REFERRED¬TO¬THE¬%!#¬WHEN¬ARTHRITIS WAS¬SUSPECTED¬AND¬WERE¬INCLUDED¬IN¬THE¬COHORT¬WHEN¬ARTHRITIS¬WAS¬FOUND¬AT¬PHYSICAL¬EX AMINATION¬!T¬BASELINE¬BLOOD¬SAMPLES¬WERE¬TAKEN¬!T¬PRESENT¬MORE¬THAN¬¬PATIENTS¬ARE¬ INCLUDED¬4WO¬WEEKS¬AFTER¬INCLUSION

(27) ¬¬PATIENTS¬HAD¬THE¬DIAGNOSIS¬2!¬ACCORDING¬TO¬THE¬ ¬!#2¬CRITERIA¬AND¬¬PATIENTS¬HAD¬AN¬ARTHRITIS¬THAT¬COULD¬NOT¬BE¬CLASSIl¬ED¬ACCORDING¬ TO¬ONE¬OF¬THE¬!#2¬CRITERIA¬AND¬WERE¬THEREFORE¬CALLED¬UNDIFFERENTIATED¬ARTHRITIS¬5! ¬!FTER¬ ONE¬YEAR¬OF¬FOLLOW UP

(28) ¬THE¬DISEASE¬STATUS¬OF¬ALL¬5!¬PATIENTS¬WAS¬EXAMINED¬IN¬ORDER¬TO¬DETER MINE¬WHETHER¬THEY¬HAD¬DEVELOPED¬2!¬ACCORDING¬TO¬THE¬!#2 CRITERIA¬)T¬MIGHT¬BE¬POSSIBLE¬ THAT¬SOME¬PATIENTS¬DID¬NOT¬FULl¬L¬THE¬!#2¬CRITERIA¬FOR¬2!¬AT¬ONE¬YEAR¬BUT¬DEVELOPED¬2!¬AT¬A. .

(29) LATER¬TIME¬POINT¬)NHERENT¬TO¬THE¬DESIGN¬OF¬AN¬INCEPTION¬COHORT¬THE¬DURATION¬OF¬FOLLOW UP¬ DIFFERS¬WITHIN¬THE¬STUDY¬POPULATION¬(OWEVER

(30) ¬AT¬THE¬MOMENT¬OF¬ANALYSIS¬THE¬MAJORITY¬OF¬ PATIENTS¬ ¬HAS¬BEEN¬FOLLOWED¬FOR¬MORE¬THAN¬ONE¬YEAR¬MEAN¬FOLLOW UP¬¬YEARS

(31) ¬3$¬ YEARS ¬AND¬ONLY¬¬OF¬THE¬PATIENTS¬THAT¬DID¬NOT¬CLASSIFY¬AS¬2!¬AT¬ONE¬YEAR¬DEVELOPED¬2! LATER¬ON¬IN¬THE¬DISEASE¬COURSE ,ABORATORY¬INVESTIGATIONS "ASELINE¬LABORATORY¬PARAMETERS¬DETERMINED¬USING¬BLOOD¬SAMPLES¬THAT¬WERE¬TAKEN¬AT¬INCLU SION ¬INCLUDED¬)G-¬RHEUMATOID¬FACTOR¬2&

(32) ¬%,)3! ¬AND¬ANTI ##0¬ANTIBODIES¬%,)3!

(33) ¬)M MUNOSCAN¬2!¬-ARK¬

(34) ¬%URO $IAGNOSTICA

(35) ¬!RNHEM

(36) ¬4HE¬.ETHERLANDS ¬4HE¬CUT OFF¬LEVEL¬FOR¬ ANTI ##0¬ANTIBODY¬POSITIVITY¬WAS¬ACCORDING¬TO¬THE¬MANUFACTURERS¬INSTRUCTION¬SET¬AT¬A¬LEVEL OF¬ ¬ ARBITRARY¬ UNITS¬ 4HE¬ (,! $2"¬ SUB TYPING¬ WAS¬ PERFORMED¬ BY¬ POLYMERASE¬ CHAIN¬ REACTION¬USING¬SPECIl¬C¬PRIMERS¬AND¬HYBRIDISATON¬WITH¬SEQUENCE¬SPECIl¬C¬OLIGONUCLEOTIDES 4HE¬SHARED¬EPITOPE¬ALLELES¬WERE¬(,! $2"

(37) ¬

(38) ¬

(39) ¬

(40) ¬

(41) ¬

(42) AND¬ ¬/F¬¬FROM¬THE¬¬5!¬PATIENTS¬BOTH¬DATA¬ON¬3% ALLELES¬AND¬ANTI ##0¬ANTI. #HAPTER¬. BODIES¬WERE¬AVAILABLE. . 3TATISTICAL¬ANALYSIS /DDS¬RATIOS¬WERE¬CALCULATED¬AND¬PROPORTIONS¬WERE¬COMPARED¬BY¬THE¬CHI SQUARE¬TEST¬$IFFER ENCES¬IN¬MEANS¬BETWEEN¬GROUPS¬WERE¬ANALYSED¬USING¬THE¬-ANN¬7HITNEY¬TEST¬OR¬T TEST¬WHEN¬ APPROPRIATE¬4HE¬QUESTION¬WHETHER¬3% ALLELES¬AND¬ANTI ##0¬ANTIBODIES¬BOTH¬INDEPENDENTLY CONTRIBUTE¬TO¬PROGRESSION¬OF¬2!¬WAS¬INVESTIGATED¬WITH¬A¬STRATIl¬CATION¬PROCEDURE

(43) ¬AS¬WELL¬ AS¬WITH¬LOGISTIC¬REGRESSION¬ANALYSIS¬)N¬THIS¬LOGISTIC¬REGRESSION¬ANALYSIS¬THE¬DISEASE¬OUTCOME WAS¬ ENTERED¬ AS¬ DEPENDENT¬ VARIABLE¬ AND¬ ANTI ##0¬ ANTIBODIES¬ AND¬ 3% ALLELES¬ AS¬ POSSIBLY¬ EXPLANATORY¬VARIABLES¬WITH¬A¬BACKWARD¬SELECTION¬PROCEDURE¬THE¬SIGNIl¬CANT¬INDEPENDENT VARIABLES¬WERE¬SELECTED¬&OR¬ALL¬TESTS

(44) ¬P VALUES¬OF¬¬¬WERE¬CONSIDERED¬SIGNIl¬CANT¬. 2%35,43¬!.$¬$)3#533)/.. /UTCOME¬OF¬5! /F¬¬PATIENTS¬WITH¬5!¬AT¬THE¬TWO¬WEEKS¬VISIT

(45) ¬¬DEVELOPED¬2!¬DURING¬THE¬l¬RST¬YEAR¬OF¬ FOLLOW UP

(46) ¬¬PATIENTS¬DEVELOPED¬OTHER¬RHEUMATOLOGIC¬DISEASES¬REACTIVE¬ARTHRITIS

(47) ¬PSORIATIC ARTHRITIS

(48) ¬ 3,%

(49) ¬ ETC ¬ AND¬ ¬ PATIENTS¬ REMAINED¬ UNCLASSIl¬ED¬ PERSISTENT¬ 5! ¬ &OR¬ FURTHER¬ ANALYSIS¬ THE¬ PATIENTS¬ WITH¬ PERSISTENT¬ 5!¬ AND¬ WITH¬ OTHER¬ RHEUMATOLOGIC¬ DIAGNOSIS¬ WERE DESCRIBED¬AS¬THE¬NON 2!¬GROUP¬#HARACTERISTICS¬OF¬THE¬PATIENTS¬THAT¬DEVELOPED¬2!¬AND¬THE NON 2!¬GROUP¬ARE¬DEPICTED¬IN 4ABLE¬¬)N¬UNIVARIATE¬ANALYSIS

(50) ¬THE¬PRESENCE¬OF¬3% ALLELES

(51) 2&¬AND¬ANTI ##0¬ANTIBODIES¬WERE¬ALL¬ASSOCIATED¬WITH¬SIGNIl¬CANTLY¬HIGHER¬ODDS¬RATIOS¬TO¬ DEVELOP¬2!¬/2¬

(52) ¬¬AND¬¬RESPECTIVELY

(53) ¬4ABLE¬ ¬.

(54) (,! SHARED¬EPITOPE¬ALLELES¬RISK¬FACTOR¬FOR¬ANTI ##0¬ANTIBODIES. 4ABLE¬¬"ASELINE¬CHARACTERISTICS¬OF¬PATIENTS¬WITH¬UNDIFFERENTIATED¬ARTHRITIS¬AT¬TWO¬WEEKS¬THAT¬DID¬ AND¬DID¬NOT¬DEVELOP¬2!¬DURING¬THE¬l¬RST¬YEAR¬OF¬FOLLOW UP. 2!¬N. NON 2!¬N. 0. /2¬#). !GE¬YR

(55) ¬MEAN¬¢¬3$. ¬¢¬. ¬¢¬. . n. 'ENDER¬&-. . . . ¬ . 3%¬POSITIVE. ¬. ¬. . ¬ . !NTI ##0¬POSITIVE. ¬. ¬. . ¬ . 2&¬POSITIVE. ¬. ¬. . ¬ . ¬3%¬DATA¬WAS¬MISSING¬IN¬¬OF¬THE¬5! 2!¬PATIENTS¬AND¬IN¬¬OF¬THE¬5! NON 2!¬PATIENTS ¬ !NTI ##0¬ ANTIBODY¬ DATA¬ WAS¬ MISSING¬ IN¬ ¬ OF¬ THE¬ 5! 2!¬ PATIENTS¬ AND¬ ¬ OF¬ THE¬ 5! NON 2! PATIENTS. !SSOCIATION¬BETWEEN¬3% ALLELES¬AND¬PRESENCE¬OF¬AUTO ANTIBODIES 4O¬DETERMINE¬WHETHER¬THE¬3% ALLELES¬CORRELATE¬WITH¬2&

(56) ¬WITH¬ANTI ##0¬ANTIBODIES¬OR¬WITH¬ BOTH¬AUTO ANTIBODIES

(57) ¬THE¬ASSOCIATIONS¬BETWEEN¬3% ALLELES¬AND¬ANTI ##0¬AND¬THE¬ASSOCIA TIONS¬BETWEEN¬3% ALLELES¬AND¬2&¬WERE¬INVESTIGATED¬IN¬THE¬¬5!¬PATIENTS¬)N¬UNIVARIATE ANALYSIS

(58) ¬ THE¬ 3% ALLELES¬ WERE¬ ASSOCIATED¬ WITH¬ BOTH¬ 2&¬ AND¬ ANTI ##0¬ ANTIBODIES¬ /2¬

(59) ¬ #)¬

(60) ¬ P¬ AND¬ /2¬

(61) ¬ #)¬

(62) ¬ P¬ RESPECTIVELY ¬ !S¬ ANTI ##0 POSITIVITY¬IS¬CORRELATED¬WITH¬2&¬POSITIVITY

(63) ¬THE¬ASSOCIATION¬BETWEEN¬3% ALLELES¬AND¬ANTI ##0 ANTIBODIES¬WAS¬ASSESSED¬IN¬BOTH¬THE¬2& POSITIVE¬AND¬2& NEGATIVE¬PATIENTS¬)N¬2& NEGATIVE PATIENTS¬ THE¬ PRESENCE¬ OF¬ 3% ALLELES¬ WAS¬ ASSOCIATED¬ WITH¬ A¬ HIGHER¬ ODDS¬ RATIO¬ TO¬ DEVELOP¬ ANTI ##0¬ ANTIBODIES¬ /2¬

(64) ¬ #)¬

(65) ¬ P ¬ 3IMILARLY

(66) ¬ IN¬ 2& POSITIVE¬ PATIENTS¬ THE¬PRESENCE¬OF¬3% ALLELES¬CONFERRED¬A¬HIGHER¬ODDS¬RATIO¬TO¬HAVE¬ANTI ##0¬ANTIBODIES¬/2¬

(67) ¬¬#)¬

(68) ¬P ¬4HESE¬DATA¬INDICATE¬THAT¬THE¬3% ALLELES¬ARE¬ASSOCIATED¬WITH¬ THE¬PRESENCE¬OF¬ANTI ##0¬ANTIBODIES¬INDEPENDENT¬OF¬THE¬PRESENCE¬OR¬ABSENCE¬OF¬2&¬.EXT¬ IT¬WAS¬ASSESSED¬WHETHER¬THE¬3% ALLELES¬ARE¬ASSOCIATED¬WITH¬2&

(69) ¬INDEPENDENT¬OF¬THE¬ANTI ##0 ANTIBODIES¬)N¬BOTH¬THE¬ANTI ##0¬POSITIVE¬AND¬ANTI ##0¬NEGATIVE¬PATIENT¬GROUPS

(70) ¬THE¬3% ALLELES¬WERE¬NOT¬ASSOCIATED¬WITH¬THE¬PRESENCE¬OF¬2&¬P¬AND¬¬RESPECTIVELY

(71) ¬INDICATING¬ THAT¬AFTER¬CORRECTION¬FOR¬THE¬PRESENCE¬OR¬ABSENCE¬OF¬ANTI ##0¬ANTIBODIES¬THE¬3% ALLELES¬DO¬ NOT¬CONFER¬RISK¬TO¬2&¬POSITIVITY¬)N¬CONCLUSION

(72) ¬THE¬3% ALLELES¬ARE¬PRIMARILY¬CORRELATED¬WITH¬ THE¬PRESENCE¬OF¬ANTI ##0¬ANTIBODIES¬BUT¬NOT¬WITH¬THE¬PRESENCE¬OF¬2& 3% ALLELES¬AND¬ANTI ##0¬ANTIBODIES¬IN¬PROGRESSION¬FROM¬5!¬TO¬2! 3UBSEQUENTLY

(73) ¬THE¬INm¬UENCE¬OF¬3% ALLELES¬ON¬THE¬PROGRESSION¬FROM¬5!¬TO¬2!¬WAS¬EXAMINED 5NIVARIATE¬ANALYSIS¬ASSESSING¬THE¬ASSOCIATION¬BETWEEN¬PATIENT¬CHARACTERISTICS¬AND¬DISEASE¬ OUTCOME¬REVEALED¬THAT¬THE¬PRESENCE¬OF¬3% ALLELES¬AND¬ANTI ##0¬ANTIBODIES¬AT¬BASELINE¬WERE¬ BOTH¬ASSOCIATED¬WITH¬THE¬DEVELOPMENT¬OF¬2!¬SEE 4ABLE¬ ¬(OWEVER

(74) ¬AS¬THE¬PRESENCE¬OF¬ 3% ALLELES¬AND¬ANTI ##0¬ANTIBODIES¬ARE¬CORRELATED

(75) ¬THE¬INDIVIDUAL¬EFFECT¬OF¬3% ALLELES¬ON¬THE DEVELOPMENT¬OF¬2!¬WAS¬DETERMINED¬BY¬STRATIl¬CATION¬FOR¬ANTI ##0¬ANTIBODIES¬"OTH¬IN¬THE¬ ANTI ##0¬POSITIVE¬AND¬IN¬THE¬ANTI ##0¬NEGATIVE¬5! PATIENTS

(76) ¬THE¬PRESENCE¬OF¬3% ALLELES¬WAS¬ NOT¬ASSOCIATED¬WITH¬THE¬DEVELOPMENT¬OF¬2!¬4ABLE¬ ¬4HESE¬DATA¬ARE¬IMPORTANT¬AS¬THEY¬. .

(77) 4ABLE¬¬.UMBER¬OF¬5! PATIENTS¬THAT¬DURING¬ONE¬YEAR¬OF¬FOLLOW UP¬DID¬NOT¬AND¬DID¬DEVELOP¬2!

(78) STRATIl¬ED¬FOR¬BASELINE¬ANTI ##0¬ANTIBODIES¬AND¬3% ALLELES. NON 2!¬N¬. 2!¬N¬. 3%¬n. ¬. ¬. 3%¬. ¬. ¬. 3%¬n. ¬¬. ¬. 3%¬. ¬¬. ¬. ANTI ##0¬n. ¬. ¬. ANTI ##0¬. ¬¬. ¬. ANTI ##0¬n. ¬. ¬. ANTI ##0¬. ¬. ¬. 0. /2¬#). . ¬ . . ¬ . . ¬ . . ¬ . 3TRATIl¬CATION¬FOR¬ANTI ##0¬ANTIBODIES ANTI ##0¬n ANTI ##0. 3TRATIl¬CATION¬FOR¬3% ALLELES 3%¬n 3%¬. INDICATE¬ THAT¬ THE¬ 3% ALLELES¬ DO¬ NOT¬ CORRELATE¬ WITH¬ 2!¬ DEVELOPMENT¬ IN¬ PATIENTS¬ WITH¬ 5!¬ WHEN¬STRATIl¬ED¬FOR¬THE¬PRESENCEABSENCE¬OF¬ANTI ##0¬ANTIBODIES 4O¬ ASSESS¬ THE¬ EFFECT¬ OF¬ THE¬ ANTI ##0¬ ANTIBODIES¬ INDEPENDENT¬ OF¬ 3%¬ ALLELES

(79) ¬ THE¬ RISK¬ TO¬ DEVELOP¬2!¬WAS¬DETERMINED¬IN¬3% POSITIVE¬AND¬3% NEGATIVE¬5! PATIENTS¬SEPARATELY¬4ABLE. #HAPTER¬. ¬4HIS¬ANALYSIS¬SHOWED¬THAT¬IN¬THE¬3% POSITIVE¬AS¬WELL¬AS¬IN¬THE¬3% NEGATIVE¬5!¬PATIENTS. . THE¬PRESENCE¬OF¬ANTI ##0¬ANTIBODIES¬WAS¬SIGNIl¬CANTLY¬ASSOCIATED¬WITH¬THE¬DEVELOPMENT¬OF¬ 2!¬/2¬¬AND¬¬RESPECTIVELY )N¬A¬LOGISTIC¬REGRESSION¬ANALYSIS¬WITH¬A¬BACKWARD¬SELECTION¬PROCEDURE¬ENTERING¬THE¬DIS EASE¬OUTCOME¬2!¬VERSUS¬NON 2! ¬AS¬DEPENDENT¬VARIABLE¬AND¬THE¬3% ALLELES¬AND¬ANTI ##0¬ ANTIBODIES¬AS¬POSSIBLY¬EXPLANATORY¬VARIABLES

(80) ¬THE¬ANTI ##0¬ANTIBODIES¬WERE¬THE¬ONLY¬IN DEPENDENT¬FACTOR¬THAT¬SIGNIl¬CANTLY¬ASSOCIATED¬WITH¬THE¬DEVELOPMENT¬OF¬2!¬WITH¬AN¬ODDS¬ RATIO¬OF¬¬P ¬4HIS¬ODDS¬RATIO¬RESULTING¬FROM¬MULTIVARIATE¬ANALYSIS¬IS¬NOT¬IMPOR TANTLY¬DIFFERENT¬FROM¬THE¬ODDS¬RATIO¬FOR¬ANTI ##0¬ANTIBODIES¬ON¬THE¬DEVELOPMENT¬OF¬2!¬AS¬ OBSERVED¬IN¬UNIVARIATE¬ANALYSIS¬/2¬

(81) ¬SEE 4ABLE¬ )N¬CONCLUSION

(82) ¬THESE¬DATA¬SHOW¬THAT¬AFTER¬STRATIl¬CATION¬FOR¬3% ALLELES¬THE¬ANTI ##0¬ANTI BODIES¬CONFER¬A¬HIGH¬RISK¬TO¬DEVELOP¬2!

(83) ¬WHEREAS¬AFTER¬STRATIl¬CATION¬FOR¬ANTI ##0¬ANTIBOD IES¬THE¬3% ALLELES¬ARE¬NOT¬ASSOCIATED¬WITH¬PROGRESSION¬TO¬2!¬4OGETHER¬THESE¬DATA¬INDICATE THAT¬THE¬3% ALLELES¬PRIMARILY¬PREDISPOSE¬TO¬THE¬PRESENCE¬OF¬ANTI ##0¬ANTIBODIES¬AND¬ARE¬NOT AN¬INDEPENDENT¬RISK¬FACTOR¬FOR¬THE¬DEVELOPMENT¬OF¬2! !SSOCIATION¬BETWEEN¬3% ALLELES¬AND¬ANTI ##0¬ANTIBODY¬LEVEL )N¬CLASSIC¬STUDIES¬PERFORMED¬IN¬MICE¬ON¬THE¬GENETICAL¬BACKGROUND¬ASSOCIATED¬WITH¬ANTIBODY¬ PRODUCTION¬ IT¬ HAS¬ BEEN¬ SHOWN¬ THAT¬ MAJOR¬ HISTOCOMPATIBILITY¬ ALLELES¬ ACT¬ AS¬ )MMUNE¬ 2E SPONSE¬GENES¬)R GENES ¬THAT¬CONTROL¬THE¬MAGNITUDE¬AND¬SPECIl¬CITY¬OF¬ANTIBODY¬PRODUCTION IN¬A¬DOMINANT¬FASHION¬ ¬)N¬THESE¬MICE¬THE¬MAGNITUDE¬OF¬THE¬ANTIBODY¬RESPONSE¬OF¬THE l¬RST¬GENERATION¬OFFSPRING¬WAS¬COMPARABLE¬TO¬THE¬MAGNITUDE¬OF¬THE¬HIGH¬RESPONDING¬PARENT

(84) ¬ DENOTING¬THAT¬IN¬MICE¬HOMOZYGOSITIY¬FOR¬-(# GENES¬DID¬NOT¬IMPROVE¬THE¬LEVEL¬OF¬ANTIBODY¬.

(85) (,! SHARED¬EPITOPE¬ALLELES¬RISK¬FACTOR¬FOR¬ANTI ##0¬ANTIBODIES. &IGURE¬¬,EVELS¬OF¬ANTI ##0¬ANTIBODIES¬ARBITRARY¬UNITS ¬IN¬ANTI ##0¬POSITIVE¬2!¬ PATIENTS¬WITHOUT¬AND¬WITH¬3% ALLELES 4HE¬MEDIAN¬ANTI ##0¬ANTIBODY¬LEVEL¬IS¬DEPICTED 4HE¬MEAN¬ANTI ##0¬ANTIBODY¬LEVELS¬FOR¬THE¬ANTI ##0¬POSITIVE¬2!¬PATIENTS¬WERE¬MEAN¬¬3%-¬

(86) N ¬FOR¬CARRYING¬TWO¬3% ALLELES

(87) ¬¬3%-¬

(88) ¬N ¬FOR¬CARRYING¬¬3% ALLELE¬AND¬¬3%-¬

(89) ¬N ¬FOR¬CARRYING¬NO¬3% ALLELES¬4HE¬MEDIAN¬ANTI ##0¬ANTIBODY¬LEVELS¬FOR¬THE¬SUBGROUP¬ANTI ##0¬POSITIVE 5!¬PATIENTS¬THAT¬PROGRESSED¬TO¬2!¬WERE¬¬)12¬

(90) ¬N ¬FOR¬CARRYING¬¬3% ALLELES

(91) ¬¬)12¬

(92) ¬N ¬FOR¬CARRYING¬¬3% ALLELE¬AND¬¬)12¬

(93) ¬N ¬FOR¬CARRYING¬NO¬3% ALLELES. PRODUCTION¬COMPARED¬TO¬HETEROZYGOSITY¬ ¬!S¬THE¬CURRENT¬DATA¬REVEALED¬THAT¬THE¬3% ALLELES¬ ARE¬ASSOCIATED¬WITH¬ANTI ##0¬ANTIBODIES

(94) ¬WE¬WISHED¬TO¬INVESTIGATE¬WHETHER¬THE¬CHARACTER ISTICS¬OF¬THE¬3% ALLELES¬RESEMBLE¬SUCH¬A¬CLASSIC¬)R GENE¬4HUS¬WE¬WISHED¬TO¬ANALYSE¬WHETHER THE¬LEVEL¬OF¬ANTI ##0¬ANTIBODIES¬PRESENT¬IN¬SERUM¬WAS¬CORRELATED¬TO¬THE¬PRESENCE¬OF¬3% AL LELES¬4O¬THIS¬END¬THE¬CORRELATION¬BETWEEN¬THE¬PRESENCE¬OF¬3% ALLELES¬AND¬LEVEL¬OF¬ANTI ##0 ANTIBODIES¬WAS¬ASSESSED¬IN¬ALL¬ANTI ##0¬POSITIVE¬PATIENTS¬THAT¬AT¬ONE YEAR¬FOLLOW UP¬HAD¬THE¬ DIAGNOSIS¬2!¬/F¬A¬TOTAL¬NUMBER¬OF¬¬2!¬PATIENTS¬¬2!¬DIAGNOSED¬AT¬TWO¬WEEKS¬FOL LOW UP¬AND¬¬PATIENTS¬THAT¬PROGRESSED¬FROM¬5!¬TO¬2!¬DURING¬THE¬l¬RST¬YEAR¬OF¬FOLLOW UP

(95) ¬PATIENTS¬HAD¬ANTI ##0¬ANTIBODIES¬OF¬WHICH¬¬HARBOURED¬3% ALLELES¬4HE¬ANTI ##0¬ ANTIBODY¬LEVELS¬OF¬ANTI ##0 POSITIVE¬3% POSITIVE¬AND¬ANTI ##0 POSITIVE¬3% NEGATIVE¬PATIENTS¬ ARE¬DEPICTED¬IN¬&IGURE¬¬3% POSITIVE¬PATIENTS¬HAD¬A¬SIGNIl¬CANTLY¬HIGHER¬LEVEL¬OF¬ANTI ##0¬ ANTIBODIES¬N¬

(96) ¬MEAN¬

(97) ¬3%-¬¬ARBITRARY¬UNITS ¬THAN¬3% NEGATIVE¬PATIENTS¬N¬

(98) MEAN¬

(99) ¬ 3%-¬ ¬ ARBITRARY¬ UNITS

(100) ¬ P ¬ 0ATIENTS¬ CARRYING¬ ONE¬ 3% ALLELE¬ DISPLAYED¬ A SIGNIl¬CANTLY¬ HIGHER¬ LEVEL¬ OF¬ ANTI ##0¬ ANTIBODIES¬ N

(101) ¬ MEAN¬ ¬ 3%-¬ ¬ ARBITRARY¬ UNITS ¬COMPARED¬TO¬PATIENTS¬WITHOUT¬3% ALLELES¬P ¬0ATIENTS¬WITH¬TWO¬3% ALLELES¬DID NOT¬HAVE¬A¬SIGNIl¬CANTLY¬HIGHER¬ANTI ##0¬LEVEL¬N

(102) ¬MEAN¬

(103) ¬3%-¬¬ARBITRARY¬UNITS COMPARED¬TO¬PATIENTS¬CARRYING¬ONE¬3% ALLELE¬P ¬4HUS

(104) ¬THE¬CURRENT¬DATA¬SHOW¬THAT¬IN¬ ANTI ##0 POSITIVE¬PATIENTS¬THE¬PRESENCE¬OF¬3% ALLELES¬IS¬ASSOCIATED¬WITH¬HIGHER¬LEVELS¬OF¬ANTI ##0¬ANTIBODIES¬AND¬INDICATE¬THAT¬THE¬PRESENCE¬OF¬ONE¬OR¬TWO¬3% ALLELES¬DOES¬NOT¬RESULT¬IN¬ AN¬APPARENT¬DIFFERENCE¬IN¬ANTI ##0¬ANTIBODY¬LEVEL¬4HIS¬OBSERVATION¬IS¬COMPATIBLE¬WITH¬THE NOTION¬THAT¬THE¬3% ALLELES¬ARE¬)R GENES¬FOR¬THE¬DEVELOPMENT¬OF¬ANTI ##0¬ANTIBODIES. .

(105) #/.#,53)/.. 2ECENTLY

(106) ¬WE¬REPORTED¬THAT¬THE¬3% ALLELES¬WERE¬ONLY¬ASSOCIATED¬WITH¬ANTI ##0 POSITIVE¬2!¬ AND¬NOT¬WITH¬ANTI ##0 NEGATIVE¬DISEASE

(107) ¬INDICATING¬THAT¬THE¬3% ALLELES¬ARE¬NOT¬ASSOCIATED WITH¬2!¬AS¬SUCH¬BUT¬RATHER¬WITH¬A¬DISTINCT¬PHENOTYPE¬OF¬THE¬DISEASE¬7E¬NOW¬EXTEND¬THESE¬ l¬NDINGS¬BY¬SHOWING¬THAT¬THE¬3% ALLELES¬ARE¬NOT¬AN¬INDEPENDENT¬RISK¬FACTOR¬FOR¬THE¬DEVELOP MENT¬ OF¬ 2!¬ AFTER¬ CORRECTION¬ FOR¬ ANTI ##0 ANTIBODY¬ STATUS¬ 4HE¬ 3% ALLELES¬ WERE¬ HOWEVER¬ ASSOCIATED¬ WITH¬ THE¬ PRESENCE¬ OF¬ ANTI ##0¬ ANTIBODIES¬ -OREOVER

(108) ¬ THE¬ PRESENCE¬ ABSENCE¬ OF¬ 3% ALLELES¬ WAS¬ CORRELATED¬ WITH¬ THE¬ LEVELS¬ OF¬ ANTI ##0¬ ANTIBODIES

(109) ¬ SUGGESTING¬ THAT¬ THE¬ 3% ALLELES¬ ACT¬ AS¬ CLASSIC¬ )R GENES¬ FOR¬ THE¬ DEVELOPMENT¬ OF¬ ANTI ##0¬ ANTIBODIES¬ !LTHOUGH¬ NO FORMAL¬CONCLUSIONS¬ON¬CAUSALITY¬CAN¬BE¬DRAWN¬FROM¬THIS¬ASSOCIATION¬STUDY

(110) ¬THESE¬l¬ND INGS¬SUGGEST¬THAT¬ANTI ##0¬ANTIBODIES¬MEDIATE¬THE¬ASSOCIATION¬BETWEEN¬3% ALLELES¬AND¬2! )T¬ WOULD¬ BE¬ OF¬ INTEREST¬ TO¬ REPLICATE¬ THE¬ l¬NDINGS¬ OF¬ THE¬ PRESENT¬ STUDY¬ BY¬ FOLLOWING¬ THE DEVELOPMENT¬OF¬ANTI ##0¬ANTIBODIES¬AND¬2!¬IN¬HEALTHY¬ASYMPTOMATIC¬PERSONS¬WITH¬AND¬ WITHOUT¬3% ALLELES¬.EVERTHELESS

(111) ¬THE¬PRESENT¬DATA¬CONSTITUTE¬AN¬IMPORTANT¬REl¬NEMENT¬OF¬ THE¬LONG KNOWN¬ASSOCIATION¬BETWEEN¬(,!¬AND¬2!¬BY¬INDICATING¬THAT¬THE¬3% ALLELES¬DO¬NOT¬. #HAPTER¬. PRIMARILY¬ASSOCIATE¬WITH¬2!

(112) ¬BUT¬RATHER¬WITH¬ANTI ##0 POSITIVITY. .

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(114) ¬ 4HOMSON¬ 7

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