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¬. 3MOKING¬IS¬A¬RISK¬FACTOR¬FOR¬ANTI ##0 ANTIBODIES¬ONLY¬IN¬RHEUMATOID¬ARTHRITIS PATIENTS¬THAT¬CARRY¬(,! $2"¬SHARED EPITOPE¬ALLELES. 30¬,INN 2ASKER !(-¬VAN¬DER¬(ELM¬ ¬VAN¬-IL &!¬VAN¬'AALEN -¬+LOPPENBURG 220¬DE¬6RIES 3¬LE¬#ESSIE &#¬"REEDVELD 2%-¬4OES 47*¬(UIZINGA !NN¬2HEUM¬$IS¬ .

(3) !"342!#4. /BJECTIVES¬4O¬STUDY¬THE¬GENE ENVIRONMENT¬INTERACTION¬BETWEEN¬TOBACCO EXPOSURE¬4% AND¬SHARED EPITOPE¬3% ¬ALLELES¬ON¬AUTOANTIBODIES¬IN¬RHEUMATOID¬ARTHRITIS¬2! ¬AND¬UNDIF FERENTIATED¬ARTHRITIS¬5! -ETHODS &ROM¬INCIDENT¬CASES¬OF¬ARTHRITIS¬N

(4) ¬PATIENTS¬THAT¬DID¬NOT¬FULl¬LL¬ANY¬CLAS SIl¬CATION¬ CRITERIA¬ AT¬ THE¬ TWO¬ WEEKS¬ VISIT

(5) ¬ 5!¬ N

(6) ¬ AS¬ WELL¬ AS¬ PATIENTS¬ THAT¬ FULl¬LLED¬ THE¬!#2¬CRITERIA¬FOR¬2!¬N ¬WERE¬IDENTIl¬ED¬)G-¬2HEUMATOID¬&ACTOR¬2&

(7) ¬ANTI CYCLIC CITRULLINATED¬PEPTIDE¬##0 ¬ANTIBODIES¬AND¬(,! $2"¬ALLELES¬WERE¬DETERMINED¬ 2ESULTS )N¬2!¬AN¬INTERACTION¬WAS¬FOUND¬BETWEEN¬4%¬AND¬3%¬FOR¬THE¬PRESENCE¬OF¬ANTI ##0 ANTIBODIES

(8) ¬AS¬THE¬ODDS¬RATIO¬/2 ¬FOR¬ANTI ##0¬ANTIBODIES¬OF¬PATIENTS¬HAVING¬BOTH¬4%¬AND¬ 3%¬WAS¬HIGHER¬THAN¬THE¬SUMMED¬/2S¬OF¬PATIENTS¬HAVING¬ONLY¬4%¬OR¬3%¬/2¬4% 3% ¬

(9) 4% 3% ¬

(10) ¬AND¬4% 3% ¬

(11) ¬ALL¬RELATIVE¬TO¬4% 3% ¬!¬SIMILAR¬EFFECT¬WAS¬FOUND¬FOR¬2&

(12) ¬BUT¬ STRATIl¬CATION¬ REVEALED¬ THAT¬ THE¬ INTERACTION¬ PRIMARILY¬ ASSOCIATES¬ WITH¬ THE¬ ANTI ##0¬ ANTI BODY¬RESPONSE¬)N¬PATIENTS¬WITH¬5!¬AT¬TWO¬WEEKS¬OR¬WITH¬PERSISTENT¬5!¬AFTER¬ONE¬YEAR¬NO¬ INTERACTION¬BETWEEN¬4%¬AND¬3%¬WAS¬OBSERVED¬FOR¬THE¬PRESENCE¬OF¬AUTOANTIBODIES #ONCLUSIONS¬ 4%¬ INCREASES¬ THE¬ RISK¬ FACTOR¬ FOR¬ ANTI ##0¬ ANTIBODIES¬ ONLY¬ IN¬ 3% POSITIVE¬ #HAPTER¬. 2! PATIENTS¬4HE¬GENE ENVIRONMENT¬INTERACTION¬BETWEEN¬SMOKING¬AND¬3%¬LEADING¬TO¬AUTO. . ANTIBODIES¬IS¬SPECIl¬C¬FOR¬2!¬AND¬IS¬NOT¬OBSERVED¬IN¬5!.

(13) 3MOKING¬RISK¬FACTOR¬FOR¬ANTI ##0¬POSITIVE¬2!. ).42/$5#4)/.. )N¬THE¬SEARCH¬FOR¬THE¬ETIOLOGY¬OF¬2HEUMATOID¬ARTHRITIS¬2! ¬GENETIC¬PREDISPOSITION

(14) ¬ENVI RONMENTAL ¬ AND¬ DIETARY¬ RISK¬ FACTORS¬ MAY¬ PRESENT¬ CLUES¬ FOR¬ PATHOGENESIS¬ ¬ 4HE¬ MOST¬ IMPORTANT¬GENETIC¬RISK¬FACTOR¬FOR¬THE¬DEVELOPMENT¬OF¬2!¬IS¬THE¬PRESENCE¬OF¬(,!¬#LASS¬)) ALLELES¬THAT¬SHARE¬THE¬CONSERVED¬AMINO¬ACID¬SEQUENCE¬CALLED¬THE¬3HARED¬%PITOPE¬3% ¬ ¬ 4HESE¬ 3% RESIDUES¬ CONSTITUTE¬ A¬ PART¬ 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¬A¬PEPTIDE¬TO¬ARTHRITOGENIC¬4 CELLS 4HE¬MOST¬PROMINENT¬ENVIRONMENTAL¬RISK¬FACTOR¬FOR¬2!¬IS¬SMOKING¬SMOKERS¬HAVE¬INCREASED LEVELS¬OF¬2HEUMATOID¬&ACTOR¬2& ¬

(15) ¬ARE¬MORE¬PRONE¬TO¬DEVELOP¬2!¬ ¬AND¬DE VELOP¬ MORE¬ SEVERE¬ DISEASE¬ ¬ )NTERACTION¬ BETWEEN¬ ENVIRONMENTAL¬ AND¬ GENETIC¬ RISK¬ FACTORS¬POINTS¬TO¬THE¬EXISTENCE¬OF¬DISEASE SPECIl¬C¬PATHOGENIC¬PATHWAYS¬INVOLVED¬IN¬DISEASE¬ INDUCTION¬OR¬PROGRESSION &OR¬2!¬0ADYUKOV¬ET¬AL¬RECENTLY¬DESCRIBED¬A¬GENE ENVIRONMENT INTERACTION¬BETWEEN¬SMOK ING¬AND¬3%¬THAT¬PROVIDES¬RISK¬/2¬¬¬#)¬ ¬FOR¬2& POSITIVE¬BUT¬NOT¬2& NEGATIVE¬ 2!¬IN¬A¬LARGE¬COHORT¬OF¬¬2& POSITIVE¬AND¬¬2& NEGATIVE¬PATIENTS¬WITH¬2!¬ ¬2E CENTLY

(16) ¬WE¬IDENTIl¬ED¬IN¬TWO¬LARGE¬COHORTS¬FROM¬BOTH¬THE¬53!¬AND¬FROM¬%UROPE¬BY¬DIFFER ENT¬GENETIC EPIDEMIOLOGICAL¬METHODS¬ASSOCIATION¬AND¬LINKAGE ¬THAT¬(,! $2"¬ALLELES¬ARE¬ ONLY¬A¬RISK¬FACTOR¬FOR¬2!¬PATIENTS¬THAT¬HAVE¬ANTI ##0¬ANTIBODIES¬AND¬NOT¬IN¬THE¬ABSENCE¬OF¬ ANTI ##0¬ANTIBODIES

(17) ¬SUGGESTING¬DIFFERENT¬PATHOGENIC¬PATHWAYS¬FOR¬ANTI ##0¬POSITIVE¬AND¬ NEGATIVE¬2!¬ ¬ 4HIS¬STUDY¬INVESTIGATES¬WHETHER¬THE¬ GENE ENVIRONMENT¬ INTERACTION¬ SMOKING SHARED¬ EPI TOPE¬IS¬ALSO¬PRESENT¬FOR¬THE¬ANTI ##0¬ANTIBODY¬RESPONSE¬AND¬WHETHER¬THIS¬INTERACTION¬WAS MORE¬PRONOUNCED¬FOR¬THE¬DEVELOPMENT¬OF¬2&¬COMPARED¬TO¬THE¬DEVELOPMENT¬OF¬ANTI ##0¬ ANTIBODIES¬3ECONDLY

(18) ¬THIS¬STUDY¬AIMED¬TO¬ASSESS¬WHETHER¬THE¬INTERACTION¬SMOKING¬AND¬3% IS¬SPECIl¬C¬FOR¬PATIENTS¬WITH¬2!¬OR¬IS¬ALSO¬PRESENT¬IN¬UNDIFFERENTIATED¬ARTHRITIS¬5! ¬4O¬THIS END¬PATIENTS¬WITH¬ARTHRITIS¬THAT¬DID¬NOT¬FULl¬LL¬ANY¬CLASSIl¬CATION¬CRITERIA¬AT¬PRESENTATION¬AND PATIENTS¬WITH¬PERSISTENT¬5!¬AT¬ONE YEAR¬FOLLOW UP¬WERE¬USED¬4HESE¬PATIENTS¬HAVE¬A¬SPON TANEOUS¬REMISSION¬RATE¬OF¬ABOUT¬¬ ¬AND¬MIGHT¬HAVE¬DIFFERENCES¬IN¬THE¬UNDERLYING PATHOGENESIS¬)F¬THE¬INTERACTION¬BETWEEN¬SMOKING¬AND¬3%¬THAT¬LEADS¬TO¬AUTOANTIBODY¬FOR MATION¬IS¬SPECIl¬C¬FOR¬THE¬PATHOGENESIS¬OF¬2!

(19) ¬IT¬IS¬HYPOTHESIZED¬THAT¬SUCH¬AN¬INTERACTION¬ WILL¬NOT¬BE¬SEEN¬IN¬PATIENTS¬WITH¬AN¬UNDIFFERENTIATED¬ARTHRITIS¬OF¬WHICH¬CLINICAL¬FOLLOW UP HAS¬LEARNED¬THAT¬THESE¬PATIENTS¬HAVE¬NOT¬DEVELOPED¬2!. .

(20) 0!4)%.43¬!.$¬-%4(/$3. 0ATIENTS &OR¬THIS¬STUDY

(21) ¬THE¬,EIDEN¬%ARLY¬!RTHRITIS¬#LINIC¬%!#

(22) ¬A¬POPULATION BASED¬INCEPTION¬CO HORT¬ OF¬ PATIENTS¬ WITH¬ NEWLY¬ DIAGNOSED¬ EARLY¬ ARTHRITIS¬ WAS¬ USED¬ FOR¬ FURTHER¬ READING¬ SEE¬ ¬2!¬WAS¬DIAGNOSED¬ACCORDING¬TO¬THE¬!MERICAN¬#OLLEGE¬OF¬2HEUMATOLOGY¬!#2 ¬CRI TERIA¬OF¬ ¬0ATIENTS¬WHO¬COULD¬NOT¬BE¬PROPERLY¬CLASSIl¬ED¬ACCORDING¬TO¬ONE¬OF¬THE¬ !#2 CRITERIA¬ AT¬ ¬ WEEKS¬ FOLLOW UP¬ WERE¬ CATEGORIZED¬ AS¬ HAVING¬ 5!¬ ¬ 4HIS¬ POPULATION OF¬5!¬PATIENTS¬WAS¬FURTHER¬DIVIDED¬IN¬PATIENTS¬THAT¬ ¬HAD¬DEVELOPED¬2!

(23) ¬ ¬REMAINED¬ UNCLASSIl¬ED¬PERSISTENT¬5! ¬OR¬ ¬HAD¬DEVELOPED¬OTHER¬RHEUMATIC¬DISEASES¬SUCH¬AS¬SPON DYLARTHROPATHIES

(24) ¬OSTEOARTHRITIS

(25) ¬GOUT

(26) ¬REACTIVE¬ARTHRITIS¬AT¬ONE¬YEAR¬FOLLOW UP¬&IGURE¬ !T¬INCLUSION¬IN¬THE¬%!# COHORT

(27) ¬FOR¬EACH¬PATIENT¬THE¬SMOKING¬STATUS¬CIGARETTES

(28) ¬CIGARS WAS¬REGISTERED¬AS¬PAST

(29) ¬CURRENT¬OR¬NEVER¬SMOKERS¬#URRENT¬AND¬PAST¬SMOKERS¬WERE¬CLASSIl¬ED AS¬TOBACCO¬EXPOSURE¬POSITIVE¬4% ¬AND¬NEVER¬SMOKERS¬AS¬TOBACCO¬EXPOSURE¬NEGATIVE¬4% ¬"ASELINE¬LABORATORY¬PARAMETERS¬INCLUDED¬# REACTIVE¬PROTEIN¬#20

(30) ¬)G-¬RHEUMATOID¬ FACTOR¬%,)3!¬AS¬PREVIOUSLY¬DESCRIBED¬

(31) ¬ANTI ##0¬ANTIBODIES¬%,)3!

(32) ¬)MMUNOSCAN¬2! -ARK¬

(33) ¬%URO $IAGNOSTICA

(34) ¬!RNHEM

(35) ¬4HE¬.ETHERLANDS¬AND¬!XIS 3HIELD

(36) ¬$UNDEE

(37) ¬5+ ¬AND #HAPTER¬. (,! #LASS¬))¬ALLELES¬4HE¬(,! $2"¬SUB TYPING¬WAS¬PERFORMED¬BY¬POLYMERASE¬CHAIN¬RE. . ACTION¬USING¬SPECIl¬C¬PRIMERS¬AND¬HYBRIDISATION¬WITH¬SEQUENCE SPECIl¬C¬OLIGONUCLEOTIDES¬ 3HARED¬EPITOPE¬ALLELES¬WERE¬$2"¬

(38) ¬

(39) ¬

(40) ¬

(41) ¬

(42) ¬

(43) ¬ ¬AND¬. ¬ ¬0ATIENTS¬HOMOZYGOUS¬AND¬HETEROZYGOUS¬FOR¬SHARED¬EPITOPE¬WERE¬BOTH¬CLASSIl¬ED¬ AS¬3%¬POSITIVE¬-ISSING¬DATA¬FOR¬THE¬WHOLE¬COHORT¬OF¬¬PATIENTS¬RANGED¬FOR¬SEVERAL¬ITEMS¬ %DVHOLQH. ($& Q . 8$ Q . 3HUVLVWHQW8$ Q . 5$ Q . 5$ Q . 2WKHU Q \ HDU. 8$ 8QGLIIHUHQWLDWHG$UWKULWLV 5$ 5KHXPDWRLG$UWKULWLV &IGURE¬¬&LOW¬CHART¬EARLY¬ARTHRITIS¬PATIENTS. 2WKHU Q . ZHHNV. \HDU.

(44) 3MOKING¬RISK¬FACTOR¬FOR¬ANTI ##0¬POSITIVE¬2!. 3%

(45) ¬4%¬ANTI ##0¬AND¬2&¬BETWEEN¬ ¬!N¬ANALYSIS¬OF¬THE¬BASELINE¬VALUES¬OF¬PATIENTS WITH¬MISSING¬DATA POINTS¬REVEALED¬NO¬DIFFERENCES¬TO¬THOSE¬PATIENTS¬WITHOUT 3TATISTICAL¬ANALYSIS /DDS¬RATIOS¬WERE¬CALCULATED¬FOR¬THE¬PRIMARY¬OUTCOME¬MEASURES¬2&¬AND¬ANTI ##0¬ANTIBOD IES¬3TRATIl¬ED¬ANALYSIS¬WAS¬PERFORMED¬FOR¬BOTH¬ANTI ##0 POSITIVE¬AND¬ANTI ##0¬NEGATIVE AS¬WELL¬AS¬2& POSITIVE¬AND¬2& NEGATIVE¬STRATA¬#HI SQUARE¬ANALYSIS¬WAS¬PERFORMED¬ON¬¬BY ¬TABLES. 2%35,43. 0ATIENT¬CHARACTERISTICS "ETWEEN¬¬AND¬

(46) ¬¬PATIENTS¬WERE¬INCLUDED¬IN¬THE¬%!# COHORT¬!T¬TWO¬WEEKS¬ FOLLOW UP

(47) ¬¬PATIENTS¬DID¬NOT¬FULl¬LL¬ANY¬CLASSIl¬CATION¬CRITERIA¬AND¬WERE¬THUS¬CLASSIl¬ED AS¬5!¬!T¬THIS¬TIME¬¬PATIENTS¬FULl¬LLED¬THE¬!#2¬CRITERIA¬FOR¬2!¬/F¬THE¬¬5!¬PATIENTS

(48) ¬ AFTER¬ONE¬YEAR¬FOLLOW UP¬¬PATIENTS¬WERE¬DIAGNOSED¬AS¬HAVING¬2!¬)N¬¬PATIENTS¬THE¬ DIAGNOSIS¬REMAINED¬5!¬PERSISTENT¬5! ¬AND¬IN¬THE¬OTHER¬¬PATIENTS¬ANOTHER¬RHEUMATIC DISORDER¬SUCH¬AS¬SPONDYLARTHROPATHY

(49) ¬OSTEOARTHRITIS

(50) ¬PSORIATIC¬ARTHRITIS

(51) ¬ETC¬WAS¬IDENTIl¬ED &IGURE¬ ¬ 4HE¬ TOTAL¬ NUMBER¬ OF¬ PATIENTS¬ FROM¬ THE¬ COHORT¬ THAT¬ WAS¬ IDENTIl¬ED¬ AS¬ HAVING¬ 2!¬AT¬ONE¬YEAR¬WAS¬¬&ROM¬THE¬PATIENTS¬CLASSIl¬ED¬AS¬PERSISTENT¬5!¬AT¬ONE¬YEAR

(52) ¬¬ DEVELOPED¬2!¬DURING¬FURTHER¬FOLLOW UP¬+6ERPOORT

(53) ¬UNPUBLISHED¬DATA "ASELINE¬PATIENT¬CHARACTERISTICS¬OF¬PATIENTS¬THAT¬AT¬TWO¬WEEKS¬PRESENTED¬WITH¬2!¬OR¬5!¬ ARE¬GIVEN¬IN¬4ABLE¬¬THE¬DATA¬ON¬THE¬5!¬PATIENTS¬ARE¬PRESENTED¬FOR¬BOTH¬THE¬5!¬PATIENTS¬ 4ABLE¬ 0ATIENT¬CHARACTERISTICS¬AT¬BASELINE¬OF¬PATIENTS¬THAT¬PRESENTED¬WITH¬2!

(54) ¬PATIENTS¬THAT¬ PRESENTED¬WITH¬5!¬AND¬DEVELOPED¬2!¬AFTER¬¬YEAR¬AND¬PATIENTS¬THAT¬PRESENTED¬WITH¬5!¬AND¬HAD OTHER¬DIAGNOSES¬THAN¬2!¬AFTER¬ONE¬YEAR¬FOLLOW UP. 2!¬AT¬¬WEEKS N. 5!A2! N. 5!ANON¬2! N. P. !GE¬YR¬MEAN. . . . . &EMALE¬. . . . NS. #20¬MGL

(55) ¬MEAN. . . . . )G-¬2&¬ ¬. . . . . !NTI ##0¬ ¬. . . . ¬. 3HARED¬%PITOPE¬ ¬. . . . . 4OBACCO¬EXPOSURE¬ ¬. . . . NS. 3HARED¬%PITOPE¬ ¬MEANS¬PRESENCE¬OF¬¬OR¬¬SHARED¬EPITOPE¬ALLELES 4OBACCO¬EXPOSURE¬ ¬MEANS¬CURRENT¬AND¬PAST¬SMOKERS¬AS¬INDICATED¬IN¬THE¬MEDICAL¬HISTORY¬. 0¬VALUES¬WERE¬DETERMINED¬FOR¬5!A2!¬VERSUS¬5!ANON¬2!¬ #OMPARISON¬OF¬2!¬AT¬¬WEEKS¬VERSUS¬5!A2!¬REVEALED¬NO¬SIGNIl¬CANT¬DIFFERENCES. .

(56) THAT¬DEVELOPED¬2!

(57) ¬AS¬THE¬5!¬PATIENTS¬THAT¬HAD¬PERSISTENT¬5!¬AFTER¬ONE YEAR¬FOLLOW UP 5!¬PATIENTS¬THAT¬DID¬NOT¬DEVELOP¬2!¬WERE¬YOUNGER¬AT¬PRESENTATION¬THAN¬THE¬PATIENTS¬THAT¬ DEVELOPED¬2!¬MEAN¬¬YEARS

(58) ¬VS¬¬YEARS

(59) ¬P ¬4HE¬5!¬PATIENTS¬THAT¬DEVELOPED¬2! AFTER¬ONE¬YEAR¬HAD¬AT¬BASELINE¬HIGHER¬LEVELS¬OF¬#20

(60) ¬2&¬AND¬ANTI ##0¬ANTIBODIES¬AND¬WERE¬ MORE¬OFTEN¬3% POSITIVE¬COMPARED¬TO¬THE¬5! PATIENTS¬THAT¬HAD¬PERSISTENT¬5!¬OR¬DEVELOPED OTHER¬RHEUMATOLOGIC¬DIAGNOSIS¬4ABLE¬ ¬.O¬DIFFERENCES¬WERE¬OBSERVED¬BETWEEN¬THE¬¬ 2!¬PATIENTS¬THAT¬DEVELOPED¬2!¬AFTER¬¬YEAR¬AND¬THE¬¬PATIENTS¬WITH¬2!¬THAT¬WERE¬DIAG NOSED¬AT¬THE¬TWO¬WEEKS¬VISIT )NTERACTION¬TOBACCO¬EXPOSURE¬AND¬SHARED¬EPITOPE¬IN¬2! )N¬2!¬AND¬5!¬PATIENTS¬THE¬INTERACTION¬BETWEEN¬3%¬AND¬4%¬WAS¬ANALYZED¬/UTCOME¬PARAM ETERS¬WERE¬2&¬AND¬ANTI ##0¬ANTIBODIES )N¬ALL¬2!¬PATIENTS

(61) ¬NO¬EFFECT¬OF¬4%¬ON¬THE¬2&¬STATUS¬WAS¬SEEN¬IN¬3%¬NEGATIVE¬PATIENTS¬IN¬ CONTRAST¬TO¬A¬CLEAR¬EFFECT¬IN¬3%¬POSITIVE¬PATIENTS¬4HE¬/2¬FOR¬POSITIVE¬2&¬WAS¬¬FOR¬4% 3% ¬PATIENTS

(62) ¬¬FOR¬4% ¬3% ¬PATIENTS¬AND¬¬FOR¬4% 3% ¬PATIENTS¬ALL¬RELATIVE¬TO¬4% 3% ¬ PATIENTS¬4ABLE¬

(63) ¬SHOWING¬AN¬INTERACTION¬BETWEEN¬4%¬AND¬3%¬FOR¬THE¬DEVELOPMENT¬OF¬2& )N¬3%¬NEGATIVE¬2!¬PATIENTS

(64) ¬NO¬EFFECT¬OF¬4%¬WAS¬SEEN¬FOR¬POSITIVE¬ANTI ##0¬ANTIBODIES¬IN¬ #HAPTER¬. CONTRAST¬TO¬A¬CLEAR¬EFFECT¬IN¬THE¬3%¬POSITIVE¬GROUP¬4HE¬/2¬FOR¬POSITIVE¬ANTI ##0¬ANTIBODIES¬. . WAS¬¬FOR¬4% ¬3% ¬PATIENTS

(65) ¬¬FOR¬4% ¬3% ¬PATIENTS¬AND¬¬FOR¬4% 3% ¬PATIENTS

(66) ¬AGAIN ALL¬RELATIVE¬TO¬4% 3% ¬PATIENTS¬!S¬THE¬ODDS¬RATIO¬FOR¬ANTI ##0¬ANTIBODIES¬OF¬PATIENTS¬HAVING BOTH¬4%¬AND¬3%¬WAS¬HIGHER¬THAN¬THE¬SUMMED¬/2S¬OF¬PATIENTS¬HAVING¬ONLY¬4%¬OR¬3%

(67) ¬AN¬ INTERACTION¬WAS¬FOUND¬BETWEEN¬4%¬AND¬3%¬FOR¬THE¬PRESENCE¬OF¬ANTI ##0¬ANTIBODIES¬4HE DIFFERENCE¬BETWEEN¬THE¬4% ¬3% ¬PATIENTS¬AND¬THE¬4% ¬3% ¬PATIENTS¬WAS¬SIGNIl¬CANT¬BOTH¬FOR¬ )G- 2&¬AND¬FOR¬ANTI ##0¬4ABLE¬ 0RESUMING¬THAT¬2& POSITIVE¬AND¬ANTI ##0¬POSITIVE¬PATIENTS¬PARTLY¬OVERLAP¬EACH¬OTHER

(68) ¬A¬ STRATIl¬ED¬ANALYSIS¬WAS¬DONE¬FOR¬BOTH¬2& POSITIVE¬AND¬2& NEGATIVE¬AND¬ANTI ##0¬POSITIVE¬ AND¬NEGATIVE¬PATIENTS¬4HE¬RESULTS

(69) ¬SHOWN¬IN 4ABLE¬

(70) ¬DEMONSTRATE¬THAT¬WHEN¬STRATIl¬ED¬FOR THE¬PRESENCEABSENCE¬OF¬ANTI ##0¬ANTIBODIES

(71) ¬NO¬SIGNIl¬CANT¬INTERACTION¬IS¬FOUND¬BETWEEN¬ 4%¬ AND¬ 3%¬ IN¬ RELATION¬ TO¬ THE¬ PRESENCE¬ OF¬ 2&¬ 7HEN¬ STRATIl¬ED¬ FOR¬ 2&

(72) ¬ IN¬ THE¬ 2&¬ NEGATIVE GROUP¬AN¬INTERACTION¬BETWEEN¬4%¬AND¬3%¬WAS¬OBSERVED¬FOR¬THE¬DEVELOPMENT¬OF¬ANTI ##0¬ ANTIBODIES¬4HESE¬DATA¬SUGGEST¬THAT¬THE¬INTERACTION¬BETWEEN¬4%¬AND¬3%¬PRIMARILY¬ASSOCIATES¬ WITH¬POSITIVE¬ANTI ##0¬ANTIBODIES¬AND¬NOT¬WITH¬POSITIVE¬2& )NTERACTION¬TOBACCO¬EXPOSURE¬AND¬SHARED¬EPITOPE¬IN¬5! )N¬THE¬WHOLE¬GROUP¬OF¬PATIENTS¬WHO¬PRESENTED¬WITH¬5!

(73) ¬THE¬COMBINATION¬OF¬4%¬AND¬3% DID¬NOT¬SIGNIl¬CANTLY¬INCREASE¬THE¬RISK¬FOR¬THE¬PRESENCE¬OF¬POSITIVE¬2&¬OR¬ANTI ##0¬ANTIBOD IES¬4ABLE¬ ¬4HE¬/2¬FOR¬POSITIVE¬ANTI ##0¬ANTIBODIES¬IN¬4% ¬3% ¬PATIENTS¬WITH¬5!¬WAS¬ INCREASED¬ COMPARED¬ TO¬ 4% 3% ¬ /2¬ ¬ ¬ #)¬

(74) ¬ BUT¬ ADDITION¬ OF¬ 4%¬ TO¬ THE.

(75) 3MOKING¬RISK¬FACTOR¬FOR¬ANTI ##0¬POSITIVE¬2!. 4ABLE¬ /DDS¬RATIOS¬FOR¬DEVELOPING¬2&¬AND¬ANTI ##0¬ANTIBODIES¬IN¬THE¬PRESENCE¬OF¬4OBACCO %XPOSURE¬4% ¬ANDOR¬SHARED¬EPITOPE¬ALLELES¬3% ¬IN¬ALL¬2HEUMATOID¬!RTHRITIS¬PATIENTS¬AT¬¬YEAR. 4%. 3%. 2& . 2&. /2. ¬#). n. n. . . . P. n. . . . . . n. . . . . ¬. . . . . ¬. /. 4%. 3%. ANTI ##0¬. ANTI ##0¬. /2. P. n. n. . . . n. . . . . . n. . . . . ¬. . . . . ¬ ¬/. ANTI ##0. 4%. 3%. 2&¬ ¬. 2& ¬. /2. ¬#). P. n. n. . . . n. . . '. '. . . . . ¬r ¬r. n. . . . . . n. n. n. . . . n. n. . . . . . n. n. . . . . ¬r. . . . ¬r. . n. . 2&. 4%. 3%. ANTI ##0¬. ANTI ##0¬ ¬ /2. ¬#). P. n. n. . . . n. . . . . . n. . . . . ¬r. . . . . ¬r. /. / n. n. n. . . . n. n. . . . . . . . . ¬r. . . . ¬r. n. n. . n. . /. ¬4% 3% ¬VERSUS¬4% 3% ¬/2¬¬#)¬

(76) ¬P ¬4% 3% ¬VERSUS¬4% 3% ¬/2¬¬#)¬

(77) ¬P r¬#OMPARISON¬4% 3% ¬VERSUS¬4% 3% ¬NOT¬SIGNIl¬CANT /¬0 VALUE¬OF¬#HI SQUARE¬ANALYSIS¬OF¬¬BY¬¬TABLE. .

(78) 4ABLE¬ /DDS¬RATIOS¬FOR¬DEVELOPING¬2&¬AND¬ANTI ##0¬ANTIBODIES¬IN¬THE¬PRESENCE¬OF¬4OBACCO %XPOSURE¬4% ¬ANDOR¬SHARED¬EPITOPE¬ALLELES¬3% ¬IN¬PATIENTS¬WITH¬5NDIFFERENTIATED¬!RTHRITIS¬5! !¬!LL¬5!¬PATIENTS¬AT¬TWO¬WEEKS. 4%. 3%. )G-¬2&¬. )G-¬2&¬n. /2¬. ¬#). P. n. n. . . . n. . . ¬. . . n. . . ¬. . ¬r. . . ¬. . ¬r. 4%. 3%. ANTI ##0¬. ANTI ##0¬n. /2. ¬#). P. n. n. . . . n. . . ¬. . . n. . . ¬. . ¬r¬. . . ¬. . ¬r¬. /. ¬/. #HAPTER¬. "¬3UBGROUP¬OF¬5!¬PATIENTS¬WHO¬DEVELOP¬2!¬WITHIN¬ONE¬YEAR. . 4%. 3%. )G-¬2&¬. )G-¬2&¬n. /2¬. n. n. . . . ¬#). P. n. . . n. . . . . . . . ¬r. . . . . ¬r. 4%. 3%. ANTI ##0¬. ANTI ##0¬n. /2. ¬#). n. P. n. . . . n. . . . . . n. . . . . ¬r. . . . . ¬r. /. / #¬3UBGROUP¬OF¬PERSISTENT¬5!¬PATIENTS¬AT¬ONE¬YEAR. 4%. 3%. )G-¬2&¬. )G-¬2&¬n. /2¬. n. n. . . . ¬#). P. n. . . n. . . . . . . . . . . ¬r. . ¬r /. 4%. 3%. ANTI ##0¬. ANTI ##0¬n. /2. n. n. . . . ¬#). P. n. . . n. . . . . . . . . . . ¬r. . ¬r /. r¬#OMPARISON¬4% 3% ¬VERSUS¬4% 3% ¬NOT¬SIGNIl¬CANT /¬0 VALUE¬OF¬#HI SQUARE¬ANALYSIS¬OF¬¬BY¬¬TABLE.

(79) 3MOKING¬RISK¬FACTOR¬FOR¬ANTI ##0¬POSITIVE¬2!. PRESENCE¬OF¬3%¬DID¬NOT¬SIGNIl¬CANTLY¬INCREASE¬THE¬RISK¬OF¬HAVING¬ANTI ##0¬ANTIBODIES¬/2¬ ¬RELATIVE¬TO¬/2¬OF¬

(80) TABLE¬! ¬ 3UBSEQUENTLY

(81) ¬ WE¬ ASSESSED¬ WHETHER¬ IN¬ THE¬ SUBGROUP¬ 5!¬ PATIENTS¬ THAT¬ DEVELOPED¬ 2! N ¬ SMOKING¬ COMBINED¬ WITH¬ PRESENCE¬ OF¬ 3%¬ INCREASED¬ THE¬ RISK¬ OF¬ HAVING¬ ANTI ##0¬ ANTIBODIES¬4HEREFORE¬THE¬NON SMOKING¬3%¬NEGATIVE¬5!¬PATIENTS¬THAT¬DEVELOPED¬2!¬WERE COMPARED¬TO¬SMOKING¬3%¬NEGATIVE¬5!¬PATIENTS¬THAT¬DEVELOPED¬2!¬PATIENTS¬/2¬

(82) ¬AS¬ WELL¬AS¬TO¬NON SMOKING¬3% POSITIVE¬ PATIENTS¬ WITH¬ 5!¬ THAT¬ DEVELOPED¬ 2!¬ /2¬ ¬AND¬ l¬NALLY¬ TO¬ SMOKING

(83) ¬ 3% POSITIVE¬ PATIENTS¬ WITH¬ 5!¬ THAT¬ DEVELOPED¬ 2!¬ /2¬ ¬ )N¬ THIS¬ SMALLER¬GROUP¬OF¬2!¬PATIENTS¬A¬TREND¬FOR¬THE¬INTERACTION¬OF¬3%¬AND¬4%¬TO¬INCREASE¬THE¬RISK¬ OF¬HAVING¬ANTI ##0¬ANTIBODIES¬WAS¬OBSERVED¬#ALCULATIONS¬FOR¬OUTCOME¬2&¬SHOWED¬SIMILAR RESULTS¬4ABLE¬" 4HE¬SAME¬CALCULATIONS¬WERE¬REPEATED¬FOR¬PATIENTS¬WITH¬PERSISTENT¬5!¬N ¬!LTHOUGH¬ THE¬NUMBER¬OF¬ANTI ##0¬POSITIVE¬5!¬PATIENTS¬IS¬LOW

(84) ¬NO¬EFFECT¬OF¬TOBACCO¬EXPOSURE¬COM BINED¬WITH¬3%¬ON¬THE¬RISK¬OF¬HAVING¬ANTI ##0¬ANTIBODIES¬OR¬2&¬WAS¬OBSERVED¬4ABLE¬# 4HUS

(85) ¬THE¬INTERACTION¬OF¬3%¬AND¬TOBACCO¬EXPOSURE¬WAS¬FOUND¬FOR¬THE¬PRESENCE¬OF¬2&¬AND¬FOR ANTI ##0¬ANTIBODIES¬IN¬PATIENTS¬WITH¬2!¬AND¬IN¬THOSE¬5!¬PATIENTS¬THAT¬DEVELOP¬2!¬WITHIN¬ ONE¬YEAR¬BUT¬NOT¬IN¬PATIENTS¬WITH¬PERSISTENT¬5!. $)3#533)/.. !¬STRONG¬GENE ENVIRONMENT¬INTERACTION¬BETWEEN¬4%¬AND¬3%¬FOR¬THE¬PRESENCE¬OF¬AUTOANTI BODIES¬WAS¬OBSERVED¬)NTRIGUINGLY

(86) ¬THIS¬GENE ENVIRONMENTAL¬INTERACTION¬WAS¬ONLY¬PRESENT¬ IN¬PATIENTS¬WITH¬2!¬AND¬NOT¬OBSERVED¬IN¬PATIENTS¬WITH¬PERSISTENT ¬5!¬3TRATIl¬ED¬ANALYSIS¬ FOR¬THE¬DIFFERENT¬AUTOANTIBODY¬RESPONSES¬)G-¬2&¬AND¬ANTI ##0¬SHOWED¬THAT¬THE¬INTERAC TION¬IS¬PRIMARILY¬FOR¬THE¬ANTI ##0¬RESPONSE !¬RECENT¬3WEDISH¬STUDY¬DEMONSTRATED¬THAT¬A¬GENE ENVIRONMENT¬INTERACTION¬BETWEEN¬3% AND¬ SMOKING¬ RESULTS¬ IN¬ AN¬ ELEVATED¬ RISK¬ SPECIl¬CALLY¬ FOR¬ 2& POSITIVE¬ 2!¬ ¬ 4HESE¬ DATA¬ WERE¬REPLICATED¬AS¬WELL¬AS¬EXTENDED¬IN¬THE¬PRESENT¬STUDY¬2EPLICATION¬BY¬A¬SEPARATE¬GROUP¬ IN¬A¬SEPARATE¬COHORT¬MINIMIZES¬THE¬RISK¬THAT¬THE¬CURRENT¬l¬NDINGS¬ARE¬FALSE¬POSITIVE¬ ¬ "OTH¬THE¬3WEDISH¬AND¬THE¬CURRENT¬DATA¬DEMONSTRATE¬THE¬LACK¬OF¬A¬RELATION¬BETWEEN¬SMOK ING¬AND¬AUTOANTIBODIES¬IN¬3% NEGATIVE¬2!

(87) ¬INDICATING¬THAT¬THIS¬INTERACTION¬IS¬PREFERENTIAL FOR¬A¬GIVEN¬PATHOGENETIC¬PATHWAY¬IN¬3% POSITIVE¬2!¬4O¬SPECIFY¬THIS¬PATHOGENETIC¬PATHWAY¬ WITH¬REGARD¬TO¬THE¬SPECIl¬CITY¬OF¬THE¬AUTOANTIBODY¬RESPONSE

(88) ¬THE¬STRATIl¬ED¬ANALYSIS¬FOR¬ANTI ##0¬POSITIVITY¬YIELDED¬NO¬ADDITIONAL¬EFFECT¬OF¬SMOKING¬ON¬RISK¬TO¬DEVELOP¬2&¬)N¬CONTRAST THE¬STRATIl¬ED¬ANALYSIS¬FOR¬2&¬INDICATED¬THAT¬SMOKING¬MORE¬THAN¬DOUBLED¬THE¬RISK¬IN¬THE¬ 3% POSITIVE¬ PATIENTS¬ TO¬ DEVELOP¬ ANTI ##0¬ ANTIBODIES¬ 4HESE¬ DATA¬ SUGGEST¬ THAT¬ THE¬ GENE ENVIRONMENT¬INTERACTION¬BETWEEN¬SMOKING¬AND¬3%¬LEADING¬TO¬AUTOANTIBODIES¬IS¬PRIMARILY¬. .

(89) ASSOCIATED¬WITH¬THE¬ANTI ##0¬RESPONSE¬ !PART¬ FROM¬ THE¬ SPECIl¬CITY¬ OF¬ THIS¬ GENE ENVIRON MENT¬INTERACTION

(90) ¬OUR¬GROUP¬HAS¬RECENTLY¬DESCRIBED¬THAT¬3%¬IS¬ONLY¬A¬RISK¬FACTOR¬FOR¬ANTI ##0¬POSITIVE¬2!¬AND¬NOT¬FOR¬ANTI ##0¬NEGATIVE¬2!¬ ¬4HE¬CURRENT¬DATA¬DO¬NOT¬ALLOW THE¬ANALYSIS¬OF¬SMOKING¬AS¬A¬RISK¬FACTOR¬FOR¬ANTI ##0¬POSITIVE¬2!¬VERSUS¬ANTI ##0¬NEGATIVE 2!¬BECAUSE¬NO¬DATA¬OF¬SMOKING¬IN¬A¬MATCHED¬GROUP¬OF¬THE¬GENERAL¬POPULATION¬ARE¬KNOWN (OWEVER¬GIVEN¬THE¬FACT¬THAT¬3%¬ALONE¬IS¬NOT¬A¬RISK¬FACTOR¬FOR¬ANTI ##0¬NEGATIVE¬2!¬

(91) ¬THE GENE ENVIRONMENT¬INTERACTION¬BETWEEN¬SMOKING¬AND¬3%¬LEADING¬TO¬ANTI ##0¬ANTIBODIES SEEMS¬CHARACTERISTIC¬FOR¬ANTI ##0¬POSITIVE¬2!¬)NDEED¬NO¬EFFECT¬OF¬SMOKING¬WAS¬OBSERVED IN¬ THE¬ 3% NEGATIVE¬ PATIENTS¬ SEE¬ 4ABLE¬ ¬ 4HESE¬ DATA¬ ARE¬ IN¬ LINE¬ WITH¬ OUR¬ PREVIOUSLY¬ RE PORTED¬HYPOTHESIS¬THAT¬DIFFERENT¬PATHOGENETIC¬PATHWAYS¬OPERATE¬IN¬ANTI ##0¬NEGATIVE¬2!¬ AS¬COMPARED¬TO¬ANTI ##0¬POSITIVE¬2!¬4HE¬DEMONSTRATION¬OF¬THESE¬PATHOGENETIC¬PATHWAYS¬ IS¬DIFl¬CULT¬BECAUSE¬IT¬IS¬NOT¬KNOWN¬WHICH¬PROTEINS¬ARE¬CITRINULLATED¬AS¬A¬RESULT¬OF¬SMOKING

(92) ¬ NOR¬IS¬IT¬KNOWN¬IF¬OR¬HOW¬SMOKING¬BREAKS¬NORMAL¬TOLERANCE¬TO¬CITRINULLATED¬SELF PROTEINS )N¬THIS¬STUDY¬THE¬DIAGNOSIS¬PERSISTENT¬2!¬WAS¬DEl¬NED¬AS¬THE¬PRESENCE¬OF¬ARTHRITIS¬THAT¬DID¬ NOT¬FULl¬LL¬ANY¬OF¬THE¬CLASSIl¬CATION¬CRITERIA¬AFTER¬ONE YEAR¬FOLLOW UP¬4HIS¬MAY¬LEAD¬TO¬SOME¬ MISCLASSIl¬CATION¬BECAUSE¬A¬SMALL¬PROPORTION¬OF¬5!¬PATIENTS¬ONLY¬DEVELOP¬2!¬AFTER¬A¬LONGER¬ #HAPTER¬. TIME¬PERIOD¬(OWEVER

(93) ¬IN¬PREVIOUS¬ANALYSIS¬OF¬THIS¬COHORT¬THIS¬CONCERNED¬ONLY¬LESS¬THAN. . ¬ OF¬ THE¬ PATIENTS¬ WITH¬ PERSISTENT¬ 5!¬ AT¬ ONE¬ YEAR¬ -ORE¬ IMPORTANTLY

(94) ¬ NO¬ INTERACTION BETWEEN¬SMOKING¬AND¬SHARED¬EPITOPE¬WAS¬OBSERVED¬AT¬ALL¬IN¬THE¬PERSISTENT¬5!¬GROUP !¬WEAKNESS¬OF¬THE¬CURRENT¬STUDY¬IS¬THAT¬THE¬INFORMATION¬ON¬4%¬IS¬LIMITED¬TO¬PATIENT¬HISTORY TAKING¬AND¬PATIENTS¬WERE¬NOT¬ASKED¬ABOUT¬THE¬NUMBER¬OF¬PACK YEARS¬SMOKING¬4HEREFORE NO¬CONCLUSION¬ON¬THE¬MINIMAL¬EXPOSURE¬CAN¬BE¬DRAWN )N¬ SUMMARY

(95) ¬ SMOKING¬ WAS¬ CONl¬RMED¬ TO¬ BE¬ A¬ RISK¬ FACTOR¬ FOR¬ ANTI ##0¬ ANTIBODIES¬ IN¬ THE PRESENCE¬OF¬SHARED¬EPITOPE¬ALLELES¬IN¬PATIENTS¬WITH¬2!¬)N¬5!¬NO¬INTERACTION¬BETWEEN¬4% AND¬3%¬WAS¬DEMONSTRATED¬FOR¬THE¬PRESENCE¬OF¬AUTOANTIBODIES.

(96) 3MOKING¬RISK¬FACTOR¬FOR¬ANTI ##0¬POSITIVE¬2!. 2%&%2%.#%3 ¬. ¬. ¬. ¬. ¬. ¬. ¬. ¬. ¬ ¬. ¬ ¬. ¬. ¬. ¬. ¬. ¬. ¬. ¬ ¬. ¬ ¬. ¬ ¬ ¬ ¬. ¬ ¬. ¬ ¬. ¬ ¬. ¬ ¬ ¬ ¬. !HO¬+

(97) ¬(ELIOVAARA¬-¬2ISK¬FACTORS¬FOR¬RHEUMATOID¬ARTHRITIS¬!NN¬-ED¬¬ 0ATTISON¬$*

(98) ¬3YMMONS¬$0

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(103) ¬3KOGH¬4

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(105) ¬3OKKA¬4

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(112) ¬RHEUMATOID¬FACTORS

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(119) ¬ GENDER¬ AND¬ RHEUMATOID¬ ARTHRITIS EPIDEMIOLOGICAL¬ CLUES¬ TO¬ ETIOL OGY¬2ESULTS¬FROM¬THE¬BEHAVIORAL¬RISK¬FACTOR¬SURVEILLANCE¬SYSTEM¬*OINT¬"ONE¬3PINE¬ 3ILMAN¬!*

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(126) ¬USING¬INCIDENT¬CASES¬!NN¬2HEUM¬$IS¬¬ ¬ 'OODSON¬.*

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(173) ¬POPULATIONS

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