the influence of hla–drb1 alleles and rheumatoid factor on disease outcome in an inception cohort...

ARTHRITIS & RHEUMATISMVol. 42, No. 10, October 1999, pp 2174–2183© 1999 American College of Rheumatology

THE INFLUENCE OF HLA–DRB1 ALLELES ANDRHEUMATOID FACTOR ON DISEASE OUTCOME IN AN INCEPTIONCOHORT OF PATIENTS WITH EARLY INFLAMMATORY ARTHRITIS

BEVERLEY HARRISON, WENDY THOMSON, DEBORAH SYMMONS, BILL OLLIER, NICOLA WILES,TONY PAYTON, ELIZABETH BARRETT, and ALAN SILMAN

Objective. There are conflicting data concerningthe role of HLA–DRB1 alleles in disease outcome inearly rheumatoid arthritis. The exact role of thesealleles in short-term outcome is determined in thislarge, prospective, population-based study.

Methods. We recruited 532 patients with inflam-matory polyarthritis from the Norfolk Arthritis Registerand typed their sera for HLA–DRB1 alleles using poly-merase chain reaction–based methods. Disease outcomewas assessed at 2 years in terms of persistent jointinflammation, functional disability, and radiologic ero-sions. Results are expressed as risk ratios (RR) with95% confidence intervals (95% CI).

Results. There was no influence of HLA–DRB1alleles, in any combination, on the likelihood of diseasepersistence, and only a modest effect on functionaldisability (Health Assessment Questionnaire score >1).The most obvious effect was on the development oferosions (RR 1.9, 95% CI 1.4–2.6 for those who carriedat least 1 DRB1 shared epitope [SE] allele), withslightly greater effects for those who were homozygousfor SE-bearing alleles (RR 2.5, 95% CI 1.8–3.6). Thiseffect of HLA–DRB1 was restricted to patients whosesera were negative for rheumatoid factor. Among pa-tients with erosions, HLA–DRB1 had no influence onthe severity of radiologic damage (defined as the num-ber of eroded joints, or total Larsen score).

Conclusion. These data do not support routine

HLA–DRB1 screening of patients with early arthritis toidentify those at risk for subsequent severe disease.

In 1978, Stastny reported the association ofHLA–DRw4 with rheumatoid arthritis (RA) (1). Subse-quent clinical studies of patients from a wide range ofpopulations (2) led to the hypothesis that susceptibilityto RA was due to a consensus sequence of amino acidsencoded by particular HLA–DRB1 alleles—the “sharedepitope” (SE) (3). However, the association of the SEwith RA is much weaker in community-based cohortsthan in those from hospital clinics, suggesting that thesegenes exert their influence on disease severity/progression rather than on susceptibility (4,5).

RA is a heterogeneous disorder, with an outcomethat ranges from complete resolution of symptoms tosevere incapacity. In the last 20 years, there has beenconsiderable interest in studying outcome in RA and,especially, in determining whether it can be predicted inan individual patient using variables measured at pre-sentation. Disease outcome in RA can be measured in anumber of ways, although many studies have focused onpredicting radiologic outcome. Prospective studies haveidentified a large number of clinical and demographicfactors associated with an adverse prognosis, defined notonly in terms of radiologic damage but also as functionaldisability or disease persistence. Those most consistentlyreported include female sex (6–8), a high level ofinflammation (9–13), and rheumatoid factor (RF) posi-tivity (6,8,14,15).

One major area of interest, therefore, is the roleof genetic factors, specifically HLA–DRB1, in predictingdisease outcome. A number of prospective studies haveinvestigated the role of SE-positive alleles on the devel-opment of radiologic erosions in early RA (duration,5years). The 9 published studies (16–24) have yielded

Supported by the Arthritis Research Campaign, UK.Beverley Harrison, MD, MRCP, Wendy Thomson, PhD,

Deborah Symmons, MD, FRCP, Bill Ollier, PhD, Nicola Wiles, BSc,Tony Payton, MSc, Elizabeth Barrett, MSc, Alan Silman, MD, FRCP:University of Manchester, Manchester, UK.

Address reprint requests to Alan Silman, MD, FRCP, Arthri-tis Research Campaign Epidemiology Research Unit, Stopford Build-ing, University of Manchester, Manchester M13 9PT, UK.

Submitted for publication February 22, 1999; accepted inrevised form May 27, 1999.

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conflicting findings (Table 1). For example, 4 showed apositive association (17,19,23,24), and 5 showed noassociation (16,18,20–22). Although many of these stud-ies were small, there were also clear differences in bothpatient selection and radiologic assessment. However, itis not possible to explain the differences in the studies’conclusions using these factors. Similarly, there has beenno consensus about whether HLA–DRB1 alleles areassociated with other aspects of outcome in early RA,including functional disability and disease remission(16,19–21,25–28).

The Norfolk Arthritis Register (NOAR) was estab-lished in 1989 to investigate etiologic and prognostic factorsamong patients newly presenting with inflammatory poly-arthritis (29). One of the strengths of the NOAR is theselection of patients based on primary care visits, usingbroad entry criteria. We have recently shown that HLA–DRB1 alleles in general have little influence on diseasesusceptibility in a large cohort of patients referred to theNOAR with early inflammatory polyarthritis (30). Theseresults were independent of whether patients satisfied

classification criteria for RA at initial presentation. Wetherefore hypothesized that these alleles would have aneffect on disease severity at followup.

In this study of a large, population-derived sam-ple of .500 patients with incident inflammatory polyar-thritis, we assessed the influence of HLA–DRB1 alleleson disease outcome at 2 years. We defined an adverseoutcome in 3 separate ways: persistent synovitis, func-tional disability, and radiologic damage. We investigateda number of HLA–DRB1 phenotypic (*0101/*0102, any*04 allele, *0401, *0404, any SE allele) and genotypic (1copy of SE, 2 copies of SE, *04/*04, *0401/*0404)combinations. We also assessed the interaction betweenHLA–DRB1 and outcome using other predictors previ-ously identified in the NOAR cohort, namely, being RFpositive, being female, and having a disease duration of.3 months prior to seeking medical attention (31–33).

PATIENTS AND METHODSThe Norfolk Arthritis Register. Patients were recruited

from the NOAR, which aims to ascertain all incident cases of

Table 1. Previous studies investigating the influence of HLA–DR4 and/or shared epitope (SE)–bearing alleles on the development of radiologicerosions in patients with early (,5 years) rheumatoid arthritis (RA)

Study, location (ref.) Study population*

% with erosions(disease durationat measurements)

% positive forDR4 and/or SE

% with erosionsin DR41 vs.

DR42 or SE1vs. SE2

Calculated risk ratio(95% confidence

interval)

Van Zeben et al1991, TheNetherlands (16)

127 women, ages 20–50, with definiteRA (,5 years) attending a hospitalclinic

76 (mean 6–7years)

50 DR4 80 in DR4171 in DR42

1.1 (0.9–1.4)

Emery et al 1992,UK (17)

49 patients with symmetric, peripheralpolyarthritis (mean duration 13weeks) referred to an early arthritisclinic

51 (4 years) 73 SE 58 in SE131 in SE2

1.9 (0.8–4.5)

Paimela et al 1993,Finland (18)

87 patients with definite RA (,1year) seen at a hospital clinic

68 (3 years) 68 DR4 67 in DR4171 in DR42

1.0 (0.7–1.3)

Gough et al 1994,UK (19)

120 patients with RA (1987 ACRcriteria) (mean duration 7.4months) seen at an early arthritisclinic

Not reported 64 SE Not reported Not reported; commentthat SE associatedwith erosions

Suarez-Almazor et al1995, Canada (20)

101 patients with RA (1987 ACRcriteria) with disease onset in 1985referred from the local community

72 (6–7 years)† 54 DR456 SE†

70 in SE176 in SE2†

0.9 (0.7–1.2)

Eberhardt et al 1996,Sweden (21)

99 patients with definite RA (,2years) referred from primary care

91 (5 years) 68 DR487 SE

92 in SE183 in SE2

1.1 (0.9–1.4)

Higami et al 1997,Japan (22)

161 patients with polyarthritis (,1year) seen at a hospital clinic

83 (1 year) 65 SE 85 in SE180 in SE2

1.1 (0.9–1.2)

Wagner et al 1997,Germany (23)

55 patients with RA (1987 ACRcriteria) (,2 years) seen at ahospital clinic

62 (median 18months)

40 DR464 SE

80 in SE135 in SE2

2.3 (1.2–4.3)

Plant et al 1998,UK (24)

83 patients with nonerosive probable/definite RA (,3 years) seen at ahospital clinic

77 (8 years) 53 DR469 SE

83 in SE165 in SE2

1.3 (0.9–1.7)

* Definite RA 5 RA according to the 1958 criteria of the American College of Rheumatology (ACR; formerly, the American RheumatismAssociation).† Data obtained from a personal communication.

INFLUENCE OF HLA–DRB1 ALLELES AND RF ON RA OUTCOME 2175

adults newly presenting with inflammatory polyarthritis toprimary care facilities. The Register covers a population ofalmost 500,000, predominantly European Caucasians (99%).Patients are eligible for inclusion if they have synovial swellingof $2 peripheral joints which has persisted for $4 weeks.Patients are excluded if they have an alternative specificdiagnosis that accounts for their symptoms (other than RA,psoriatic arthritis, or viral arthritis). Within 2 weeks of notifi-cation, patients are visited at home by a trained research nursewho performs a structured clinical evaluation and takes bloodfor RF estimation and DNA extraction.

Laboratory data. DNA was extracted by phenol–chloroform extraction from blood treated with EDTA toprevent coagulation. HLA–DRB1 phenotypes and DR4 sub-types were determined using a semiautomated, commerciallyavailable reverse dot-blot hybridization method, INNO-LiPA(Murex Diagnostics, Dartford, UK), according to the manu-facturer’s instructions. Reaction patterns were interpretedusing INNO-LiPA software. Sera were analyzed for RF usinga tube latex dilution method (a titer $1:40 was consideredpositive).

Study population. Between 1991 and 1994, 629 patientswere referred to NOAR and their sera successfully typed forDRB1 alleles. Of these patients, 599 had RF measured atbaseline, and 532 of these were followed up annually for $2 years.

Followup data. Clinical interviews and examinationswere performed by a research nurse using a structured proto-col. The following joints were palpated for the presence of softtissue swelling: distal interphalangeal joints, proximal inter-phalangeal (PIP) joints, metacarpophalangeal (MCP) joints,wrists, elbows, shoulders, knees, ankles, and metatarsophalan-geal (MTP) joints. At each visit, patients were asked tocomplete the Health Assessment Questionnaire (HAQ), whichis scored from 0 to 3 (34). At the 1-year followup visit, patientswho satisfied $2 of the American College of Rheumatology(ACR; formerly, the American Rheumatism Association) 1987criteria (35) were asked to have radiographs taken of theirhands and feet. We restricted radiologic assessment to reducethe number of patients with mild disease (and thereforeunlikely to have erosions) who would be exposed to radiation.

Radiographs were read by 2 observers working inde-pendently, using Larsen’s grading system (36). The followingjoints were scored from 0 to 5: PIP, MCP, wrists, and MTPII–V. Patients were classified as having erosion if their Larsenscore was $2 in any of the joints assessed. A third observeracted as arbiter in case of disagreement about whether patientshad erosion. In addition, patients were assigned a total Larsenscore, which could range from 0 to 190, and the total numberof eroded joints was calculated. At the second-year assessmentvisit, patients were again asked to have radiographs taken ifthey satisfied $2 of the 1987 ACR criteria (and if radiographswere not available at 1 year) and/or were recorded as having noerosions at the 1-year visit. This study used the latest availableradiographic finding.

Definition of disease outcome. Disease outcome wasdefined at 2 years, in the following 3 separate ways:

Persistent disease. Persistent disease was defined aseither soft tissue swelling in $1 of the joints assessed, ordisease requiring treatment with disease-modifying antirheu-matic drugs or steroids in the previous 3 months. Patients withpersistent disease were divided by tertiles according to the total

number of swollen joints. Data were available for all 532patients.

Functional disability. Functional disability was classi-fied using the following 2 approaches: 1) patients were consid-ered to have at least “moderate” functional disability if theirHAQ scores were $1 (which represents, on average, “somedifficulty” within each of the 8 categories covered by thequestionnaire), and 2) patients with at least “mild” functionaldisability (defined as a HAQ score $0.5) were divided bytertiles. Data were available for 527 patients (99%).

Radiologic damage. Patients were classified as havingerosions or not according to the Larsen grading system.Patients with erosions were divided by tertiles according to thenumber of eroded joints, and also classified separately by thetotal Larsen score. Data were available for 359 patients (67%).

Statistical analysis. The frequencies of HLA–DRB1phenotypes and genotypes were compared using risk ratios(RR) and 95% confidence intervals (95% CI). Patients wereclassified as SE positive if their sera contained any of thefollowing HLA–DRB1 alleles: *0101, *0102, *0401, *0404,*0405, *0408, *1001, or *1402. Allelic combinations wereanalyzed for their association with disease outcome. Pheno-types included *0101 or *0102, any *04 allele, *0401, *0404,and any SE allele, while genotypes included 1 copy of SE, 2copies of SE, *04/*04, and various combinations of SE-bearingalleles, including the “compound heterozygote” *0401/*0404(37). In each case, the referent group comprised patients whowere SE negative. Separate analyses were undertaken toinvestigate whether particular alleles were associated withdisease outcome in terms of persistent disease, functionaldisability, and radiologic erosions. Further analyses were un-dertaken for each of the outcomes in patients stratified by sex(women/men), initial disease duration ($3 months/,3months), and baseline RF status (positive/negative).

RESULTS

Three hundred thirty-eight patients (64%) werefemale, and the median age at symptom onset was 55 years(range 16–88). The median disease duration at the initialassessment visit was 28 weeks, and 408 patients (77%) hada disease duration of ,1 year. At this visit, 254 patients(48%) satisfied the 1987 ACR classification criteria. By 2years of followup, allowing patients to satisfy disease crite-ria, cumulatively, 376 patients (71%) could be classified ashaving RA. One hundred forty-eight patients (28%) wereRF positive at baseline. The proportion of seropositivepatients was higher among those whose sera contained $1DR4 allele (36%), especially DRB1 *0404 (46%). Therewere no important differences in the frequency of DRB1alleles between men and women, or between patients whopresented within 3 months of disease onset compared withthose who presented later.

HLA–DRB1 alleles and persistent disease. At 2years, 419 patients (79%) were classified as havingpersistent disease (see above), but HLA–DRB1 alleles

2176 HARRISON ET AL

had no influence on this (Table 2). There were also nosignificant differences when the group was stratified bysex, initial disease duration, and RF status. There was noinfluence of any genotypic combination, including ho-mozygosity for SE-bearing alleles. Further, when thedata from the 419 patients with persistent disease weredivided by tertiles based on the total number of swollenjoints, there was no difference in the frequency of DRB1alleles between those in the highest tertile and those inthe lowest tertile (data not shown).

HLA–DRB1 alleles and functional disability. Ofthe 527 patients who completed the HAQ at 2 years, 205(39%) had a score of $1. The presence of HLA–DRB1

alleles had only a very modest influence on the devel-opment of functional disability as defined as a HAQscore $1 (Table 3); this influence was more marked inmen. Any effect was restricted to those with a diseaseduration at presentation of $3 months and those whowere RF negative. Further, among those with a HAQscore of $0.5, when the data were divided by tertiles,there was no difference in the frequency of HLA–DRB1alleles between those with the highest (1.75–3) and thosewith the lowest (0.5–0.88) HAQ scores (data not shown).Similar to the data on disease persistence, there was noevidence of any increased effect in patients who werehomozygous for SE-bearing alleles.

Table 2. The influence of HLA–DRB1 alleles on the development of persistent synovitis at 2 years*

Whole group(n 5 532)

Women(n 5 338)

Men(n 5 194)

Disease duration$3 months(n 5 408)

Disease duration,3 months(n 5 124)

RF positive(n 5 148)

RF negative(n 5 384)

No. (%) of patientswith persistentdisease

419 (79) 265 (78) 154 (79) 328 (80) 91 (73) 136 (92) 283 (74)

HLA–DRB1 phenotype*0101 or *0102 1.0 (0.9–1.2) 1.0 (0.9–1.2) 1.0 (0.8–1.2) 1.1 (1.0–1.2) 0.8 (0.6–1.2) 1.0 (0.9–1.3) 1.0 (0.9–1.2)Any *04 allele 1.1 (1.0–1.2) 1.1 (1.0–1.3) 1.1 (0.9–1.2) 1.1 (1.0–1.3) 1.0 (0.8–1.2) 1.1 (1.0–1.3) 1.0 (0.9–1.2)*0401 1.1 (1.0–1.3) 1.2 (1.0–1.3) 1.1 (1.0–1.3) 1.2 (1.1–1.3) 1.0 (0.8–1.3) 1.1 (1.0–1.3) 1.1 (1.0–1.3)*0404 1.1 (1.0–1.2) 1.1 (0.9–1.3) 1.0 (0.8–1.3) 1.1 (1.0–1.3) 1.0 (0.6–1.4) 1.1 (1.0–1.3) 1.0 (0.8–1.2)Any SE allele 1.1 (1.0–1.2) 1.1 (1.0–1.2) 1.0 (0.9–1.2) 1.1 (1.0–1.2) 0.9 (0.7–1.1) 1.1 (1.0–1.3) 1.0 (0.9–1.2)

HLA–DRB1 genotype1 copy of SE 1.1 (1.0–1.2) 1.1 (1.0–1.2) 1.0 (0.8–1.2) 1.1 (1.0–1.2) 0.9 (0.7–1.1) 1.1 (1.0–1.3) 1.0 (0.9–1.1)2 copies of SE 1.1 (1.0–1.3) 1.1 (0.9–1.3) 1.1 (0.9–1.3) 1.1 (1.0–1.3) 1.0 (0.8–1.4) 1.1 (0.9–1.3) 1.0 (0.9–1.3)*04/*04 1.2 (1.0–1.3) 1.2 (1.0–1.4) 1.1 (0.9–1.4) 1.3 (1.1–1.4) 0.9 (0.5–1.4) 1.1 (0.9–1.3) 1.2 (1.0–1.4)*0401/*0404 1.3 (1.1–1.4) † 1.2 (0.9–1.4) 1.3 (1.1–1.5) † 1.1 (0.9–1.3) †

* Values are risk ratios (RR) (95% confidence intervals) for persistent disease, except where indicated. The referent group is the patients who wereshared epitope (SE) negative. RF 5 rheumatoid factor.† Unable to calculate RR (cell contains 0).

Table 3. The influence of HLA–DRB1 alleles on the development of functional disability (HAQ score $1) at 2 years*


Women(n 5 334)

Men(n 5 193)

Disease duration$3 months(n 5 405)

Disease duration,3 months(n 5 122)

RF positive(n 5 147)


No. (%) of patientswith HAQ score $1

205 (39) 147 (44) 58 (30) 167 (41) 38 (31) 72 (49) 133 (35)

HLA–DRB1 phenotype*0101 or *0102 1.2 (0.9–1.6) 1.3 (0.9–1.7) 1.0 (0.5–2.0) 1.3 (0.9–1.8) 0.8 (0.4–1.7) 1.2 (0.7–1.9) 1.1 (0.8–1.6)Any *04 allele 1.3 (1.0–1.7) 1.3 (1.0–1.6) 1.6 (1.0–2.6) 1.5 (1.2–2.0) 0.8 (0.4–1.3) 1.1 (0.8–1.7) 1.4 (1.0–1.8)*0401 1.4 (1.1–1.8) 1.3 (1.0–1.7) 1.5 (0.9–2.5) 1.5 (1.1–2.0) 0.9 (0.5–1.6) 1.0 (0.7–1.6) 1.5 (1.1–2.0)*0404 1.3 (1.0–1.9) 1.1 (0.7–1.7) 2.0 (1.2–3.4) 1.6 (1.1–2.2) 0.3 (0.3–1.7) 1.2 (0.7–1.9) 1.2 (0.8–2.0)Any SE allele 1.3 (1.0–1.6) 1.3 (1.0–1.6) 1.4 (0.8–2.2) 1.4 (1.1–1.8) 0.8 (0.5–1.4) 1.1 (0.8–1.6) 1.3 (1.0–1.7)

HLA–DRB1 genotype1 copy of SE 1.3 (1.0–1.6) 1.3 (1.0–1.6) 1.3 (0.8–2.1) 1.3 (1.0–1.8) 0.9 (0.5–1.6) 1.1 (0.7–1.7) 1.3 (0.9–1.7)2 copies of SE 1.4 (1.0–1.9) 1.3 (0.9–1.9) 1.7 (1.0–3.2) 1.7 (1.2–2.3) 0.4 (0.1–1.5) 1.1 (0.7–1.8) 1.5 (1.0–2.2)*04/*04 1.1 (0.7–1.6) 1.0 (0.6–1.7) 1.3 (0.6–3.0) 1.4 (0.9–2.1) † 0.8 (0.4–1.5) 1.2 (0.6–2.2)*0401/*0404 1.3 (0.7–2.2) 1.0 (0.4–2.5) 1.9 (0.9–4.0) 1.5 (0.9–2.6) † 0.7 (0.3–1.8) 1.9 (1.0–3.7)

* Values are RR (95% confidence intervals) for functional disability, except where indicated. The referent group is the patients who were SEnegative. HAQ5Health Assessment Questionnaire (see Table 2 for other definitions).† Unable to calculate RR (cell contains 0).


HLA–DRB1 alleles and radiologic damage. Themedian time from disease onset to the latest availableradiograph was 26 months (interquartile range 18–34months). Of the 359 patients who underwent radiogra-phy, 146 (41%) had developed radiologic erosions. Incontrast with disease persistence and functional disabil-ity, we found that HLA–DRB1 alleles had a moremarked influence on whether patients developed radio-logic erosions (Table 4). For example, the relative risk(or risk ratio) of developing erosions among patientswhose sera had any DRB1*04 allele was 2.2 (95% CI1.6–3.0) compared with patients who were SE negative.Similarly, patients who were SE positive were almosttwice as likely to develop erosions compared with thosewho were SE negative. Those with 2 copies of the SEwere more likely to develop erosions (RR 2.5, 95% CI1.8–3.6) than those with only 1 copy (RR 1.8, 95% CI1.3–2.4), providing some evidence for a gene-dose effect.The most interesting results emerged when the cohortwas stratified by RF status. This clearly showed that theinfluence of HLA–DRB1 alleles on the development oferosions was only apparent in seronegative patients, andthat these genes did not influence radiologic outcome inpatients who were RF positive. Also of interest, HLA–DRB1 alleles had a stronger influence on the develop-ment of erosions in women and among patients whopresented within 3 months of disease onset.

To determine whether HLA–DRB1 alleles influ-enced the degree of radiologic damage in those patientswho had already developed erosions, the data weredivided by tertiles according to the number of eroded

joints and the total Larsen score. There was no differ-ence in the frequency of HLA–DRB1 alleles betweenthose in the highest and lowest tertiles, suggesting thatthese genes influenced susceptibility to, but not severityof, erosive damage (Table 5).

Given that we found both RF and HLA–DRB1alleles to be associated with the development of ero-sions, we divided the cohort into risk groups based onbaseline RF and DRB1 status. We then calculated therisk of developing erosions for each of these groups,which is equivalent to the positive predictive value(PPV) for erosions. The results for patients stratified byRF and SE status are illustrated in Table 6. For example,the PPV for erosions in patients who were RF positivewas high at 65%. This rose only slightly to 68% forpatients who were both RF and SE positive. Thissuggests that knowledge of SE status offers little addi-tional power to predict erosions beyond that of RFstatus alone. However, it was possible to identify pa-tients at very low risk for erosions if they were both RFnegative and SE negative (PPV 16%). Similar resultswere obtained when individual phenotypes and geno-types were examined (data not shown).

DISCUSSION

Previous studies have provided conflicting find-ings concerning whether HLA–DR4 and/or SE areassociated with outcome in patients with early RA(16–28). It is likely that these differences reflect variabil-ity in case selection, radiographic assessment, and small

Table 4. The influence of HLA–DRB1 alleles on the development of radiologic erosions*


Women(n 5 240)

Men(n 5 119)

Delay inpresentation$3 months(n 5 281)

Delay inpresentation,3 months

(n 5 78)RF positive(n 5 118)


No. (%) of patientswith erosions

146 (41) 89 (37) 57 (48) 126 (45) 20 (26) 77 (65) 69 (29)

HLA–DRB1 phenotype*0101 or *0102 1.6 (1.1–2.4) 1.8 (1.1–3.3) 1.3 (0.7–2.2) 1.3 (0.9–2.0) 3.7 (1.2–11.2) 1.0 (0.6–1.6) 2.2 (1.2–3.9)Any *04 allele 2.2 (1.6–3.0) 2.6 (1.7–4.0) 1.6 (1.0–2.5) 1.8 (1.3–2.5) 4.1 (1.5–11.6) 1.3 (1.0–1.9) 2.6 (1.6–4.3)*0401 2.3 (1.7–3.1) 2.7 (1.8–4.2) 1.7 (1.1–2.8) 1.9 (1.4–2.7) 4.6 (1.6–13.1) 1.4 (1.0–1.9) 3.0 (1.8–4.9)*0404 2.1 (1.4–3.1) 2.5 (1.4–4.4) 1.5 (0.9–2.6) 1.9 (1.3–2.7) † 1.3 (0.9–1.9) 2.3 (1.2–4.6)Any SE allele 1.9 (1.4–2.6) 2.3 (1.5–3.5) 1.5 (0.9–2.3) 1.6 (1.2–2.2) 3.8 (1.4–10.5) 1.2 (0.9–1.7) 2.4 (1.5–3.9)

HLA–DRB1 genotype1 copy of SE 1.8 (1.3–2.4) 2.0 (1.3–3.1) 1.4 (0.9–2.3) 1.5 (1.5–2.1) 3.4 (1.2–9.7) 1.2 (0.8–1.7) 2.1 (1.3–3.5)2 copies of SE 2.5 (1.8–3.6) 3.3 (2.1–5.2) 1.6 (0.9–2.8) 2.1 (1.5–3.0) 5.6 (1.8–17.2) 1.3 (0.9–1.9) 3.7 (2.2–6.4)*04/*04 2.5 (1.6–3.7) 3.0 (1.7–5.2) 1.8 (1.0–3.2) 2.0 (1.3–3.0) 6.6 (1.9–22.1) 1.3 (0.8–1.9) 3.1 (1.5–6.7)*0401/*0404 2.6 (1.6–4.2) 2.9 (1.3–6.5) 2.0 (1.1–3.6) 2.1 (1.3–3.4) † 1.2 (0.6–2.3) 4.2 (2.0–8.5)

* Values are RR (95% confidence intervals) for erosions, except where indicated. The referent group is the patients who were SE negative. See Table2 for definitions.† Unable to calculate RR (cell contains 0).

2178 HARRISON ET AL

sample size. In the NOAR, we have attempted toovercome these difficulties in a large population-basedstudy of unselected patients newly presenting with in-flammatory polyarthritis, and we have shown that HLA–DRB1 alleles have an important influence on the devel-opment of radiologic erosions. However, after 2 years offollowup, there was no association with persistent jointinflammation and only a very modest association withfunctional disability. Partly due to our large sample size,we have been able to calculate robust estimates of riskreflected in the very narrow CI surrounding the RR.

Two-year followup data were not available for 67patients (11%). Of these, 16 (24%) had died, 17 (25%)had moved, 28 (42%) had refused further followup, and6 (9%) could not be traced. There were no differences inHLA–DRB1 SE status in those patients not followed up(38% were SE negative versus 40% of those followed

up). It is unlikely, however, that there would be selectivedifferences in the associations between HLA–DRB1 andoutcome between those with and without followup,although the frequencies of the different outcomescould well be different.

The results of previous studies investigating ero-sions in patients with early disease have been outlined inTable 1. All of these studies were based on hospital clinicattenders, although some aimed to recruit cases morewidely, either from the local population (20,21) or byinvitation to attend early arthritis clinics (17,19). All but2 studies required patients to satisfy classification crite-ria for RA. We have previously shown that these criteriaare unsuitable for use in early disease (38), and there-fore believe it is inappropriate to investigate the role ofgenetic factors in disease pathogenesis/outcome amongpatients preselected on this basis. It is interesting to notethat our results are in accordance with those of the otherUK studies (17,19,24), even though selection criteriawere quite different. Therefore, cultural and ethnicdifferences among patients between studies need to beconsidered, particularly when genetic differences existbetween populations.

The prevalence of erosions in previous studiesranges from 51% at 4 years in a cohort of British patientswith symmetric inflammatory polyarthritis (17) to 91%at 5 years in a group of Swedish patients with definiteRA (21). In the NOAR study, we found that only 40% ofpatients had developed erosions at a median diseaseduration of 26 months. This is due to the nature of thestudy population, since the study aimed to recruit allpatients presenting with joint swelling to primary care.When data were examined from a separate group of

Table 5. The influence of HLA–DRB1 alleles on the severity of radiologic damage (analysis restricted to patients with erosions [n 5 146])*

Whole group

Total number of eroded joints Total Larsen score

Middle tertile(2–3 eroded joints)†

Upper tertile(4–18 eroded joints)†

Middle tertile(Larsen score 10–22)†

Upper tertile(Larsen score 23–63)†

HLA–DRB1 phenotype*0101 or *0102 1.6 (1.1–2.4) 1.2 (0.8–2.0) 0.9 (0.5–1.7) 1.4 (0.8–2.4) 1.4 (0.8–2.5)Any *04 allele 2.2 (1.6–3.0) 1.1 (0.7–1.6) 1.1 (0.7–1.7) 1.1 (0.7–1.8) 1.2 (0.7–2.0)*0401 2.3 (1.7–3.1) 1.0 (0.7–1.6) 1.0 (0.6–1.7) 1.0 (0.6–1.7) 1.2 (0.7–2.1)*0404 2.1 (1.4–3.1) 1.1 (0.7–2.0) 1.3 (0.8–2.2) 1.1 (0.6–2.1) 1.2 (0.6–2.3)Any SE allele 1.9 (1.4–2.6) 1.1 (0.7–1.7) 1.0 (0.6–1.6) 1.1 (0.7–1.9) 1.2 (0.7–2.0)

HLA–DRB1 genotype1 copy of SE 1.8 (1.3–2.4) 1.1 (0.7–1.7) 0.9 (0.5–1.5) 1.2 (0.7–1.9) 1.2 (0.7–2.0)2 copies of SE 2.5 (1.8–3.6) 1.1 (0.6–1.9) 1.3 (0.8–2.1) 1.0 (0.5–2.0) 1.4 (0.8–2.4)*04/*04 2.5 (1.6–3.7) 1.2 (0.6–2.2) 1.4 (0.9–2.4) 1.2 (0.6–2.5) 1.5 (0.8–2.8)*0401/*0404 2.6 (1.6–4.2) 1.2 (0.5–3.0) 1.6 (1.0–2.7) 0.6 (0.1–3.1) 1.3 (0.6–2.9)

* Values are risk ratios (95% confidence intervals). The referent group is patients who were shared epitope (SE) negative.† Risk ratios are calculated by comparing middle and upper tertiles with lower tertiles in exposed and referent groups.

Table 6. Positive predictive values for the development of erosionsaccording to baseline RF and SE status*

Risk groupNo. (%) of patientswith erosions (PPV)

RF positive 77 (65)(n 5 118)

RF negative 69 (29)(n 5 241)

RF positive/SE positive 54 (68)(n 5 80)

RF positive/SE negative 19 (56)(n 5 34)

RF negative/SE positive 52 (39)(n 5 134)

RF negative/SE negative 17 (16)(n 5 106)

* PPV 5 positive predictive value (see Table 2 for other definitions).


NOAR patients who had radiographs obtained at 5years, it was found that the prevalence of erosions roseto 53% (39). However, a change of this magnitude wouldbe unlikely to influence our conclusions. Among patientswho had already developed erosions, we found noassociation with the severity of erosions judged by thetotal Larsen score or the number of eroded joints. Thisis compatible with the findings of some studies(11,16,24,26,40) but not others (18,41,42).

In contrast with radiologic damage, we found thatHLA–DRB1 alleles had only a very modest influence onthe development of functional disability. In5 previous studies of patients with early RA(16,20,21,25,26), 4 also showed no association betweenDR4 and/or SE and functional disability measured be-tween 2 and 7 years using the HAQ score (20,21,25,26).However, this result is not surprising, since it is likelythat outcomes such as functional disability will bestrongly influenced by demographic, cultural, and psy-chological factors, while radiologic damage more closelyreflects aspects of disease pathogenesis. It is moredifficult to explain the variable association of HLA–DRB1 alleles and disease persistence. For example, of 6studies investigating early disease, 1 showed an associa-tion with the proportion of patients who satisfied theACR remission criteria (43) at the latest visit (16), 1showed an association with the proportion of patientswho satisfied RA classification criteria at 4 years (27),and 1 showed a weak association with persistent inflam-mation (according to clinical or laboratory evidence) at1 year (19). The others showed no association with theproportion of patients who satisfied the ACR remissioncriteria at 2 or 5 years (21) or a mean of 6.2 years (28),or who had a “remittive” disease course for 6–7 years(20). It is likely that the differences between studies aredue to the widely different definitions of remission.

In accordance with the findings of others(37,40,44), we have found some evidence for a gene-doseeffect on the development of radiologic damage in RA.However, this effect was only modest. We also foundthat DR4-bearing alleles had a greater effect than thosecarrying DR1. We could find little evidence for thehypothesis that particular combinations of SE alleleswere associated with a more severe outcome. However,there was a suggestion that the combination ofDRB1*0401/*0404 was slightly more important, as re-ported recently (19,45). Of particular interest was theobservation that DRB1 alleles were associated witherosions only in patients who were seronegative for RF,which has been reported previously (17). The associationof RF and DR4/SE has been investigated previously

(Table 7), although the results are not conclusive, andhas been the subject of previous discussion (46–49). Inthe NOAR study, we found that patients who were SEpositive, particularly with the allele DRB1*0404, wereapproximately twice as likely to be RF positive. Thissuggests that DRB1 alleles and RF production areassociated, but not strongly. Further, the association isnot necessarily direct, and may be mediated by othermajor histocompatibility complex–encoded alleles inlinkage disequilibrium with DR4, e.g., tumor necrosisfactor a polymorphisms (50,51).

We also found that the effect of DRB1 alleles wasinfluenced by sex and initial disease duration in additionto RF status. Previous studies of patients with estab-lished RA have shown an increased frequency of DR4 inmales (44,52,53). However, this is not apparent in stud-ies of patients with early disease (16,18,20,30). A num-ber of previous studies (6–8) including our own (31,32)have shown that women have an adverse prognosis. Ofinterest, we found that the effect of DRB1 alleles onerosive damage was slightly more pronounced in women.This was also noted by Young et al in patients with earlyRA (40). However, we found no difference in HLAphenotype or erosive status between men and women.We also found that genetic influences on erosions weresignificantly greater in patients who sought medical carewithin 3 months of disease onset, compared with thosewho did so later.

Further, the prevalence of erosions was almosttwice as high in patients who presented at $3 monthssince disease onset (45%) compared with those whopresented earlier (26%). We have previously found thatinitial disease duration (before presentation) is an im-portant independent risk factor for the development oferosions (33), and is not simply explained by saying thatpatients who present earlier have self-limiting disease.There are a number of possible explanations. Delay inpresentation might reflect a slower onset of disease, lackof belief that treatment will provide benefit, or lack ofopportunity for early disease-modifying treatment, whenit has the greatest potential to suppress inflammation(54–56). Therefore, we suggest that late seekers ofmedical care already have an adverse prognosis notinfluenced further by genetic factors.

Finally, in this group of patients newly presentingwith inflammatory polyarthritis, we have found little tosupport a policy of routine screening for DRB1 alleles toidentify those at risk for an adverse prognosis. Forexample, patients who are RF positive already have ahigh risk for developing erosions (65%), which rises toonly 68% for patients who are also SE positive. How-

2180 HARRISON ET AL

ever, we did note that for patients who were seronega-tive, our knowledge of their SE status enabled us toidentify those at very low risk for erosions. The issue ofgenetic screening is complex (57–59), and it is importantthat findings from single studies are not extrapolated toothers that have recruited patients using different selec-tion criteria, since PPV and NPV are closely related tothe prevalence of the outcome under investigation.

To summarize, in a study of a large cohort ofpatients newly presenting with inflammatory polyarthri-tis, we have found that HLA–DRB1 alleles are associ-ated with the development of radiologic erosions, butnot with functional disability or persistent joint inflam-mation at 2 years. HLA–DRB1 alleles have no furtherinfluence on the amount of radiologic damage beyondthe development of erosions. This genetic influence on

Table 7. Previous studies reporting the prevalence of RF according to HLA–DRB1 phenotype in patients with early (,5 years) rheumatoidarthritis (RA)*

Study, location (ref.) Study population% positive for DR4

and/or SE% RF

positive

% RF positive withDR41 vs. DR42or SE1 vs. SE2

Calculated risk ratio(95% confidence

interval)

Silman et al 1986,UK (25)

59 patients with definiteRA (,18 months)attending a hospitalclinic

48 DR4 71 at baseline 79 with DR4165 with DR42

1.2 (0.9–1.7)

Van Zeben et al1991, TheNetherlands (16)

127 women, ages 20–50,with definite RA (,5years) attending ahospital clinic

50 DR4 61 “ever”RF positive

83 with DR4138 with DR42

2.2 (1.6–3.1)

Van der Heijde et al1992, TheNetherlands (60)

147 patients withdefinite RA (,1year) attending ahospital clinic


1.4 (1.1–1.7)

Salmon et al 1993,UK (27)

55 patients withsymmetric, peripheralarthritis (,5 months)referred to an earlysynovitis clinic

71 SE(DR1 or DR4)

29 at baseline 31 with SE125 with SE2

1.2 (0.5–3.2)

Paimela et al 1993,Finland (18)

87 patients with definiteRA (,1 year) seen ata hospital clinic


1.1 (0.8–1.6)

Nelson et al 1994,US (61)

183 women withdefinite RA (,18months) recruitedfrom the localpopulation


1.9 (1.4–2.5)

Suarez-Almazor et al1995, Canada (20)

101 patients with RA(1987 ACR criteria)with disease onset in1985 referred fromthe local community

54 DR456 SE†

59 “ever”RF positive

66 with DR4151 with DR42

1.3 (0.9–1.8)

Eberhardt et al 1996,Sweden (21)

99 patients with definiteRA (,2 years)referred fromprimary care

68 DR487 SE

74 at baseline 77 with DR4171 with DR42

1.1 (0.8–1.4)

Wagner et al 1997,Germany (23)

55 patients with RA(1987 ACR criteria)(,2 years) seen at ahospital clinic

40 DR464 SE


1.0 (0.7–1.5)

NOAR (presentstudy)

532 patients withinflammatorypolyarthritis (medianduration 28 weeks)referred fromprimary care

45 DR459 SE


1.7 (1.3–2.3)

* Definite RA 5 RA according to the 1958 criteria of the American College of Rheumatology (ACR; formerly, the American RheumatismAssociation). NOAR 5 Norfolk Arthritis Register. (See Table 2 for other definitions).† Data obtained from a personal communication.


outcome is apparent only in patients who are seronega-tive for RF at baseline, and is particularly important inpatients who present within 3 months of symptom onset.Based on the findings of our study, we would notrecommend screening for DRB1 alleles in routine clin-ical practice among patients newly presenting with in-flammatory polyarthritis.

ACKNOWLEDGMENTS

We are grateful for the support of the general practi-tioners and hospital doctors in the Norwich Health Authorityfor their dedication in referring patients for study. In particu-lar, we thank Professor David Scott, consultant rheumatolo-gist, Norfolk & Norwich Hospital. We also thank the followingNOAR staff and research nurses for their hard work: JoanBarnard, Diane Bunn, Jacqueline Chipping, Linda Galpin, SueIvins, and Sue Whiting.

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