Search tips
Search criteria 


Logo of annrheumdAnnals of the Rheumatic DiseasesVisit this articleSubmit a manuscriptReceive email alertsContact usBMJ
Ann Rheum Dis. 1996 January; 55(1): 34–39.
PMCID: PMC1010079

Associations of HLA-DRB and -DQB genes with two and five year outcome in rheumatoid arthritis.


OBJECTIVE--To evaluate the clinical usefulness of genomic HLA typing during the first five years of established rheumatoid arthritis (RA). METHODS--The HLA-DRB and -DQB alleles were determined by restriction length polymorphisms and polymerase chain reaction amplification with sequence specific primers in 99 Swedish patients with RA. Clinical features after two and five years disease duration were related to the genetic pattern. Seventy four patients were seropositive, 25 had nodules, 90 developed erosions, and 15 required joint replacements. Twelve patients were in remission after five years. Disability was assessed by health assessment questionnaire, and radiographic damage in hands and feet by the Larsen method. RESULTS--Eighty seven per cent of the patients carried the conserved third hypervariable region sequence (HVR3), 32% had DRB1*04 on one allele, and 26% had DRB1*04 on both alleles (all frequencies significantly greater than in controls). Frequencies of DRB1*04 associated DQB*0301 and *0302 were normal. Patients carrying DRB1*04 on both alleles tended to have more radiographic changes after two years, but this difference had diminished after five years. Disability did not vary with regard to the genotype. Homozygous HVR3 patients had about three times greater risk of undergoing joint replacement. Homozygosity for HVR3 and presence of DQB*0302 both tended to be associated with erosive disease. CONCLUSIONS--We confirmed a strong association of disease with the presence of the shared epitope on one or two alleles. However, genotype was not strongly associated with disease severity after two and five years disease duration, and thus the value of genomic typing to select patients for early aggressive therapy is questionable.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.1M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Heikkilä S, Isomäki H. Long-term outcome of rheumatoid arthritis has improved. Scand J Rheumatol. 1994;23(1):13–15. [PubMed]
  • Pincus T, Callahan LF, Sale WG, Brooks AL, Payne LE, Vaughn WK. Severe functional declines, work disability, and increased mortality in seventy-five rheumatoid arthritis patients studied over nine years. Arthritis Rheum. 1984 Aug;27(8):864–872. [PubMed]
  • Vandenbroucke JP, Hazevoet HM, Cats A. Survival and cause of death in rheumatoid arthritis: a 25-year prospective followup. J Rheumatol. 1984 Apr;11(2):158–161. [PubMed]
  • Eberhardt K, Larsson BM, Nived K. Early rheumatoid arthritis--some social, economical, and psychological aspects. Scand J Rheumatol. 1993;22(3):119–123. [PubMed]
  • Stastny P, Ball EJ, Khan MA, Olsen NJ, Pincus T, Gao X. HLA-DR4 and other genetic markers in rheumatoid arthritis. Br J Rheumatol. 1988;27 (Suppl 2):132–138. [PubMed]
  • Wordsworth BP, Lanchbury JS, Sakkas LI, Welsh KI, Panayi GS, Bell JI. HLA-DR4 subtype frequencies in rheumatoid arthritis indicate that DRB1 is the major susceptibility locus within the HLA class II region. Proc Natl Acad Sci U S A. 1989 Dec;86(24):10049–10053. [PubMed]
  • Pile K, Gibson K, Jessop J, Camilleri J, Emberton R, Wordsworth P. HLA-DR4 subtyping by single-strand polymorphism analysis. Lancet. 1993 Jul 31;342(8866):300–301. [PubMed]
  • Wordsworth BP, Stedeford J, Rosenberg WM, Bell JI. Limited heterogeneity of the HLA class II contribution to susceptibility to rheumatoid arthritis is suggested by positive associations with HLA-DR4, DR1 and DRw10. Br J Rheumatol. 1991 Jun;30(3):178–180. [PubMed]
  • Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 1987 Nov;30(11):1205–1213. [PubMed]
  • Olsen NJ, Callahan LF, Brooks RH, Nance EP, Kaye JJ, Stastny P, Pincus T. Associations of HLA-DR4 with rheumatoid factor and radiographic severity in rheumatoid arthritis. Am J Med. 1988 Feb;84(2):257–264. [PubMed]
  • Young A, Corbett M, Winfield J, Jaqueremada D, Williams P, Papasavvas G, Hay F, Roitt I. A prognostic index for erosive changes in the hands, feet, and cervical spines in early rheumatoid arthritis. Br J Rheumatol. 1988 Apr;27(2):94–101. [PubMed]
  • Möttönen TT. Prediction of erosiveness and rate of development of new erosions in early rheumatoid arthritis. Ann Rheum Dis. 1988 Aug;47(8):648–653. [PMC free article] [PubMed]
  • van Zeben D, Hazes JM, Zwinderman AH, Cats A, Schreuder GM, D'Amaro J, Breedveld FC. Association of HLA-DR4 with a more progressive disease course in patients with rheumatoid arthritis. Results of a followup study. Arthritis Rheum. 1991 Jul;34(7):822–830. [PubMed]
  • Eberhardt K, Grubb R, Johnson U, Pettersson H. HLA-DR antigens, Gm allotypes and antiallotypes in early rheumatoid arthritis--their relation to disease progression. J Rheumatol. 1993 Nov;20(11):1825–1829. [PubMed]
  • Paimela L, Leirisalo-Repo M, Helve T, Koskimies S. The prognostic value of HLA DR4 and B27 antigens in early rheumatoid arthritis. Scand J Rheumatol. 1993;22(5):220–224. [PubMed]
  • Weyand CM, Xie C, Goronzy JJ. Homozygosity for the HLA-DRB1 allele selects for extraarticular manifestations in rheumatoid arthritis. J Clin Invest. 1992 Jun;89(6):2033–2039. [PMC free article] [PubMed]
  • Weyand CM, Hicok KC, Conn DL, Goronzy JJ. The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis. Ann Intern Med. 1992 Nov 15;117(10):801–806. [PubMed]
  • Salmon M, Wordsworth P, Emery P, Tunn E, Bacon PA, Bell JI. The association of HLA DR beta alleles with self-limiting and persistent forms of early symmetrical polyarthritis. Br J Rheumatol. 1993 Jul;32(7):628–630. [PubMed]
  • Gough A, Faint J, Salmon M, Hassell A, Wordsworth P, Pilling D, Birley A, Emery P. Genetic typing of patients with inflammatory arthritis at presentation can be used to predict outcome. Arthritis Rheum. 1994 Aug;37(8):1166–1170. [PubMed]
  • Sansom DM, Amin SN, Bidwell JL, Klouda PT, Bradley BA, Evison G, Goulding NJ, Hall ND, Maddison PJ. HLA-DO-related restriction fragment length polymorphisms in rheumatoid arthritis: evidence for a link with disease expression. Br J Rheumatol. 1989 Oct;28(5):374–378. [PubMed]
  • Clarkson R, Bate AS, Grennan DM, Chattopadhyay C, Sanders P, Davis M, Kelly C. DQw7 and the C4B null allele in rheumatoid arthritis and Felty's syndrome. Ann Rheum Dis. 1990 Dec;49(12):976–979. [PMC free article] [PubMed]
  • Singal DP, Green D, Reid B, Gladman DD, Buchanan WW. HLA-D region genes and rheumatoid arthritis (RA): importance of DR and DQ genes in conferring susceptibility to RA. Ann Rheum Dis. 1992 Jan;51(1):23–28. [PMC free article] [PubMed]
  • McMahon MJ, Hillarby MC, Clarkson RW, Hollis S, Grennan DM. Major histocompatibility complex variants and articular disease severity in rheumatoid arthritis. Br J Rheumatol. 1993 Oct;32(10):899–902. [PubMed]
  • Lanchbury JS, Jaeger EE, Sansom DM, Hall MA, Wordsworth P, Stedeford J, Bell JI, Panayi GS. Strong primary selection for the Dw4 subtype of DR4 accounts for the HLA-DQw7 association with Felty's syndrome. Hum Immunol. 1991 Sep;32(1):56–64. [PubMed]
  • Eberhardt KB, Rydgren LC, Pettersson H, Wollheim FA. Early rheumatoid arthritis--onset, course, and outcome over 2 years. Rheumatol Int. 1990;10(4):135–142. [PubMed]
  • DIAGNOSTIC criteria for rheumatoid arthritis: 1958 revision by a committee of the American Rheumatism Association. Ann Rheum Dis. 1959 Mar;18(1):49–53. [PMC free article] [PubMed]
  • Truedsson L, Sjöholm AG, Sturfelt G. Complement activating rheumatoid factors in rheumatoid arthritis studied by haemolysis in gel: relation to antibody class and response to treatment with podophyllotoxin derivatives. Clin Exp Rheumatol. 1985 Jan-Mar;3(1):29–37. [PubMed]
  • Gustafsson K, Wiman K, Emmoth E, Larhammar D, Böhme J, Hyldig-Nielsen JJ, Ronne H, Peterson PA, Rask L. Mutations and selection in the generation of class II histocompatibility antigen polymorphism. EMBO J. 1984 Jul;3(7):1655–1661. [PubMed]
  • Larhammar D, Schenning L, Gustafsson K, Wiman K, Claesson L, Rask L, Peterson PA. Complete amino acid sequence of an HLA-DR antigen-like beta chain as predicted from the nucleotide sequence: similarities with immunoglobulins and HLA-A, -B, and -C antigens. Proc Natl Acad Sci U S A. 1982 Jun;79(12):3687–3691. [PubMed]
  • Olerup O, Zetterquist H. HLA-DRB1*01 subtyping by allele-specific PCR amplification: a sensitive, specific and rapid technique. Tissue Antigens. 1991 May;37(5):197–204. [PubMed]
  • Zetterquist H, Olerup O. Identification of the HLA-DRB1*04, -DRB1*07, and -DRB1*09 alleles by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours. Hum Immunol. 1992 May;34(1):64–74. [PubMed]
  • Olerup O, Aldener A, Fogdell A. HLA-DQB1 and -DQA1 typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours. Tissue Antigens. 1993 Mar;41(3):119–134. [PubMed]
  • Ekdahl C, Eberhardt K, Andersson SI, Svensson B. Assessing disability in patients with rheumatoid arthritis. Use of a Swedish version of the Stanford Health Assessment Questionnaire. Scand J Rheumatol. 1988;17(4):263–271. [PubMed]
  • Wollheim FA, Pettersson H, Saxne T, Sjöblom KG. Radiographic assessment in relation to clinical and biochemical variables in rheumatoid arthritis. Scand J Rheumatol. 1988;17(6):445–453. [PubMed]
  • Pinals RS, Masi AT, Larsen RA. Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis Rheum. 1981 Oct;24(10):1308–1315. [PubMed]
  • Kazis LE, Anderson JJ, Meenan RF. Health status as a predictor of mortality in rheumatoid arthritis: a five-year study. J Rheumatol. 1990 May;17(5):609–613. [PubMed]
  • Pincus T, Callahan LF. Rheumatology function tests: grip strength, walking time, button test and questionnaires document and predict longterm morbidity and mortality in rheumatoid arthritis. J Rheumatol. 1992 Jul;19(7):1051–1057. [PubMed]
  • Brook A, Corbett M. Radiographic changes in early rheumatoid disease. Ann Rheum Dis. 1977 Feb;36(1):71–73. [PMC free article] [PubMed]
  • MacGregor AJ, Silman AJ. Epidemiological approaches to the immunogenetics of autoimmune rheumatic disease. Ann Rheum Dis. 1993 Apr;52(4):310–313. [PMC free article] [PubMed]
  • Eberhardt K, Fex E, Johnsson K, Geborek P. Hip involvement in early rheumatoid arthritis. Ann Rheum Dis. 1995 Jan;54(1):45–48. [PMC free article] [PubMed]
  • Plant MJ, Saklatvala J, Borg AA, Jones PW, Dawes PT. Measurement and prediction of radiological progression in early rheumatoid arthritis. J Rheumatol. 1994 Oct;21(10):1808–1813. [PubMed]

Articles from Annals of the Rheumatic Diseases are provided here courtesy of BMJ Publishing Group