Hellenic Medical journal (J997) 1,9-11

SHORT REPORT

it) 1997 Smith-Gordon

Rheumatoid arthritis in Southern Europe:

clinical and genetic peculiarities

A. Drosos

In Northern Europe and the USA most RA patients express particular HIA-DRPl alleles that share avery conserved hypervariable region, the 'shared epitope', which determines susceptibility to RA.Following on Greek studies indicating a high frequency of Ro(SSA) antibodies in sera, 108 Greek(loannina) and 107 UK (Guy's) patients who were evaluated by one investigator showed severer RA inthe Guy's patients and in the Greek patients more frequent manifestations of Sjogren's Syndrome andRo(SSA) antibodies. Further studies suggested that HIA-DRP is less frequent in Greek and Spanish RApatients than in Northern European patients. The possible role of HIA-DRPl should motivatefurther studies of the genetic and environmental differences in RA in different regions.

Rheumatoid arthritis (RA) is a common autoimmunedisease of unknown cause. The symptoms and signsof the disease are caused by a chronic inflammatoryprocess in the synovial membrane. Extra-articular orsystemic manifestations such as fever, anaemia,rheumatoid nodules, pleurisy may occur with consid­erable frequency1-3. The clinical heterogeneity of RAis well known. More than 50% of patients have seri­ously progressive disease leading to joint destruction.In some cases extra-articular manifestations can belife-threatening. This illustrates the double aspect ofthe disease, articular and systemic4. Although thepathogenesis is unknown, several reports provide

evidence suggesting that both genetics and envir<;?n­mental factors determine host susceptibility to RA5, •

In Northern Europe and in the USA, most-fatientswith RAexpress particular HL\-DR,81 alleles7 . Thesealleles share a very conserved 3rd hypervariableregion, the 'shared epitope', which determines hostsusceptibility to RA10. How the 'shared epitope' influ­ences the development of RAis still unknown. Studieshave shown that patients who express the 'sharedepito~' have more severe disease than patients whod 11,12 H . duC •o not . owever, genetic lerences eXlst amongcountries and between Europe and the USA. Thesedifferences may reflect different clinical expressionand different outcome in these patients.

In 1984 studies from Ioannina, a small city in North­West Greece, have shown that RA patients had a highfrequency of Ro(SSA) antibodies in their sera andthese patients experienced a high frequency of D­penicillamine (DP) side-effectsI3. One year later thesame investigators reported that Ro(SSA) positive RApatients were predominantly female, had high inci­dence of positive minor salivary gland biopsy com­patible with Sjogren's Syndrome (SS) and experienceda high frequency of DP side-effects14. In 1987 another

study by the same university centre in Greece showedthat extra-articular manifestations in RA wereobserved in lower frequency compared to those

15reported by others .

To answer the question as to whether theseRO(SSA) positive patients represent an overlapbetween RA. SS or lupus these authors conducted alongitudinal study comparing 25 Ro(SSA) positiveversus 50 Ro(SSA) negative RA patients. The majorconclusions from this study were that 80% of allpatients had features of erosive arthritis. The Ro(SSA)positive patients had more often features of sec­ondary SSand once more these patients presented DPside-effects16. Regarding the prevalence of secondarySS in Greek patients the same group of investigatorsshowed that SS was common (31%), benign and sub­clinical, requiring specific testing for its diagnosis17.

These clinical and serological differences observedin Greek RA patients prompted the investigators toconduct a comparative clinical study between Greekand British RApatients. For this reason 108 Greek and107 British consecutive unselected RA patients, beingfollowed-up at the Ioannina University Hospital andGuy's Hospital London, respectively, were evaluatedby the same investigator. The major conclusions fromthis study were that (a) British patients had moresevere articular and extra-articular manifestations, (b)British patients had more severe joint damage onradiological examination, and, (c) Greek RA patientsmore frequently had features of SSmanifestations andRo(SSA) antibodies in their sera 18. Two years later, in1994, another study coming from Spain compared 63RA patients followed-up at the Alicante General

Dr A. Drosos, Department of Rheumatology, Universityof loannina Medical School, loannina, Greece.

10

Hospital. with 63 British RA patients followed-up atGuy's Hospital London, confirmed the Greek resultsthat RA in Spain was milder with less extra-articularmanifestations 19.

To clarify these clinical and serological differencesobserved between Greek and British patients we con­ducted an immunogenetic study. We examined HLA­class II DNA polymorphism in 92 Greek RA patientsand compared these findings with those of 84 healthyethnically matched individuals. HLA-DRB polymor­phism was characterized by restriction fragmentlength polymorphism (RFLP) and DRB subtypes wereexamined by polymerase chain reaction (PCR). ampli­fication and oligonucleotide hybridization. Our resultsshowed that RA in Greece is associated with the sameHU.-DR,8 alleles which confer susceptibility inNorthern European Caucasians. However, whereas83% of Northern European patients carry the I-il.ADR,8motif, this was found in only 43.5% of Greek RApatients. Thus, most patients with RA lack this puta­tive Hl.A epitope and probably this reflects differ­ences in disease expression in Greeks20• Recently.another stUdy from Southern France (Marseille)reported that despite the fact that 76% of RA patientsexpress the 'shared epitope', most of them do nO(develop extraarticular manifestations. This may becaused by the low frequency ofID.A-DRtH 0401 allelefound in this population 21•

Finally, to examine whether ID.A-DR4 is a severitymarker for RA patients we evaluated 84 Greek RApatients. HLA-DR typing was performed by RFLPsandHLA-DR4 subtypes by PCR. Twenty-five percent ofour patients were DR4+. There were no differencesbetween the DR4+ and DR4- patients with respect todisease duration. severity of arthritis, functional andanatomical joint score. There were no statistical differ­ences in the clinical manifestations among patientswith different DR4 subcypes. Our results showed thatHU.-DR4 is not a severity marker in Greek RApatients and indicate further differences in the clinicalexpression of RA observed in Greece22.

From these data we can conclude that in SouthernEurope RA seems to be milder than in NorthernE 19. 21. 23 nu be be . S thurope . s may cause 10 ou emEurope many patients with RA do not express theHU.-DR,81 allele that contains the 'shared epitope'.Further European studies between countries orbetween Europe and the USA may provide inform­ation regarding the role of genetics and/or theenvironment in the differences observed between RAin Southern and Northern European countries.

References

Harris ED Jr. Rheumatoid arthritis. Pathophysiology andimplication for therapy. N Engl] Med 1990; 322: 1277-89.

2 Seon DL. Symmons DP, Coulton BL, Popert A]. Long termoutcome of t:re:lting rheumatoid arthritis: results after 20years. Lancet 1990; 1: 1108-11.

3 Vlachoyiannopoulos PG, MOUlSOPOulos HM. Rheumatoidarthritis in South-Eastern Europe. Bailleres Clin RheUIIJaIOi1992; 6: 211-33.

4 PIncus T, Callahan LP. The 'side effects' of rbewJratcidarthritis joint desauction, ciliabillty and ear\y rnorulIty. Br]RheumaIOI1993; 32 (suppl.): 28-37.

5 Deighton CM..Wa!er DJ, Griffiths ID, Roberu DF. The:c0n­tribution of HL\ to rheumatoid arthritis. C1in Gcndics1989; 36: 178-82.

6 Grege= DK..HLA associations with rheumatoid arthritis.A piece of the puzzle. ] Rhewnatol 1992; 19 (suppl32).7-11.

7 Panayi GS, Wooley P, Batchelor JR. Genetic ba.si.s ofrheumatoid disease: HL\ antigens, di.se2.se !II:IJ1ih:swionand toxic reaction to drugs. Br Med] 1978; 2: 13~28.

8 SWtny P. As.sociation of the B cell alloantigen DRW4 withrheumatoid arthritis. N Engl] Med 1978; 298: 869-71.

9 Nepom G.T.• Han.sen].A., Nepom 8.S. The molecubrbasisfor HLA class II a.ssociations with rheumatoid arthritis. JC1inImmunoll987; 7: 1-7.

10 Gregersen PL. Silver ]., Winchester R.]. The shared epi­rope hypotbcsi.s. An approach ro understanding the molec­ular genetics of susceptibility to rheumatoid arthritis.Arthritis Rbcwn 1987; 30: 1205-13.

11 Weyand C.• Congping x., Goronzy ].]. Homozygosity forme HLA-DR,81 allele selects for e:xIraarticular maniCesIa­tions in rheumatoid arthritis. ] C1in lnvest 1992; 89:2033-39.

12 Weyand C.• Hicok K., Conn D., Goronzy ].]. The inftuenceof HLA-DR,81 genes on disea.sc severity in rbeumatoidarthritis. Ann Intern Med 1992; 117: 801-06.

13 MoutsopouIos HM, Giotaki H. Maddison P], Mavridis AK.Drosos AA..Skopouli FN. Antibodies to cellular;uuigem inGreek paticms with autoimmune rheumatic c:iiseascs:AmiRo(SSA) anIibody a possible marker of penicillamine-Dintolerance. Ann Rheum Di.s 1984; 43: 285--87.

14 MoutsopouJos rIM, Skopouli FN, Sarr.l.s AI(, T""~ K,Mavridi.s AlC, Constantopoulos SH, Maddi.son PJ.Anti Ro(SSA) positive rheumatoid arthritis (RA): a dini­coserologial group of patients with high incidence of D­penicillamine side effects. Ann Rheum Dis 1985; 44:215-19.

15 Andonopoulos M, Galanopoulou V, Drosos AA.MoutsopouJos !cL\!. Rhewnatoid arthritis in Greece.Manifestations in different age groups. Rheumatollnt 1987;7: 101~5.

16 Skopouli FN, Andonopoulos AP, MoutsopoWos HM.Clinical impliotions of the presence of me anti-Ro(SSA)antibodies in patients with RA. ] Autoimmunity 1988; 3:381-88.

17 AndonopouJos!\P, Drosos AA, Skopouli FN: AJaitidi.s NC,MoutsopouJos HM. Secondary Sjogren's syndrome inrheumatoid arthritis.] Rheumatol1987; 14: 1098-1103.

18 Drosos AA..Unchbury ]S, Panayi GS, MoutsopoWos HM.Rheumatoid arthritis in Greek and British patients. A com­parative dinial, radiological and serological stUdy.Arthritis Rheum 1992; 35: 745-48.

19 Rodna E, Tc:re.sa M, Pascua1 E, Gibson T. Differencesbetween Spanish and British patients in severity ofrheumatoid arthritis. Comment on the article by Droso.s etal. Arthritis Rheum 1994; 37: 147-48.

20 Boki KA, Panayi GS, Vaughan RW, Drosos AA..MoutsopouJos HM, Lanchbury ]S. Hl.A cUss II sequencepolymorphisms and susceptibility to rheumatoid arthritisin Greeks. Arthritis Rheum 1992; 35: 749-755.

21 Benazet]F, Reviron D, Mercier P, RoW!:H, RoudierJ. HLA­DRP1 alle1es associated with rheumatoid arthritis inSoumern France. Absence of c:xtraanicular d.ise:I.scdespite:expression of me shared epitope. J Rheumatol 1995; 22:607-10.

Rhewnatoid arthritis in Southern Europe 11

22 Bold KA, Droeos AA, Tzioufas AG, Lancbury}S, Panayi GS,MouuopoWOII MM. F<r..Irnln"rion of HLA·DR4 as a severitymarker for rheumatoid arthritis In Greek patients. RheumDis 1993; 52: 517-19.

23 Dmsos AA, MoutsOpOUlos MM. Rheumatoid arthritis InGreece: c:lInical. serological and genetic c:on.siderations.CIn Exp Rheumato11995; 13 (supp1.12) 57-512.