Article Text

Lack of association between HLA DRB1* alleles and RS3PE syndrome
  1. E TOUSSIROT,
  2. S BERTHIER,
  3. D WENDLING
  1. Department of Rheumatology, University Hospital J Minjoz, Boulevard A Fleming, 25030, Besançon Cédex, France
  2. Histocompatibility Laboratory, Blood Transfusion Centre, Boulevard A Fleming, 25030 Besançon Cédex, France
  1. Professor D Wendling.
  1. P TIBERGHIEN
  1. Department of Rheumatology, University Hospital J Minjoz, Boulevard A Fleming, 25030, Besançon Cédex, France
  2. Histocompatibility Laboratory, Blood Transfusion Centre, Boulevard A Fleming, 25030 Besançon Cédex, France
  1. Professor D Wendling.

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In 1985, McCarty and colleagues reported a series of patients characterised by symmetrical and acute synovitis, marked pitting oedema, seronegativity resulting from the absence of rheumatoid factors (RF), increased acute phased reactants, lack of bony erosions on radiography, and benign and short course (RS3PE syndrome: remitting seronegative symmetrical synovitis with pitting oedema).1Most patients were older men. A pitting oedema was also observed in other conditions (polymyalgia rheumatica (PMR) and late onset peripheral spondylarthropathy (LOPS)).2 3 Whether the RS3PE syndrome represents a distinct clinical entity remains controversial.

This syndrome was initially reported to be associated with HLA-B (B7) rather than HLA-DR (DR4) antigens.1 4Recently, an association with HLA-A2 was reported.5 The association between RA and HLA-DRB1* alleles expressing the shared epitope (SE) (*0401, *0404, *0405, *0408, *0101, *0102, *1001, *1402) is well established. Older age onset RA and seronegative RA are known to be poorly or slightly related to DR4.6 7 Futhermore, an association was reported between the HLA-DR antigens that contain the SE and PMR.8

We studied the HLA-DR polymorphism in RS3PE syndrome patients: HLA-DRB1* typing (PCR-SSO; people who typed as HLA-DR1 or DR4 had a subtyping for HLA-DRB1*0101 to *0104 and HLA DRB1 *0401 to *0422) was performed in 12 white patients (eight male and four female; mean age: 72, range: 62–84) admitted to our department during the past 10 years. They all had typical RS3PE syndrome with acute onset symmetrical polysynovitis involving the wrists, metacarpophalangeal and proximal interphalangeal joints, tenosynovitis of the flexor of the hands, and a marked pitting oedema. Three patients had a carpal tunnel syndrome and one had had a PMR five years before this polyarthritis with pitting oedema resolving with corticosteroid treatment. For seven patients, shoulders and/or pelvic girdle were affected. The erythrocyte sedimentation rate (ESR) ranged from 20 to 100 mm 1st h and the C reactive protein (CRP) concentration was between 5 and 170 mg/l. RF (nephelometry) were negative as well as antinuclear antibodies. No bony erosions were observed on both hand and foot radiographs. A synovial biopsy was performed in three cases giving non-specific synovitis. All the patients were treated with corticosteroids (⩽10 mg/day) with resolution of the oedema after one month. The mean duration of this treatment was 50 months (range 6 months–10 years). All the patients were contacted for long term follow up (mean period: 53 months; range: 6 months–10 years). The prognosis was good and no malignancy occurred during this period. Two patients had one relapse of polyarthritis with prominent pitting oedema and they developed a PMR and a polymyositis, respectively. RF remained negative in all the patients and no hand bony erosions were observed on the outcome radiographs.

Four patients were DRB1*04 (*0401:1, *0404:2, *0405:1), one DRB1*01, and one DRB1*1001 (table 1). In our region, the frequencies of HLA DRB1*0401, *0404, *0405, and *0101 were determined to be 7.7%, 2.8%, 2.8%, and 13.4% in a control group of 104 healthy subjects. The frequencies of these alleles in 104 RA patients (15 seronegative, 89 seropositive) were *0401: 26.9% (χ2 test, p < 0.0001), *0404: 12.5% (p=0.04), *0405: 4.8% (p = 0.8), and *0101: 34.6 % (p = 0.03). Frequencies of all the allelic subtypes that contained the SE tended to be increased in RS3PE patients (41.6%) and seronegative RA (53.3%) but this increase was not statistically significant (controls : 35.8%; χ2 test: p = 0.8 and p = 0.29, respectively) (table 1). In addition, there were no significant differences in the age of onset of acute polyarthritis, ESR, CRP concentration, duration of corticosteroid treament or PMR-like clinical presentation (shoulder and/or pelvic girdle pain) between RS3PE patients with and without the SE.

Table 1

HLA DRB11-150 frequencies in RS3PE patients. Comparative study with seronegative RA and controls

Our data suggest that there is no association between HLA-DRB1* alleles and RS3PE syndrome. A slight increase in DRB1* alleles encompassing the SE was observed in this series, but without significance. The overrepresentation of the SE in the RA group argues against a poor expression of this motif in our RA patients. As it has been previously reported, HLA-DRB1*01 and *04 were slightly increased in our seronegative RA patients. In the RS3PE patients, there was no influence of the SE on the clinical presentation. In general, all of our patients had a favourable outcome and none had developed bony erosions on radiographs or typical RA. Thus, it may be suggested that this good outcome could be related to the poor expression of the shared motif in these patients. It may also be advanced that HLA-DRB1* typing in patients with RS3PE syndrome provides no useful information. As a link with HLA B7 and/or A2 has been reported, analysis of HLA A and B locus may only be performed in RS3PE syndrome. The long term follow up of patients with RS3PE syndrome has provided the diagnosis of more well defined conditions such as RA, PMR, spondylarthropathies, and malignancies.9 10 As it has been previously suggested,9 10 RS3PE could be considered as a heterogenous syndrome and this may explain the lack of association with a specific HLA-DR antigen.

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