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Lung disease is one of the extra-articular manifestations of rheumatoid arthritis (RA) and includes pleuritis, parenchymal nodules, interstitial fibrosis, and obstructive airway disease.1Increased risk of pulmonary infection and bronchiectasis (BC) are also seen.1 2 An association between RA and BC has been reported in some series of patients with RA, with an estimated prevalence of 5%.1 2 With the use of high resolution computed tomography (CT), this prevalence has been found to be higher, ranging from 6 to 50%.3 It has been claimed that the severity of the polyarthritis is similar in patients with and without BC.4 However, some authors noted a severe disease in patients with RA with BC when the polyarthritis preceded the lung disease.5 Additionally, patients with RA with BC had a reduced five year survival rate compared with those without BC.6 Secondary Sjögren's syndrome, recurrent pulmonary infections, and genetic background have been proposed to explain the relation between these two conditions.2 In this way, RA with BC has been found to be associated with HLA-DR1 and DQB1*0601.7 The association between RA and HLA-DRB1* alleles expressing the shared epitope (SE) (DRB1 *0101, *0102, *0401, *0404, *0405, *0408, *1001, *1402 alleles) is well established. The presence of these alleles in RA has been reported to be associated with disease severity, and particularly with extra-articular manifestations, such as vasculitis or subcutaneous nodules.8 9 Whether RA with BC is associated with the SE or not has not been previously examined. Thus in this study we determined the HLA-DRB1* alleles in patients with RA with and without BC (RA/BC+ and RA/BC−, respectively) with a special emphasis on the expression of the SE.
Between 1997 and 1998, 46 inpatients and outpatients fulfilling the 1987 American College of Rheumatology criteria for RA were included to determine the prevalence of BC. They all underwent high resolution CT of the chest. HLA-DRB1* typing was performed using the PCR-SSO method (people who typed as DRB1*01 and *04 had a subtyping for HLA-DRB1*0101 to *0104 and DRB1*0401 to *0422, respectively (PCR-SSP)). One hundred and four unrelated healthy subjects without any history of lung disease were used as controls for HLA-DRB1* comparisons.
The results of the clinical features, laboratory investigations, and CT findings of this series have been previously published.10BC was found in 50% of patients. Most of them had not been previously diagnosed with BC before the study and were free of respiratory symptoms. No differences were found between patients with and without BC for age (RA/BC+ v RA/BC− 59.1v 60.1 years), sex ratio (16 women and 7 menv 18 women and 5 men), disease duration (10.6 v 9.6 years), positivity for rheumatoid factors (91% v 91%), bony erosions, use of corticosteroids or immunosuppressive drugs, respiratory manifestations, or smoking. Additionally, extra-articular manifestations were present in eight RA/BC+ (35%) and six (26%) RA/BC− patients (χ2 test between the two groups: p=0.7).
In eastern France, patients with RA express the SE with a significant prevalence of HLA-DRB1*0101, DRB1*0401, and DRB1*0404.11 Similar findings were seen in this RA series, with a higher frequency of the SE and DRB1*0401 in the two RA groups than in the healthy controls (table 1). The SE was expressed in 15/23 (65%) of RA/BC+ patients, 14 /23 (61%) of RA/BC− patients, and 37/104 (36%) of controls (χ2 test between the three groups: p=0.007). Analysing the DRB1*04 subtypes, we noted that the frequency of DRB1*0401 was significantly higher in the RA/BC+ group (39%) than in the RA/BC− (17%) and control (6%) groups (χ2 test between the three groups: p<0.0001). However, when the frequency of DRB1*0401 was compared between the RA/BC+ and RA/BC− groups, the results did not reach significance (χ2 test between the two groups: p=0.19). Moreover, the DRB1*0401 frequency was significantly higher in RA/BC+ patients than in controls (39% v 6%; χ2 test between the two groups: p=0.00003; OR 10.5; CI 2.84 to 40.21), and, conversely, no difference was found between the RA group without BC and the controls (17% v 6%; χ2test between the two groups: p=0.15). Finally, the frequency of the other alleles expressing the SE (DRB1*0101, *0404, *0405, *0408, *1001) did not differ between the two RA groups and the controls (table1).
Our data suggest that DRB1*0401, but not the other RA linked alleles, was significantly associated with patients with BC. A slight increase in the prevalence of this allele was also seen in the RA/BC+ group as compared with the other patients, but not significantly. This may be explained by the small number of patients in each group (n=23). The relation of the alleles encompassing the SE with disease severity is still discussed, but an association with certain DRB1*04 subtypes has been reported in patients originating from North America and northern Europe.8 9 In fact, DRB1*0401 and *0404 appear to be strongly associated with severe manifestations of the disease, such as nodules or vasculitis.8 In this study, patients with BC significantly expressed DRB1*0401. The coexistence of RA and BC has been associated with a poor prognosis and a more severe disease in some studies.5 6 Thus it is tempting to speculate that this might be related to the expression of the DRB1*0401 allele, as suggested by our results. Thus patients with RA expressing DRB1*0401 should be considered to have a higher risk of developing BC and these patients should be regarded with caution and an awareness of the possibility of extra-articular manifestations and therefore, disease severity.
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