1600 LETTERS

R, Gibson T: Seronegative and seropositive rheumatoid arthritis: similar diseases. Br J Rheumatol 26:172-180, 1987

5 . Panayi GS: Does rheumatoid arthritis have a clinicopathological spectrum similar to that of leprosy? Ann Rheum Dis 41: 102-103, 1982

Comment on the article by Calin et al

To the Editor: Despite the data presented by Calin et a1 (Calin A,

Elswood J, Klouda FT: Destructive arthritis, rheumatoid factor, and HLA-DR4: susceptibility versus severity, a case-control study. Arthritis Rheum 32: 1221-1225, 1989), we question whether the true influence of HLA-DR4 and rheumatoid factor (RF) positivity in the occurrence of ero- sive disease in rheumatoid arthritis (RA) can ever be sorted out. In fact, the authors’ data show a higher radiographic score for seropositive patients (regardless of their DR4 status), as compared with seronegative patients, and a higher radiographic score for DR4 positive patients (regardless of their R F status), as compared with DR4 negative patients. In subsequent analyses, the radiographic scores for pairs of patients, matched for disease duration and with different RF and DR4 statuses, were compared. The most significant difference was obtained when examining the radiographic scores of DR4 positive, RF positive patients and those of DR4 negative, RF negative patients, suggesting that either these 2 variables are interrelated or they do indeed have an additive effect.

As an alternate approach, we would like to suggest examining the data with a multiple regression analysis, where the dependent variable will be the radiographic score, and the independent variables will be RF status, HLA-DR4 status, and disease duration. Results could demonstrate that both HLA-DR4 and RF positivity are independent risk factors, or they could be eliminated if both are so intimately related. Of course, the validity of any analysis depends on the validity of radiograph readings. It seems to us that the grading system used by Calin et al is a bit subjective. It would be of interest to know whether the radiographs were read blindly and by more than one observer, and, if so, what was the intra- and interobserver reliability.

As the authors point out in their discussion, the different subanalyses performed to sort out which of these 2 markers is more important in explaining the severity of RA (as determined radiographically) are relatively weak since no adjustment for multiple comparisons was made. The analysis we are suggesting, by including data from all patients, may demonstrate the actual contribution of both DR4 and RF status to disease severity in RA. As our understanding of this disorder improves, so will our knowledge of its different subsets. For now, however, clinical features, serologic tests, and genetic markers need to be considered together when studying disease severity in RA.

Alfred Bartolucci, PhD Graciela S. Alarcon, MD. MPH The University of Alabama

at Birmingham

Reply To the Editor:

That there is a relationship between HLA-DR4 and destructive arthropathy, regardless of rheumatoid factor status, is now well accepted. For example, a recent Dutch study confirmed that HLA-DR4 is associated with seroneg- ative as well as seropositive rheumatoid arthritis (RA), but the authors concluded that the DR4 positive seronegative entity was preferentially associated with antiperinuclear factor (1). Moreover, as we pointed out (2), DR4 may also be associated with other destructive arthropathies, as shown by a recent study from India, in which systemic-onset seroneg- ative juvenile chronic arthritis was DR4 positive in those with destructive joint disease but not in those with less dramatic arthropathy (3).

HLA-DR4 does not help to determine whether sero- negative “rheumatoid arthritis” is related to the seropositive disease. Panayi argues that rheumatoid factor (RF) merely relates to the extraarticular manifestations of disease, but in their article, he and his colleagues reported that the seroneg- ative group had more wrist involvement and less proximal interphalangeal joint involvement (4). Although the first finding did not reach statistical significance, both were findings we described in an earlier article (5). Further studies will be necessary to determine whether the seronegative and seropositive entities are part of the same or different rheu- matologic spectra.

Regarding the letter from Bartolucci and Alarc6n, the radiographs were indeed read blindly, as stated in the article. Two observers reviewed the films and, where nec- essary, a blinded consensus result was given. Regarding their second point (the value of multiple regression analysis), I would agree that this may be of benefit. However, the outstanding problem still relates to the entry criteria for diagnosis. For example, does an HLA-DR4 negative, RF negative individual with minimal erosive disease have a mild form of RA or an entirely different entity? It is this issue that has not been resolved.

Andrei Calin, MD, FRCP Royal National Hospital

for Rheumatic Disease Bath, England

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Boerbooms AMT, Westgeest AAA, Reekers P, van de Putte LBA: lmmunogenetic heterogeneity of seronegative rheumatoid arthritis and the antiperinuclear factor. Ann Rheum Dis 49:15-17, 1989 Calin A, Elswood J. Klouda PT: Destructive arthritis, rheuma- toid factor, and HLA-DR4: susceptibility versus severity, a casexontrol study. Arthritis Rheum 32: 1221-1225. 1989 Singh G, Mehra N K , Taneja V , Seth V , Malaviya AN, Ghai OP: Histocompatibility antigens in systemic-onset juvenile rheuma- toid arthritis (letter). Arthritis Rheum 32:1492-1493, 1989 Panayi GS, Celinska E, Emery P, Griffin J , Welsh KI, Grahame R, Gibson T: Seronegative and seropositive rheumatoid arthritis: similar diseases. Br J Rheumatol 26: 172-180, 1987 Burns TM, Calin A: The hand radiograph as a diagnostic discrim- inant between seropositive and seronegative ‘rheumatoid arthri- tis’: a controlled study. Ann Rheum Dis 42:605412, 1983