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To the Editor:

Recently, we showed that variant mannose-binding lectin (MBL) genotypes were associated with radiographic outcome in Danish patients with rheumatoid arthritis (RA) (1). Therefore, it was with great interest that we read that our results have now been confirmed in a study of Southern Chinese patients (2). Ip and colleagues reported that a variant MBL genotype was found significantly more often in patients with erosive disease (52 of 127) than in those with nonerosive disease (16 of 84) (P = 0.001) (2). Their results also confirmed that serum MBL levels do not vary with disease activity (3). The mean duration of RA in the Chinese patients was ∼7 years; therefore, the number of patients in this population who had early RA may be too small for separate statistical analysis.

It would be interesting if Ip et al compared the relative risk of developing erosions in RA patients with low-producing MBL genotypes who had early-stage disease (e.g., duration <3 years) with that in similar patients who had later-stage RA. Neither our study cohort nor the Chinese study cohort was an inception cohort; i.e., both studies included patients with disease of varying duration. This design may introduce a bias, because RA patients with severe or permanent symptoms are more likely to seek medical attention than are those with milder or fluctuating symptoms. Therefore, many patients with mild RA may be included in an inception cohort, while patients with later stages of disease are more likely to be part of a major cohort from which patients with mild RA may have withdrawn. Consequently, a study group comprising patients who had established RA but varying disease duration at the time of inclusion would be more homogeneous than an inception cohort. It could be hypothesized that in both the Danish and Chinese noninception cohorts (1, 2), MBL-sufficient patients with mild RA never presented for evaluation and thus were not included. Therefore, the difference in outcome between MBL-sufficient and MBL-insufficient patients may have been smaller than it would have been in an inception cohort.

The data shown in Figure 1 support the above hypothesis. As illustrated, 140 RA patients from the Danish cohort (1) are divided into 2 groups, 1 comprising 79 patients with short disease duration (<3 years) at the time of inclusion and 1 comprising 61 patients with longer disease duration (4–26 years). In 15 patients with MBL insufficiency and short duration of disease, the relative risk (RR) of radiographically evident erosion occurring in subsequent years was 4.1 (P < 0.0001), whereas in 9 patients with MBL insufficiency and longer disease duration the RR was 1.8 (P = 0.17). Furthermore, although the gene frequencies did not differ between the 140 RA patients and the background population, the frequency of homozygous variant genotypes in the 79 patients with short disease duration was higher than that in the background population (6.3% versus 2.8%).

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Figure 1. Kaplan-Meier plots of radiographic events, defined as the occurrence of 30% of maximal radiographic destruction, in rheumatoid arthritis (RA) patients grouped according to mannose-binding lectin (MBL) sufficiency (normal genotype or heterozygous genotype with high-expressive promoters) or MBL insufficiency (homozygous variant genotype or heterozygous genotype with low-expressive promoters).

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Two recent inception cohort studies of arthritis patients from early-arthritis clinics showed significant associations between variant MBL genotypes and radiographic progression (4) and between low serum levels of MBL and radiographic progression (5) within the first year after onset of RA. These results confirm that studies including only patients with recent-onset disease are probably more sensitive for detecting differences than are studies including patients with long-term disease.

The optimum prognostic study is probably based on a population of patients with early RA. Because such studies are few and are followed for only a limited period of time, it is currently necessary to investigate less optimum study populations in order to get information about the long-term prognosis. However, this should be done with care, and the influence of possible selection bias on the results should always be discussed in detail.

Acknowledgements

Supported by the Danish Rheumatism Association and the Danish Insurance Association

REFERENCES

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  • 1
    Graudal NA, Madsen HO, Tarp U, Svejgaard A, Jurik AG, Graudal HK, et al. The association of variant mannose-binding lectin genotypes with radiographic outcome in rheumatoid arthritis. Arthritis Rheum 2000; 43: 51521.
  • 2
    Ip WK, Lau YL, Chan SY, Mok CC, Chan D, Tong KK, et al. Mannose-binding lectin and rheumatoid arthritis in southern Chinese. Arthritis Rheum 2000; 43: 167987.
  • 3
    Graudal NA, Homann C, Madsen HO, Svejgaard A, Jurik AG, Graudal HK, et al. Mannan binding lectin in rheumatoid arthritis: a longitudinal study. J Rheumatol 1998; 25: 62935.
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    Jacobsen S, Madsen HO, Klarlund M, Jensen T, Skjødt H, Jensen KE, et al. The influence of mannose binding lectin polymorphisms on disease outcome in early polyarthritis. J Rheumatol 2001; 28: 93542.
  • 5
    Saevarsdottir S, Vikingsdottir T, Vikingsson A, Manfredsdottir V, Geirsson AJ, Valdimarsson H. Low mannose binding lectin predicts poor prognosis in patients with early rheumatoid arthritis: a prospective study. J Rheumatol 2001; 28: 72834.

Niels A. Graudal MD*, Peter Garred MD†, Hans O. Madsen MSc†, Arne Svejgaard MD†, Ulrik Tarp MD‡, Anne Grethe Jurik MD‡, Hans K. Graudal MD‡, * Gentofte University Hospital, † Copenhagen University Hospital Copenhagen, Denmark, ‡ Århus University Hospital Århus, Denmark