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primarily on tender and swollen joint count with small contributions from erythrocyte sedimentation rate and pa- tient global assessment. Because of the dependence of the DAS on tender and swollen joint count, its content validity is, by definition, less than that of the ACR improvement criteria, and it is therefore likely to be less responsive to change than the ACR improvement criteria.

Third, the EULAR response criteria merge two concepts that, on their face, seem combinable: response to treatment and absolute disease activity (partial remission). In other fields (e.g., oncology), such concepts have been separated, and the application of the EULAR criteria reveals why this is so. Patients whose disease status is modest and who are near a threshold for partial remission would have to improve only modestly to meet EULAR criteria for re- sponse, but, if patients started out with very severe and active disease, responding would require a much greater change in a disease activity. Investigators testing their new drug using the EULAR criteria would certainly want it to be evaluated only in those with moderate disease activity, because its performance in patients with severe disease activity would look temble. The ACR criteria were devel- oped across a range of disease seventies and should perform consistently irrespective of the level of active disease at study initiation.

Finally, while comparisons of the EULAR and ACR response criteria are needed, I am sorry to say that a valid comparison is not likely to emanate from the EULAR group. They have neither measured nor included the most respon- sive element in the ACR definition of improvement, physi- cian global assessment, and have insisted upon creating a third stratum of the ACR improvement criteria that, in our trial data, is artificially empty (without patients), but serves the purpose of making the comparison EULAR criteria look especially responsive. Until, there is a comparison that appropriately incorporates all of the measures in the ACR improvement criteria, compares them with all of those in the EULAR response criteria, and evaluates the relative sensi- tivity to change, it will be difficult to determine which set of measures is better and whether we might be able to reach some common ground by incorporating positive features of both. It is likely that measuring 3 levels of improvement as advocated by the EULAR group is valuable, but use of the DAS, a complex function of mostly tender and swollenjoint counts, may be inferior to use of the more multidimensional and simpler core set. Comparisons will be best believed if they emanate from third parties who are not involved in the development of either of these improvement criteria.

1.

David T. Felson, MD, MPH Chairperson, ACR Committee on

Outcome Measures in RA Trials Boston University School of Medicine Boston, MA

Felson DT, Anderson JJ, Boers M, Bombardier C, Chernoff M, Fried B, Furst D, Goldsmith C, Kieszak S, Lightfoot R, Paulus H, Tugwell P, Weinblatt M, Widmark R, Williams HJ, Wolfe F: The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. Arthritis Rheum 36:729-740, 1993

2. Goldsmith CH, Boers M, Bombardier C, Tugwell P: Criteria for clinically important changes in outcomes: development, scoring and evaluation of rheumatoid arthritis patient and trial profiles. J Rheumatol 20561465, 1993

3. Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, Katz LM, Lightfoot R Jr, Paulus H, Strand V, Tugwell P, Weinblatt M, Williams HJ, Wolfe F, Kieszak S: American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 38:727- 735, 1995

4. Tugwell P, Pincus T, Yocum D, Stein M, Gluck 0, Kraag G , McKendry R, Tesser J, Baker P, Wells G : Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthri- tis. N Engl J Med 333:137-141, 1995

Monoclonal antiphospholipid antibodies and germline V, genes: comment on the article by Harmer et a1

To the Editor: In their report of a new human monoclonal antiphos-

pholipid antibody (l), Harmer and colleagues make 2 main claims. The first claim is that the IgM monoclonal antibody, BH1, is representative of serum antibodies relevant to the antiphospholipid syndrome (APS) in the patient from whom it is derived. While it is recognized that the clinical features of APS are more closely associated with levels of IgG antiphospholipid antibodies (aPL), the authors point out that they may occur in the presence of IgM aPL alone. Interest- ingly, however, the patient they describe had markedly raised IgG aPL levels. Furthermore, the binding properties of BH1 are shown to be much closer to those of the patient’s serum IgG than IgM. This argues against BHl being repre- sentative of a population of pathologically relevant IgM antibodies in this individual.

Harmer et a1 also conclude that the antibody, BHl, is encoded by a new germline gene, BHGH1. A complete map of the human V, locus on chromosome 14 has been pro- duced by studies of genomic material from several different haplotypes (2,3). Comparison of the sequences of genes on this map with a large database of rearranged VH sequences suggests that it is unlikely that any unmapped functional V, genes exist (3,4). Rather than being a new gene, it therefore seems likely that BHGHl is simply an allelic variant of the known germline gene, V3-33 (previously known as hy3019b9). The total of 5 nucleotide differences between BHGHl and V3-33 is within the range previously quoted for differences between allelic variants in the vH3 family (5). As noted by the authors, this germline gene is a member of the fetally expressed repertoire. The description of an IgM monoclonal autoantibody that is encoded by an unmutated germline gene from this repertoire is reminiscent of previous findings from sequence analysis of anti-DNA antibodies.

Anisur Rahman, MA, MRCP David A. Isenberg, MD, FRCP David S. Latchman, DSc University College London, UK

1 . Harmer IJ, Loizou S, Thompson KM, So AKL, Walport MJ, Mackworth-Young C: A human monoclonal antiphospholipid

LETTERS

antibody that is representative of serum antibodies and is germ- line encoded. Arthritis Rheum 38:1068-1076, 1995 Matsuda F, Shin EK, Nagaoka H, Matsumura R, Haino M, Fukita Y, Taka-ishi S, Imai T, Riley JH, Anand R, Soeda E, Honjo T: Structure and physical map of 64 variable segments in the 3‘ 0.8-megabase region of the human immunoglobulin heavy chain locus. Nature Genet 3:88-94, 1993 Cook GP, Tomlinson IM, Walter G, Riethman H, Carter NP, Buluwela L, Winter G, Rabbitts TH: A map of the human immunoglobulin V, locus completed by analysis of the telomeric region of chromosome 14q. Nature Genet 7: 162-168, 1994 Cook GP, Tomlinson IM: The human immunoglobulin V, rep- ertoire. Irnmunol Today 16:237-242, 1995 Tomlinson IM, Walter G, Marks JD, Llewellyn MB, Winter G: The repertoire of human germline V, sequences reveals about fifty groups of V, segments with different hypervariable loops. J Mol Biol 227:776-798, 1992

Reply To the Editor:

The clinical features of APS can be associated with either IgG or IgM aPL, alone or in combination. Serum IgG aPL found in patients with APS bind almost exclusively to negatively charged phospholipids. Serum IgM aF’L from the majority of patients exhibit similar specificity, although some also recognize neutral phospholipids.

The study patient from whom our monoclonal anti- body, BH 1, was derived has had consistently raised levels of serum IgG and IgM aPL since primary APS was first diagnosed. Her serum IgM does indeed bind neutral phos- pholipids in a direct assay, but, as we point out in our article, but do not show, the IgM anticardiolipin activity was not inhibited by neutral phospholipids. We would, therefore, suggest that BHl is representative of the relevant IgM aPL population in the patient’s serum. As Rahman et al point out, BH1 does appear representative of serum IgG aPL in the patient; this is illustrated by its specificity in direct binding assays, and its ability to inhibit the binding of serum IgG aPL to cardiolipin. Far from detracting from our hypothesis, these data add weight to our suggestion that BHl is repre- sentative of serum aPL that are associated with disease pathology.

The difference between distinct VH genes and allelic

variants is imprecise. In the case of the vH3 family, it has been suggested that V, segments with identical translated complementarity-determining regions (CDRs) 1 and 2, but up to 6 nucleotide differences, may be allelic variants of a single gene (1). The total of 5 nucleotide differences between BHGHl and V3-33 is within this range; however, their translated amino acid sequences differ at 4 positions; 2 positions, 50 and 52, are found in CDR2. V3-33 is closely related to, but not an allelic variant of, V3-30, (1.9IIIDP-49) (2) from which it also differs by 5 nucleotides, but differs by only 2 residues in the translated sequence, one in CDIU and the other at the C-terminus. We have repeated our search of the EMBL database and have found that BHGHl is identical to the recently described germline gene, COS3 (Tomlinson IM, Walter G, Cook GP, Winter G: unpublished data; GenBank accession number Z17389), and to the V, gene, 55-3.21, encoding a heavy chain rearrangement that has been isolated from fetal liver (4). The location of COS3 has not yet been determined.

Ian J. Harmer, MSc Sozos Loizou, PhD Alex K. L. So, PhD, MRCP Mark J. Walport, PhD, FRCP Charles Mackworth-Young, MD, FRCP Royal Postgraduate Medical School London, England Keith M. Thompson, PhD University of Oslo Rheumatism Hospital Oslo, Norway

I . Tomlinson IM, Walter G, Marks JD, Llewellyn MB, Winter G: The repertoire of human germline V, sequences reveals about fifty groups of V, segments with different hypervariable loops. J Mol Biol 227:776-798, 1992

2. Cook GP, Tomlinson IM, Walter G, Riethman H, Carter NP, Buluwela L, Winter G, Rabbits TH: A map of the human immunoglobulin V, locus completed by analysis of the telomeric region of chromosome 1%. Nature Genet 7: 162-168, 1994

3. Cuisinier AM, Gauthier L, Boubli L, Fougereau M, Tonnelle C: Mechanisms that generate human immunoglobulin diversity op- erate from the 8th week of gestation in fetal liver. Eur J Immunol 23:llO-118, 1993