186 LETTERS

patients with rheumatoid arthritis, and the effects of methylpred- nisolone. Arthritis Rheum 1996;39:216-25.

7. Youssef PP, Triantafillou S, Parker A, Coleman M, Roberts- Thomson PJ, Ahern MJ, et al. Effects of pulse methylprednisolone on cell adhesion molecules in the synovial membrane in rheumatoid arthritis: reduced E-selectin and intercellular adhesion molecule 1 expression. Arthritis Rheum 1996;39:1970-9.

8. Tak PP, Taylor PC, Breedveld FC, Smeets TJM, Daha MR, Kluin PM, et al. Decrease in cellularity and expression of adhesion molecules by anti-tumor necrosis factor a monoclonal antibody treatment in patients with rheumatoid arthritis. Arthritis Rheum

9. Corkill MM, Kirkham BW, Haskard DO, Barbatis C, Gibson T, Panayi S. Gold treatment of rheumatoid arthritis decreases synovial expression of the endothelial leukocyte adhesion receptor ELAM-1. J Rheumatol 1991;18:1453-60.

1996;3Y: 1077-81.

To the Editor: We thank Dr. Smith for his interest in our review. H e

raises several interesting questions, which remain unanswered at this juncture, regarding the interplay of cytokines, adhesion molecules, and clinical measures in R A patients. Further, we agree with the majority of the points raised, particularly in terms of the need for further prospective studies of cell adhesion molecules in patients with active RA.

As to our assertion that polymorphonuclear cells (PMN) have been studied less intensively than lymphocytes in RA, we stand corrected. We should perhaps have simply stated that they have been less widely studied, for as pointed out both by Dr. Smith and in a recent excellent review (l), the study of neutrophils in R A has certainly been intensive. There is indeed a fair amount of literature indicating that PMN may play a critical role in the pathogenesis of RA. Possible functions include production of proinflammatory cytokines (in SF) re- sponsible for recruitment and activation of leukocytes at the site, and, perhaps more importantly, mediation of the break- down of hyaluronan in SF and the destruction of cartilage at the pannus border (1).

Dr. Smith and colleagues have made several contribu- tions to this body of literature. Early work investigated the result of pulse methylprednisolone (MP) therapy on 40 RA patients. Although no placebo group was included, rapid improvement was noted in all measured clinical parameters; in the majority of the parameters, the improvement persisted for 8 weeks (2). As part of the analysis, leukocyte subsets were studied prospectively in 10 of these patients (3,4). While peripheral blood (PB) showed the expected neutrophilia, peaking at day 3 and returning to baseline by 2 weeks, in SF there was a rapid and statistically significant decrease in the absolute numbers of PMN, which persisted for at least 2 weeks. More recent work has further characterized these changes (5). Following pulse MP treatment, there were significant de- creases in C D l l b and CD18 expression in SF PMN at 4 hours and 24 hours; this was accompanied by an increase in L- selectin levels. PB PMN showed smaller decreases, but inter- estingly, in L-selectin as well as C D l l b and CD18. In a separate study (6), the counterreceptors on synovial endothe- lial cells were assessed by sequential biopsy before and after pulse M P treatment in 9 patients. A rapid and substantial decrease in synovial endothelial cell expression of E-selectin,

and a smaller reduction in intercellular adhesion molecule 1 expression, was noted. Unfortunately, no quantitation of PMN in the biopsy specimens is mentioned.

These results are consistent with others cited in our review, indicating that corticosteroids decrease expression of a variety of adhesion molecules, on a variety of cell types, in RA.

Christopher F. Mojcik, MD, PhD Buyer Pharmaceutical West Haven, CT Ethan M. Shevach, MD National Institute of Allergy and Infectious Disease National Institutes of Health Bethesdu, M D

1. Edwards SW, Hallett MB. Seeing the wood for the trees: the forgotten role of neutrophils in rheumatoid arthritis. Immunol Today 1997;18:320-4.

2. Smith MD, Bertouch JV, Smith AM, Weatherall M, Ahern MJ, Brooks PM, et al. The clinical and immunological effects of pulse methylprednisolone therapy in rheumatoid arthritis. I. Clinical effects. J Rheumatol 1988;15:229-32.

3. Smith MD, Ahern MJ, Brooks PM, Roberts-Thomson PJ. The clinical and immunological effects of pulse methylprednisolone therapy in rheumatoid arthritis. I!. Effects on immune and inflam- matory indices in peripheral blood. J Rheumatol 1988;15:233-7.

4. Smith MD, Ahern MJ, Brooks PM, Roberts-Thomson PJ. The clinical and immunological effects of pulse methylprednisolone therapy in rheumatoid arthritis. 111. Effects on immune and inflam- matory indices in synovial fluid. J Rheumatol 1988;15:238-41.

5. Youssef P, Roberts-Thomson P, Ahern M, Smith M. Pulse meth- ylprednisolone in rheumatoid arthritis: effects on peripheral blood and synovial fluid neutrophil surface phenotype. J Rheumatol 1995;22:2065-71.

6. Youssef PP, Triantafillou S, Parker A, Coleman M, Roberts- Thomson PJ, Ahern MJ, et al. Effects of pulse methylprednisolone on cell adhesion molccules in the synovial membrane i n rheumatoid arthritis: reduced E-selectin and intercellular adhesion molecule 1 expression. Arthritis Rheum 1996:39:1970-9.

Predictive value of the presence or absence of palpable tendon friction rubs in scleroderma: comment on the article by Steen and Medsger

To the Editor: I read with interest the report by Steen and Medsger

on palpable tendon friction rubs in patients with sclcroderma (Stcen VD, Medsger TA Jr. The palpable tendon friction rub: an important physical examination finding in patients with systemic sclerosis. Arthritis Rheum 1997;40:1146-S1.). It is a fascinating article that shows how, even in these times of advanced medical tcchnology, physical examination is still the most informative study any patient may have.

The authors show how palpable tendon friction rub is strongly associated with the development of diffuse cutaneous scleroderma, more severe disease, truncal skin thickening, and decreased survival. They describe that tendon rubs had a 93%) positive predictive value (PPV) for the diagnosis of diffuse scleroderma, and a 97% negative predictive value (NPV). In addition, among patients with early disease (<5 years) and no truncal skin thickening at the initial visit, tendon rubs had a PPV of 85% and an NPV of 83%' for progression to truncal

LETTERS 187

skin involvement. There seems to be an error in the calculation of the PPV and NPV in both situations. According to the numbers presented in the article, tendon rubs would have a PPV of 91% and a NPV of 68% for the diagnosis of diffuse scleroderma. In addition; for progression to truncal skin involvement, the PPV would be 75% and the NPV 73%.

Although in the case of tendon rubs as a predictor for the diagnosis (development) of diffuse scleroderma the differ- ence in the estimation of the PPV may not have any practical relevance (93% versus 9l%,), in the case of the NPV it does (97% versus 68%). Based on the NPV reported, a patient in whom no tendon rubs were found at the physical examination would have a probability of developing diffuse scleroderma of only 396, instead of 32%. Use of an NPV of 97% could lead to a false sense of security in a physician caring for a given patient: at an early phase of the disease, when a therapeutic intervention might be successful, the physician might believe there is a very low probability that the patient will develop diffuse scleroderma, and thus might not prescribe appropriate treatment.

In the case of tendon rubs as predictor of truncal skin involvement, the reported values overestimate both the PPV and the NPV by 10 points.

Besides these observations, I congratulate the authors for this very interesting study that will contribute to the progress of the knowledge of scleroderma.

Jorge Sinchez-Guerrero, MD, MS Instituto Nacional de la Nutricibn Salvador Zubirun Mexico City, Mexico

Reply To the Editor:

I appreciate Dr. Sanchez-Guerrero’s careful review and helpful comments concerning the report on palpable tendon friction rubs in scleroderma. H e is correct in pointing out that our calculations of the PPV and NPV for patients with diffuse scleroderma were inaccurate. The PPV is 91%, and the NPV 68%. However, he couldn’t calculate the PPV and NPV for patients with symptoms of <S years duration who develop diffuse scleroderma, because those numbers were not given in the article. Table 2 includes all of the patients, not just those with symptoms of <5 years. There were 123 patients with symptoms of <5 years who developed diffuse skin disease (75 had tendon rubs) and 241 patients who never developed truncal skin thickening (13 had tendon rubs). I believe that this does yield an 85% PPV and an 83% NPV as stated in thc report. Rather than using all the patients, I thought that knowing this information in patients with early disease was particularly important. Clinically, the presence of tendon fric- tion rubs is definitely more significant than the absence of them, which is consistent with these data.

Virginia D. Steen, M D Georgetown University School of Medicine Washington, DC

Association of a polymorphism in the collagen I a1 gene with osteoporosis in French women

To the Editor: Osteoporosis is a very common disease, characterized

by reduced bone maw and increased fracture risk, with a strong genetic component. Bone mineral density (BMD), the major determinant of osteoporotic fractures, is under genetic control, with several genes (notably vitamin D receptor and estrogen receptor genes) most likely contributing to the natural varia- tion in BMD seen in the general population.

Recently it has been shown that a polymorphic Spl binding site in the first intron of the collagen 1 a1 gene (COLIAI ), representing a gene encoding some bone matrix proteins, contains a particular allele that is overrepresented among osteoporotic women (1). This polymorphic variation in the C O L l A l gene, which relates to different binding affinities for the corresponding transcriptional control factor, has been reported to be associated with BMD in 2 unrelated popula- tions in the UK (I) , and also in a Danish population (2). We investigated the relationship between this polymorphism and osteoporosis in France, and showed that allele s at the COLl A1 locus is also overrepresented among French patients.

The polymorphism was typed, as in previous studies, by polymerase chain reaction of genomic DNA. The presence of the Msc I restriction site was denoted by allele s, and its absence by allele S. Table 1 shows that the genotypic propor- tions for the Spl binding site polymorphism were in quasi- perfect Hardy-Weinberg equilibrium (x’ = 0.02) in a group of 107 randomly selected unrelated adult blood donors of both sexes from the Paris area; in this group of controls, the frequency of the s allele was 0.13.

After approval by the local ethics committee, we isolated DNA from blood leukocytes of 110 osteoporotic and osteopenic French women. Osteoporosis and osteopenia were defined, according to the World Health Organization recom- mendations (3) , based on BMD at the lumbar spine and/or femoral neck. BMD was measured by dual x-ray absorptio- metry. Patients were all postmenopausal and ranged in age from 45 to 90 years (mean 5 SD 63.1 i 12.3 years); 75% of them were osteoporotic, and 40% had suffered osteoporotic fractures. None of the patients were receiving hormone re- placement therapy or other treatments known to have an effect on bone.

The frequency distributions of COLIAI genotypes in

Table 1. Genotypic distributions of the 3 genotypes (homozygous SS, heterozygous SS, homozygous s s ) in French controls and women with osteoporosis*

Controls (n = 107)

Wornen with osteoporosis! ostcopcnia (n = 110)

SS S S F S

81 (75.7) [80.8]

2 (1.9) [1.8] 24 (22.4) [24.3]

68 (61.8) [68.4] 40 (36.3) [35.0]

2 (1.8) 14.41

’* Values arc the number (96) of subjects. Valucs in brackets arc the expected genotypic proportions under Hardy-Weinberg equilibrium.