Rheumatoid Arthritis: Radiographic Progression Is Getting Milder

To the Editor:

Dr. Sokka and colleagues¹ have made an important contribution to the growing evidence that outcomes in rheumatoid arthritis (RA) have been improving over time. We believe, however, that Sokka, et al are too even-handed in their discussion of the 3 explanations for their data: (1) self-selection, (2) milder disease, and (3) improvement in treatment. While these potential explanations are not mutually exclusive, we believe that the overwhelmingly dominant cause must be the great increase in use of disease modifying antirheumatic drugs (DMARD) proven to retard functional decline and radiographic progression.

Self-selection of milder patients is effectively precluded by the entry criteria Sokka, et al have used. They present compelling graphic evidence of individual patient trends across cohorts showing nearly identical baseline values but a profound reduction in the number of patients with high radiographic progression slopes; this reduction is even more striking in the seropositive patients. The differences over time are due to an almost complete absence of rapid radiographic deterioration in the later cohorts, consistent with more aggressive tratment.

To address the question whether RA is becoming a milder disease, one needs to examine data from successive incidence cohorts where baseline health status measurements have been performed consistently over the years. We analyzed baseline functional disability in a large (n = 3035) prospective muticenter study, and found no substantial changes over a 20 year period in baseline values of early RA cases. On the other hand, we found a 2% annual decline in functional disability in our cohorts over the past 2 decades^2,3. Sokka, et al report the same thing with radiographic endpoints; no difference in median Larsen scores at baseline over time, but large differences after 5 years.

In contrast to the stability of baseline severity over time, there have been dramatic changes toward DMARD based treatment strategies⁴, with reduction in duration of disease at first DMARD, and increases in the number of DMARD per patient, relative effectiveness of available DMARD, numbers of patients taking DMARD and DMARD combinations, and percentage of courses on DMARD over time^2,5. For a strongly positive effect from these well documented trends not to have occurred would have to mean that all of our clinical trials and observational studies have been wrong. We now have better treatments and better treatment strategies and better functional outcomes and better radiographic outcomes. We should not be afraid to connect the dots.

ESWAR KRISHNAN, MD, MPhil; JAMES F. FRIES, MD, ARAMIS Program, Stanford University, 1000 Welch Road, Suite 203, Palo Alto, California 94304, USA.

REFERENCES

1. Sokka T, Kautiainen H, Hakkinen A, Hannonen P. Radiographic progression is getting milder in patients with early rheumatoid arthritis. Results of 3 cohorts over 5 years. J Rheumatol 2004; 31:1073–82.

2. Krishnan E, Fries JF. Reduction in long-term functional disability in rheumatoid arthritis from 1977 to 1998: a longitudinal study of 3035 patients. AM J Med 2003; 115:371-6.

3. Krishnan E, Fries JF. Time trends in cumulative disability in rheumatoid arthritis 1960–1998. Arthritis Rheum 2002; 44:378.

4. Fries JF. Reevaluating the therapeutic approach to rheumatoid arthritis: the "sawtooth" strategy. J Rheumatol 1990; 17 Suppl 22:12–5.

5. Ward MM, Fries JF. Trends in antirheumatic medication use among patients with rheumatoid arthritis, 1981–1996. J Rheumatol 1998; 25:408–16.

Dr. Sokka, et al reply

To the Editor:

We are delighted that Dr. Krishnan and Dr. Fries make a point we wanted to make in our report, but a long and tedious review process (including previous journals) tempted us not to emphasize the effects of DMARD, especially those of methotrexate, as the most important basis of reduction of radiographic damage.

TUULIKKI SOKKA, MD, PhD; PEKKA HANNONEN, MD, PhD, Department of Medicine, Jyväskylä Central Hospital, Keskussairaalantie 19, FIN-40620 Jyväskylä, Finland.

Steroids and Myocardial Infarction in Rheumatoid Arthritis

To the Editor:

Dessein, et al¹ have put forward evidence to support the thesis that the use of systemic steroids may in large part be responsible for premature myocardial infarction in patients with rheumatoid arthritis (RA). I was particularly pleased to see this data as I often feel we have been crying out in the wilderness for the last 30 years based, admittedly, on less impressive clinical data^2,3. They modify their conclusion with the sentence, "The use of glucocorticoids in RA may merely reflect more aggressive disease". I suspect it was put in to appease some reviewers, but while it is often accepted as "common sense," there really is no evidence to support it.

Quite apart from the fact that we are still discussing how exactly to predict who will actually have severe disease, Crisswell, et al⁴ pointed out some years ago that the training and views of the prescribing physician are often more relevant than the characteristics of the patient in making a decision regarding steroid use. I think more rheumatologists have a growing intuition that steroids are harmful. Thus, with the biologics, a reduction or discontinuation of steroids is already considered as a measure of success. I think the current data will certainly add weight to that impression.

ANTHONY S. RUSSELL, FRCPC, Division of Rheumatology/Clinical Immunology, Department of Medicine, University of Alberta, 562 Heritage Medical Research Centre, Edmonton, Alberta T6E 3S2, Canada.

REFERENCES

1. Dessein PH, Joffe BI, Stanwix AE, Christian BF, Veller M. Glucocorticoids and insulin sensitivity in rheumatoid arthritis. J Rheumatol 2004;31:867–74.

2. Glass D, Russell AS, Snaith ML, Daly JR. Possible unnecessary prolongation of corticosteroid therapy in rheumatoid arthritis. Lancet 1971;2:334–7.

3. Ramos-Remus C, Sibley J, Russell AS. Steroids in rheumatoid arthritis: the honeymoon revisited [editorial]. J Rheumatol 1992; 19:667-70.

4. Crisswell LA, Such CL, Yelin CH. Differences in the use of second line agents and prednisone for treatment of rheumatoid arthritis by rheumatologists and non-rheumatologists. J Rheumatol 1997; 24:2283-90.

Dr. Dessein and Dr. Stanwix reply

To the Editor:

The encouraging comments made by Dr. Russell regarding our investigation on the adverse effects of glucocorticoids on insulin sensitivity in rheumatoid arthritis (RA) are welcome¹. More evidence that glucocorticoids may be responsible for a substantial proportion of cardiovascular events in RA was recently reported by Wolfe, et al^2,3. Thus, in 12,142 patients, prednisone use was complicated by a significant 70% increased incidence of acute myocardial infarction (AMI)². Further, in another large cohort study by the same investigators, the use of corticosteroids was an independent predictor for the development of diabetes mellitus, while diabetic patients with RA experienced a 3-fold increased incidence of AMI³. These results support our findings, since insulin resistance is a pathogenetic mechanism of diabetes. Suissa, et al also found a 70% increased occurrence of AMI with selective cyclooxygenase-2 inhibitors, while traditional nonsteroidal antiinflammatory agents had no effect on cardiovascular event rates, and disease modifying agents including leflunomide, methotrexate, and anti-tumor necrosis factor-a agents were protective⁴.

Dr. Russell raises the discussion that the extensive use of glucocorticoids in RA is driven by the training and views of the prescribing physician rather than disease severity, and that the availability of biologicals may improve the situation. Recent reports reveal that oral predniso(lo)ne may still often be "routinely" prescribed in RA. In a recent investigation on adalimumab, concomitant standard antirheumatic therapy included the use of oral glucocorticoids in 52.7% of patients⁵. Even more convincing, Nell, et al reported that 60% of patients with very early RA (median disease duration of 3 months) and 55% of patients with late early RA (median disease duration 12 months) were receiving corticosteroids before DMARD initiation⁶.

Many RA patients cannot afford biologicals, and safety issues may first need to be more thoroughly addressed in areas where tuberculosis is highly prevalent, for example in South Africa. Hence, glucocorticoids are still bound to constitute an important part of RA treatment for a considerable time in the future, at least in the form of bridge therapy upon initiation of traditional disease modifying agents and/or leflunomide, since the latter agents typically take months to alleviate RA symptoms and signs.

Based on reported clinical trials, we have previously suggested that pulsed (intraarticular, intramuscular, or intravenous) glucocorticoids are more beneficial and better tolerated than chronic oral pharmacological dose (e.g., > 4 mg prednisone per day) of glucocorticoids in RA⁷. This and more recent evidence is summarized in Table 1^7-11. In our latest report, high doses of pulsed glucocorticoids were also associated with decreased insulin sensitivity. However, several patients had received intravenous doses as high as 3 g methylprednisolone administered over 3–5 days. Encouragingly, low dose intraarticular pulses do not seem to have longterm adverse effects on insulin sensitivity when used as bridge therapy¹⁰.

Table 1. Effects of oral pharmacological and pulsed glucocorticoids in RA7-11.

Maybe the time has come to reconsider the route of administration of glucocorticoids in RA¹¹.

PATRICK H. DESSEIN, MD, FCP(SA), Department of Rheumatology, Johannesburg Hospital and Milpark Hospital, University of the Witwatersrand; ANNE E. STANWIX, MRCP(UK), Department of Rheumatology, Johannesburg Hospital, University of the Witwatersrand, Johannesburg, South Africa.

Address reprint requests to Dr. P.H. Dessein, PO Box 1012, Melville 2109, Johannesburg, South Africa.

REFERENCES

1. Dessein PH, Joffe BI, Stanwix AE, Christian BF, Veller M. Glucocorticoids and insulin sensitivity in rheumatoid arthritis. J Rheumatol 2004;31:867-74.

2. Wolfe F, Michaud K. Prednisone but not biologics or disease modifying agent is associated with increased risk of myocardial infarction in persons with RA. Ann Rheum Dis 2004;63 Suppl 1:69.

3. Wolfe F, Michaud K. Corticosteroids increase the risk of diabetes mellitus in RA and contribute to the risk of myocardial infarction and heart failure. Ann Rheum Dis 2004;63 Suppl 1:495.

4. Suissa S, Bernatsky S, Hudson M, Kezouh A. Disease modifying agent use and the risk of acute myocardial infarction in rheumatoid arthritis. Ann Rheum Dis 2004;63 Suppl 1:69.

5. Furst DE, Schiff MH, Fleischmann RM, et al. Adalimumab, a fully human anti-tumor necrosis factor-a monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). J Rheumatol 2003;30:2563-71.

6. Nell VPK, Machold KP, Eberl G, Stamm TA, Uffmann M, Smolen JS. Benefit of very early referral and very early therapy with disease-modifying antirheumatic drugs in patients with early rheumatoid arthritis. Rheumatology Oxford 2004;43:906-14.

7. Dessein PH, Shipton EA, Budd K. Oral low-dose glucocorticosteroids as compared with intravenous methylprednisolone pulses in the treatment of rheumatoid arthritis. Rheumatology Oxford 1999;38:1304-5.

8. Jacobs JWG, Beenen R, Evers AWM, van Jaarsveld CHM, Kraaimaar FW, Bijlsma JWJ. Short term effects of corticosteroid pulse treatment on disease activity and the wellbeing of patients with active rheumatoid arthritis. Ann Rheum Dis 2001;60:61-4.

9. Green M, Marzo-Ortega H, McGonagle D, et al. Persistence of mild, early inflammatory arthritis. Arthritis Rheum 1999;42:2184-8.

10. Dessein PH, Joffe BI, Stanwix AE. Effects of disease modifying agents and dietary intervention on insulin resistance and dyslipidemia in inflammatory arthritis — a pilot study. Arthritis Res 2002;4:R12.

11. Smith MD, Roberts-Thomson PJ, Ahern MJ. The role of intravenous methylprednisolone pulses in the management of rheumatoid arthritis. Rheumatology Oxford 2000;39:1296-7.

Sensitivity and Specificity of Anti-a-Fodrin Antibodies in Primary Sjögren's Syndrome

To the Editor:

We read with interest the report by Ruffatti, et al¹, whose results correspond to our recent findings suggesting a low sensitivity and a high specificity of IgA and IgG-type anti-a-fodrin antibodies.

In 1998, at the Department of Clinical Immunology, University of Debrecen, we investigated anti-a-fodrin antibodies in 67 patients with primary Sjögren's syndrome (SS), 20 with rheumatoid arthritis (RA), 21 with systemic lupus erythematosus (SLE), 20 with secondary SS associated with RA, and 17 with secondary SS associated with SLE, and in 30 healthy blood donors. Autoantibodies against class IgA and IgG-type a-fodrin were detected by the same commercial ELISA kit used by Ruffatti, et al. In the year 1998, European Community Study Group criteria² were used to diagnose SS. The sensitivity for IgA and IgG anti-a-fodrin for SS was 37.3% and 38.8%, respectively. The specificity was 93.3% for both isotypes³.

In 2003, we repeated the measurement of anti-a-fodrin in the sera of 46 patients with SS and healthy blood donors, using the American-European Consensus criteria⁴ for SS and using the same ELISA kit for detection of antibodies. The sensitivity for IgA and IgG anti-a-fodrin was 17.3% and 28.2%, the specificity 93.3% and 100%, respectively.

Similarly to Ruffatti, et al we also concluded that the antibodies against anti-a-fodrin are not sufficiently sensitive for diagnostic markers for SS, especially after the diagnostic criteria have been made more rigorous. Interestingly, we did find correlation between the presence of anti-SSA and IgG-type anti-a-fodrin autoantibodies, and we suggest using anti-a-fodrin autoantibodies in screening patients followed serologically and clinically for early diagnosis of SS.

ANTÓNIA SZÁNTÓ, MD; ISTVÁN CSÍPO, PhD; MARGIT ZEHER, MD, PhD, Division of Clinical Immunology, Medical and Health Science Center, University of Debrecen, Móricz Zs. Krt. 22, H-4004 Debrecen, Hungary. Address reprint requests to Dr. Szántó: szantonia@freemail.hu

REFERENCES

1. Ruffatti A, Ostuni P, Grypiotis P, et al. Sensitivity and specificity for primary Sjögren's syndrome of IgA and IgG anti-a-fodrin antibodies detected by ELISA. J Rheumatol 2004;31:504-7.

2. Vitali C, Bombardieri S, Moutsopoulos HM, et al. Preliminary criteria for the classification of Sjögren's syndrome. Results of a prospective concerted action supported by the European Community. Arthritis Rheum 1993;36:340-7.

3. Szanto A, Csípo I, Zeher M. Prevalence of anti-a-fodrin autoantibodies in our patients with Sjögren's syndrome [Hungarian]. Hungarian Immunology 2003;2:40-4.

4. Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002;61:554-8.

Dr. Ruffatti, et al reply

To the Editor:

We thank Dr. Szántó and colleagues for their interest in our article¹. The results they report² confirm low sensitivity of IgA and IgG anti-a-fodrin antibodies for primary Sjögren's syndrome (SS) using ELISA. Indeed, we found a similar low prevalence for both IgA and IgG anti-a-fodrin antibodies in primary SS sera: 32.5% vs 37.3% and 21.1% vs 38.8%, respectively. These findings are in keeping with other recent studies^3,4, which appeared while our report was being evaluated for publication, that reported a low frequency of anti-a-fodrin antibodies in primary SS patients on the basis of various techniques including immunoprecipitation, immunoblotting, and ELISA. On the other hand, we observed specificity of both IgA and IgG anti-a-fodrin antibodies lower than that reported by Szántó, et al²: 68.1% versus 93.3% and 79% versus 93.3%, respectively. This difference could be due to a variation in the number of control subjects. Moreover, the specificity of anti-a-fodrin antibodies for primary SS presently is debatable, probably because the numbers of patients with connective tissue diseases reported in the control groups were not homogeneous^1-4.

Most studies showing a high prevalence of anti-a-fodrin antibodies in primary SS^5-8 utilized the European Community Study Group criteria⁹ for classification. Using the same criteria we observed a low prevalence of anti-a-fodrin antibodies in patients with primary SS, in agreement with Szántó, et al. When antibody frequency in primary SS patients classified according to the European criteria was compared with that in patients classified according to the San Diego criteria¹⁰ a higher antibody prevalence was found in the latter group^3,11. The difference, however, was statistically significant in only one of the 2 studies¹¹. According to Szántó, et al, a low prevalence of IgA and IgG anti-a-fodrin antibodies was recently reported⁴ in primary SS patients meeting the American/European Consensus criteria¹².

Due to the low sensitivity of anti-a-fodrin antibodies confirmed by recent reports^2-4 and by our experience¹, we are doubtful about the use of these antibodies as a diagnostic marker. On the basis of Ulbricht's study¹³ describing normalization of anti-a-fodrin antibodies after 3 months of successful therapy and a correlation between antibody concentration and the degree of lymphocytic infiltration in the salivary glands, it remains to be seen if anti-a-fodrin antibodies may be considered an early marker for disease activity of primary SS.

AMELIA RUFFATTI, MD, Associate Professor of Rheumatology; PANAGIOTIS GRYPIOTIS, PhD, Research Biologist; PIERANTONIO OSTUNI, MD, Assistant Professor of Rheumatology, Department of Medical and Surgical Sciences, Rheumatology Unit, University of Padova, Via Giustiniani 2, 35128 Padova, Italy. Address reprint requests to Dr. Ruffatti: E-mail: amelia.ruffatti@unipd.it

REFERENCES

1. Ruffatti A, Ostuni P, Grypiotis P, et al. Sensitivity and specificity for primary Sjögren's syndrome of IgA and IgG anti-a-fodrin antibodies detected by ELISA. J Rheumatol 2004;31:504-7.

2. Szanto A, Csípo I, Zeher M. Prevalence of anti-a-fodrin autoantibodies in our patients with Sjögren's syndrome [Hungarian]. Hungarian Immunology 2003;2:40-4.

3. Nordmark G, Rorsman F, Rönnblom L, et al. Autoantibodies to a-fodrin in primary Sjögren's syndrome and SLE detected by an in vitro transcription and translation assay. Clin Exp Rheumatol 2003;21:49-56.

4. Zandbelt MM, Vogelzangs J, van de Putte LB, van Venrooij WJ, van den Hoogen FH. Anti-a-fodrin antibodies do not add much to the diagnosis of Sjögren's syndrome. Arthritis Res Ther 2004;6:R33-8.

5. Watanabe T, Tsuchida T, Kanda N, Mori K, Hayashi Y, Tamaki K. Anti-a-fodrin antibodies in Sjögren's syndrome and lupus erythematosus. Arch Dermatol 1999;135:535-9.

6. Witte T, Matthias T, Arnett FC, et al. IgA and IgG autoantibodies against a-fodrin as marker for Sjögren's syndrome. J Rheumatol 2000;27:2617-20.

7. Maeno N, Takei S, Imanaka H, et al. Anti-a-fodrin antibodies in Sjögren's syndrome in children. J Rheumatol 2001;28:860-4.

8. Kobayashi I, Kawamura N, Okano M, et al. Anti-a-fodrin autoantibody is an early diagnostic marker for childhood primary Sjögren's syndrome. J Rheumatol 2001;28:363-5.

9. Vitali C, Bombardieri S, Moutsopoulos HM, et al. Preliminary criteria for the classification of Sjögren's syndrome. Results of a prospective concerted action supported by the European Community. Arthritis Rheum 1993;36:340-7.

10. Fox RI, Robinson CA, Curd JG, Kozin F, Howell FV. Sjögren's syndrome. Proposed criteria for classification. Arthritis Rheum 1986;29:577-85.

11. Witte T, Matthias T, Oppermann M, et al. Prevalence of antibodies against a-fodrin in Sjögren's syndrome: comparison of 2 sets of classification criteria. J Rheumatol 2003;30:2157-9.

12. Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002;61:554-8.

13. Ulbricht KU, Schmidt RE, Witte T. Antibodies against alpha-fodrin in Sjögren's syndrome. Autoimmun Rev 2003;2:109-13.

Usefulness of Bone Ultrasound Techniques in Pediatric Rheumatic Diseases

To the Editor:

We read with interest the article by Hartman, et al¹ on the validity of quantitative ultrasound bone sonometry as a screening tool for the diagnosis of osteoporosis in children with chronic rheumatic diseases (CRD), compared to the conventional dual x-ray absorptiometry (DXA).

In this cross-sectional study, using an ultrasound bone sonometer device at distal third of radius and mid-shaft of tibia, reduced values of speed of sound were found in 15 out of 39 children with CRD. Bone mineral density (BMD) at the lumbar spine and speed of sound values at the radius showed a significant correlation. Hartman and colleagues conclude that quantitative ultrasound bone sonometry, giving results largely comparable to those of lumbar DXA, might be used as a screening tool for osteoporosis in pediatric CRD.

We agree: as the authors correctly report, several other studies have highlighted quantitative ultrasound techniques as an appealing alternative to measure bone status in children^2-7. With its low cost, portability, and short duration of examination, this radiation-free assessment is indicated as a useful measurement tool of bone status in CRD. Indeed, quantitative ultrasound provides evidence not only on bone mineralization, as DXA does, but also on bone structure and elasticity⁸.

The authors did not mention the possibility that in children with rheumatic diseases bone status can also be reliably monitored over time by quantitative ultrasound. In a one year longitudinal study, we reported contact ultrasound bone analysis at the calcaneus (CUBA) as a noninvasive and feasible tool for assessment and monitoring of bone status in 67 children with CRD⁹. Our study population included 46 with juvenile idiopathic arthritis, 11 juvenile dermatomyositis, and 10 systemic lupus erythematosus, in an age range of 2.8 to 18.1 years; among these children, in contrast to Hartman's analysis, 7 were younger than 4 years old. Assuming appropriate reference values adjusted for age, and with strategies to obtain their collaboration, the CUBA method seems reliable as well in this age group.

Not surprisingly, we have seen that changes in prospective bone density measures during the course of illness are related to the treatment given: patients who were taking corticosteroids experienced decreased bone mass, while those taking alendronate or having intraarticular steroid injection showed an increase in quantitative ultrasound values after one year.

Although DXA remains the gold standard to measure BMD, we feel the current literature provides supportive evidence to introduce quantitative ultrasound into routine clinical investigations and followup of bone assessment in childhood CRD.

Osteoporosis is one of the major causes of comorbidity in these young patients; to carry out the best available treatment¹⁰, evaluating bone status at disease onset and with periodic measurements should be considered in any child with CRD.

GABRIELE SIMONINI, MD, Fellow in Pediatric Rheumatology, Department of Paediatrics — Rheumatology Unit, University of Florence; ROLANDO CIMAZ, MD, Assistant Professor, Pediatrics, Istituti Clinici di Perfezionamento, Milano; FERNANDA FALCINI, MD, Associate Professor of Pediatrics, Department of Pediatrics, Rheumatology Unit, University of Florence, Via Pico della Mirandola 24, 50132 Firenze, Italy.

REFERENCES

1. Hartman C, Shamir R, Eshach-Adiv O, Iosilevsky G, Brik R. Assessment of osteoporosis by quantitative ultrasound versus dual energy x-ray absorptiometry in children with chronic rheumatic diseases. J Rheumatol 2004;31:981–5.

2. Van Rijn RR, van der Sluis IM, Lequin MH, et al. Tibial quantitative ultrasound versus whole body and lumbar spine DXA in a Dutch pediatric and adolescent population. Invest Radiol 2000;35:548-52.

3. Njeh CF, Shaw N, Gardner-Medwin JM, Boivin CM, Southwood TR. Use of quantitative ultrasound to assess bone status in children with juvenile idiopathic arthritis: a pilot study. J Clin Densitom 2000;3:251-60.

4. Falcini F, Bindi G, Ermini M, et al. Comparison of quantitative calcaneal ultrasound and dual energy X-ray absorptiometry in the evaluation of osteoporotic risk in children with chronic rheumatic diseases. Calcif Tissue Int 2000;67:19-23.

5. Van den Bergh JP, Noordam C, Ozyilmaz A, Hermus AR, Smals AG, Otten BJ. Calcaneal ultrasound imaging in healthy children and adolescents: relation of the ultrasound parameters BUA and SOS to age, body weight, height, foot dimensions and pubertal stage. Osteoporosis Int 2000;11:967-76.

6. Mughal MZ, Ward K, Qayyum N, Langton CM. Assessment of bone status using the contact ultrasound bone analyser. Arch Dis Child 1997;76:535-6.

7. Mughal MZ, Langton CM, Utretch G, Morrison J, Specker BL. Comparison between broad-band ultrasound attenuation of the calcaneum and total body mineral density in children. Acta Paediatr 1996;85:663-5.

8. Njeh CF, Fuerst T, Diesel E, Genant HK. Is quantitative ultrasound dependent on bone structure? A reflection. Osteoporosis Int 2001;12:1-15.

9. Falcini F, Bindi G, Simonini G, et al. Bone status evaluation with calcaneal ultrasound in children with chronic rheumatic diseases. A one year followup study. J Rheumatol 2003;30:179–84.

10. Rabinovich CE. Osteoporosis: A pediatric perspective. Arthritis Rheum 2004;50:1023-5.

Drs. Hartman and Brik reply

To the Editor:

We thank Drs. Simonini, Cimaz, and Falcini for their letter and for reporting their own experience, which lends gratifying support to our findings. It was interesting to learn from their data that quantitative ultrasound bone sonometry can be reliably employed also in patients who are younger than 4 years. There is enough evidence now in the literature that quantitative ultrasound bone sonometry is a noninvasive and safe technique that appears to be ideal for repeated use even in very young children.

CORINA HARTMAN, MD, Pediatric Gastroenterology Unit, Meyer Children's Hospital; RIVA BRIK, MD, Associate Professor of Pediatrics, Department of Pediatrics and Pediatric Rheumatology Unit, Meyer Children's Hospital of Haifa and Faculty of Medicine, Technion, Haifa, Israel.