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INSTRUCTIONS FOR LETTERS TO THE EDITOR

Editorial comment in the form of a Letter to the Editor is invited; however, it should not exceed 800 words, with a maximum of 10 references and no more than 2 figures (submitted as camera ready hard copy per Journal Guidelines) or tables and no subdivision for an Abstract, Methods, or Results. Letters should have no more than 3 authors. Full name(s) and addresses of the author(s) should accompany the letter as well as the telephone number, fax number, or E-mail address.

Contact. The Managing Editor, The Journal of Rheumatology, 920 Yonge Street, Suite 115, Toronto, Ontario M6J 3G7, CANADA. Tel: 416-967-5155; Fax: 416-967-7556; E-mail: jrheum@jrheum.com. Financial associations or other possible conflicts of interest should always be disclosed.

Letters

Methotrexate as a Possible Trigger of Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis

To the Editor:

We read with interest the article by Ravelli, et al 1 describing a patient with systemic juvenile idiopathic arthritis (SJIA) who developed a clinical picture and laboratory abnormalities compatible with the diagnosis of macrophage activation syndrome (MAS).

The disturbing statement suggesting the possibility that methotrexate (MTX) could be responsible for this severe complication motivated us to search through Medline for other reported cases and to consider other possible triggers of MAS in this patient. With this objective we believe it important to emphasize some aspects of this case report.

First, the marked increase in the serum ferritin level deserves further consideration. Hyperferritinemia is a very good marker of activity in adult onset Still's disease, and to a lesser extent in SJIA (juvenile onset Still's disease)2,3. Increased serum levels of ferritin may be the result of several factors including increased synthesis of ferritin by proliferated and erythrophagocytosed monocytes-macrophages and ferritin released from the various tissues damaged by chemical factors from activated monocytes-macrophages4. Taking these factors into consideration we find it reasonable to assume that the activity of the disease per se could have been the trigger of MAS in this patient.

On the other hand, low dose MTX has become widely used for both JIA and rheumatoid arthritis, and it is now often the first agent selected in children with established JIA. The toxicity profile of this agent is well known and has been the subject of numerous reports5. Extensive research in Medline entries for the past 15 years failed to reveal reports with similar experience to Ravelli, et al's report, with the exception of a 14-year-old boy, described by the same group, who developed MAS 2 weeks after an 11 month course of oral MTX8. The causal association of MTX and MAS in this other patient is also uncertain.

In view of the above concerns, we are reluctant to accept that MTX may induce MAS. Low dose MTX is an invaluable therapeutic modality for the management of JIA and several other rheumatic disorders, and while it is important to encourage the continuous surveillance and reporting of adverse side effects, it is also important, and prudent, to avoid generating undue alarm regarding uncertain and not well proven effects.

RUTH ERASO, MD; ABRAHAM GEDALIA, MD; LUIS R. ESPINOZA, MD, Children's Hospital, LSU Health Sciences Center, New Orleans, LA, USA.

REFERENCES

1. Ravelli A, Caria MC, Buratti S, Malattia C, Temporini F, Martini A. Methotrexate as a possible trigger of macrophage activation syndrome in systemic juvenile idiopathic arthritis. J Rheumatol 2001;28:865-7.

2. Sobieska M, Fassbender K, Aeschlmann A, Bourgeois P, Mackiewicz S, Müller W. Still's disease in children and adults: a distinct pattern of acute-phase proteins. Clin Rheumatol 1998;17:258-60.

3. Lin S-J, Chao H-Ch, Yan D-Ch. Different articular outcomes of Still's disease in Chinese children and adults. Clin Rheumatol 2000; 19:127-30.

4. Esumi N, Irushima S, Todo S, Imashuku S. Hyperferritinemia in malignant histiocytosis, virus associated hemophagocytic syndrome and familial erythrophagocytic lymphohistiocytosis. Acta Paediatr Scand 1989; 78: 268-70.

5. Singsen B, Goldobach-Mansky R. Methotrexate in the treatment of juvenile rheumatoid arthritis and other pediatric rheumatic and non-rheumatic disorders. Rheum Dis Clin North Am 1997;23:811-40.

6. Graham L, Myones B, Rivas-Chacon R, Pachman L. Morbidity associated with long-term methotrexate therapy in juvenile rheumatoid arthritis. J Pediatr 1992;120:468-72.

7. Keim D, Ragsdale C, Heidelberger K, Sullivan D. Hepatic fibrosis with the use of methotrexate sodium tablets in healthy volunteers. Arthritis Rheum 1992;35:761.

8. Ravelli A, De Benedetti F, Viola S, Martini A. Macrophage activation syndrome in systemic juvenile rheumatoid arthritis successfully treated with cyclosporine. J Pediatrics 1996;128:275-8.

Drs. Ravelli and Martini reply

To the Editor:

Dr. Eraso, et al assume that in our patient the activity of the disease itself, and not methotrexate (MTX), could have been the trigger of macrophage activation syndrome (MAS). They base their hypothesis on the fact that serum ferritin levels were high and that hyperferritinemia has been shown to be a marker of disease activity in systemic juvenile idiopathic arthritis (SJIA). Although we thank Dr. Eraso and colleagues for their interest in our observation1, we cannot share their opinion. Indeed, although it is true that hyperferritinemia represents a marker of disease activiy in SJIA2, it is also true that it represents one of the laboratory hallmarks of MAS. Indeed, during MAS, serum ferritin levels reach values that are often much higher than those observed during active SJIA3,4. In our patient, serum ferritin concentration, which was high (207 ng/ml) when her disease was very active (with fever, rash, polyarthritis, erythrocyte sedimentation rate 89 mm/h, and C-reactive protein at 9.9 mg/l) increased to 10,143 ng/ml at the time of the development of MAS. Recently, by reviewing the literature as well as our personal experience on JIA associated MAS, we found that a serum ferritin level ³ 10,000 ng/ml has one of the highest sensitivity and specificity among the clinical and laboratory variables that could be regarded as potential diagnostic criteria for this complication (unpublished observation).

Therefore, in our opinion, the high serum ferritin levels cannot be taken as evidence to support the hypothesis that disease activity was the trigger of MAS in our patient, This, of course, does not mean that we can exclude such hypothesis. The triggers of MAS are unknown and may be related to disease activiy, exogenous factors, or a combination of both. In previous observation in SJIA, the causal involvement of exogenous factors, such as infections of drugs, in triggering MAS has always been based on a close temporal relation in the absence of other potentially eliciting factors5.

As stated in our paper, we could not find any evidence that nonsteroidal antiinflammatory drug therapy, viral infection, or disease flare could have been responsible for the development of this complication. On the contrary, the short time interval between MTX dosing and the occurrence of clinical signs of MAS and the characteristics of clinical symptoms, which were consistent with hypersensitivity or idiosyncratic reaction, suggested that MTX could have been the trigger of MAS in our patient. As Dr. Eraso, et al point out, the causal association between MTX and MAS was less clear in the patient previously reported by our group6. However, in that patient the time course of the clinical events also suggested a link between MTX toxic effects and the development of MAS, although the time interval was greater than in the present one.

We understand the concerns of Dr. Eraso, et al, who express their reluctance to accept the notion that MTX may induce MAS. We were also prudent in claiming this association by indicating MTX in the title of the paper as "possible" trigger of MAS in SJIA. Nevertheless, other exceedingly rare complications of MTX therapy, such as acute pneumonitis and Hodgkin's lymphoma, have been reported in children with JIA7.8. Because children with SJIA are known to be extremely vulnerable to toxic events and distinctively susceptible to the development of MAS and several drugs have been incriminated as possible triggers of this complication, it is perhaps not unexpected that an adverse reaction to MTX may under certain circumstances elicit a MAS. With our report, we do not wish to generate undue alarm regarding MTX side effects, but simply convey to the pediatric rheumatology community a clinical observation that led us to suspect that MTX may act as an inciting factor of MAS in children with SJIA.

ANGELO RAVELLI. MD; ALBERTO MARTINI, MD, Pediatria II, Istituto G. Gaslini, Università di Genova, Genova, Italy.

REFERENCES

1. Ravelli A, Caria MC, Buratti S, Malattia C, Temporini F, Martini A. Methotrexate as a possible trigger of macrophage activation syndrome in systemic juvenile idiopathic arthritis. J Rheumatol 2001;28:865-7.

2. Pelkonen P, Swanljung K, Siimes MA. Ferritinemia as an indicator of systemic disease activity in children with systemic juvenile rheumatoid arthritis. Acta Paediatr Scand 1986;75:64-8.

3. Ravelli A, Viola S, De Benedetti F, Magni-Manzoni S, Tzialla C, Martini A. Dramatic efficacy of cyclosporine A in macrophage activation syndrome [letter]. Clin Exp Rheumatol 2000;19:108.

4. Coffernils M, Soupart A, Pradies O, Feremans W, Nève P, Decaux G. Hyperferritinemia in adult onset Still's disease and the hemophagocytic syndrome. J Rheumatol 1992;19:1425-7.

5. Prieur AM, Stéphan JL. Macrophage activation syndrome in children with joint diseases. Rev Rheum Engl ED 1994;61:385-8.

6. Ravelli A, De Benedetti F, Viola S, Martini A. Macrophage activation syndrome in systemic juvenile rheumatoid arthritis. J Pediatr 1996;28:275-8.

7. Cron RQ, Sherry DD, Wallace CA. Methotrexate-induced hypersensitivity pneumonitis in a child with juvenile rheumatoid arthritis. J Pediatr 1998;132:901-2.

8. Padeh S, Sharon N, Schiby G, Rechavi G, Passwell JH. Hodgkin's lymphoma in systemic onset juvenile rheumatoid arthritis after treatment with low dose methotrexate. J Rheumatol 1997; 24:2035-7.

 

Macrophage Activation Syndrome Is Hemophagocytic Lymphohistiocytosis — Need for the Right Terminology

To the Editor:

We read with great interest the paper by Ravelli, et al1. While we agree with the authors that methotrexate could possibly trigger macrophage activation syndrome (MAS) in systemic onset juvenile idiopathic arthritis (JIA), we would like to see the term MAS replaced by hemophagocytic lymphohistiocytosis (HLH). Historically the term MAS has been used to describe this potentially life threatening complication associated with systemic JIA. In 1987 the Writing Group of the Histiocyte Society recommended a division of the histiocytic disorders into 3 classes to include primary and secondary causes of hemophagocytosis like that seen in systemic JIA2.

We feel it is important for the pediatric rheumatology community to use the same terminology as pediatric hematologists to avoid confusion. Also, literature searches will enable more articles, particularly ones written by hematologists, to be picked up. It may also encourage pediatric rheumatologists to consider treatment options successful in treatment of other HLH syndromes for refractory cases. Several causative genes have recently been described with the primary form of HLH3,4. Hemophagocytosis is seen as a secondary phenomenon in a number of autoimmune conditions, and looking at all of them in conjunction with systemic JIA may lead to better understanding of this potentially life threatening complication.

ATHIMALAIPET V. RAMANAN, MRCP(UK); EILEEN M. BAILDAM, FRCPCH(UK), Department of Paediatric Rheumatology; ROBERT F. WYNN, FRCPCH(UK), Department of Paediatric Haematology, Royal Manchester Children's Hospital, Manchester, UK.

REFERENCES

1. Ravelli A, Cristina Caria M, Buratti S, Malattia C, Temporini F, Martini A. Methotrexate as a possible trigger of macrophage activation syndrome in systemic juvenile idiopathic arthritis. J Rheumatol 2001;28:865-7.

2. Writing Group of the Histiocyte Society. Histiocytosis syndromes in children. Lancet 1987;1:208.

3. Ohadi M, Lalloz MR, Sham P, et al. Localisation of a gene for familial hemophagocytic lymphohistiocytosis at chromosome 9q21.3-22 by homozygosity mapping. Am J Hum Genet 1999;64:165-71.

4. Dufourcq-Lagelouse R, Jabado N, Le-Deist F, et al. Linkage of familial hemophagocytic lymphohistiocytosis to 10q21-22 and evidence for heterogeneity. Am J Hum Genet 1999;64:172-9.

Drs. Ravelli and Martini reply

To the Editor:

We thank Dr. Ramanan and colleagues for their interest in our report. The term macrophage activation syndrome (MAS) is commonly used to identify the hemophagocytic syndrome that may develop in children with chronic rheumatic diseases, particularly systemic juvenile idiopathic arthritis. Because MAS belongs to the group of hemophagocytic syndromes that are associated with an underlying systemic disease, such as immunodeficiency, hematological neoplasia, or autoimmune disorders, we believe that the proposal of Dr. Ramanan and colleagues to rename MAS according to the classification of histiocytosis syndromes in children warrants consideration. The choice of the more suitable term to label this complication of chronic rheumatic diseases should be important for future discussion.

ANGELO RAVELLI, MD; ALBERTO MARTINI, MD, Pediatria II, Istituto G. Gaslini, Università di Genova, Genova, Italy.

 

Prevalence of Spondyloarthropathy in Japan

To the Editor:

The recent report of Hukuda, et al1 concluded that the annual incidence and the prevalence of spondyloarthropathy (SpA) in Japanese were less than 1/10 and 1/200, respectively, of those among Caucasians. Since any prevalence divided by the corresponding annual incidence roughly indicates out of how many years after diagnosis the patients were included into the prevalence study (average observation period, maximally from diagnosis to death), their conclusions1 would imply a 20-fold longer observation period in Caucasian than in Japanese patients with SpA. This is highly unlikely.

In the Japanese study1, a SpA prevalence of 9.5/100,000 and an incidence rate of 0.48 per 100,000 person-years were reported, resulting in a ratio of 19.8 years. As may be seen in Table 1, this is in accord with the prevalence-to-incidence ratios of 18-22 years reported for ankylosing spondylitis (AS) in other studies. Thus the discrepancy must be connected with the comparison made between Japanese and Caucasians. The prevalence of SpA in Japanese was estimated on the basis of hospital derived data, whereas the prevalence in Caucasians used for comparison was taken from a blood donor study2. As shown by Gran3 and by Boyer4, hospital based studies usually reveal only the more severe and typical cases normally diagnosed in clinical routine, whereas in blood donor studies or population surveys a greater insight into the full disease spectrum is gained by including more cases that normally remain undiagnosed in clinical routine.

Table 1. Incidence rate and prevalence of AS and SpA as found in hospital-based studies and as found by intensive search in blood donor or population studies.

Data on the total prevalence of SpA in Caucasians are rather limited. On the basis of the blood donor study2 and a population based survey8, values between 0.47% and 1.9% have been reported. A way to derive the prevalence of AS and SpA from limited hospital data has been reported9: According to the national database (25,852 patients with inflammatory rheumatic diseases) of the German collaborative arthritis centers10, 15% of the AS patients registered in this database are members of the AS society in Germany (Deutsche Vereinigung Morbus Bechterew, DVMB). In the same year, the DVMB membership register counted 14,239 patient members. Under the assumption that the degree of organization in the self-help society of the patients registered in the national database is representative for all diagnosed AS patients in Germany, a total of about 95,000 diagnosed AS patients = 0.12% of the general population (82 million for Germany11) can be calculated. As already mentioned, this result strongly depends on the representativity of the 15% proportion of DVMB members in the national database. Possibly, relatively more DVMB members than patients who do not make use of the information distributed by the patient organization consult the highly specialized centers contributing to the national database. Thus, the real prevalence of diagnosed AS may be essentially higher. Nevertheless, this way to estimate the prevalence of a disease seems interesting enough to be reported and, moreover, the rate of membership in a patient organization can easily be assessed in future trials.

The ratio between the prevalence of AS and SpA has been reported to be about 1:22, and the same ratio was found in the national database10,12. In Japanese1 this ratio was found to be 1:1.5. One reason for the difference may be the low number of undifferentiated SpA detected1. These proportions highlight that AS is the most frequent SpA subtype. If these ratios are taken into account, the ratio of 1/30 between the prevalence of AS in Japanese and Caucasians reported1 and the ratio of 1/200 for SpA contradict each other.

Using the ratio of 1:2 between the prevalence of AS and SpA as indicated above, the prevalence of diagnosed SpA patients in Germany can be estimated to be at least 190,000 = 0.23% of the general population (Table 1).

It has to be stressed once more that the prevalence of diagnosed AS or SpA reported in hospital based studies probably does not reflect the true prevalence. As shown13, AS in women has been underdiagnosed in former decades, and this underdiagnosis governs the percentage of women among diagnosed AS patients even today. Further, a comparison of the age distribution of the DVMB membership with that expected from the age distribution of the German population11 and from the distribution of the age at diagnosis of AS13 shows that male AS patients older than 65 years are also underrepresented in the patient organization9. This may indicate that AS was underdiagnosed in former decades in men as well. Further, the lack of appropriate therapies may have prevented a considerable number of patients consulting the rheumatological centers.

In addition, it has to be stressed that the lifetime incidence of the disease is always higher than the prevalence based on the whole population. A prevalence of 0.12% and 0.23% for AS and SpA, respectively, means that at least 0.21% and 0.41% of the population will be diagnosed with AS or SpA, respectively, during their lifetime9.

All these points lead to an underestimation of the prevalence of AS and SpA, which is probably essentially higher than the values indicated in Table 1. Accordingly, higher prevalence values for AS and SpA in Caucasians than those found in hospital based studies have been reported in population based studies2,8.

Nevertheless, by comparing the results shown in Table 1, it seems that the annual incidence and the prevalence of AS and SpA in Japanese are less than about 1/20 of those among Caucasians. The reportedly lower prevalences of HLA-B2714 and of psoriasis15 in Japanese certainly contribute to this result.

ERNST FELDTKELLER, Prof. Dr. rer nat, Ankylosing Spondylitis International Federation, Michaeliburgstr. 15, D-81671 München; JÜRGEN BRAUN, Prof. Dr. med., Rheumazentrum Ruhrgebiet, St.-Josefs-Krankenhaus, Landgrafenstrasse 15, D-44652 Herne, Germany.

REFERENCES

1. Hukuda S, Minami M, Saito T, et al. Spondyloarthropathies in Japan: Nationwide questionnaire survey performed by The Japan Ankylosing Spondylitis Society. J Rheumatol 2001;28:554-9.

2. Braun J, Bollow M, Remlinger G, et al. Prevalence of spondylarthropathies in HLA-B27 positive and negative blood donors. Arthritis Rheum 1998;41:58-67.

3. Gran JT, Husby G. Ankylosing spondylitis. Prevalence and demography. In: Klippel JH, Dieppe PA, editors. Rheumatology. 2nd ed. London: Mosby; 1998:6.15.1-6.

4. Boyer GS, Templin DW, Bowler A, et al. A comparison of patients with spondyloarthropathy seen in specialty clinics with those identified in a community-wide epidemiologic study. Has the classic case misled us? Arch Intern Med 1997;157:2111-7.

5. van der Linden SM, Valkenburg HA, de Jongh BM, Cats A. The risk of developing ankylosing spondylitis in HLA-B27 positive individuals. Arthritis Rheum 1984;27:241-9.

6. Carbone LD, Cooper C, Michet CJ, Atkinson EJ, O'Fallon WM, Melton LJ. Ankylosing spondylitis in Rochester, Minnesota, 1935-1989. Is the epidemiology changing? Arthritis Rheum 1992;35:1476-82.

7. Kaipiainen-Seppanen O, Aho K, Heliovaara M. Incidence and prevalence of ankylosing spondylitis in Finland. J Rheumatol 1997;24:496-9.

8. Saraux A, Guedes C, Allain J, et al. Prevalence of rheumatoid arthritis and spondyloarthropathy in Brittany, France. J Rheumatol 1999;26:2622-8.

9. Feldtkeller E. Erkrankungsalter und Diagnoseverzögerung bei Spondylarthropathien. Z Rheumatol 1999;58:21-30.

10. Zink A. Epidemiologie der rheumatischen Versorgung in Deutschland. Z Rheumatol 1995;54:184-91.

11. Statistisches Bundesamt. Statistisches Jahrbuch der Bundesrepublik Deutschland 1996. or www.statistik-bund.de/basis/d/bevoe/bevoetab4.htm

12. Zink A, Listing J, Klindworth C, Zeidler H, for the German Collaborative Arthritis Centers. The national database of the German collaborative arthritis centres: I. Structure, aims, and patients. Ann Rheum Dis 2001;60:199-206.

13. Feldtkeller E, Bruckel J, Khan MA. Scientific contributions of ankylosing spondylitis patient advocacy groups. Curr Opin Rheumatol 2000;12:239-47.

14. Khan MA. HLA-B27 and its subtypes in world populations. Curr Opin Rheumatol 1995;7:263-9.

15. Yip SY. The prevalence of psoriasis in the Mongoloid race. J Am Acad Dermatol 1984;10:965-8.

Drs. Hukuda and Shichikawa reply

To the Editor:

We greatly appreciate the kind and excellent comments from Dr. Feldtkeller and Dr. Braun on our study of SpA in Japan1. Their arguments concern 2 points: (1) improper selection of a Western paper for international comparison of prevalence of SpA and (2) surveys based on hospital derived data.

The problem we encountered in comparing our data with Caucasian data was the limited number of epidemiological studies available for our purpose even in the Western literature. The survey by Dr. Braun and colleagues in blood donors2 was the only study we could identify at the time on Medline Express. Unfortunately we did not notice the unlikely discrepancy between incidence and prevalence from the viewpoint of observation length in our conclusions. After learning that the prevalence of SpA is 0.21% in the USA (Lawrence)3, 0.23-0.4% in Germany (Feldtkeller), and 0.47% in France4, we agree that the figure of 1.9% (Braun) is too high and specific, in that 19 out of 20 patients with SpA from among blood donors are HLA-B27 positive. Since the figure of 0.23% also came from Germany, it is more proper to take this as the comparison counterpart as Dr. Feldtkeller suggests, and we completely agree with him.

We agree with Dr. Feldtkeller and Dr. Braun in their view that the discrepancy of prevalence ratio of AS and SpA between Germany (2.0) and Japan (1.5) is due to the scarcity of undifferentiated SpA (USpA) in the latter. We are surprised to see that their USpA cases are all HLA-B27 positive. On the other hand, the AS/SpA ratio revealed by a national survey in the US was 1.6 and similar to ours, although they excluded USpA2. Therefore the figure of 0.0095% that we proposed as the prevalence of SpA based on several assumptions might be regarded as close to prevalence, based on population study, despite our hospital based survey method. This is what we think at present, but it should be ascertained by a population study in the future since prevalence may be influenced by the change of diagnostic criteria as well as the process of time.

Shichikawa, a coauthor of our study, conducted a population study between 1961 and 1992 (unpublished in Western literature) on rheumatic diseases in several cities, towns, and villages in the Kinki district, in central Japan. His survey revealed only one case of AS with peripheral involvement among 17,931 adults (0.0056%). This is quite close to the prevalence of AS estimated in the present survey. Another population study by Shichikawa performed in a countryside community revealed no radiographic sacroiliitis among 3000 male inhabitants above the age of 30 years. Those data also underscore the rarity of this disease in Japan and are thought to support our assumption in the present study.

However, more precise international comparison requires more information. That RA and SpA have almost the same frequency in France indicates the prevalence of this disease is expected to rise in Europe as well as in Japan when its diagnosis becomes easier and awareness of it among medical professionals is further promoted. It is of great interest for us to determine the prevalence of SpA in our country, where incidence of HLA-B27 is extremely low.

SINSUKE HUKUDA, MD, Tane-daini Hospital, Osaka; KANJI SHICHIKAWA, MD, Yukioka Hospital, Osaka, Japan.

REFERENCES

1. Hukuda S, Minami M, Saito T, et al. Spondyloarthropathies in Japan: Nationwide questionnaire survey performed by The Japan Ankylosing Spondylitis Society. J Rheumatol 2001;28:554-9.

2. Braun J, Bollow M, Remlinger G, et al. Prevalence of spondylarthropathies in HLA-B27 positive and negative blood donors. Arthritis Rheum 1998;41:58-67.

3. Lawrence RC, Helmick CG, Arnett FC, et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 1998;41:778-99.

4. Saraux A, Guedes C, Allain J, et al. Prevalence of rheumatoid arthritis and spondyloarthropathy in Brittany, France. J Rheumatol 1999;26:2622-8.

 

Bone Involvement in Psoriatic Arthritis

To the Editor:

We read with interest the article by Frediani, et al1 reporting a high occurrence of low bone mass in patients with psoriatic arthritis (PsA). We also performed a cross sectional study in which we assessed whether patients with PsA had both bone mass and bone metabolism abnormalities. Our study group included 24 outpatients consecutively enrolled over a 9 month period with peripheral PsA fulfilling the criteria of Wright and Moll2. There were 12 men and 12 women (6 of them were menopausal). The following measures of activity or severity of PsA were determined: morning stiffness duration, number of painful and swollen joints, Ritchie Articular Index3, Health Assessment Questionnaire score4, short form of the Arthritis Impact Measurement Scales 2 (AIMS-SF-2)5, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) level. Calcium intakes, alcohol consumption, and the level of physical activity were also recorded. Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry on a Hologic QDR-2000® (Hologic, Waltham, MA, USA) at the lumbar spine and the nondominant femoral neck. Quantitative ultrasound (US) measurements were performed on the nondominant heel with an Achilles® instrument (Lunar, Madison, WI, USA). Two variables were measured: broadband ultrasound attenuation (BUA) and speed of sound (SOS). A third variable, the stiffness index (SI), that is, a combination of both BUA and SOS, was also calculated.

Finally, biological markers of bone turnover were also measured. Serum osteocalcin (OC) and bone alkaline phosphatase (BAP) indicated bone formation, whereas type I C-terminal telopeptide (ICTP) and urinary type I collagen C-telopeptide breakdown products (second urine void, CTX) indicated bone resorption. Blood and urine samples were collected between 7:30 AM and 9:00 AM after an overnight fast. Serum samples were stored frozen at -80° until assay.

The control group consisted of 48 age and sex matched subjects recruited among health care staff members and patients who attended the clinic for disorders unrelated to bone (i.e., low back pain or sciatica without osteoarthritis on radiographs). The following variables were measured in control patients: BMD, BUA, SOS, SI, and biological markers of bone turnover.

Neither patients nor controls were receiving drugs that could affect bone mass or bone metabolism and particularly corticosteroids.

We found a borderline significant decrease for BMD in patients with PsA compared with control patients (Table 1) at both the lumbar spine: -6.0% (95% CI -12.9%/ 0.9%, p = 0.08) and femoral neck: -7.4% (95% CI -15.1%/ 0.3%, p = 0.06). We also found a significant decrease in patients with PsA compared with controls for both SOS: -1.8% (95% CI -15.1%/-0.7%, p = 0.01) and SI: -17.8% (95% CI -29.7%/-5.9%, p = 0.004). BUA was not significantly decreased in patients with PsA: -4.7% (95% CI -9.9%/ 0.4%, p = 0.07).

Table 1. BMD and bone ultrasound measurements for patients with PsA and controls.

The sole marker of bone turnover significantly different for PsA patients compared with control patients was ICTP: 4.81 ± 1.50 versus 3.23 ± 1.39 ng/ml, respectively; p < 0.01.

Significant correlations were found for PsA patients between BMD and age at both the lumbar spine (r = -0.33, p < 0.05) and femoral neck (r = -0.5, p < 0.01). Also in the PsA group BMD was significantly correlated with body mass index (BMI) at the lumbar spine (r = 0.32, p < 0.05) and femoral neck (r = 0.45, p < 0.01). SI was significantly correlated with age (r = -0.37, p < 0.05) but with neither SOS nor BUA. Quantitative US measurements were not correlated with BMI. Neither BMD (at lumbar spine and femoral neck) nor quantitative US measurements were correlated with clinical and biological measures of activity or severity of PsA, nor with calcium intake, alcohol consumption, or level of physical activity.

Both BAP and ICTP were correlated with CRP level: r = 0.3, p < 0.05 and r = 0.57, p < 0.01, respectively. In the same manner BAP and ICTP were correlated with ESR: r = 0.31, p < 0.05 and r = 0.75, p < 0.01.

Thus our study favored a slight (but not significant) decrease in BMD for patients with PsA in contrast with the study by Frediani, et al1, but in accord with another recent study6. Moreover, our quantitative ultrasound measurements are in agreement with those of Frediani, et al1 and suggest that this tool is useful for assessing bone involvement in PsA. Other studies are needed for data on low bone mass in PsA.

BERNARD CORTET, MD, Hospital Practitioner; MARIE-HÉLÈNE TROUVÉ, MD, Registrar; RENÉ-MARC FLIPO, MD, Professor of Rheumatology, Department of Rheumatology, CHRU Lille, Hôpital R. Salengro, 2 Avenue Oscar Lambret, 59037 Lille Cedex, France. E-mail: bcortet@chru-lille.fr

REFERENCES

1. Frediani B, Allegri A, Falsetti P, et al. Bone mineral density in patients with psoriatic arthritis. J Rheumatol 2001;28:138-43.

2. Wright V, Moll JMH. Seronegative polyarthritis. Amsterdam: Elsevier North Holland Publishing Company; 1976.

3. Ritchie DM, Boyle JA, McInnes JM, et al. Clinical studies with an articular index for the assessment of joint tenderness in patients with rheumatoid arthritis. Q J Med 1968;37:393-406.

4. Guillemin F, Briancon S, Pourel J. [Measurement of the functional capacity in rheumatoid polyarthritis: a French adaptation of the Health Assessment Questionnaire (HAQ)] in French. Rev Rhum Mal Osteoartic 1991;58:459-65.

5. Guillemin F, Coste J, Pouchot J, Ghezail M, Bregeon C, Sany J, and the French Quality of Life in Rheumatology Group. The AIMS2-SF. A short form of the Arthritis Impact Measurement Scales 2. Arthritis Rheum 1997;40:1267-74.

6. Nolla JM, Fiter J, Rozadilla A, et al. Bone mineral density in patients with peripheral psoriatic arthritis. Rev Rhum Engl Ed 1999;66:457-61.

To the Editor:

We read the interesting article by Frediani, et al on bone mineral density (BMD) in patients with psoriatic arthritis (PsA)1. We had previously reported on this topic2. We describe our additional experience in order to complete the information reported by Frediani, et al, as our study was also performed using dual energy x-ray absorptiometry (DEXA), which has become the preferred technique for detecting osteopenia.

We studied 52 patients with active non-axial PsA and 52 controls matched for sex, age, and menopause status; all controls were patients with soft tissue rheumatism who were otherwise healthy. Patients were divided into 3 groups: men (n = 19), premenopausal women (n = 14), and postmenopausal women (n = 19). No patient had previously received steroid treatment; all were undergoing nonsteroidal antiinflammatory drug therapy and 19 (36%) were receiving disease modifying antirheumatic drugs. BMD (g/cm2) at the lumbar spine (L2-L4) and femoral neck was measured by DEXA with a Hologic QDR 1000 unit. Table 1 shows the demographic, clinical, and densitometric data of patients and controls.

Table 1. Demographic, clinical, and densitometric data in patients with PsA and controls.

In the overall PsA population, disease duration [mean 5.9 (SD 5.8) years] was negatively correlated with BMD at lumbar spine (r = -0.39) and femoral neck (r = - 0.29); erythrocyte sedimentation rate [mean 17.8 (SD 13.6) mm/h] was not correlated with BMD. According to the World Health Organization categories, 22 (42%) patients presented low bone mass (osteopenia) and 7 (13%) patients osteoporosis at the lumbar spine; 23 (44%) patients presented low bone mass and 4 (8%) patients osteoporosis at the femoral neck.

We agree with Frediani, et al that it would be interesting to conduct longitudinal studies to assess the problem of bone loss in patients with PsA.

JOAN M.NOLLA, MD; JORDI FITER, MD; ANTONI ROZADILLA, MD; CARMEN GÓMEZ-VAQUERO, MD, Rheumatology Department, Ciutat Sanitària i Universitària de Bellvitge, Feixa Llarga s/n, 08907 L'Hospitalet, Barcelona, Spain. E-mail: 28634apj@comb.es

REFERENCES

1. Frediani B, Allegri A, Falsetti P, et al. Bone mineral density in patients with psoriatic arthritis. J Rheumatol 2001; 28: 138-43.

2. Nolla JM, Fiter J, Rozadilla A, et al. Bone mineral density in patients with peripheral psoriatic arthritis. Rev Rhum (Engl Ed) 1999; 10: 457-61.

Dr. Frediani replies

To the Editor:

I have read with much interest the studies by Cortet and Nolla. Cortet's study noted a difference between the results obtained by quantitative ultrasound (QUS) and those obtained by dual energy x-ray absorptiometry (DEXA). This difference was not noted in our study. Nor did we note this difference between DEXA and QUS in other studies we carried out in patients with rheumatoid arthritis or with postmenopausal osteoporosis. In our study of the 2 methods (QUS and DEXA) we employed equipment manufactured by Lunar, and this could be important. In Nolla's study the osteoporosis seemed to be present only at the femoral level, and only in subjects in menopause. It could be important to know the activity of the disease in premenopausal patients: in our subjects the disease was probably more severe. Indeed, in all our patients there was severe synovitis, shown by ultrasonography, in at least 5 joints.

BRUNO FREDIANI, MD, Institute of Rheumatology, University of Siena, Siena, Italy.



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