interesting to know whether patients with thrombosis were concomitantly treated ... Aspirin for primary thrombosis prevention in the antiphos- pholipid syndrome: ...
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DOI 10.1002/art.23221
Does oral glucosamine prevent subchondral bone loss in an animal model of osteoarthritis? Comment on the article by Wang et al To the Editor: In the recent study by Wang et al (1), the authors concluded that after anterior cruciate ligament transection (ACLT), changes in subchondral bone begin early and simultaneously with cartilage degradation and that oral glucosamine hydrochloride has a protective effect (1). They based this conclusion on distal femur and proximal tibia bone mineral density measured by dual x-ray absorptiometry (DXA) and on subchondral bone measurements obtained using subchondral trabecular bone turnover testing and histomorphometric techniques. Nonetheless, at least partial bone loss due to immobilization after surgery cannot be ruled out. Also, a favorable effect of glucosamine could have been due to its analgesic properties, facilitating activity, rather than to a direct effect on bone subchondral turnover (2,3). DXA measurements at other anatomic sites, such as the lumbar spine or the whole femur or tibia, would have helped to exclude the possibility of juxtaarticular bone loss due to immobilization. We have demonstrated (in an experimental model of osteoporosis in rabbits) that bone loss develops to different degrees according to the region analyzed (4,5). We therefore suggest that the authors should have performed DXA at different anatomic regions, and should have obtained sequential measurements. Wang and colleagues pointed out that cartilage ulcerations were more marked on the caudal (posterior) tibial articular surface. They imputed this finding to biomechanical alterations caused by the instability induced by ACLT. We have described the same findings in experimental rabbit models of osteoarthritis induced either by partial medial meniscectomy or by partial medial meniscectomy plus ACLT (5,6). Although the severity of cartilage deterioration increased when ACLT was performed in addition to meniscectomy, abnormalities followed the same anatomic distribution, being more intense in the posterior articular tibial surface. Since partial medial meniscectomy does not cause gross joint instability, we hypothesized that this distribution of abnormalities on the articular surface is due mainly to the particular biomechanical characteristics of the gait of the rabbit, an animal that usually stands and walks with the knee in a semiflexed position, and not to biomechanical instability secondary to ACL insufficiency. Santos Castan ˜eda, MD Hospital de la Princesa Universidad Auto ´noma Raquel Largo, PhD Emilio Calvo, MD Gabriel Herrero-Beaumont, MD Fundacio ´n Jime´nez Dı´az Universidad Auto ´noma Madrid, Spain 1. Wang SX, Laverty S, Dumitriu M, Plaas A, Grynpas MD. The effects of glucosamine hydrochloride on subchondral bone changes in an animal model of osteoarthritis. Arthritis Rheum 2007;56: 1537–48.
2. Reginster JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere O, et al. Long-term effects of glucosamine sulfate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet 2001;357:251–6. 3. Herrero-Beaumont G, Roman Ivorra JA, Trabado MC, Blanco FJ, Benito P, Martin-Mola E, et al. Glucosamine sulfate in the treatment of knee osteoarthritis symptoms: a randomized, double-blind, placebo-controlled study using acetaminophen as a side comparator. Arthritis Rheum 2007;56:555–67. 4. Castaneda S, Largo R, Calvo E, Rodriguez-Salvanes F, Marcos ME, Diaz-Curiel M, et al. Bone mineral measurements of subchondral and trabecular bone in healthy and osteoporotic rabbits. Skeletal Radiol 2006;35:34–41. 5. Calvo E, Castaneda S, Largo R, Fernandez-Valle ME, RodriguezSalvanes F, Herrero-Beaumont G. Osteoporosis increases the severity of cartilage damage in an experimental model of osteoarthritis in rabbits. Osteoarthritis Cartilage 2007;15:69–77. 6. Calvo E, Palacios I, Delgado E, Ruiz-Cabello J, Hernandez P, Sanchez-Pernaute O, et al. High-resolution MRI detects cartilage swelling at the early stages of experimental osteoarthritis. Osteoarthritis Cartilage 2001;9:463–72.
DOI 10.1002/art.23160
Need for additional trials of primary prophylaxis in patients with high-risk antiphospholipid antibody profiles: comment on the article by Erkan et al To the Editor: We read with interest the article by Erkan et al (1) regarding the prospective Antiphospholipid Antibody Acetylsalicylic Acid (APLASA) study. The authors reported that asymptomatic individuals with persistent antiphospholipid antibody positivity do not benefit from prophylactic treatment with low-dose aspirin. Although these results appear clear-cut, we think that they deserve some comments. The first issue is the possibility of a so-called aspirin resistance in some patients. Indeed, more patients in the aspirin group than in the placebo group experienced an incident thrombotic episode. Because up to 40% of patients in the study were treated with nonsteroidal antiinflammatory drugs (NSAIDs), some of which can be associated with actual resistance to aspirin, in particular ibuprofen (2), it could be interesting to know whether patients with thrombosis were concomitantly treated with NSAIDs before the episode. The second issue regards compliance that was assessed by selfreporting only. The third issue pertains to the risk profile of the patients included in the study. An incidence of thrombosis lower than that expected might be attributable to the inclusion in this study of lupus anticoagulant (LAC)–negative patients with low titers of anticardiolipin antibodies and/or IgA anticardiolipin antibodies; such antibody profiles are not part of the diagnostic criteria for definite antiphospholipid syndrome (3). These low-risk patients represent 42% of patients included in the study. In the decision analysis that we performed with a theoretical Markov model (4), we were able to stratify the risk of thrombosis associated with antiphospholipid antibodies in 2 ways: first, according to the underlying disease, systemic lupus erythematosus, in which the annual incidence of thrombosis is high because of additional risk factors, and second, according
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to the antibody pattern, because the presence of LAC is associated with a higher risk of thrombosis than is the presence of anticardiolipin antibodies alone (5). Our results indicated that patients with a higher risk profile were more likely to benefit from such treatment. In the APLASA study, one of the patients in the aspirin group had venous thromboembolism while hospitalized for pneumonia; the benefit of aspirin for the prevention of venous thromboembolism is definitely lower than the benefit for arterial thrombosis. Thus, the question arises as to whether this event occurred despite adequate heparin prophylaxis. Finally, one additional factor that may have contributed to the negative result of the APLASA study is that smoking and other cardiovascular risk factors tended to be more frequent in the aspirin group, although this difference did not reach statistical significance. In conclusion, we believe that additional trials of primary prophylaxis should be conducted in patients with high-risk antiphospholipid antibody profiles or additional cardiovascular risk factors. Denis Wahl, MD, PhD Thomas Lecompte, MD Nancy University Hospital and INSERM U734 Vandoeuvre, France Henri Bounameaux, MD Geneva University Hospital Geneva, Switzerland 1. Erkan D, Harrison MJ, Levy R, Peterson M, Petri M, Sammaritano L, et al. Aspirin for primary thrombosis prevention in the antiphospholipid syndrome: a randomized, double-blind, placebo-controlled trial in asymptomatic antiphospholipid antibody–positive individuals. Arthritis Rheum 2007;56:2382–91. 2. Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, Tournier B, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 2001;345:1809–17. 3. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295–306. 4. Wahl DG, Bounameaux H, de Moerloose P, Sarasin FP. Prophylactic antithrombotic therapy for patients with systemic lupus erythematosus with or without antiphospholipid antibodies: do the benefits outweigh the risks? A decision analysis. Arch Intern Med 2000;160:2042–8. 5. Wahl DG, Guillemin F, De Maistre E, Perret C, Lecompte T, Thibaut G. Risk for venous thrombosis related to antiphospholipid antibodies in systemic lupus erythematosus: a meta-analysis. Lupus 1997;6:467–73.
DOI 10.1002/art.23190
Reply To the Editor: We thank Drs. Wahl, Lecompte, and Bounameaux for their interest in our randomized controlled trial of primary thrombosis prevention in patients with antiphospholipid antibodies (aPL).
First, Wahl et al mention the possibility of aspirin resistance in our cohort. We did not investigate aspirin resistance, because the definition and the clinical significance of aspirin resistance are still controversial, and because tests to detect aspirin resistance are not standardized (1,2). Of the 10 study subjects in whom primary or secondary outcomes developed, only 2 were receiving nonsteroidal antiinflammatory drugs at the time of their events (1 arterial and 1 venous); none were receiving ibuprofen. Second, Wahl et al question the method that we used to assess compliance. We agree that a biologic test would have been the ideal tool with which to assess compliance. Nevertheless, we repeatedly reminded patients about the importance of adherence to the protocol, and such an approach is more consistent with real-world clinical practice experience. Third, Wahl et al question the aPL risk profile of the participants. We agree that the aPL profile significantly influences the risk of thrombosis. When we designed our study almost 8 years ago, the updated Sapporo classification criteria for the antiphospholipid syndrome (APS) (3) did not exist. However, we chose to randomize patients based on a 2-tier thrombosis risk profile, as follows: individuals at low risk (anticardiolipin antibody [aCL] IgG/IgM/IgA 20–39 units) and individuals at high risk (positive lupus anticoagulant [LAC] test result and/or aCL IgG/IgM/IgA ⱖ40 units). The aCL IgA isotype is not part of the original (4) or the updated (3) Sapporo classification criteria for APS; our purpose in using the presence of aCL IgA as an inclusion criterion was to understand the association between this isotype and aPLrelated clinical manifestations. Only 7 of 172 patients (4%) had isolated aCL IgA positivity (4 patients with aCL IgA 20–39 units and 3 patients with aCL IgA ⱖ40 units) and negative results of an LAC test. We also agree that “patients with a higher risk profile were more likely to benefit” from prevention, but the nature of the prevention modalities other than elimination of non-aPL thrombosis risk factors is still to be determined. The deep vein thrombosis in our hospitalized patient occurred in the absence of heparin prophylaxis. Finally, although the traditional cardiovascular risk factors were more common in the group randomized to receive aspirin, the differences were not statistically significant. Doruk Erkan, MD Michael D. Lockshin, MD Hospital for Special Surgery Weill Medical College of Cornell University New York, NY 1. Wong S, Appleberg M, Ward CM, Lewis DR. Aspirin resistance in cardiovascular diseases: a review. Eur J Endovasc Surg 2004;27: 456–65. 2. Cattaneo M. Resistance to antiplatelet drugs: molecular mechanisms and laboratory detection. J Thromb Haemost 2007;5 Suppl 1:230–7. 3. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295–306. 4. Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette JC, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999;42:1309–11.
