Minocycline for the Treatment of Takayasu Arteritis

TO THE EDITOR: Background: Takayasu arteritis is a type of chronic vasculitis that primarily affects large elastic arteries. It tends to progress despite treatment with glucocorticoids or immunosuppressive agents (1, 2). Recently, we reported that matrix metalloproteinases (MMPs) might contribute to the pathogenesis and exacerbation of Takayasu arteritis and that circulating levels of MMPs could be diagnostic markers of the disease (3). While many MMP inhibitors are under development (4), minocycline has established MMP inhibitor activity that is independent of antimicrobial activity (5).

Objective: To assess the effect of combination treatment with minocycline and glucocorticoid for active Takayasu arteritis.

Methods and Findings: Of 35 consecutive patients with Takayasu arteritis who were referred to the Department of Internal Medicine and Molecular Science, Osaka University Hospital, from October 2001 to July 2004, 15 were receiving prednisolone therapy for active disease. Eleven of these 15 patients gave informed consent and enrolled in the study. Each fulfilled more than 3 of the American College of Rheumatology criteria for Takayasu arteritis (1) and were evaluated according to the National Institute of Health criteria for disease activity (disease activity score) (2). The Ethics Committee of Osaka University Graduate School of Medicine approved the study protocol.

The patients were treated with oral minocycline (100 mg twice daily) for 3 months without changes in prednisolone dosage. The Table shows changes from baseline to 3 months for disease activity score; C-reactive protein level; erythrocyte sedimentation rate; and levels of MMP-2, MMP-3, and MMP-9. The mean disease activity score improved from 2.8 (SD, 0.8) to 0.7 (SD, 1.0) (P = 0.004). Mean erythrocyte sedimentation rate and C-reactive protein values decreased in all patients from 50 mm/h (SD, 25) to 35 mm/h (SD, 21) (P = 0.003) and from 17.8 mg/L (SD, 13.7) to 8.9 mg/dL (SD, 17.9) (P = 0.026), respectively. Nine of 11 patients were considered to be in remission according to disease activity score. Furthermore, the mean serum MMP-3 and MMP-9 levels decreased from 141.9 (SD, 57.3) to 65.0 (SD, 41.1) (P = 0.004) and from 116.6 (SD, 52.3) to 47.1 (SD, 15.5) (P = 0.004), respectively. Mean serum MMP-2 levels did not change (943.2 [SD, 198.5] to 932.6 [SD, 180.3]).

Discussion: In recent years, minocycline has been used to treat a variety of diseases, including rheumatoid arthritis, osteoarthritis, osteoporosis, and cancer (5). Actions of minocycline in these diseases are thought to be independent of antimicrobial activity and are related to pleiotropic effects, including inhibition of MMP activities (5). We previously showed that MMPs might contribute to the pathogenesis and exacerbation of Takayasu arteritis (3), and those findings prompted us to test the pleiotropic effects of minocycline on patients with this disorder. In our case series, we observed a marked reduction of erythrocyte sedimentation rate and C- reactive protein values as well as disease activity score. In association with these improvements, circulating MMP-3 and MMP-9 levels also decreased. These results need confirmation in larger, controlled studies.

Conclusion: Minocycline may be a valuable additive to steroids or an alternative to immunosuppressive agents for patients with Takayasu arteritis and should be tested in randomized, controlled trials.

References

1. Arend WP, Michel BA, Bioch DA, Hunder GG, Calabrese LH, Edworthy SM, et al. The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum. 1990;33:1129-34. [PMID: 1975175]

2. Kerr GS, Hallahan CW, Giordano J, Leavitt RY, Fauci AS, Rottem M, et al. Takayasu arteritis. Ann Intern Med. 1994;120:919-29. [PMID: 7909656]

3. Matsuyama A, Sakai N, Ishigami M, Hiraoka H, Kashine S, Hirata A, et al. Matrix metalloproteinases as novel disease markers in Takayasu arteritis. Circulation. 2003;108:1469-73. [PMID: 12952836]

4. Matter H, Schudok M. Recent advances in the design of matrix metalloprotease inhibitors. Curr Opin Drug Discov Devel. 2004;7:513- 35. [PMID: 15338961]

5. Cooper SM. Tetracyclines. In: Ruddy S, Harris ED, Sledge CB, eds. Kelley’s Textbook of Rheumatology. Philadelphia: WB Saunders; 2001:913-20.

Akifumi Matsuyama, MD, PhD

Naohiko Sakai, MD, PhD

Masato Ishigami, MD, PhD

Hisatoyo Hiraoka, MD, PhD

Shizuya Yamashita, MD, PhD

Osaka University Graduate School of Medicine

Osaka 565-0871, Japan

Potential Financial Conflicts of Interest: None disclosed.

Copyright American College of Physicians Sep 6, 2005