Antibiotics for rheumatoid arthritis?

Minocycline shows promise in some patients

Graciela S. Alarcón, MD, MPH

VOL 105 / NO 4 / APRIL 1999 / POSTGRADUATE MEDICINE

CME learning objectives

• To review the possible mechanisms of action of minocycline and related compounds in rheumatoid arthritis
• To assess study findings on minocycline therapy for rheumatoid arthritis
• To learn which patients may beneift from minocycline therapy for rheumatoid arthritis

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Preview: Rheumatoid arthritis is a painful, chronic disease that affects an estimated 2 million Americans. Although no single pharmacologic agent is completely effective against the disease, some patients have shown significant improvement when treated with minocycline. Dr Alarcón summarizes the outcomes of studies to date and offers her recommendations.

In recent years, the use of antibiotics (primarily tetracycline analogues) to treat rheumatoid arthritis has seen a resurgence of interest. US and European studies (1-3) have validated the usefulness of minocycline (Minocin) in treatment of the disease; despite these studies, most rheumatologists remain unconvinced of the value of antibiotic therapy for rheumatoid arthritis (4). There is, of course, no dispute over proper use of antibiotics in treatment of musculoskeletal infections (including infectious arthritis) or "reactive arthritis" subsequent to an infection that had been untreated, partially treated, or even properly treated.

Possible mechanism of action

The mechanism of action of minocycline and related compounds in rheumatoid arthritis is unclear. The use of antibiotic therapy for rheumatoid arthritis was pioneered some 50 years ago by Dr Thomas McPherson Brown, who claimed that the disease was caused by Mycoplasma infection in the joints. To date, evidence is insufficient to confirm the infectious nature of rheumatoid arthritis, although studies using state-of-the-art methods are being conducted to test this theory.

The antirheumatic effect of minocycline could be related to its immunomodulatory and anti-inflammatory properties. Minocycline interferes with the production of prostaglandins and leukotrienes (5-7), scavenges oxygen radicals (8), interferes with the expression of nitrous oxide synthase (9), and enhances natural inhibitors of matrix metalloproteinases (10,11), which are important mediators of tissue destruction in rheumatoid arthritis and other chronic inflammatory and non-inflammatory arthropathies (12,13). The net result is decreased matrix metalloproteinase activity and tissue destruction. These effects have been observed in humans as well as in experimental models of arthritis. In one study (14), a significant reduction in collagenase activity in paired synovial tissue or fluid samples was noted in rheumatoid arthritis patients given minocycline for 10 days.

Studies of minocycline

Minocycline is a semisynthetic tetracycline with a prolonged half-life and an excellent toxicity profile. Its efficacy in rheumatoid arthritis has been reported in three double-blind, controlled studies (1-3) and two open trials (15-17). Table 1 summarizes the demographic and clinical features of the patients participating in the double-blind studies, in which minocycline was consistently more effective than placebo. In the study by Tilley and coworkers (3), patients who exhibited the "severity" genetic factor known as rheumatoid epitope and were given minocycline had fewer erosions than patients in the placebo group who also exhibited the rheumatoid epitope; this strongly supports the role of minocycline as a modifier of disease progression in rheumatoid arthritis (18,19). On the other hand, data from O'Dell and associates (1) showing adequate response to the compound even in patients with seropositivity for rheumatoid factor (another marker of severe disease and joint destruction) strongly suggest that there is a limited window of opportunity to prevent or modify the occurrence of tissue destruction (20).

Table 1. Characteristics of rheumatoid arthritis patients treated with minocycline in double-blind, controlled studies
Characteristics	Study
	O'Dell et al (1) (n=46)	Kloppenburg et al (2) (n=80)	Tilley et al (3) (n=219)
Age (mean yr)	41	56	54
Sex (% female)	72	68	78
Race (% white)	NA*	100	66
Disease duration (mean yr)	0.4	13	9
Seropositivity for IgM-RF (%)	100	89	56
ESR (mean mm/hr)	32	50	34
Functioning score** (mean)	NA*	1.7	0.9
ESR, erythrocyte sedimentation rate. *Not available. **Measured by Health Assessment Questionnaire (range, 0-3).

In chronic diseases such as rheumatoid arthritis, it is necessary to demonstrate a therapy's short- and long-term efficacy as well as its tolerability. Preliminary longitudinal data (21) suggest that the efficacy of minocycline therapy for rheumatoid arthritis is sustained over 3 years. Data are reassuring concerning the tolerability and safety of minocycline (table 2), but as experience accumulates and more patients are treated, less common complications may occur (table 3). It should be noted that some of the less common toxic effects (specifically, lupus-like manifestations) have been reported in relatively young adults receiving minocycline therapy for acne (22-24).

Table 2. Common toxic effects reported in double-blind, controlled studies of minocycline therapy*
Effects	Frequency (%)
Gastrointestinal	0-58
Dizziness	0-40
Rash	0-15
Pneumonitis	0-3
Headaches	0-20
*A third study,1 discussed herein, reported no common toxic effects. Data from Kloppenburg et al (2) and Tilley et al (3).

Who might benefit?

Physicians need to determine which rheumatoid arthritis patients are likely to benefit from minocycline therapy. No data categorically establish how these patients will respond to this or any other disease-modifying antirheumatic drug. If anything, minocycline may be a reasonable alternative for treating patients with a benign prognosis. This practice would seem reasonable (although the Food and Drug Administration has not approved minocycline for rheumatoid arthritis), but it is more likely to be adopted by subspecialists who have prescribed this agent in the context of the double-blind studies discussed herein (1-3).

Table 3. Less common toxic effects reported in double-blind, controlled studies of minocycline therapy

Acute hepatic injury Exfoliative dermatitis Interstitial nephritis Interstitial pneumonitis Intracranial hypertension Lupus-like syndrome* Persistent skin and mucosal pigmentation**

*Arthralgias, arthritis, skin rashes, abnormal results on serologic studies. **Bluish pigmentation (mongolian spots in skin). Data from O'Dell et al (1), Kloppenburg et al (2), and Tilley et al (3).

Conclusion

Antibiotics are clearly indicated for the treatment of defined musculoskeletal infections and of reactive arthritis secondary to known causal pathogens that are still recoverable. In cases of rheumatoid arthritis, minocycline can be an effective alternative therapy, but probably should not be tried in severe and potentially very destructive disease (25). Physicians need to familiarize themselves with the defined toxicity profile of the tetracyclines before prescribing them to patients with rheumatoid arthritis.

References

1. O'Dell JR, Haire CE, Palmer W, et al. Treatment of early rheumatoid arthritis with minocycline or placebo: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 1997;40(5):842-8
2. Kloppenburg M, Breedveld FC, Terwiel JP, et al. Minocycline in active rheumatoid arthritis: a double-blind, placebo-controlled trial. Arthritis Rheum 1994;37(5):629-36
3. Tilley BC, Alarcón GS, Heyse SP, et al, for the MIRA Trial Group. Minocycline in rheumatoid arthritis: a 48-week, double-blind, placebo-controlled trial. Ann Intern Med 1995;122(2):81-9
4. Panush RS, Thoburn R. Should minocycline be used to treat rheumatoid arthritis? Bull Rheum Dis 1996;45(2):2-5
5. Pruzanski W, Greenwald RA, Street IP, et al. Inhibition of enzymatic activity of phospholipases A2 by minocycline and doxycycline. Biochem Pharmacol 1992;44(6):1165-70
6. ElAttar TM, Lin HS, Shultz R. Effect of minocycline on prostaglandin formation in gingival fibroblasts. J Periodontal Res 1988;23(5):285-6
7. Golub LM, McNamara TF, D'Angelo G, et al. A non-antibacterial chemically-modified tetracycline inhibits mammalian collagenase activity. J Dent Res 1987;66(8):1310-4
8. van Barr HM, van de Kerkhof PC, Mier PD, et al. Tetracyclines are potent scavengers of the superoxide radical. (Letter) Br J Dermatol 1987;117(1):131-2
9. Amin AR, Attur MG, Thakker GD, et al. A novel mechanism of action of tetracyclines: effects on nitric oxide synthases. Proc Natl Acad Sci USA 1996;93(24):14014-9
10. Golub LM, Ramamurthy N, McNamara TF, et al. Tetracyclines inhibit tissue collagenase activity: a new mechanism in the treatment of periodontal disease. J Periodontal Res 1984;19(6):651-5
11. Smith RL, Schurman DJ, Kajiyama G, et al. The effect of antibiotics on the destruction of cartilage in experimental infectious arthritis. J Bone Joint Surg [Am] 1987;69(7):1063-8
12. Krane SM. Mechanisms of tissue destruction in rheumatoid arthritis. In: McCarty DJ, Koopman WJ, eds. Arthritis and allied conditions: a textbook of rheumatology. 12th ed. Philadelphia: Lea & Febiger, 1993:763-9
13. Zvaifler NJ, Firestein GS. Pannus and pannocytes: alternative models of joint destruction in rheumatoid arthritis. Arthritis Rheum 1994;37(6):783-9
14. Greenwald RA, Golub LM, Lavietes B, et al. Tetracyclines inhibit human synovial collagenase in vivo and in vitro. J Rheumatol 1987;14(1):28-32
15. Breedveld FC, Dijkmans BA, Mattie H. Minocycline treatment for rheumatoid arthritis: an open dose finding study. J Rheumatol 1990;17(1):43-6
16. Langevitz P, Bank I, Zemer D, et al. Treatment of resistant rheumatoid arthritis with minocycline: an open study. J Rheumatol 1992;19(10):1502-4
17. Paulus HE. Minocycline treatment of rheumatoid arthritis. (Editorial) Ann Intern Med 1995;122(2):147-8
18. Bluhm GB, Sharp JT, Tilley BC, et al. Radiographic results from the Minocycline in Rheumatoid Arthritis (MIRA) Trial. J Rheumatol 1997;24(7):1295-302
19. Reveille JD, Alarcón GS, Fowler SE, et al, for the MIRA Trial Group. HLA-DRB1 genes and disease severity in rheumatoid arthritis. Arthritis Rheum 1996;39(11):1802-7
20. Harris ED Jr. Rheumatoid arthritis: pathophysiology and implications for therapy. N Engl J Med 1990;322(18):1277-89 [Erratum, N Engl J Med 1990;323(14):996]
21. O'Dell J, Haire C, Palmer W, et al. Minocycline therapy for early rheumatoid arthritis (RA): continued efficacy at three years. (Abstr) Arthritis Rheum 1997;40:S219
22. Knights SE, Leandro MJ, Khamashta MA, et al. Minocycline induced lupus. (Abstr) Arthritis Rheum 1997;40:S107
23. Akin E, Miller LC, Tucker LB, et al. Minocycline related lupus-like syndrome: possible association with anti neutrophil cytoplasmic antibodies. (Abstr) Arthritis Rheum 1997;40:S191
24. Elkayam O, Levartovsky D, Brautbar C, et al. Minocycline (MNC) induced immunologic phenomena: clinical, immunological and genetic characteristics of 6 patients. (Abstr) Arthritis Rheum 1997;40:S267
25. Alarcón GS. Minocycline for the treatment of rheumatoid arthritis. Rheum Dis Clin North Am 1998;24(3):489-99

INFORMATION FOR PHYSICIANS AND PATIENTS

Resources on arthritis

Arthritis Foundation
1330 W Peachtree St
Atlanta, GA 30309
404-872-7100
www.arthritis.org

National Institute of Arthritis and Musculoskeletal and Skin Diseases Information Clearinghouse
National Institutes of Health
1 AMS Circle
Bethesda, MD 20892-3675
301-495-4484
www.nih.gov/niams/healthinfo/

Dr Alarcón is Jane Knight Lowe Professor of Medicine in Rheumatology and associate director, Arthritis and Musculoskeletal Diseases Center, University of Alabama School of Medicine, Birmingham. Correspondence: Graciela S. Alarcón, MD, MPH, Division of Clinical Immunology and Rheumatology, University of Alabama School of Medicine, Birmingham, University Station, 1813 Sixth Ave S, MEB 615, Birmingham, AL 35294. E-mail: graciela.alarcon@ccc.uab.edu.

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