Tetracyclines (Minocycline, Doxycycline, Tetracycline)

The following research is a sampling of the early open trials that were conducted to test the safety and efficacy of minocycline as a therapeutic agent for rheumatoid arthritis (RA) and the subsequent calls that were made for controlled trials. In addition to the controlled trials that followed, commentaries, analyses, and reviews by experts at prestigious medical centers around the world are also included here.

This is an impressive archive of research for the use of tetracycline antibiotics to treat RA. However, it is pertinent to note that antibiotic therapy is a slow therapy and that study time-frames may be limited in this context. Additionally, in order to reduce the variables in study parameters that can complicate results, a standard medication dose is commonly selected and researchers will also often design patient cohorts with recently diagnosed, mild disease (or other similar characteristics, such as, age, race, or gender). This shouldn’t be perceived as an indication of whether or not minocycline will work for patients of longer disease duration or more severe disease or that there is a one-size-fits-all dose. In Dr. Brown’s 5-decades of clinical experience as a practicing rheumatologist and the many thousands of patients he treated, he determined that antibiotic therapy could also provide significant benefit for the sickest of patients, although damage already incurred by the disease could not be reversed. Indeed, many patients, hearing of Dr. Brown’s successes, sought out his clinic when all other treatment options had failed, so he frequently encountered severe, long-standing rheumatic patients seeking relief for their suffering, and many would be admitted to his hospital clinic for initial assessment and treatment that was carefully titrated on an individualized basis.

Reconsidering the Use of Minocycline in the Preliminary Treatment Regime of Rheumatoid Arthritis. Heydari-Kamjani M, Demory Beckler M, Kesselman M M (August 08, 2019) Cureus 11(8): e5351. doi:10.7759/cureus.5351

Researchers at the College of Osteopathic Medicine, Nova Southeastern University, in Fort Lauderdale, Florida, are encouraging rheumatologists to take a second look at the use of minocycline, long-regarded as controversial, stating that it may be a valuable first-line disease-modifying anti-rheumatic drug (DMARD) in the treatment of early RA. They point to microbiome dysbiosis, due to chronic mucosal infections – oral, pulmonary, and gut – as being the gateway that provides the inflammatory terrain necessary to trigger the production of auto-antibodies, and, thus, the breaking of self-tolerance. Describing the numerous and well-recognized disease-modifying properties and anti-microbial effects of tetracyclines, as well as numerous recent studies pointing to microbiome disturbances as a root cause of RA, these researchers recommend that minocycline, which is largely well-tolerated with minimal side-effects, be used as a first-line therapeutic agent to limit pathogenic microbes at treatment onset.

RBF Commentary: The recommendation by these authors, published 30 years after the passing of Dr. Thomas McPherson Brown, is in alignment with his decades of clinical research and practice in the field of rheumatology, identifying chronic infections as both etiologic and pathogenic in RA (and other rheumatic diseases). A major difference, however is that Dr. Brown recognized that it was the chronic and persistent nature of causative pathogens as continuing to drive the bacterial allergy state and that antibiotics should be tailored to the individual patient’s pathogen load until remission in both labs and symptoms are achieved. Early intervention is important to help prevent tissue damage, but Brown’s approach was with a long-term view, not exclusively as an early intervention. Also that early worsening as a result of the Jarish-Herxheimer (or “herx”) effect is a potent clinical sign that the treatment is reaching its intended target, which is not mentioned by these authors.

“If mycoplasmas were difficult to isolate, in theory they would be even more difficult to eradicate, since they were either intercellular or under a great deal of inflammatory tissue. Because of that difficulty, I had no hesitancy about relentlessly pursuing the treatment with Aureomycin. If one were to think of rheumatoid arthritis as an ordinary infection, common sense would say to quit treatment if the patient didn’t become well within a few days. But if the disease were viewed instead as a bacterial allergy, common sense would say to persist. That recognition of the true nature of the disease was an important turning point in understanding how it could eventually be subdued.”

— The New Arthritis Breakthrough: The Only Medical Therapy Clinically Proven to Produce Long-term Improvement and Remission of RA, Lupus, Juvenile RS, Fibromyalgia, … & Other Inflammatory Forms of Arthritis by Henry Scammell

Minocycline and doxycycline therapy in community patients with rheumatoid arthritis: prescribing patterns, patient-level determinants of use, and patient-reported side effects. Arthritis Res Ther. 2011;13(5):R168.

Between 1998 to 2009, the University of Nebraska Medical Center conducted an observational, long-term study of 15,716 rheumatoid arthritis (RA) patients to analyze the prescribing patterns of minocycline or doxycycline by rheumatologists, the patient-level factors that determined their use, and the side-effects reported by patients. Although these study authors confirm that minocycline and doxycycline are well-tolerated, it was concluded that rheumatologists do not view minocycline or doxycycline as first line disease-modifying anti-rheumatic drugs (DMARDs). Instead, they are used more often in patients with long-standing disease that is refractory to other treatments.

RBF Commentary: The American College of Rheumatology (ACR) describes minocycline as a DMARD for use in mild RA, but the results of this study indicate that minocycline or doxycycline are prescribed more often as a last-line drug for patients that are refractory to other treatments. Both the ACR Fact Sheet and the results of this observational study indicate, therefore, that these DMARDs are useful not just for treating mild RA but also for long-standing, progressively severe disease. 

Tetracycline Antibiotics for Treating Rheumatoid Arthritis: A Systematic Review and Meta-Analysis. Arthritis Rheum 2009;60 Suppl 10 :406 DOI: 10.1002/art.25489.

A British reviewer at the the 2009 ACR/ARHP Annual Scientific Meeting in Philadelphia, in the fall of 2009, presented the results of a comprehensive meta-analysis of research databases from the 1940s to the present day, which was to assess the effectiveness of tetracycline antibiotics for rheumatoid arthritis (RA). He reported that tetracyclines help “… to modify the inflammatory process in various ways unrelated to their antimicrobial activities. These include effects on matrix metalloproteinases, Nitric oxide, phospholipase A2, inflammatory cytokines, immunomodulatory and anti-oxidant effect, as well as effects on angiogenesis, apoptosis, MAP kinases, TGF beta and poly (ADP-ribose) polymerase-1.” In concluding, the reviewer stated that tetracyclines, “… may be potentially effective and reasonably safe in RA.”

Tetracyclines: Nonantibiotic properties and their clinical implications. J Am Acad Dermatol. 2006 Feb;54(2):258-65.

A comprehensive overview of the non-antibiotics properties of tetracycline antibiotics and their numerous beneficial applications, including their success in small and large-scale clinical trials for rheumatic diseases, like rheumatoid arthritis and scleroderma.

Treatment of early seropositive rheumatoid arthritis: Doxycycline plus methotrexate versus methotrexate alone. Arthritis Rheum. 2006 Feb;54(2):621-7. University of Nebraska Medical Center, Omaha.

In a 2-year, placebo-controlled clinical study of 66 seropositive, treatment-naïve rheumatoid arthritis (RA) patients,  patients were divided into 3 groups. The first receiving 100mg doxycycline twice a day in addition to methotrexate,  the second group was administered low dose doxycycline (20mg) twice a day in addition to methotrexate, and the third group was given a placebo in place of doxycycline and methotrexate. Methotrexate doses were titrated every 3 months during the study to help patients attain a 50% (ACR50) positive response by the end of the study. Conclusions drawn from this study were that patients treated with methotrexate and doxycycline had a superior response, meeting the goal of a 50% improvement, compared to those taking methotrexate only. The authors report a similar response between the high and low dose doxycycline groups, which they suggest may be due to its anti-metalloproteinase (ant-MMP) effects being more important than the antimicrobial effects.

RBF Commentary: Dr. Brown’s approach to treating RA with low, intermittent doses of a tetracycline antibiotic was formulated as a result of years of clinical experience in order to offset the Jarisch-Herxheimer response, but also to prevent bacterial hypersensitivity from occurring and the production of excessive circulation of immune-complexes (bound, deleterious antibody-antigen complexes). Dr. Brown also rationalized that mycoplasmas were slow-growing and slow-replicating organisms that didn’t require high doses to achieve a beneficial result. In the above study and in accordance with Brown’s treatment approach, it must be considered that the DMARD effects of methotrexate masked the herxheimer reaction and also limited the bacteriostatic effects of the doxycycline so that the antibiotic worked more as a DMARD and less for its anti-microbial effects. 

Should tetracycline treatment be used more extensively for rheumatoid arthritis? Metaanalysis demonstrates clinical benefit with reduction in disease activity. J Rheumatol.2003 Oct:30(10):2112-22.

A meta-analysis of research databases, conducted by the Division of Rheumatology at the Toronto Western Hospital, in Canada, in order to determine if the effectiveness of tetracycline was greater than that of conventional treatment or placebo, using the criteria for reduction of disease activity as defined by the American College of Rheumatology (ACR). The results of this analysis were that tetracyclines, especially minocycline, provided patients with significant clinical improvement in disease activity with comparatively low risk of side-effects, although the reviewers discussed the lack of obtainable detailed analysis of individual side-effects. They called for further research to compare tetracyclines to newer disease-modifying drugs to assess comparative safety, efficacy, and cost-effectiveness.

Treatment of early seropositive rheumatoid arthritis: a two-year, double-blind comparison of minocycline and hydroxychloroquine.  Arthritis & Rheumatism 2001 Oct;44(10):2235-41

A 2-year double-blind, placebo-controlled study of 60 treatment-naïve patients at the University of Nebraska Medical Center was conducted to compare the effectiveness of minocycline (100mg twice daily) with hydroxychloroquinine (200mg twice daily) in early seropositive rheumatoid arthritis (RA). The conclusions reached by these researchers were that minocycline is an effective DMARD for early, seropositive RA and that the minocycline-treated group did not require as much prednisone, were more likely to be able to stop prednisone and to achieve 50% improvement by American College of Rheumatology criteria (ACR50).

Tetracyclines for the treatment of rheumatoid arthritis. Expert Opin Investig Drugs. 2000 Jul;9(7):1491-8.

A review of the evidence-based science for the use of tetracylines for the treatment of rheumatoid arthritis (RA) was conducted by a physician-researcher at the University of Alabama. This reviewer drew upon two open trials conducted by Dr. Brown and colleagues in the 1980s, as well as from researchers in the subsequent 2 decades (Kloppenburg et al; The Netherlands; the MIRA trial; O’Dell et al).

Benefits and risks of minocycline in rheumatoid arthritis. Rheumatic Disease Unit, Chaim Sheba Medical Center Tel Hashomer, Israel Drug Saf 2000 May; 22(5):405-14

Israeli reviewers examined the results of 3 double-blind placebo-controlled trials for the use of minocycline in rheumatoid arthritis, describing both the clinical successes and the common mild, as well as infrequent, but more serious, side-effects of this treatment. They state that in one 3-year trial follow-up that 50% of seropositive RA patients still taking minocycline were close to or had reached clinical remission. They concluded that patients receiving minocycline, especially with mild, early disease, may experience benefit from the treatment.

Treatment of Seropositive Rheumatoid Arthritis with Minocycline, Four-Year Followup of a Double Blind, Placebo-Controlled Trial. Arth & Rhu, 1999, 42:8, 1691-1695

Researchers at the University of Nebraska Medical Center, ran a double-blind, placebo-controlled study of early, seropositive rheumatoid arthritis (RA) patients. Conclusions drawn were that of those they were able to follow for 4 years after trial commencement, frequent remissions were achieved in patients taking minocycline with early, seropositive RA and DMARD support was less common than compared to those treated with conventional therapy. Although its mechanism of action was not well understood at the time, these researchers reported that minocycline is effective for early RA.

Treatment of DMARDs-Resistant Rheumatoid Arthritis with Minocycline – A Local Experience Among The Chinese. Rheumatol Int. 1998;17(6):245-7.

Taiwanese researchers conducted a study in which DMARD-resistant patients were prescribed minocycline (100mg twice daily) in addition to their previously ineffective DMARDs. Although minocycline’s mechanism of action was poorly understood at the time and the authors speculate that treatment success is attributable to immune-modulating effects, it was concluded that minocycline demonstrated “dramatic” results within one month of treatment and no adverse events were noted.

Treatment of early rheumatoid arthritis with minocycline or placebo: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 1997 May;40(5):842-8.

Researchers at the University of Nebraska conducted a 6-month randomized, double-blind, placebo-controlled trial of minocycline (100mg twice daily), studying 46 rheumatoid arthritis (RA) patients with seropositive RA of less than one year’s duration to determine its safety and effectiveness. By 3 months, 18 of the 23 patients receiving minocycline (not placebo) had reached 50% (ACR50) improvement. Among this group of 18 patients, 15 (65%) of the 23 patients in the RA group receiving minocycline had achieved a 50% improvement (ACR50) by the end of the 6 month trial.

Minocycline for The Treatment of Rheumatoid Arthritis. Rheum Dis Clin North Am. 1998 Aug;24(3):489-99.

Research at the University of Alabama to examine tetracycline and its derivatives, to provide a risk-benefit assessment, as well as a discussion of its place as a therapeutic treatment strategy, was conducted.

Do Minocycline and Other Tetracyclines Have a Place in Rheumatology? Rev Rheum Engl Ed, 1997; 64:7-9, 474-480.

French researchers rationalize the use of minocycline for the treatment of rheumatoid arthritis (RA) based on the successful use of antibiotic therapy for chlamydia-induced reactive arthritides, as well as referencing two controlled studies of minocycline in RA, in which this antibiotic was used as an adjunct to another DMARD or as a single therapy. The authors also examine the possible immune-modulating effects of minocycline on blocking collagenase, the joint destructive enzyme in RA, concluding that in spite of its unknown (at that time) mechanisms of action, sufficient evidence had already been shown for its use as an effective RA treatment.

Tetracycline Prevents Cancellous Bone Loss and Maintains Near-Normal Rates of Bone Formation in Streptozotocin Diabetic Rats. Bone, 1997; Aug. 21:2, 147-153.

An American study of diabetic rats, who are prone to osteopenia and cancellous bone loss, who were treated with minocycline for 26 days, exhibited normal bone formation, preserved growth plate thickness, and prevented cancellous bone loss, as compared to control rats on placebo and minocycline-treated rats without diabetes.

Minocycline in Rheumatoid Arthritis. Isr J Med Sci, 1996, 32, 327-330. Abstract unavailable, but may be purchased or with subscription to the journal in which this study is published.

Minocycline in Rheumatoid Arthritis. Arth & Rheum, 1995, 40:5, 794-796.

Abstract unavailable, but may be purchased or with subscription to the journal in which this study is published.

Minocycline Treatment of Rheumatoid Arthritis. (Editorials) Ann Int Med, 1995, 122:2, 147-148.

Harold E. Paulus, MD, at the University of California, Los Angeles, School of Medicine, reported that upon reviewing a number of successful trials (open trials, as well as, MIRA, Kloppenburg/Netherlands studies) of minocycline as a treatment for rheumatoid arthritis (RA). In addition to the past successes of Dr. Thomas McPherson Brown (in a retrospective cohort study of 98 patients) and an earlier study by Sanchez (1968), these successes were largely discounted due to one study conducted in 1971. In the latter study, a placebo-controlled group of 30 RA patients who were randomly assigned to take either a placebo or one dose of tetracycline (250mg) per day for one year, failed to exhibit any notable benefits from the antibiotic.

RBF Commentary: Tetracycline is the oldest in this class of bacteriostatic antibiotics and, having inferior tissue penetration, Dr. Brown found that higher doses (titrated to patient tolerance) were required to achieve the same results as those seen with either minocycline or doxycycline (see final notes in Dr. Brown documentary).

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