Treatment of early Rheumatoid Arthritis with minocycline or placebo. Results of a Randomized, double‐blind, placebo‐controlled trial

O'Dell, James Robert; Haire, Claire E.; Palmer, William; Drymalski, Walter; Wees, Steven; Blakely, Kent; Churchill, Melvin; Eckhoff, P. James; Weaver, Arthur L.; Doud, Deborah K.; Erikson, N; Dietz, Fred; Olson, Richard R.; Maloley, Pierre; Klassen, Lynell Warren; Moore, Gerald

doi:10.1002/art.1780400510

Cited by 160 publications

(74 citation statements)

References 41 publications

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“…Recently, randomized doubleblind, placebo-controlled trials have demonstrated the efficacy of minocycline in improving the clinical parameters of RA (106)(107)(108)(109). Importantly, one trial showed long-term benefit of minocycline and a decrease in radiographic progression in a subset of patients who were positive for the HLA shared epitope (HLA-DR4ϩ) (110).…”

Section: Pharmacologic Treatment Of Ramentioning

confidence: 99%

Guidelines for the management of rheumatoid arthritis: 2002 Update

2002

Arthritis & Rheumatism

1,172

176

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Section: Pharmacologic Treatment Of Ramentioning

confidence: 99%

Guidelines for the management of rheumatoid arthritis: 2002 Update

2002

Arthritis & Rheumatism

1,172

176

View full text Add to dashboard Cite

show abstract

“…Minocycline has been found to be therapeutic in multiple diseases whose pathogenesis is significantly T cell driven by modulating cellular activation and function. In rheumatoid arthritis patients, minocycline significantly improved clinical symptoms and increased the frequency of remissions leading to its usage as a disease modifying anti-rheumatic drug (7)(8)(9). Studies using CD4 ϩ T cell clones derived from the synovium of an rheumatoid arthritis patient showed that minocycline decreased activation-induced proliferation and inflammatory cytokine production (10).…”

mentioning

confidence: 99%

Minocycline Suppresses Activation of Nuclear Factor of Activated T Cells 1 (NFAT1) in Human CD4+ T Cells

Szeto¹,

Pomerantz

Graham

et al. 2011

Journal of Biological Chemistry

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Minocycline is a tetracycline family antibiotic that has antiinflammatory and immunomodulatory properties. These properties have shown promise in the treatment of conditions such as rheumatoid arthritis, Huntington disease, and multiple sclerosis. As lymphocyte activation is involved in the pathogenesis of many of these diseases, T cells are postulated to be a primary target in minocycline therapy. Previous studies have demonstrated attenuation of CD4 ؉ T cell activation by minocycline, but a specific mechanism has not been elucidated. In this study, we investigated the effect of minocycline on the activity of three key transcription factors regulating CD4 ؉ T cell activation:NF-B, AP-1 (activator protein 1), and NFAT (nuclear factor of activated T) cells. Our data demonstrate that minocycline selectively impairs NFAT-mediated transcriptional activation, a result of increased phosphorylation and reduced nuclear translocation of the isoform NFAT1. Minocycline increased the activity of the NFAT kinase GSK3 and decreased intracellular Ca 2؉ flux, both of which facilitate NFAT1 phosphorylation. These findings provide a novel mechanism for minocycline induced suppression of CD4 ؉ T cell activation and may better inform the application of minocycline as an immunomodulatory agent.The tetracycline family of antibiotics is known to have multiple biological activities distinct from their antimicrobial function. Over the past two decades, the tetracycline derivative minocycline has demonstrated neuroprotective and immunomodulatory effects in animal models of diseases, including multiple sclerosis and Parkinson and Huntington diseases (1-3). Interest in the mechanism of its neuroprotective abilities has driven extensive research on minocycline-induced effects on inflammatory signaling in monocyte lineage cells, particularly the brain-resident microglia (4 -6). Modulation of T cell activation and function has also been proposed as one of the major mechanisms of action of minocycline.T cell activation contributes to disease pathogenesis by creating an inflammatory environment that leads to cellular damage and death as well as decreased immune function. Minocycline has been found to be therapeutic in multiple diseases whose pathogenesis is significantly T cell driven by modulating cellular activation and function. In rheumatoid arthritis patients, minocycline significantly improved clinical symptoms and increased the frequency of remissions leading to its usage as a disease modifying anti-rheumatic drug (7-9). Studies using CD4 ϩ T cell clones derived from the synovium of an rheumatoid arthritis patient showed that minocycline decreased activation-induced proliferation and inflammatory cytokine production (10). Minocycline has also shown therapeutic effects on T cells in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Minocycline treatment of rodents with experimental autoimmune encephalomyelitis attenuated the severity of encephalitis, decreased T cell transmigration in vitro, and reduced CD4...

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“…Paulus criteria [6])-based definition of improvement, utilizing only a higher threshold of improvement (7,8). With potent new therapies on the horizon for RA, it may be reasonable to "raise the bar" and define RA improvement by more substantial changes in RA core set measures, such as requiring at least 50% or even 70% improvement.…”

mentioning

confidence: 99%

Should imporvement in rheumatoid arthritis clinical trials be defined as fifty percent or seventy percent improvement in core set measures, rather than twenty percent?

Felson

Anderson

Lange

et al. 1998

Arthritis & Rheumatism

150

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Objective To determine whether improvement of more than 20% in core set parameters should be required before patients are characterized as imporved in rheumatoid arthritis (RA) clinical trials. Methods Data from 6 RA trials were reanalysed to evaluate the discriminant validity (ability to differentiate active treatment from control) of 4 proposed definitions of improvement: the current American College of Rheumatology (ACR) definition (a 20% threshold for core set parameters [ACR 20]), a 50% threshold (ACR 50), a 70% threshold (ACR 70), and an ordinal definiton in which a patient could be classified in any of 3 categories (unimproved, ACR 20, or ACR 50). To evaluate the discriminant validity of these 4 definitions of improvement, we characterized each patient in each trial as improved or not, based on each definition, and computed a chi‐square value differentiating the active treatment group from the control group, with the corresponding P value. Results With an increase in the threshold from improvement, the percentage of placebo‐treated patients who were classified as experiencing response dropped dramatically in all trials, as did the percentage of patients receiving active therapy (second‐line drug, combination therapy, tumor necrosis factor p75‐Fc fusion protein. Generally, the drop in active treatment response rates was greater than the drop in placebo response rates, leaving the difference between the 2 groups less at the higher thresholds. Therefore, chi‐square values fell as the threshold for response was raised. The ordinal definition of improvement yielded chi‐square values similar to those obtained using ACR 20 alone. Conclusion Adopting a definition of efficacy in RA trials that requires 50% or 70% improvement in core set parameters would likely compromise statistical power and make it more difficult to distinguish between 2 treatments with different efficacy. ACR 20 should continue to be the primary measure of efficacy in RA trials, with higher thresholds for improvement being determined and reported as secondary efficacy measures.

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Treatment of early Rheumatoid Arthritis with minocycline or placebo. Results of a Randomized, double‐blind, placebo‐controlled trial

Cited by 160 publications

References 41 publications

Guidelines for the management of rheumatoid arthritis: 2002 Update

Guidelines for the management of rheumatoid arthritis: 2002 Update

Minocycline Suppresses Activation of Nuclear Factor of Activated T Cells 1 (NFAT1) in Human CD4+ T Cells

Should imporvement in rheumatoid arthritis clinical trials be defined as fifty percent or seventy percent improvement in core set measures, rather than twenty percent?

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