Antibiotics in the macrolide class, such as clarithromycin, azithromycin, and roxithromycin, developed to treat gram-negative anaerobic bacteria, have been studied extensively for their use in rheumatoid arthritis (RA) for both their antimicrobial and immune-modulatory effects. The following selection of studies describes their mechanism of action and significant success in treating RA in treatment-naive, early seropositive RA, as well as disease-modifying anti-rheumatic drug (DMARD) -resistant, active RA.
Note: Some of these studies were conducted outside of the United States where the macrolide antibiotic, roxithromycin, is not currently available.
Macrolide Hybrid Compounds: Drug Discovery Opportunities in Anti- Infective and Anti-inflammatory Area. Curr Top Med Chem. 2017;17(8):919-940.
Croatian researchers have been working on new hybrid macrolide compounds, combining the antimicrobial effects of the antibiotics with corticosteroid and non-steroidal anti-inflammatory drugs. Reductions of inflammation in various diseases, such as rheumatoid arthritis, inflammatory bowel disease, and asthma, were safer in the hybrid antibiotics than steroidal drugs used alone in in-vivo studies of animal models.
Modulation of immunological responses and amelioration of collagen-induced arthritis by the novel roxithromycin derivative 5-I. Mod Rheumatol. 2015 Jul;25(4):562-70. doi: 10.3109/14397595.2014.983262. Epub 2015 Mar 24.
Japanese researchers created a new synthesized version of a macrolide antibiotic, with less antimicrobial activity to demonstrate the immune-modulatory effects of macrolides both in-vitro and in-vivo in a mouse model of collagen-induced arthritis, which closely resembles rheumatoid arthritis (RA). They concluded that the new synthetic macrolide may be useful as a therapeutic agent for human RA as a result of its ability to inhibit expression of Th1, Th17, proinflammatory cytokines, and also to inhibit the migration of activated T-cells.
Clarithromycin in rheumatoid arthritis: the addition to methotrexate and low-dose methylprednisolone induces a significant additive value – a 24-month single-blind pilot study. Rheumatology International; , Volume 33, Issue 11, pp 2833-2838.
In this 2-year study, Italian researchers sought to compare the efficacy of the addition of clarithromycin to methotrexate (MTX) and methylprednisolone (MP) in a group of 32 consecutively randomized rheumatoid arthritis (RA) patients with active disease. With the addition of a 4-week cycle of clarithromycin to one patient group receiving MTX and MP, remissions were induced in the majority of patients within 4 weeks, with an ACR70 (70% improvement in clinical disease parameters) response rate. The same result took 3 months (3 times as long) for patients only receiving MTX and MP. This study indicates that the results of using the antibiotic, clarithromycin, as an adjunct to conventional medications, is superior than conventionally-used DMARDs and MP alone.
Antibiotics for the treatment of rheumatoid arthritis. Int J Gen Med. 2013 Dec 27;7:43-7. doi: 10.2147/IJGM.S56957.
A Turkish researcher reviews the use and effects of antibiotic therapy for rheumatoid arthritis (RA) and its possible infectious causes from as early as the 1930s with the use of sulphasalzine and, followed soon after, with tetracyclines, through to the present day and the double-blind randomized, placebo-controlled studies for the therapeutic value of other antibiotics, such as levofloxacin and macrolide antibiotics (clarithromycin and roxithromycin). Described as protein synthesis inhibitors, macrolides work by inhibiting the biosynthesis of gram-negative anaerobic bacterial proteins. In this review of a collection of studies, the most common and less frequent adverse events are also described.
Treatment of rheumatoid arthritis with roxithromycin: a randomized trial. Postgrad Med. 2011 Sep;123(5):220-7. doi: 10.3810/pgm.2011.09.2478.
In this 6-month, randomized, double-blind, placebo-controlled trials of 100 rheumatoid arthritis (RA) patients with active disease, Turkish researchers aimed to evaluate the efficacy of a macrolide antibiotic, roxithromycin (this antibiotic is unavailable in the US), in patients who had not responded to disease-modifying anti-rheumatic drugs (DMARDs). Patients received 300mg roxithromycin to be taken orally, once daily, or an inactive placebo. When the study concluded, improvements in the roxithromycin-treated group far exceeded the placebo group with roxithromycin-treated patients achieving either ACR20, ACR50 and ACR70 improvement response rates. The authors speculate on a microbial cause for RA due to high titer antibody responses to oral anaerobic bacteria found in RA patient serum and synovial fluids, suggesting that roxithromycin’s significant effects in improving the signs and symptoms of RA is due to its antimicrobial activity.
Rheumatoid arthritis is linked to oral bacteria: etiological association. Mod Rheumatol. 2009;19(5):453-6. doi: 10.1007/s10165-009-0194-9. Epub 2009 June 24.
A prolific researcher of infectious causes for rheumatoid arthritis (RA) and its treatment with antibiotic therapy, at the Division of Rheumatology of Nazilli State Hospital, in Nazilli, Turkey, reviewed the evidence of periodontitis and the role of causative organisms that are directly associated with the etiopathogenesis of RA. Additionally, this researcher states that findings of anerobic bacteria, such as, Porphyromonas gingivalis, Tannerella forsythensis, and Prevotella intermedia that have been identified in RA synovial fluid can be treated with antibiotics, such as ornidazole, levofloxacin, and clarithromycin that have been shown to be effective in RA.
Efficacy of roxithromycin in adult patients with rheumatoid arthritis who had not received disease-modifying antirheumatic drugs: a 3-month, randomized, double-blind, placebo-controlled trial. Clin Ther. 2009 Aug;31(8):1754-64. doi: 10.1016/j.clinthera.2009.08.014.
The object of this short, 3-month, randomized, double-blind, placebo-controlled trial of roxithromyin was to evaluate the efficacy by American College of Rheumatology (ACR) and DAS28 score criteria of roxithromycin (300mg once daily) in early, seropositive, treatment-naiive rheumatoid arthritis (RA). As compared to the placebo, non-treated group (15 patients), the roxithromycin group (16 patients) had varying degrees of treatment responses in ACR indices (ACR20, ACR50 and ACR70) by the end of the 3-month study with significant improvements in signs and symptoms and minimal adverse events (2 placebo drop-outs and 1 roxithromycin drop-out due to vomiting). As a relationship between disease activity and serum or joint antibodies to anaerobic bacteria are found in the RA patients, this author called for more study to investigate this association.
Effects of clarithromycin in patients with active rheumatoid arthritis. Curr Med Res Opin. 2007 Mar;23(3):515-22.
The object of this 6-month randomized, double-blind, placebo-controlled study was to evaluate clarithromycin’s (500mg daily) efficacy, safety and tolerability in 81 early, seropositive rheumatoid arthritis (RA) patients using the American College of Rheumatology (ACR) measure of improvement criteria (ACR20, ACR50 and ACR70 responses). The antibiotic was well tolerated with no dose-limiting toxic effects and results confirmed the effectiveness of clarithromycin for active rheumatoid arthritis against placebo with significant improvements seen in signs and symptoms of RA.
Roxithromycin specifically inhibits development of collagen induced arthritis and production of proinflammatory cytokines by human T cells and macrophages. J Rheumatol. 2005 Sep;32(9):1765-74.
A Japanese study at the University of Tokyo for the use of roxithromycin (RXM) was conducted using mice with collagen-induced arthritis (CIA) to examine its mechanism of action on T-cells and the inflammatory response. Findings were that this macrolide antibiotic inhibited the production of pro-inflammatory cytokines, such as tumor necrosis factor (TNF) and interlukin-6 (IL-6) by T-cells and macrophages. As a result, treated mice with CIA demonstrated reductions in disease severity and serum IL-6, as well as inhibition of leukocyte migration into swollen joints that cause damage to bones and cartilage. The authors concluded that RXM may be useful for inflammatory diseases, such as rheumatoid arthritis and Crohn’s disease.
Macrolide antibiotics: current and future uses. Expert Opin Pharmacother. 2004 Mar;5(3):541-50.
A French reviewer examines the scientific literature to comment on the use of macrolide antibiotics for inflammatory diseases of unknown etiology and discusses whether their mode of action is primarily to eliminate an unidentified infectious pathogen causing chronic inflammation, or if macrolides have immune-modulatory properties that account for their value in inflammatory response reduction.
Clarithromycin in rheumatoid arthritis patients not responsive to disease-modifying antirheumatic drugs: an open, uncontrolled pilot study. Clin Exp Rheumatol. 2002 May-Jun;20(3):373-8
A small, 6-month, open, uncontrolled pilot study of 18 patients was conducted by Italian researchers after discovering that 2 rheumatoid arthritis (RA) patients with active disease experienced improvements after being treated with clarithromycin for the stomach infection, Helicobacter pylori. All 18 patients in the study had previously been taking disease-modifying anti-rheumatic drugs (DMARDs), but had ceased their use due to lack of efficacy or severe side-effects at least one month prior to study commencement. Clarithromycin was administered 500mg twice daily for 10 days, followed by 250mg twice daily for maintenance during the remainder of the study. The authors concluded that patients who are not responsive or unable to tolerate DMARDs may receive benefit from clarithromycin therapy, but due to the small study size, no definitive conclusions regarding efficacy could be made.
Anti-inflammatory effects of macrolide antibiotics. Eur J Pharmacol. 2001 Oct 19;429(1-3):209-29.
Croatian researchers discuss the immune-modulatory effects of macrolide antibiotics, including an array of inflammatory mediators and processes, and their effects on leucocyte and neutrophil inhibition. They speculate on the use of macrolide antibiotics, which may provide opportunities for a new therapeutic approach to inflammatory diseases.
Inhibitory effect of clarithromycin on costimulatory molecule expression and cytokine production by synovial fibroblast-like cells. Clin Exp Immunol. 1996 Jun;104(3):501-8.
Japanese researchers at the University of Nagasaki School of Medicine conducted in-vitro studies to determine whether clarithromycin had an immune-modulatory effect on synovial fibroblast-like cells, using synovial tissue harvested from the joints of rheumatoid arthritis and osteoarthritic patients. They were able to conclude that clarithromycin had significant immune-suppressive effects on these joint tissue samples, “… inhibiting costimulatory molecule expression, cytokine production and antigen-specific T cell proliferation induced by synoviocytes.”