Treatment of rheumatoid arthritis with ornidazole. A randomized, double-blind, placebo-controlled study

Sir, In many previous studies, rheumatoid arthritis (RA) has been found at high frequencies in individuals with periodontitis, and RA resembles periodontitis in many pathological aspects [1, 2]. HLA-DR4 tissue antigens are found at high frequencies both in patients with periodontitis and in those with RA. HLA-DR4 tissue antigens and their subtypes are directly associated with each disease [3, 4]. High levels of oral anaerobic bacterial antibodies and heat-shock proteins have been found in the serum and synovial fluid of RA patients [5, 6]. Ornidazole is a nitroimidazole antiprotozoal drug that also has potent antibacterial activity against anaerobes, including Bacteroides and Clostridium species. This was a 3-month, randomized, double-blind, placebo-controlled study. A total of 160 patients (median age 53 yr, range 19–69, 125 female) with active RA were randomly assigned to receive 1000 mg ornidazole (n = 53), 500 mg ornidazole (n = 55) or placebo (n = 52). Patients enrolled in this study met the American College of Rheumatology (ACR) criteria for the diagnosis of RA. This study was approved by the local ethics committee and was carried out in accordance with the ethical principles of the Declaration of Helsinki. Before entering this study, all patients gave informed consent. The percentage change from baseline to 3 months in the swollen joint count and tender joint count was the primary measure of efficacy. Secondary end-points included pain, quality of life, duration of morning stiffness, erythrocyte sedimentation rate, C-reactive protein level, and physician's and patient's global assessments. The data were also analysed to determine the numbers of patients meeting ACR criteria for 20, 50 and 70% improvement. The values were compared using analysis of variance. The percentages of patients with ACR 20, ACR 50 and ACR 70 responses were compared using the χ2 test. A significantly greater percentage of patients treated with 1000 mg ornidazole met the ACR 20% improvement criteria (i.e. achieved an ACR 20 response) at 3 months compared with patients who received placebo (62.0 vs 32.4%; P<0.001). Greater percentages of patients treated with 1000 mg ornidazole also achieved ACR 50 responses (38.3 vs 10.9%; P<0.001) and ACR 70 responses (19.6 vs 1.2%; P<0.001) compared with patients who received placebo. Ornidazole treatment was also associated with significant reductions in pain and duration of morning stiffness, significant improvement in the quality of life and physician's and patient's global assessments, and significant reductions in disease activity as assessed by objective laboratory measures (erythrocyte sedimentation rate and C-reactive protein level) (Table 1). Ornidazole was well tolerated. There were no dose-limiting toxic effects. The most frequently reported adverse events in the 1000- and 500-mg ornidazole treatment groups (seen in at least 5% of patients, and excluding worsening of RA) were headache (18.9 and 14.5%, respectively), dry mouth (16.7 and 12.3%, respectively) and nausea (13.2 and 9.1%, respectively). Effect of treatment on measures of disease activity at 3 months Values of continuous variables are mean±s.d. aP values were obtained from analysis of variance. b0 is best and 10 worst. c0 = no difficulty, 3 = unable to perform activity. VAS, visual analogue scale; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; HAQ, Health Assessment Questionnaire. Effect of treatment on measures of disease activity at 3 months Values of continuous variables are mean±s.d. aP values were obtained from analysis of variance. b0 is best and 10 worst. c0 = no difficulty, 3 = unable to perform activity. VAS, visual analogue scale; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; HAQ, Health Assessment Questionnaire. The results of this randomized, double-blind trial show the clinical efficacy of ornidazole in patients with active RA. Treatment with ornidazole for 3 months was associated with a reduction in disease activity, as assessed by a number of clinical end-points, biochemical markers of disease and quality of life. Ornidazole produced significant and sustained reductions in disease activity. The few adverse events noted—headache, dry mouth and nausea—were mild and easily managed. Ornidazole, a synthetic nitroimidazole derivative, is used in the treatment of infections caused by periodontopathic bacteria. Porphyromonas gingivalis, Prevotella intermedia, Prevotella melaninogenica and Bacteroides forsythus are Gram-negative anaerobic bacteria and are considered to be directly responsible for the periodontitis (periodontopathic bacteria). P. gingivalis has arginine- and lysine-specific proteinases. The citrullination or deamination of arginine residues in autoantigenic proteins (profilaggrin/filaggrin, fibrinogen/fibrin, keratin and vimentin) creates epitopes that are targeted by rheumatoid autoantibodies [7]. Arginine is the most important of the amino acids associated with autoantigenicity in proteins. RA patients have significantly fewer galactose residues on their IgG Fc compared with age-matched healthy control subjects. A lack of terminal galactose residues early in disease is associated with a worse prognosis [8]. Prevotella melaninogenica, as a saccharolytic bacteria, disintegrates galactose. Consequently, P. melaninogenica causes this condition by binding to the Fc region of the IgG molecule and metabolizing galactose with its enzymes. P. melaninogenica and P. intermedia heat shock proteins of approximately 70 kDa have been found in periodontal disease processes [9]. Hsp 70 antibodies have been detected in the synovial tissue of RA patients, and when the hsp 70 expression is induced with certain stress-stimulating factors, pro-inflammatory cytokines (TNF α, IL-1, IL-6) develop in the RA synovium [10]. Ornidazole treatment in RA is very economical compared with other treatments. It can be concluded from this study that ornidazole is an effective treatment for RA. The above evidence indicates that antibodies formed against oral anaerobic bacteria could be important in the aetiopathogenesis of RA. However, further studies are needed to confirm this. The authors have declared no conflicts of interest.