Rectal Ozone Added to Methotrexate in Rheumatoid Arthritis: A 60-Patient Randomised Study (2016)

Background

Rheumatoid arthritis is an autoimmune condition in which persistent inflammation damages the joints. Methotrexate is the standard first-line medicine. Oxidative stress - an excess of reactive oxygen molecules over the body's antioxidant defences - is known to be raised in rheumatoid arthritis and to feed the inflammation.

The research group behind this study, led by Professor Olga Sonia León Fernández at the University of Havana with Dr Renate Viebahn-Hänsler in Germany, had previously shown in rats with experimentally induced arthritis that medical ozone reduced inflammation, lowered the inflammatory messengers IL-1 beta and TNF-alpha, and reduced oxidative stress. This study asked whether the same would hold in patients.

Study design

Sixty people with rheumatoid arthritis were randomly divided into two groups of 30. One group received methotrexate with folic acid and ibuprofen. The other received exactly the same, plus medical ozone given as a gas by rectal insufflation. Treatment ran for 20 days.

Before and after, the researchers recorded the Disease Activity Score 28 (DAS28, the standard joint-count measure), the Health Assessment Questionnaire Disability Index (HAQ-DI), levels of anti-CCP antibodies (a blood marker specific to rheumatoid arthritis), acute-phase reactants (general blood markers of inflammation), and a panel of biochemical markers of oxidative stress, including glutathione.

This was a supervised clinical protocol delivered in a research setting, with ozone used alongside - not instead of - each person's prescribed medicine. It is a description of what was studied, not a set of instructions.

Findings

In the group that added ozone, disease activity fell, and the acute-phase inflammatory markers followed the same pattern. In the methotrexate-only group these measures showed a tendency to fall but did not change significantly over the 20 days.

Anti-CCP antibody levels fell in the ozone group. The antioxidant system strengthened and markers of oxidative damage decreased. None of these changed in the methotrexate-only group.

After treatment with methotrexate plus ozone, glutathione levels correlated with all of the clinical measures - the better the antioxidant status, the better the clinical picture.

No side effects were observed.

The full paper is behind a paywall, so we have reported what the published abstract states and have not reproduced score changes or p values.

What the authors concluded

The authors conclude that ozone increased the clinical response to methotrexate, probably because the two share therapeutic targets, and that medical ozone is capable of being a complementary therapy in the treatment of rheumatoid arthritis.

Limitations of this study

Twenty days is a short period in a lifelong condition. Methotrexate typically takes several weeks to reach its full effect, which may explain why the comparison group had shown only a tendency to improve by day 20. The abstract reports no follow-up after treatment ended, so it is not known how long the difference lasted.

The abstract does not mention a placebo or sham procedure, or blinding of patients or assessors. People who know they are receiving an extra treatment often report feeling better, and measures such as DAS28 and HAQ-DI include patient-reported elements. The blood markers are less open to this effect.

It was a single-centre study of 60 people, and the research group has a long-standing interest in ozone therapy. It has not, to our knowledge, been independently replicated.

Rheumatoid arthritis needs ongoing care from a rheumatologist, and prescribed medicines should never be stopped or changed without medical advice. Anyone considering ozone therapy alongside their treatment should discuss it with their own doctor.

Related reading

How Ozone Therapy Works: The Science in Plain Words - how a dose given in the bowel can switch on antioxidant defences throughout the body.

The Low-Dose Ozone Concept and Its Basic Biochemical Mechanisms of Action - the same authors' 2021 review, which discusses this trial.

León Fernández OS, Viebahn-Haensler R, López Cabreja G, Serrano Espinosa I, Hernández Matos Y, Delgado Roche L, Tamargo Santos B, Takon Oru G, Polo Vega JC. Medical ozone increases methotrexate clinical response and improves cellular redox balance in patients with rheumatoid arthritis. European Journal of Pharmacology. 2016;789:313-318. doi:10.1016/j.ejphar.2016.07.031