Rapid and Sustained Effect of Ozone Major Autohemotherapy for Raynaud and Hand Edema
in Systemic Sclerosis Patient: A Case Report

Felice Galluccio^1,2
1. Rheumatology & Rehabilitation, Fisiotech Lab Studio, Firenze, ITA 

2. Pain Medicine, Morphological Madrid Research Center (MoMaRC), Madrid, ESP

Abstract
Systemic sclerosis (SSc) is a complex disease characterized by vascular injury with endothelial cell and
platelet activation, immune dysregulation with inflammatory cytokines and fibroblast activation. The
Raynaud phenomenon and puffy hands and fingers are common early manifestations of the disease that
have a negative impact on patients' quality of life. Vasodilators such as calcium channel blockers, PDE5
inhibitors, and prostacyclin analogs are recommended treatments, but they often have side effects and are
not always effective. Ozone is an oxygen donor, an immunomodulator, an inducer of antioxidant enzymes
and the endothelial nitric oxide synthase, a metabolic booster, and a stem cell activator. I report the case of
a scleroderma patient treated effectively with autohemotherapy with ozone and a clear reduction of
Raynaud's episodes and resolution of the edema of the hands. Furthermore, the capillaroscopic evaluation
showed a rapid modification of the microcirculation which remained unchanged for months. Ozone therapy
is effective to treat the Raynaud phenomenon and hand edema and should be considered, at least, as a
complementary therapy to the standard of care, especially in patients who are unresponsive or with frequent
adverse drug reactions. Further studies will be needed to confirm the efficacy of ozone therapy in
scleroderma vasculopathy.

Introduction
The pathogenesis of systemic sclerosis (SSc) is a complex ensemble of endothelial cell injury, platelet
activation, immune dysregulation and fibroblast activation [1]. Endothelial cell injury in microvessels and
small and medium arteries may be triggered by vasculotropic viruses, inflammatory cytokines, granzymes,
autoantibodies or elevated levels of reactive oxygen species due to oxidative stress [2]. Vascular injury leads
to structural changes, loss of capillaries and vessel remodeling as well documented by nailfold
videocapillaroscopy (NVC), a non-invasive, low-cost, and rapid examination method to detect and analyze
microvascular morphology [3].
Raynaud's phenomenon is characterized by excessive and abnormal narrowing of blood vessels (vasospasm)
in the presence of triggering stimuli (temperature changes, intense emotions), altering the blood flow in the
peripheral areas of, such as the fingers, ear ad nose. In severe cases, reduced circulation in the fingers can
become chronic and lead to persistent digital ischemia, digital ulcer and gangrene [4,5].
Ozone is a highly water-soluble inorganic molecule composed of three oxygen molecules (O3). Due to the
nature of its mesomeric state, is a very unstable and reactive oxidant gas, but its use in therapeutic range
concentrations improves the endogenous antioxidant regeneration, the release of growth factors like TGF-β,
INF-γ, VEGF and FGF, and the expression of some nuclear factors (NRF-2, HIFα, NFKβ and caspase), and is
generally used in medicine for its antiseptic, pain-relieving, vasodilation of the microcirculation, regulation
of oxygen metabolism and immunomodulatory effects [6-8]. Here, I present a case of SSc with puffy fingers
and recalcitrant RP successfully treated with autohemotherapy with ozone.

Case Presentation
A 33-year-old woman diagnosed with SSc came to my attention for a puffy hand and multiple daily Raynaud
attacks, that were of increasing duration and slow resolution, severely limiting daily activities and work
abilities.
At the time of the first evaluation, the patient presented with nonpitting edema of the hand, and no history
of digital ulcers or hyperkeratosis. Hand function was preserved but painful in fist closing. Blood tests
showed ANA 1: 640 AC-29 pattern with positive anti-Scl70 and anti-Th/To. All the investigations for organ
involvement were normal. NVC reveals a scleroderma pattern active (Figures 1A, 1B).

The patient was not taking any vasoactive or immunosuppressive drug. The patient was treated only with ozone therapy with major autohemotherapy (30 μg/mL 100mL; total ozone dose per session: 3,000 μg) weekly for one month, reporting a rapid and marked clinical benefit, with a reduction of the hand edema (Figures 2A-2D) and of pain, improved hand function.

The patient experiences a marked reduction in the number of Raynaud's attacks which, when present,resolved spontaneously in a few minutes and which does not limit her even to voluntary direct cold exposure, like handling snow (Figure 3A).

Since the patient was not taking any other treatment that could affect the evaluation, I decided to perform
another capillaroscopy, also finding a marked improvement in capillaroscopic pattern (Figures 1C, 1D). The
patient had no adverse reactions or complications from the treatment.
Ozone therapy was suspended until the following winter, where at follow-up examination the NVC remained
unchanged, the Raynaud's episodes remained short-lived and of low intensity, and the patient led an active
and sporty life. The disease did not evolve, no organ involvement, and antibody panels showed a reduction
in antibody titer (1: 320 AC-29 pattern, Scl70 positive and Th/To negative).
The patient underwent a further autohemotherapy with ozone, replicating the same previous results, being
able to expose her hand directly to the cold without complications or pain (Figure 3B). At present time, the
patient is still not taking any medications.

Discussion
Ozone is an oxygen donor, an immunomodulator, an inducer of antioxidant enzymes and the endothelial
nitric oxide synthase, a metabolic booster, and a stem cell activator, resulting in neovascularization and
tissue reconstruction [6]. In fact, the SSc vasculopathy is mediated by molecules that mainly regulate cell
apoptosis, proliferation and vasoconstriction including an increase in endothelin production, reduction in
prostacyclin release and reduced production of nitric oxide synthase [5]. Furthermore, due to defective
angiogenesis and vasculogenesis, the loss of capillaries is not compensated [5].
All these features seem ideal for a potential therapeutic agent for scleroderma vasculopathy, although it is
not an “easily manageable agent,” and it requires specific knowledge and training. To the best of my
knowledge, this is the first evidence that ozone autohemotherapy could significantly and rapidly modify the
microcirculation of patients with scleroderma, especially in the early stages, reducing digital edema and RP
attacks, which results in less pain and recovery of hand function. The improvement of the microcirculation
induced by ozone therapy could finally lead to a reduced incidence of digital ulcers or at least to their faster
healing, as previously reported [9,10].
EULAR recommends nifedipine (or other calcium channel blocker) to be used as first-line therapy for RP and
sildenafil (or other PDE-5 inhibitors like tadalafil or vardenafil) in patients with SSc with severe RP and/or
those who do not satisfactorily respond to calcium channel blockers and intravenous iloprost when both oral
medications have failed. As an alternative, EULAR recommends fluoxetine, a selective serotonin reuptake
inhibitor and antidepressant, in patients who cannot tolerate or do not respond to vasodilators [11].
Side effects of these drugs are common and include hypotension, dizziness, flushing, dependent edema and
headaches for calcium channel blockers [11], vasomotor reactions, myalgias, allergic reaction, chest pain,
dyspepsia, nasal stuffiness, visual abnormalities for PDE5 inhibitors [11], apathy, lethargy, impaired

concentration, diarrhea and/or nausea, sexual dysfunction, and antidepressant discontinuation syndrome
for fluoxetine [11]. On the contrary, if performed correctly, especially with the latest generation and high
precision ozone generators as recommended by the main guidelines [12], ozone therapy has a high safety
profile and a very low incidence of side effects [13] and deserves to be properly studied for the treatment of
this disease [14].

Conclusions
In conclusion, autohemotherapy with ozone has been shown to modify not only the clinical course of RP
secondary to SSc but also to modify significantly and rapidly the function and architecture of the
microcirculation, as demonstrated by videocapillaroscopy, and this result persists unchanged for months,
despite the suspension of treatment.
I believe that ozone therapy should be considered at least a complementary therapy to the standard of care,
especially in patients who are unresponsive or with frequent adverse drug reactions. Further studies will be
needed to clarify the underline mechanism of efficacy and confirm this results in scleroderma vasculopathy.
Additional Information

Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In
compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services
info: All authors have declared that no financial support was received from any organization for the
submitted work. Financial relationships: All authors have declared that they have no financial
relationships at present or within the previous three years with any organizations that might have an
interest in the submitted work. Other relationships: All authors have declared that there are no other
relationships or activities that could appear to have influenced the submitted work.
Acknowledgements
Special thanks go to the patient who granted me the opportunity to constantly observe the effect of the
treatment and who kindly authorized this publication. I thank Prof. Tolga Ergonenc, of the Sakarya
Education and Research Hospital in Turkey, for introducing me to ozone therapy, and my colleague Marco
Capassoni, with whom I share the research and study on ozone therapy in rheumatic diseases.

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Source: Galluccio F (November 23, 2022) Rapid and Sustained Effect of Ozone Major Autohemotherapy for Raynaud and Hand Edema in Systemic Sclerosis Patient: A Case Report. Cureus 14(11): e31831. DOI 10.7759/cureus.31831