Effect of Ozone Therapy for the Treatment of Digital Ulcer in Patients With SSc
Condition: Systemic Sclerosis
MeSH terms: Scleroderma, Systemic; Scleroderma, Diffuse
Study type: Interventional

Summary: 
      Functionality in patients with SSc? Systemic Sclerosis (SSc) is a chronic connective tissue
      disease characterized by microvascular involvement, immunological dysfunction, extracellular
      matrix deposition in the skin and internal organ involvement. Vascular disease has an
      important role in the pathogenesis of SSc. Especially as a result of involvement of
      micro-vessel and digital arteries, digital ulcer (DU) formation may be seen. DUs are
      responsible for pain, poor quality of life, impairment of life activities and morbidity in
      patients with SSc. , they are correlated to disease severity and outcome. Approximately half
      of SSc patients have DU during the course of the disease. Recurrent DU is observed in 10% of
      the patients. In 75% of these patients, DU occurs 5 years after diagnosis. Patients with
      anti-SCL 70+ develop DU 5 years earlier than those with anti-centromere positive. The
      development of DU may take a long time to heal if there is underlying calcinosis. In a study,
      it was seen that the recovery of DU was 93.6 days if there is underlying calcinosis, and 76.2
      days if not. DUs can be infected and thus complicated by osteomyelitis. In a retrospective
      study, it was reported that 42% of infected DUs were associated with osteomyelitis. DU
      management is a great challenge for the clinician and requires a multidisciplinary approach.
      Ozone has a place in medical use since the 19th century, as it is an oxidant and
      disinfectant. In recent studies, it has been reported to be antiviral and bactericidal.
      Therefore, it has indications such as coronary artery disease, chronic hepatitis and chronic
      low back pain. It has also been shown to have a positive role in trophic ulcer, ischemic
      ulcer and diabetic ulcer healing. The mechanism by which ozone therapy provides wound healing
      is not fully understood. In addition, it improves microcirculation in the capillary vessels
      by improving flexibility and stability of the cell membrane and limiting the aggregation and
      adhesion of platelets.

      In the literature, it was stated in a study that ozone therapy was effective for the
      treatment of DU in SSc patients. In our study, we aimed to investigate the effect of ozone
      therapy on patients who are resistant to medical treatment and who have impaired quality of
      life for a long time.
    

Detailed description: 
      Material-Method 34 SSc patients who were followed up in Pamukkale University Rheumatology due
      to DU are going to be included in the study. SSc is diagnosed and based on the American
      College of Rheumatology/ European League Against Rheumatism (ACR/EULAR) Criteria for the
      classification of SSc. Skin thickness will be evaluated with the Modified Rodnan Score.

      DUs will be graded according to a scale developed by Amanzi et al. In 2010. Written informed
      consents were obtained from all patients before entry into the study, according to the
      Declaration of Helsinki and guidelines of the local ethics committee. The study was approved
      by Pamukkale University ethics committee. Among the patients included in the study, those
      with gangrenous ulcers, calcinosis-free ulcers, traumatic ulcers, vasculitis, active
      osteomyelitis, hyperthyroidism, pregnancy, and allergies to ozone therapy will be excluded
      from the study.

      Baseline evaluation The demographic profile of SSc patients, therapy, scleroderma type, the
      onset of reynoud phenomenon (RF) RF disease duration, RFI time with the number of daily
      attacks, active and inactive digital ulcers count, ulcer size, pain, number of pitting,
      laboratory findings, and functional scales will recorded. Antinuclear antibodies (ANA),
      anti-centromere antibodies (ACA) and anti-topoisomerase antibodies (Scl70) will be studied
      from laboratory findings. An indirect immunofluorescent assay, for semi quantitative
      determination of anti-nuclear IgG antibodies (ANA) in patients' serum NOVA LITE™ IFA HEp-2
      ANA Complete Kit was used. Antibodies to extractable nuclear antigens ACA and Scl70 are going
      to be determined by a commercial clinical enzyme linked immunosorbent assay (ELISA).

      Functional parameters such as health assessment questionnaire (HAQ), visual analogue scale
      (VAS) and Modified Hand Mobility in Scleroderma Test (HAMISm) will be evaluated before
      treatment and on the 30th day.

      Interventıon Group The treatment or clinical status of the SSc patients followed up with DU
      was reached by a blinded health professional by phone. Those who wanted to participate
      actively in the study formed the ozone group, but those who did not want to participate due
      to the pandemic constituted the control group.

      Ozone Group The treatment session of oxygen-ozone was 80 mg/mL ozone (total volume: 60-100
      mL) in a special bag using the ozone generator device (Humazon Promedic, German).

      Treatment group Similar demographic results and treatment protocols area with treatment group
      consisted of SSc patients.

      Outcomes Primary outcomes Ulcer healing was our primary outcome, which was assessed depending
      on Zhang andcolleagues ulcers grading where they graded ulcers into four levels, Grade 0 (no
      change), Grade 1 (wound size decreased less than ½); Grade 2 (wound size decreased more than
      ½) and Grade 3 (wound healing) (31). Ozone treatment were considered efficient if patients
      reached grade 1 to 3.

      Secondary outcomes For our secondary outcomes both group were subjected to the following
      after two weeks and four weeks of intervention: they were reassessed for number of Raynaud's
      attacks/day, duration of Raynaud's attack, ulcer size in mm, ulcer pain was assessed by VAS
      and functional status evaluated by HAQ and HAMISm.
    

Intervention name(s): ozone therapy
Intervention type(s): Other
Intervention description(s): The treatment session of oxygen-ozone was 80 mg/mL ozone (total volume: 60-100 mL) in a special bag using the ozone generator device (Humazon Promedic, German) five times a week for the first week.The treatment session of oxygen-ozone was 40 mg/mL ozone (total volume: 60-100 mL) in a special bag using the ozone generator device (Humazon Promedic, German) twice a week after first week.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: randomised-controlled trial
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment