1. bookVolume 8 (2021): Issue 3 (September 2021)
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30 Mar 2018
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access type Open Access

Topical use of ozone effectively alleviates the acute symptoms and quality of life of patients with moderate to severe bullous pemphigoid: a randomized controlled trial

Published Online: 21 Sep 2021
Page range: 233 - 240
Received: 01 Apr 2021
Accepted: 09 Jun 2021
Journal Details
License
Format
Journal
First Published
30 Mar 2018
Publication timeframe
4 times per year
Languages
English
Abstract Objective

To evaluate the adjuvant treatment of acute stage symptoms and quality of life of patients with bullous pemphigoid (BP) with ozone.

Methods

We included 74 patients with moderate and severe BP hospitalized from July 2018 to December 2020. The participants were randomly divided into the control group and the ozone group, with 37 patients in each group (n = 37). The control group used tap water to wash the whole body, and mupirocin ointment was used for the erosions. The ozone group used ozone water to wash the whole body, and the erosion place was coated with ozone oil. The bullous pemphigoid disease area index (BPDAI) score of BP disease was used to observe the clinical symptoms and skin lesions of the two groups before and on day 3, 7, and 14 after treatment. Pruritus and sleep were observed before and on day 3, 7, and 14 after treatment. The Dermatology Life Quality Index (DLQI) was used to observe the quality of life before and after treatment and the adverse reactions were recorded.

Results

The total BPDAI score and erythema score in the ozone group were significantly different from those in the control group on day 3, 7, and 14 after treatment (P < 0.050). The scab drying time and erosion drying time of ozone group were shorter than that of control group (P < 0.001). There were statistically significant differences between the ozone group and the control group in pruritus score and sleep score on day 3, 7, and 14 after treatment (P < 0.001). There was statistically significant difference in skin disease quality of life between the two groups 14 days after treatment (P < 0.001). No significant adverse reactions and complications were observed in both groups.

Conclusions

Ozone external use can rapidly improve the acute stage of edema erythema, erosion, and itching of BP, improve the quality of life of patients, is an effective treatment method, and worthy of clinical promotion.

Keywords

Introduction

Bullous pemphigoid (BP) is an autoimmune skin disease with subepidermal blisters and bullous blisters as the basic skin lesions, which mostly occurs in the elderly over 60 years old.1 Usually, non-specific pruritus lesions were found on limbs and trunk first, followed by typical lesions, namely erythema or normal skin, tension-type blisters, mostly hemispherical bullae, clear blisters, and negative Nissl sign. Pathological examination showed that there were a large number of inflammatory cells infiltrating into the dermis of patients with obvious inflammation, mainly eosinophil (EOS), lymphocytes, and neutrophils. Direct immunofluorescence examination of the skin showed that over 90% of Immunoglobulin G (IgG) and C3 were linearly deposited in the basement membrane zone.2 Skin damage can be limited in distribution, serious when the pan-hair body, after blister rupture form erosion. Patients with severe erythema can be accompanied by moderate to severe itching, seriously affecting the quality of life. BP tends to occur in the elderly, who are often accompanied by some chronic underlying diseases and need to be treated with multiple drugs, with a high mortality rate. According to existing literature, the mortality rate of BP patients in the first year was as high as 6–41%, which was 12.9% in China.3,4,5,6,7 At present, the majority of patients at home and abroad adopt topical glucocorticoids ointment combined with low-dose oral glucocorticoid to treat moderate and severe BP. However, it has been found in clinical practice that for patients with severe erosive exudation and with or without bacterial skin infection, topical glucocorticoid ointment could not achieve satisfactory therapeutic effects.

Discovered in the mid-19th century, ozone is an unstable gas consisting of three oxygen atoms, which is easily soluble in water and easily decomposed.8,9 At present, ozone is widely used in three forms: ozone water, ozone oil, and ozone gas (mainly used for autologous blood therapy). Studies have found that ozone water has anti-infection, anti-inflammatory, accelerated wound healing, and immune regulation effects.10 Surgical and dermatological use of ozone water in the treatment of various inflammatory and infectious diseases and achieved satisfactory results. In addition, a large number of articles in literature have reported in recent years that topical application of ozone water and ozone oil can effectively treat dermatitis, eczema, pruritus, and skin infectious diseases.11 Therefore, we use ozone water combined with ozone oil as adjuvant therapy for moderate and severe BP to evaluate its efficacy and observe adverse reactions, which may have a very important role and practical significance for clinical treatment.

Methods
Participants

The research project has been submitted to the Institutional Ethics Committee, the clinical trial has been filed at the institutional Ethics Committee and has been approved by the institution (2018, K049), and the patients’ informed consent has been obtained. Inclusion criteria: (1) According to the expert consensus of the Dermatologist branch of The Chinese Medical Doctor Association on the diagnosis and treatment of bullous pimples,12 the diagnosis was confirmed by clinical manifestations, histopathology, direct and indirect immunofluorescence test, and antibody detection of BP180 and BP230; (2) Moderate and severe BP patients with bullous pemphigoid disease area index (BPDAI)≤80. Exclusion criteria: (1) Those who are known to be allergic to ozone topical preparations; (2) Other skin diseases that may interfere with the treatment and judgment of the disease; (3) Persons with mental illness or family history; (4) Patients with multiple organ and system infections.

Estimation of sample size: The ozone group and the control group were compared to observe whether the treatment method of the ozone group was superior to the control group. The two groups were allocated in a ratio of 1:1. First, a pre-experiment was conducted to compare the mean values of the two samples according to the test of superiority. Descriptive statistical results were (5.70 ± 2.52) in the ozone group and (8.73 ± 3.18) in the control group. The threshold value of superior efficacy was set as 0.5, and the test level α = 0.05 and the test efficiency 1-β = 0.80 were set for calculation. It was determined that at least 37 effective cases should be completed in each group. Considering the possible case shedding, 80 cases are expected to be selected in this study.

Therapeutic instruments and topical drugs

Ozone therapeutic apparatus (model: HZ-2601B) is a patented technology transformation product of the Dermatology department of the Third Xiangya Hospital of Central South University and produced by Hunan Haozhi Medical Technology Co., LTD, Changsha, Hunan, China. Ozone water concentration is in the range of 3.5–7.5 mg/L. Ozone oil, namely peroxide camellia oil, is produced by Hunan Haozhi Medical Technology Co., LTD, Changsha, Hunan, China (Batch No. 20160601). The other topical drugs used are mupirocin ointment (Generic name: Mopiluoxing Ruangao, 2%: 5G/PCS, Tianjin Shike Pharmaceutical Co., LTD., Tianjin, China) and halometasonum cream (Hong Kong Bright Future Co., LTD., Hong Kong, China).

Treatment methods

In the ozone group, ozone water was used to wash the affected parts and whole body with ozone water for 5–10 min/time, once/day, and the water temperature was 35–37 °C. In the control group, chlorine was used to disinfect the affected areas and the whole body with tap water that met the prescribed standards,13 and no bath products were used, 5–10 min/time, once/day, and the water temperature was 35–37 °C. After shower, patients in both groups were given whole-body skin barrier care as follows.

Treatment of blisters: high-tension blisters with diameter of >1 cm were extracted from the lowest part of the blisters with a disposable sterile syringe. The blisters were retained to cover the wound surface to avoid secondary infection.

Scab skin removal: paraffin oil wet help scab skin soften, fall off.

Topical glucocorticoid cream care: halometasonum cream 15–45 g/day for external use according to skin lesion area.

Skin barrier repair milk (this product was jointly developed by Yuze, Shanghai Jiao Tong University Medical College Affiliated Ruijin Hospital and Shanghai Jahwa United Co., Ltd.): along the direction of hair, smooth penetration into the skin, 50 mL/day body massage until absorption, with external hormone cream interval of >30 min.

External use of mupirocin ointment for the control group; ozone oil was used externally in the ozone group, and then oil gauze was used to cover the erosion surface in both groups. When necessary, sterile gauze was outsourced for fixation.

At the same time, the two groups of patients were systematically treated with a small dose of glucocorticoid prednisone 15–30 mg/day.

Outcome measures

The skin barrier care and treatment of patients in the ozone group and the control group were completed by a group of experienced senior nurses. The index records, BPDAI score, pruritus score, and sleep-affecting score during the treatment process were performed by the other group. The grouping situation was cleared and completed by a uniformly trained nurse with a high degree.

Area index score of BPDAI

The total score of BPDAI (0–372 points) is divided into skin score (0–240 points), mucosal score (0–120 points), and lesion score (0–12 points).14 The higher the score is, the more serious the disease is. Skin score is divided into blisters or broken blisters, erythema, or papules according to the type of skin lesions; each part 0–120 points, respectively, the final score sum. Due to the small number of patients with mucous membrane involvement in this study, statistical analysis of mucous membrane was not performed in this study, so the total SCORE of BPDAI was 252 points by skin score plus damage score.

Itching degree score

1–5 points, 1 point: no pruritus; 2 points: Itch but no scratch; 3 points: Itch and scratch; 4 points: Persistent itch after scratch; 5: Severe itching and difficulty falling asleep.15

Influence of sleep degree Score

Adopt 0–3 points, 0 points: no influence; 1 point: occasional influence; 2 points: frequent influence; 3 points: can’t sleep.15

Dermatology Quality of Life Scale (DLQI)

It is divided into 10 items, and the score for each item is 0–3 points, with the total score ranging from 0 points to 30 points.16 The higher the score, the greater the severity.

Statistical methods

SPSS 23.0 statistical software was used, frequency description was used for counting data, and 2 sample test was used for comparison between groups. The measurement data are first tested for normality. If they conform to the normal distribution and have homogeneity of variance, they are described in the form of XS, and the differences of each group at different time points are compared by repeated measurement analysis of variance. If the data were not normally distributed, non-parametric statistical method was used, and Mann–Whitney U test was used for independent samples between two groups. P < 0.050 was considered statistically significant.

Results
General data of two groups of patients

From July 2018 to December 2020, 80 patients with moderate to severe BP were selected, and 6 patients finally withdrew from the study due to complications and economic and other reasons. Finally, 74 patients were randomly divided into control group and ozone group, with 37 cases in each. Among the 37 patients in ozone group, 18 were male and 19 were female, and the ratio of male to female was 0.95:1; the age of onset ranged from 60 to 89 years, with an average age of (75.50 ± 7.65) years. BPDAI score was (162.16 ± 23.37). Among the 37 patients in the control group, there were 16 males and 21 females, and the ratio of males to females was 0.76:1. The age of onset ranged from 59 to 91 years, with an average age of (74.70 ± 8.18) years. BPDAI score was (164.22 ± 22.12). The results showed that there was no significant difference in gender, age of onset and severity of disease between the two groups (P > 0.050), as shown in Table 1. The flow chart of research object screening is shown in Figure 1.

Comparison of basic data between two groups of patients.

Index Cases Gender Age (years) BPDAI score

Male Female
Ozone group 37 18 19 75.50 ± 7.65 162.16 ± 23.37
Control group 37 16 21 74.70 ± 8.18 164.22 ± 22.12
t2 0.218 −0.352 0.388
P 0.816 0.726 0.699

Note: BPDAI, bullous pemphigoid disease area index.

Figure 1

Research object screening flow chart. BPDAI, bullous pemphigoid disease area index.

Clinical observation index scores of BPDAI before and after treatment in both groups

Total BPDAI score, erythma score, and damage score in the ozone group all had interaction with treatment time (F = 8.217, P = 0.001; F = 11.182, P < 0.001; F = 0.339, P < 0.718), as shown in Table 2. There were statistically significant differences between the ozone group and the control group on the 3rd, 7th, and 14th day after treatment (P < 0.050), and there were statistically significant differences between the ozone group and the control group on the 3rd day after treatment (P < 0.050). With the extension of treatment time, the overall BPDAI score and the scores of all clinical observation indicators showed a downward trend on the whole, with different treatment methods showing different degrees of decline. The overall BPDAI score and erythema score of the ozone treatment group showed a greater decline. Thus, ozone therapy, in the elimination of BP erythema and inflammation, can be considered effective and rapid. There were no statistically significant differences in the blister score between control group and the ozone group in terms of the rate and magnitude of decline.

The test of different effect of BPDAI observation index.

Indicators Variable F P
BPDAI
Time of therapy 813.319 <0.001
Group 16.562 <0.001
Time*Group 8.217 0.001
Vesicle
Time of therapy 558.974 <0.001
Group 0.253 0.616
Time*Group 0.224 0.791
Erythema
Time of therapy 259.040 <0.001
Group 16.944 <0.001
Time*Group 11.182 <0.001
Skin lesion
Time of therapy 366.323 <0.001
Group 0.002 0.960
Time*Group 0.339 0.718

Note: BPDAI, bullous pemphigoid disease area index.

Comparison of scab drying time and erosion desiccating time between the two groups after treatment

The drying and crusting time of the ozone group was 4 days shorter than that of the control group. The drying time of the ozone group was also shorter than that of the control group, which was 6 days. The results are shown in Figure 2. Thus, ozone in the elimination of specialist symptoms for a short time has a good effect.

Figure 2

Different treatment vesicle dry scab, erosion drying time (day) box chart.

Comparison of itch scores between the two groups before and after treatment

There were statistically significant differences between the ozone group and the control group at day 3, 7, and 14 after treatment (P < 0.001). The mean pruritus score 3 days after ozone treatment was 3.41 points, 1.1 points lower than that before treatment, and 24.4% lower on average. The mean pruritus score 7 days after treatment was 2.34 points, 48.1% lower on average, reaching the standard of mild pruritus (able to live and sleep normally). Pruritus score was improved with treatment time. The pruritus score of the ozone treatment group decreased more significantly, as shown in Figure 3. Therefore, ozone therapy is effective and effective in relieving pemphigoid associated pruritus.

Figure 3

Contour plots of itch scores of the two groups at different times.

Comparison of sleep scores between the two groups before and after treatment

Both groups were able to improve sleep, but the effect of ozone group was better than that of the control group, as shown in Figure 4.

Figure 4

Sleep score profiles of the two groups at different times.

Comparison of DLQI scores between the two groups before and after treatment

After treatment, DLQI score of ozone group was (12.79 ± 1.10) points, and that of control group was (17.64 ± 1.15) points. The difference between the two groups was statistically significant (T = 31.556, P < 0.001). The results are shown in Figure 5. It can be seen that ozone therapy is effective in improving the quality of life of patients with BP.

Figure 5

Comparison of DLQI scores before and after different treatments (score) box chart.

Adverse reactions and complications

In the ozone group and the control group, 9 and 11 patients, respectively, showed aggravation of skin lesions and pain when they were just doused with ozone water and tap water. They were not given special treatment and alleviated by themselves 3 days later.

Discussion

Traditionally, BP is considered as a disease in the elderly population, and the average age of onset in different groups around the world is between 66 and 83 years old.17 With the increase of age, the incidence increases exponentially, with 190–312 cases per million people per year.18 In France, the overall estimated incidence is 21.7 cases per year (million people per year) and has increased threefold in the past 15 years.19 There is a lack of research reports on the multi-center, large-sample BP incidence in China, which is estimated in the literature to be about 1–2 cases/(million people/year), and presents an increasing trend year by year.20 A retrospective analysis in South Korea indicated that the mortality rate of BP patients was higher than that of the general population. It was reported that the mortality rate of BP patients in the first year was as high as 6–41%, and 12.9% in China.3,4,5,6,7 The pathogenesis of BP is very complex, indicating the diversity of clinical treatment approaches. Therefore, in addition to the use of glucocorticoid and other immunosuppressive agents to suppress the autoimmune response, the question of how to carry out local treatment to eliminate the impact of complement and other inflammatory cells on local skin lesions is also an important direction of current research related to BP therapy.

To reduce the system using GC and to shorten the course of the disease, the side effects of China headed by professor join anta team a dermatologist to external use GC in combination with small dose of oral GC treatment BP, found that most of the treatment effect is satisfactory, but for some accompanied by widespread erosion, bacterial skin infections, obvious itch, severe lupus patients curative effect is poorer.20 In practical work, Dermatology Department of the First Hospital of Shanxi Medical University also found that external GC was equally effective in treating BP, but for patients with serious erosion surface exudation, with or without bacterial skin infection, external GC could not achieve satisfactory results. Therefore, the rapid and effective reduction of exudation and control of inflammation and infection provide conditions for the subsequent better treatment of external GC.

Ozone water has anti-infection, anti-inflammatory, and immunomodulatory effects.21 Studies have shown that ozone can reduce the release of inflammatory factors such as TNF -, il-1 and IL-4, and promote inflammatory absorption.22 The results of this study showed that on the 3rd, 7th and 14th days after treatment, the erythrocyte score and BPDAI in the ozone group were significantly lower than those in the control group, and the differences were statistically significant. Ozone group damage grade 3 days after treatment compared with the control group showed statistical difference; we think that this may be related to the anti-inflammatory effect of ozone water. Ozone water can quickly penetrate into biological fluid, increase the local tissue oxygen content, release the top ring and Nitric Oxide (NO) vasodilatation factors, such as improving vascular permeability, and is conducive to eliminate erythema and edema.23 Compared with the control group, there was no statistically significant difference between the ozone group on day 3, 7, and 14 and the ozone group on day 7 and 14 after treatment, suggesting that ozone water has no role in controlling blisters and eliminating coloration after inflammation.

It has been reported that topical ozone can effectively improve atopic dermatitis, eczema, psoriasis and other inflammatory lesions, and can effectively relieve itching and improve patients’ quality of life.15 The results of this study showed that the pruritus score in the ozone group decreased to 2.34 ± 0.48 points 7 days after treatment, with an average decrease of 48.1%, reaching the standard of mild pruritus (patients can live and sleep normally). We hypothesized that ozonation water may alleviate itching by inhibiting the infiltration and activation of EOS in skin tissues, reducing inflammatory factors in skin lesions, promoting the regression of inflammation, and increasing skin water content through some mechanism.24

Patients with BP are often accompanied by a large number of blisters, which lead to the damage of the skin barrier after rupture. In addition, the reduction of albumin can also lead to increased exudation at the damaged site, so they are more likely to be complicated with infection.25 Therefore, prevention and treatment of infection and control of symptoms as soon as possible is an important part of the treatment of BP. Ozone treatment is specifically implemented by dermatological nurses. We first use ozone water to wash skin lesions all over the body to reduce the degree of infection and inflammation of skin lesions, and at the same time to reduce the effect of exudation and convergence of the wound, and then apply ozone oil outside the erosion site to achieve sustained anti-infection and anti-inflammatory effects. During the treatment, nurses can observe the number of new blisters, the desiccated condition of blisters and the exudation of erosive noodles of patients daily, so as to understand the changes of patients’ condition, timely communicate with doctors, and adjust the treatment plan. Wang Aiping et al.26 found that camellia oil can promote percutaneous absorption of topical drugs, and the components of camellia oil are very similar to human skin components, since they are characterized by good compatibility and no stimulation. Ozone is dissolved in camellia oil to make ozone oil, which is more stable in concentration and not easy to decay, and can slowly and continuously penetrate into subcutaneous and interstitial tissues to play its role.27 Halometasone cream is a glucocorticoid for external use and has anti-inflammatory and anti-allergic pharmacological effects.

Conclusions

The results of this study showed that ozone water combined with ozone oil can quickly promote blister drying, erosion surface drying, and wound healing, providing convenient conditions for the next external use of glucocorticoid cream. At the same time, its good anti-inflammatory and anti-infection effects can enhance the efficacy of topical glucocorticoid ointment in the treatment of BP.

The shortcoming of this study is that it was conducted in the absence of long term follow-up and there was no mechanism for more in-depth study of ozone for external use only, the concentration and dose not needed for the topical treatment of BP. In future, it is planned to further explore the clinical indications and adverse reactions of ozone treatment for BP; it is thus necessary to carry out more samples of clinical studies to verify its effectiveness and safety.

Figure 1

Research object screening flow chart. BPDAI, bullous pemphigoid disease area index.
Research object screening flow chart. BPDAI, bullous pemphigoid disease area index.

Figure 2

Different treatment vesicle dry scab, erosion drying time (day) box chart.
Different treatment vesicle dry scab, erosion drying time (day) box chart.

Figure 3

Contour plots of itch scores of the two groups at different times.
Contour plots of itch scores of the two groups at different times.

Figure 4

Sleep score profiles of the two groups at different times.
Sleep score profiles of the two groups at different times.

Figure 5

Comparison of DLQI scores before and after different treatments (score) box chart.
Comparison of DLQI scores before and after different treatments (score) box chart.

Comparison of basic data between two groups of patients.

Index Cases Gender Age (years) BPDAI score

Male Female
Ozone group 37 18 19 75.50 ± 7.65 162.16 ± 23.37
Control group 37 16 21 74.70 ± 8.18 164.22 ± 22.12
t2 0.218 −0.352 0.388
P 0.816 0.726 0.699

The test of different effect of BPDAI observation index.

Indicators Variable F P
BPDAI
Time of therapy 813.319 <0.001
Group 16.562 <0.001
Time*Group 8.217 0.001
Vesicle
Time of therapy 558.974 <0.001
Group 0.253 0.616
Time*Group 0.224 0.791
Erythema
Time of therapy 259.040 <0.001
Group 16.944 <0.001
Time*Group 11.182 <0.001
Skin lesion
Time of therapy 366.323 <0.001
Group 0.002 0.960
Time*Group 0.339 0.718

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