Combination therapy using non‐ablative fractional laser and intralesional triamcinolone injection for hypertrophic scars and keloids treatment

Abstract

Combinations of various treatment modalities were shown to be more effective than monotherapy when treating hypertrophic scars and keloids. This study was conducted to assess the effectiveness of combination therapy with non‐ablative fractional laser and intralesional steroid injection. From May 2015 to June 2017, a total of 38 patients with hypertrophic scars or keloids were evaluated. The control group of 21 patients received steroid injection alone, and 17 patients (the combined group) received 1550‐nm erbium‐glass fractional laser treatment and steroid injection simultaneously. The mean number of treatment sessions was statistically fewer in the combined group than in the control group (6.95 vs 5.47, P = .042). There was a significant difference in the patient's scale in the combined group (14.62 vs 22.82, P = .005); however, the observer's scale was not significantly different (17.92 vs 20.55, P = .549). The recurrence rate was 38.1% (8/21) in the control group and 35.3% (6/17) in the combined groups and showed no significant difference (P = .859). However, the mean remission period was statistically longer in the combined group (3.00 months vs 4.17 months, P = .042). Combination therapy with non‐ablative fractional laser and intralesional steroid injection showed better results for the treatment of hypertrophic scars and keloids with fewer treatment sessions, better patient satisfaction, and longer remission periods.

1. INTRODUCTION

When skin is injured by trauma including abrasion, laceration, piercing, surgery, or burns, the wound healing process is initiated. Wound healing is composed of three steps: inflammation, proliferation, and remodelling, which are affected by complex mechanisms. During the process of wound healing, scar formation is inevitable as a result of new tissue formation and degradation. In some cases, dysfunctions in these processes lead to abnormal extracellular matrix accumulation and unexpected cellular activity, which results in hypertrophic scars and keloids.1, 2, 3, 4

Hypertrophic scars and keloids can be classified as a group of benign hyperproliferative dermal collagen growths. Patients with these conditions often experience not only physical problems such as pain, pruritus, deformities, and restricted range of motion but also psychological concerns.2, 3, 5 Various treatment modalities are available, including pressure therapy, silicone gel sheeting or ointment massage, oral agents, intralesional steroid injections (ILIs), dermabrasion, cryotherapy, radiotherapy, lasers, and surgical excision. However, there are still debates regarding the most effective treatment, and this makes it difficult for physicians to choose and manage hypertrophic scars and keloids.4, 6, 7

Because of increasing demands for scar treatments and the limitations of previous treatment methods, various types of laser treatments have been introduced. Recently, non‐ablative fractional lasers (NAFL) have been used for scar management, and they have shown promising results.1, 5, 6, 8, 9, 10, 11, 12 The NAFL creates small columns of coagulation in skin, while keeping surrounding tissues intact. This pattern of microscopic thermal damage stimulates epidermal turnover and dermal collagen remodelling. As the stratum corneum, which contains relatively less water, remains intact and epidermal function is preserved, adverse effects and recovery time are significantly reduced in NAFL compared with other ablative devices.1, 3, 5, 8, 10, 12, 13, 14

ILI is a commonly used and well‐established therapeutic modality.7 Corticosteroid inhibits alpha₂‐macroglobulin, which acts as an inhibitor of a collagenase. Once this pathway is blocked, collagenase is activated and collagen degeneration is enabled.

Because no single modality is universally effective and combinations of treatment modalities have been shown to be more effective than monotherapy,2, 7, 12, 13, 15, 16, 17 we sought to determine the clinical efficacy of combination therapy using ILI and NAFL compared with ILI therapy alone.

2. MATERIALS AND METHODS

2.1. Ethical statement

This study was approved by the Institutional Review Board of the Catholic University of Korea (No UC19RESI0071). Analysis of all data was performed anonymously and followed the principles in the Declaration of Helsinki (1975, revised in 2008).

2.2. Patients

From May 2015 to June 2017, a total of 57 patients with hypertrophic scars or keloids were enrolled. All patients were East Asians. The diagnosis was confirmed after patients underwent a clinical assessment by a plastic surgeon. All patients' medical history, current medications, scar history, and previous scar treatments were recorded. Exclusion criteria were age under 18 years, patients' refusal to allow steroid therapy, and follow‐up loss within 6 months from the last treatment. Patients with underlying diseases such as diabetes mellitus were also excluded, because their diseases could hinder wound healing. All patients were initially asked to receive combination therapy. If the patient refused, only ILI was applied, and the patient was assigned to the control group.

2.3. Procedures

ILI was performed in the following order. A 1:1 mixture of triamcinolone acetonide (40 mg/mL) and lidocaine HCl 2% (400 mg/ 20 mL) was injected into the lesion intradermally at the rate of 0.1 mL every 1 cm². For the NAFL, a 1550‐nm fractional erbium‐glass laser (MOSAIC HP, Lutronic Co., Ltd., Seoul, Republic of Korea) was used. The parameters were set at 50 mJ/spot and 40 spots/cm², as we obtained satisfactory results for scar treatment with these parameters in our previous study.6 With a 5 × 10‐mm hand piece tip, a total of three shots were delivered to each spot without overlap between them. Immediately after the laser therapy, an ice roller was used to cool the scars and to protect them from bulk thermal damage. In all cases, ILI was performed first and then NAFL was applied.

All treatments were scheduled every 4 weeks. Between the sessions, silicone gel treatment was recommended to all patients in both groups. The patients were encouraged to apply silicone gel ointment (Kelo‐cote Scar Gel, Alliance Pharma plc, Wiltshire, United Kingdom) with gentle massage in the morning and silicone gel sheet (Cica‐care, Smith & Nephew plc, Watford, United Kingdom) in the evening. This modified protocol using both ointment and sheet can effectively enhance the patients' compliance by applying silicone component easily on the irregular or mobile surfaces (eg, face or joints) during daytime, and by preventing it from being washed away unconsciously during night‐time. The treatment sessions were ended if symptoms were resolved and if the patients were satisfied with the results.

2.4. Evaluation methods

To assess the results in each group, we used a number of sessions before the therapy stopped as our first parameter. The end points of the treatments were relief of symptoms, such as itching and pain, and patient satisfaction.

The second parameter was the Patient and Observer Scar Assessment Scale (POSAS). The POSAS was initially developed to evaluate burn scars and linear surgical scars, but it is now used as a general scar assessment tool. It is divided into two categories: patient's scale and observer's scale, hence it allows a more complete evaluation of the scar.1, 18 The patient's scale contains six indicators: pain, itching, colour, stiffness, thickness, and irregularity. The observer's scale also contains six indicators: vascularity, pigmentation, thickness, relief, pliability, and surface area. Each indicator is scored from 1 to 10, then the scale is calculated by adding all indicators. A scar score of 6 is the best, while a score of 60 indicates the worst imaginable scar. Patients were asked to submit the questionnaires of the patients' scale of POSAS before treatment and 6 months after the last session. The observer's scales were obtained from two blinded third‐party physicians. The mean scores were calculated for both groups and compared. In addition, the degree of score improvement was also evaluated. Difference between the initial score and the score after 6 months in each patient was calculated.

However, some patients re‐experienced symptoms such as pruritus and pain within 6 months of the last treatment. These patients were assigned to the recurred group. Their POSAS data were excluded from the analysis. The recurrence rate and remission period, which was counted from the last treatment to the start date of a new session, were recorded and analysed instead.

2.5. Statistical analysis

The SPSS statistical package software, version 24.0 for Windows (SPSS, Chicago, Illinois), was used for statistical analysis. Mean data were analysed with an independent sample t test and the recurrence rate was assessed by Pearson's chi‐square test. P value ≤0.05 was considered significant.

3. RESULTS

A total of 57 patients with hypertrophic scars or keloids were enrolled. All patients had Fitzpatrick skin type III‐V.19 A total of 14 patients were excluded, according to abovementioned exclusion criteria. In addition, 5 patients were dropped from the study because of complications of triamcinolone including telangiectasia, hypopigmentation, or skin atrophy. Finally, 21 patients were allocated to the control group and 17 patients to the combined group. Of which, 12 patients had hypertrophic scars and 9 patients had keloids in the control group. In the combined group, 8 patients had hypertrophic scars and 9 patients had keloids. The mean age of the scars was 15.38 months (range 6‐23) in the control group and 16.76 (range 6‐24) in the combined group, which was not statistically significant (P = .473). Patient demographics are summarised in Table 1.

Table 1.

Summary of patient demographics

	Control group	Combined group
Number of patients (male:female)	21 (8:13)	17 (9:8)
Mean age (years)	41.38 (range 18‐62)	37.23 (range 19‐62)
Type of scar
Hypertrophic scar	12	8
Keloid	9	9
Lesion age (months)	15.38 (range 6‐23)	16.76 (range 6‐24)
Location
Head and neck	2	3
Trunk	9	8
Upper extremity	2	2
Lower extremity	3	1
Joint	5	3
Aetiology
Trauma	9	8
Surgery	12	9

The mean number of treatment sessions was 6.95 in the control group and 5.47 in the combined group, which was statistically significant (P = .042).

The POSAS was divided into three categories: patient's scale (PS), observer's scale (OS), and total score (PS + OS). The initial mean PS was not significantly different between the two groups (38.38 vs 36.18, P = .580), but there was a significant difference at 6 months (23.77 vs 13.36, P = .004). The mean OS was not significantly different in both groups initially (42.08 vs 38.18, P = .302), but there was a significant difference at 6 months (24.15 vs 17.64, P = .046). The mean total score, PS + OS, showed the same tendency. There was no significant difference in the initial total score (80.46 vs 74.36, P = .347), but it was significantly different at 6 months (47.92 vs 31.00, P = .002).

According to the results, there was a significant change in PS, with 14.62 in the control group and 22.82 in the combined group (P = .005). However, the score change in OS was not statistically different (17.92 vs 20.55, P = .549). The total score (PS + OS) difference showed the same tendency as the PS (32.54 vs 43.36, P = .041). The POSAS results are summarised in Table 2 and Figure 1, and the clinical results are presented in Figures 2 and 3.

Table 2.

Summary of the results of the number of treatment sessions and POSAS

	Control group	Combined group	P value
Number of patients (excluding recurred group)	13	11
Number of treatment sessions	6.95	5.47	.042*
Patient's scale (PS)
Initial	38.38	36.18	.580
After 6 months	23.77	13.36	.004*
D‐PS	14.62	22.82	.005*
Observer's scale (OS)
Initial	42.08	38.18	.302
After 6 months	24.15	17.64	.046*
D‐OS	17.92	20.55	.549
PS + OS
Initial	80.46	74.36	.347
After 6 months	47.92	31.00	.002*
D‐(PS + OS)	32.54	43.36	.041*

Note: D is the difference between the initial score and the score after 6 months.

^* P ≤ .05.

Figure 1.

Significant differences were observed between the initial score and the score after 6 months in the patient's scale and the total score, but not in the observer's scale. PS, patient's scale; OS, observer's scale; D, the difference between the initial score and the score after 6 months, *P ≤ .05

Figure 2.

Clinical photography of 53‐year‐old male patient with hypertrophic scar on his left foot dorsum. The scar developed after a scalding burn injury 6 months ago (image on the left), and he complained of a feeling of tightness and an itching sensation. After five sessions of combination therapy (image on the right), the patient's scale score improved by 19 points (from 36 to 17), and the mean observer's scale decreased by 26 points (from 42 to 16). The symptoms were resolved, and this state was maintained during the 6 months of follow‐up. The overall condition of the scar was much improved

Figure 3.

Clinical example of a keloid scar on the anterior chest wall of 49‐year‐old female patient. The keloid scar developed as a result of surgery 23 months before. The initial patient and observer scales were 48 and 37, respectively, with symptoms of pain and itching (image on the left). After six sessions of combination treatment (image on the right), the patient's scale was decreased by 20 points (and by 28 points after 6 months), while the objective improvement was less effective (a score decrement of only 7 points)

The recurrence rate was calculated as 38.1% (8 of 21 patients) in the control group and 35.3% (6 of 17 patients) in the combined group, but this was not statistically different from Pearson's chi‐square test (P = .859). However, the mean remission period was approximately 3.00 months in the control group and 4.17 months in the combined group, and this difference was statistically significant (P = .042) (Table 3).

Table 3.

Recurrence rate and remission period in each group

	Control group	Combined group	P value
Recurrence rate	38.1% (8/21)	35.3% (6/17)	.859
Remission period (months)	3.00	4.17	.042*

*P ≤ .05.

There were several cases of minor complications including erythema, inflammation, and skin burn, but the symptoms resolved spontaneously after conservative treatment in all patients.

4. DISCUSSION

The underlying mechanism of hypertrophic scars and keloids is not fully understood. Although many treatment options are available, there are still debates on the optimal treatment method. Recently, NAFL showed promising results in the treatments of various scars.

NAFL causes small coagulation zone columns of thermal damage to the skin and stimulates the wound healing process while keeping the surrounding tissue intact. This wound healing response has been shown by conducting immunohistochemical studies and by verifying the accumulation of collagen III; heat shock proteins 70, 72, and 47; and alpha smooth muscle cell actin fibres.20, 21 Because NAFL is non‐invasive, it is an attractive treatment modality in scar management. Although previous studies on laser treatments for hypertrophic scars and keloids focused on pulsed dye lasers and ablative lasers, numerous studies have reported the effectiveness of NAFL.1, 3, 12, 14, 16, 22 NAFL not only induces collagenolysis and neocollagenesis but also reduces scar fibrotic changes, resulting in better skin with less hardening and thickening. A review of several studies showed that NAFL also efficiently improved skin outcomes with less pigmentation and vascular changes in scars.12, 23, 24, 25

Recent studies tend to show better results when various therapeutic modalities are combined and applied to hypertrophic scars and keloids compared with single therapy.2, 5, 7, 12, 15, 16, 17 This is probably because the combination method can obtain the advantages of each therapeutic method with lower rates of complications. Various methods including steroid injection, 5‐fluorouracil, other pharmacological agents, cryotherapy, pressure therapy, silicone gel dressing, radiation, and diverse types of lasers have been tried in combination therapies. Among them, ILI has been widely used as a first‐line therapy for the management of problematic scars because of its effect on fibroblast growth inhibition and promotion of collagen degeneration.4, 7 Thus, we decided to use a combination of ILI plus NAFL and compared the results to an ILI monotherapy group.

The results of this study revealed several things. First, we defined the endpoint of our treatment as the time when the symptoms (such as itching, pain, and tightness) were relieved and the patients were satisfied with the results. Patients reached the end of the treatments with fewer sessions by combining NAFL and ILI. This means that the number and the amount of steroid use could be decreased. Combination therapy enabled not only shortening of the treatment period but also reducing the possibility of adverse effects by ILI such as hypopigmentation, dermal atrophy, and telangiectasia. Second, differences between the two groups in terms of PS, OS, and total score (PS + OS) were statistically significant 6 months after the last treatment session. Although the initial scores were not significantly different between the two groups, we focused on the degree of change in the scores during follow‐up period, because the scars were different from each other initially. Interestingly, D‐OS showed no statistical difference, unlike OS itself, which means that the combination therapy was more effective in symptom control, and that patient satisfaction was greater than the improvement in the observer score. This result was similar to an intraindividual randomised controlled trial on 18 hypertrophic scars in a previous study.1 Finally, patients in the combination therapy were symptom‐free for a longer period, although the treatment was not able to lower the recurrence rate. This may be due to the synergistic effect of both treatment modalities. Although the principal reason why symptoms such as pruritus and pain were present in abnormal scars was not clearly identified, they were probably because of abnormal wound healing responses and neurogenic inflammation that occurred in those scars.26, 27 The corticosteroid injection directly interrupts this inflammatory process by inhibiting inflammatory cell migration and phagocytosis.28, 29, 30 In the combined group, the laser induced loosening of the textural arrangement of collagen bundles, and the steroid could be delivered into deeper scar levels and distributed more evenly.16, 22 We hypothesise that this contributed to prolonging the remission period compared with the control group, although the exact mechanism was not clearly understood. The order of treatments can be another issue. Some authors recommended laser treatment before ILI.16, 22 However, the NALF treatment is quite painful even if topical EMLA cream is applied 1 hour before treatment. Therefore, we chose first to inject a mixture of steroid and lidocaine and then to proceed to the laser treatment. We agree that the order of the procedure could have influenced the results, and this may need a further study.

Owing to the lack of comparative studies on the differences between NAFL devices, it was difficult to determine the ideal parameters for the treatment. We used the same parameters as in our previous study, 50 mJ/spot and 40 spots/cm².6 According to the previous literature describing the relation between energy and depth of treatment, as more energy was delivered, deeper and wider microscopic thermal injury zones (MTZs) were created, and the depth was measured as 400–1000 μm with NAFL.14, 31, 32, 33, 34 This value is much deeper than that with ablative lasers such as CO₂ and Er:YAG, which have MTZ depths that are usually limited to less than 150 μm upon histologic evaluation.31 However, there was a limitation in increasing the energy, because a few patients who were treated with higher energy in a preliminary study received deep second‐degree burns.6 There were no complications in comparative studies when treated with a lower energy setting (lower than 50 mJ/spot).5, 8, 9, 16 In addition, some studies showed that NAFL at high energy settings can cause adverse effects, such as hyperpigmentation, or scar worsening.1, 10, 12, 22, 32 It was not clearly mentioned in the literature, but a high NAFL energy setting seems to be positively related to permanent side effects. We assumed that the depth of MTZs in this study was around 800 to 1000 μm, but further studies, including histologic evaluations, are needed to optimise the parameters for scar management.

There are several limitations to our study. This study was not a prospective, randomised controlled trial. Patients who refused laser therapy because of pain, cost, or individual preference were assigned to the control group, and data analysis was performed in a retrospective manner. Also, we could not evaluate the results of hypertrophic scars and keloids separately because of the small number of cases. They are similar with respect to abnormal dermal collagen growth accumulation, but these are definitely separate diseases. Both hypertrophic scars and keloids tend to be more responsive to combination therapy than to ILI alone, but keloids were less effective in objective (OS) than subjective improvement (self‐assessed scale, PS), as with the patient in Figure 3. Further studies with larger sample sizes are needed to obtain more accurate results. In addition, results depending on the age of the scar could not be analysed for the same reason. There were only four patients in the control group and two in the combined group with scar age under 12 months. We observed a greater improvement in both PS and OS in these patients, with fewer treatment sessions, without recurrence, in the combined group. However, half of the patients recurred in the control group. Similar trends are mentioned in other studies; younger scars were more susceptible to laser therapy than older scars, but further research is needed in this field.1, 3, 5, 22 Finally, the relatively short follow‐up period and the fact that we made no distinction between scars according to their location are also study limitations.

Combination therapy with NAFL combined with traditional ILI can have promising results for the treatment of hypertrophic scars and keloids with fewer treatment sessions. Although this combination method did not lower the recurrence rate, it was more effective in relieving symptoms and providing subjective satisfaction over longer periods of time. Hence, combination therapy with NAFL and ILI may be considered as a reasonable therapeutic option for hypertrophic scars and keloids.

CONFLICT OF INTEREST

None of the authors has any financial interest in this research project or in any of the techniques, products, devices, or drugs mentioned in this manuscript.

Shin J, Cho JT, Park SI, Jung SN. Combination therapy using non‐ablative fractional laser and intralesional triamcinolone injection for hypertrophic scars and keloids treatment. Int Wound J. 2019;16:1450–1456. 10.1111/iwj.13213