An open-labelled randomised controlled trial comparing intralesional triamcinolone acetonide alone versus radioporation-assisted drug delivery in keloids

Introduction

Keloids are abnormal connective tissue responses that occur due to impaired wound healing. They can develop spontaneously, particularly in individuals with a familial or racial predisposition or due to trauma, even from minor injuries. These growths typically appear as erythematous or occasionally hyperpigmented papules and plaques on areas prone to keloid formation, such as the earlobes, chest, shoulders, upper back, nape of neck, knees, and buttocks. They can cause pain, itching, disfigurement, impaired function, and a reduced quality of life. It is quite challenging to treat keloids, and it recurs even after treatment.¹

Intralesional steroids (ILS) are considered the first line and gold standard treatment for keloids. ILS acts via various mechanisms; the most important is the inhibition of fibroblast proliferation. This takes care of excess collagen synthesis. The efficacy ranges from 50-100% according to different studies, with recurrence rates reaching as high as 50%. The treatment with intralesional corticosteroids is frequently associated with side effects like atrophy, abnormal pigmentation, and/or telangiectasias. No single treatment modality suffices alone; rather, these must be used in combination to achieve the best possible results.²

Intralesional radiofrequency ablation (ILRFA) is a relatively new treatment option for keloids. Commonly referred to as radiofrequency tissue volume reduction (RFTVR), it leads to protein denaturation and necrosis of connective tissue, resulting in scarring followed by retraction of soft tissue.³ We hereby created pores in the 3D direction of keloids and labelled them as radioporation. There are limited studies in the literature regarding the use of radiofrequency ablation for treating keloids, either alone or in combination with topical corticosteroids. Herein is an attempt to study the efficacy and safety of ILS alone versus fractional electrolysis with topical application of triamcinolone acetonide.

Methods

This was a single-centre, randomised, open-label, superiority trial conducted in a tertiary care centre. The required sample size was estimated using the formula for paired continuous outcomes. Based on prior studies and clinical judgment,² we assumed a mean detectable difference of 1.5 points in Vancouver scar scale with a standard deviation (SD) of paired differences of 2.5. Substituting these values yielded a minimum sample size of 22 participants (44 keloids). To account for an anticipated 15% dropout or non-evaluable data, the final sample size was inflated to 26 participants (52 keloids).

A total of 31 patients having at least two keloids at similar sites with size difference not exceeding 50%, and between 18-65 years were included. Patients who consented and had received prior treatment were given a washout period of 12 weeks and 4 weeks for invasive and non-invasive methods respectively. Patients with uncontrolled diabetes mellitus, uncontrolled hypertension, low platelet count, bleeding disorders, usage of anticoagulants, artificial implants, pacemakers, pregnant and lactating women, and allergy to local anaesthetics were excluded [Figure 1].

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Figure 1: Demonstrates the methodology of the study [CONSORT flowchart]. (TAC: Triamcinolone acetonide, RFA: Radiofrequency ablation, VSS: Vancouver scar scale, NPRS: Numeric pain rating scale).

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Consenting participants were randomised 1:1 using lesion-level block randomisation (block size = 2 within each subject), ensuring one lesion was allocated to A and the other to B in random order (AB or BA). Lesions were labelled as lesion 1/2 by a pre-specified rule (1 is either the lesion located in the upper aspect among two lesions or on the right side, whereas 2 is located in the lower aspect among two lesions or on the left side). For subjects with >2 eligible lesions, the two most similar lesions were selected prior to randomisation. Detailed history and examination were entered in a pre-designed proforma. The primary objective was to compare the efficacy and safety of intralesional triamcinolone acetonide alone versus fractional electrolysis with topical application of triamcinolone in the treatment of keloids, and the secondary objective was to compare the patient-reported outcomes. Before the initiation of procedures, the lesions were photographed at baseline and subsequent follow-ups. The lesions were anaesthetised with 2% lignocaine and 1/100,000 adrenaline injection subcutaneously before the administration of either of the treatments. Group A received triamcinolone acetonide (TAC) (40 mg/mL) till complete blanching of the lesion (maximum 1 mL/4cm²), at 3 weekly intervals, and group B received topical triamcinolone acetonide over radioporated keloid. Radioporation is achieved by creating multiple small windows or ports using a radiofrequency probe (using coagulation mode, depth: 8 to 10 mm, at power 10-20 watt, depending on the thickness of the tissue; Karl Leibinger Surgical Martin machine) in the keloid [demonstration Video 1]. After the topical application of triamcinolone, the lesion was covered with tegaderm for better absorption of the drug. Subsequently, the patient was advised to continue topical triamcinolone. The procedure was repeated at an interval of 3 weeks. Post-therapy follow-up was done at 18 and 24 weeks.

The primary outcome was measured in terms of reduction in Vancouver scar scale score [total score ranges from 0-13], reduction in volume of keloid, and side effects at baseline, 3, 6, 9, 12, 18, and 24 weeks. The secondary outcome measured reduction in numeric pain rating scale (NPRS) [total score ranges from 0 to 10], and reduction in pruritus symptoms (0 = no symptom, 1 = mild, 2= moderate, 3= severe) at baseline, 3, 6, 9, 12, 18, and 24 weeks. The volume of the keloid was measured using dental impression material (silicone-based). The material was used to take an impression of the keloid, and a mold was made into which water was filled, and the volume of water was measured.

Results

The median (interquartile range) age of distribution was 30 (23-34) years, with male predilection (male: female=3:1), and mean± standard duration (M±SD) duration of disease was 6.84±4.08 years. The majority of participants developed keloids following acne (n=25, 81), and only 2 (6.5%) patients had a family history of keloids [Table 1]. In group A, the mean VSS decreased from a maximum of 6.77 at baseline to a minimum of 3.46 at week 24. This change was statistically significant (95% CI −3.88 to −2.74, p <0.001). In group B, the mean VSS decreased from a maximum of 7.35 at week 0 to a minimum of 2.25 at week 24. This change was statistically significant (95% CI −5.64 to −4.56, p <0.001) [Figure 2]. Linear mixed models revealed that Group B showed significantly greater 3 weekly improvement than Group A (p<0.002), when adjusted for baseline scores [Figures 3a to 3f].

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Figure 2: Depicts the change in the Vancouver scar scale (VSS) over time between the two groups (p value represent the difference in mean VSS between group A and group B). (Group A: Intralesional triamcinolone acetonide alone; Group B: Topical triamcinolone acetonide and radioporation).

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Figure 3a: Baseline clinical image of the keloid chosen for intervention. (keloid above on intralesional triamcinolone; keloid below on radioporation-assisted drug delivery).

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Figure 3b: Comparison of improvement between the two groups at 3 weeks. (keloid above on intralesional triamcinolone; keloid below on radioporation-assisted drug delivery).

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Figure 3c: Comparison of improvement between the two groups at 6 weeks. (keloid above on intralesional triamcinolone; keloid below on radioporation-assisted drug delivery).

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Figure 3d: Comparison of improvement between the two groups at 9 weeks. (keloid above on intralesional triamcinolone; keloid below on radioporation-assisted drug delivery) .

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Figure 3e: Comparison of improvement between the two groups at 12 weeks. (keloid above on intralesional triamcinolone; keloid below on radioporation-assisted drug delivery).

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Figure 3f: Comparison of improvement between the two groups at 18 weeks. (keloid above on intralesional triamcinolone; keloid below on radioporation-assisted drug delivery).

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The mean vascularity decreased from a maximum of 1.48 at week 0 to a minimum of 0.71 at week 24 in Group A, which was statistically significant (p<0.001). Similarly, the mean vascularity decreased from a maximum of 1.55 at week 0 to a minimum of 0.46 at week 24 in group B. Significant treatment effect favoured Group B (p=0.004). Group B showed 35% greater reduction (0.46 vs 0.71) from comparable baselines.

The mean pliability significantly (p = <0.001) decreased from a maximum of 2.42 at week 0 to a minimum of 1.14 at week 24 in group A. Similarly, the mean pliability decreased from a maximum of 2.81 at baseline to 0.79 at 24 weeks in group B. At 24 weeks, the difference in pliability between the two groups was statistically significant (p=0.0024). The mean lesion height (mm) in Group A decreased from a maximum of 2.61 at week 0 to 1.23 at week 18, followed by a slight increase to 1.28 at week 24. Despite this minor rise due to unknown reason, the overall reduction in height at 24 weeks remained statistically significant (p < 0.001). In Group B, the mean height decreased from 3.01 at baseline to 0.85 at week 24, demonstrating a statistically significant reduction (p < 0.001). Group B demonstrated statistically significant better outcomes across all scar parameters after adjusting for baseline differences and accounting for the paired design [Table 2].

Overall, significant change in volume (cc) over time was seen between the two groups (p = <0.001). At 24 weeks, both groups demonstrated a statistically significant reduction in NPRS scores and pruritus severity compared with baseline (p < 0.001). Patients in both groups experienced minimal side effects, as depicted in Table 3, which were not statistically significant.

Discussion

Though keloids are very commonly encountered in daily outpatient department practice, none of the treatments has shown absolute effectiveness. Although it is not possible to completely get rid of a scar, there are various surgical and non-surgical methods that can improve its appearance. Unfortunately, the evidence of most of them is poor, and efficacy is limited. Intralesional corticosteroid is the most commonly used nonsurgical modality for keloids.⁵ It induces keloid regression through a variety of proposed mechanisms, including suppression of dermal inflammation, reduction of oxygen delivery to the wound bed via vasoconstriction, and antimitotic activity in keratinocytes and fibroblasts.⁶ Creations of channels for increasing transepidermal delivery of drugs are being tried using various modalities like fractional ablative lasers, dermabrasion, and micro-needling. Intralesional radiofrequency ablation works by direct collagen remodelling along with drug delivery to the full depth of the lesion.⁶

The mean age of participants in our study was 30.35 years, with a range of 18 to 57 years. A notable finding was the male predominance, with 24 out of 31 participants (77.4%) being male. Many studies have reported a roughly equal sex distribution or a slight female predominance, while a few studies also report a significant male predominance in their samples.^7-9 In our study, the majority of patients (80.6%) developed keloids following acne or folliculitis. Trauma was identified as the second most common cause, accounting for 12.9% of cases. Keloids developed spontaneously in only 6.5% of patients. In a study by Srivastava et al.,¹⁰ infection (62%) was the most common cause of keloid formation, followed by trauma in 27% and spontaneous keloids were observed in only 12% of patients, unlike our observation.¹⁰ On the other hand, a study by Kaushal et al.¹¹ reported that 65% of patients developed spontaneous keloids and only 8.4% of patients developed keloids following acne.¹¹ Another study by Aggarwal et al.¹² also showed a higher incidence of spontaneous keloids (38.75%) and post-trauma keloids in 30% of cases, with a lower percentage (15%) of keloids occurring after acne. The higher proportion of keloid development after acne in our study can likely be attributed to the inclusion criteria, which required participants to have more than one keloid, and the fact that post-acne keloids tend to be multiple.¹²

Keloids are frequently associated with symptoms like pain and pruritus. In our study, the most common symptom experienced was pruritus in 90.3% of patients, followed by tenderness in 38.7% and pain in 35.4%. Three patients had experienced no symptoms. In our study, we utilised the dermatology quality of life index (DLQI) questionnaire to assess the impact of keloids on the quality of life of the patients. At baseline, the mean DLQI score was 9.74, indicating a moderate effect on patients’ lives. After 12 weeks of treatment, the score decreased to 6.75, still reflecting a moderate effect, but an improvement nonetheless. By the end of the 24-week follow-up, the DLQI score further dropped to 4.93, signifying a mild effect on patients’ quality of life. Overall, these results demonstrate that both treatments led to significant improvements in quality of life for all patients undergoing treatment, with a steady reduction over time. In our study, we found VSS improved in both groups, and much more when combined with intralesional radio frequency ablation. In a previous study where eight patients with recalcitrant pre-sternal keloid were treated with the same combination therapy, after three sessions, all reported resolution of pain and itching. The mean patient-perceived improvement was 80.62 ± 9.42%, whereas the mean physician-perceived reduction in size was 63.12 ± 11.63%.⁶ Our study showed a similar reduction in volume at 24 weeks of 68%.

In a study, intralesional RFA alone was found to be effective in reducing the volume of keloid by 53.05 % with a significant reduction of keloid pliability, height, and erythema compared with baseline.⁹ This was less than our study, implying an added benefit to the application of steroid on the keloid. In another study, where 3-4 sessions of RFA were followed by intralesional steroid injection, attained a mean volume reduction of 95.4%. This could be attributed to the fact that patients received a longer course of therapy. They underwent 3-5 sessions of RFA spaced 8 weeks apart. Each RFA session was followed by an intralesional steroid injection. The steroid injections were repeated every 2 months for three sessions, with one additional session given after 6 months.⁷

Apart from triamcinolone acetonide, this technique can also be combined with topical hyaluronidase, 5-fluorouracil, verapamil, and bleomycin. However, there are no studies showing radioporation followed by these modalities. A study by Teplyi and Grebchenko¹³ investigated the use of intralesional RFA either alone or in combination with verapamil and 5-fluorouracil. The results showed that after five RFA sessions, scar volume decreased by an average of 65.3%. When verapamil and 5-fluorouracil were used together with RFA, the effect was even more pronounced, reducing scar volume by 78.3%.¹³ The combination of RFA, verapamil, and 5-fluorouracil led to a faster reduction of clinical symptoms compared to the topical application of 5-fluorouracil alone, with the combination treatment enhancing the overall effectiveness.

Various methods to improve drug delivery into keloids have been explored. In a split-side controlled study, Abd El-Deyem et al.¹⁴ showed that fractional ablative 2940 nm Er:YAG laser-assisted delivery of betamethasone was more effective than intralesional triamcinolone acetonide 10 mg/mL alone.¹⁴ However, the difference in the steroid used between the groups is an important confounding factor. In another study, conflicting results were reported, with no significant difference in clinical improvement between keloids treated with combined Er:YAG laser intralesional triamcinolone acetonide versus those treated with topical desoximetasone 0.25% ointment with 3-hour occlusion.¹⁵

In our study, the intralesional group showed continuous improvement in various parameters (VSS, pliability, height, volume, and NPRS) until the first follow-up at week 18, followed by a slight worsening by week 24. In contrast, the radioporated group demonstrated sustained improvement over time, even after treatment cessation. This suggests that while injections alone may lead to earlier recurrence after treatment stops, RFA combined with injections results in continued improvement.

Adverse effects such as atrophy, hypopigmentation, hyperpigmentation, telangiectasia, and ulceration were not significant in both groups. This was comparable to the previous review, where they found negligible side effects with triamicinolone 20 mg/mL and 40 mg/mL.¹⁶

Limitations

The study’s limitation was the short-term follow-up and no blinding, which prevented the assessment of relapse rates between the two groups. Correlation with histopathological and tissue biomarkers was not done between the groups at baseline and the end of therapy.

Conclusion

Our randomised controlled trial establishes that combined fractional electrolysis with topical triamcinolone (Group B) demonstrates superior scar modification outcomes compared to monotherapy across all evaluated VSS parameters, suggesting a paradigm shift in keloid management toward multimodal approaches. It was consistently seen in our study that in the intralesional group there was continuous improvement in various parameters (VSS, pliability, height, volume, and NPRS) till week 18, i.e., till the 1^st follow-up visit, before slightly worsening till the 2^nd and last follow-up visit at week 24. On the other hand, all the parameters showed continuous/sustained improvement over time in the radioporated group. This implies that the injections alone group was associated with earlier worsening/recurrence post stoppage of treatment, whereas RFA, along with triamcinolone, led to sustained improvement even after stoppage of treatment sessions. This study has a short follow-up period due to constraints of time; studies with longer follow-up are required to assess recurrence rates for these modalities.