Clinical efficacy of intense pulsed light combined with low‐dose intralesional corticosteroids in treating noninfectious granulomas after mesotherapy: A case series analysis

Mesotherapy is a popular cosmetic procedure for localized delivery of substances. However, due to the lack of standardized processes, there are potential risks of adverse reactions. Granulomas formation is one of the chronic reactions which impose significant physical and mental burdens on patients.


| INTRODUC TI ON
Mesotherapy is a medical technique invented by physician Pistor in 1952, 1 which initially used to deliver anesthetic into skin to relieve pain.Later, it was gradually applied to help treat skin diseases and achieve facial rejuvenation.At present, mesotherapy has been widely used in the field of cosmetic dermatology and shows great efficiency. 2 The substances of mesotherapy varies depending on the individual's needs but commonly includes hyaluronic acid, vitamins, minerals, amino acids, and medications. 3though mesotherapy is generally considered safe when performed by trained professionals using sterile techniques and approved products, there are still inherent risks associated with it. 4These adverse events can vary in severity and can be classified into infection and noninfection based on their causes.In terms of infectious causes, patients may develop nodules and cysts due to contamination from the operating environment, syringes, or injection products.When it comes to noninfectious causes, several common mild symptoms have been described, including pain, erythema, ecchymosis, and skin sensitivity.Moreover, a less frequent type of noninfectious symptom characterized by the formation of granuloma exists; however, its specific etiology remains incompletely understood and may be associated with immune function, endocrine factors, or foreign material exposure. 5,6Although the incidence rate of noninfectious granuloma is relatively low, there has been an increasing trend in recent years.The primary clinical manifestations encompass chronic and refractory papules or subcutaneous nodules that can persist for months or even years. 7sides, the diagnosis of noninfectious granuloma is based on histopathological examination, which is essential for the differential diagnosis of other infectious and noninfectious causes of granuloma and to determine the appropriate treatment.Noninfectious granuloma mainly shows the infiltration of lymphocytes, macrophages, and histiocytic cells in the dermis, sometimes, multinuclear giant cells or foreign body structures are also presented.
There are various treatment modalities available for noninfectious granuloma following mesotherapy, but a standardized approach is lacking.The primary pharmacological interventions include antiinflammatory agents, corticosteroids, immunosuppressants, and others. 8,9In terms of energy-based devices, IPL stands out as one of the most extensively used light-based therapeutic technologies in dermatology; it has great curative effect for diverse inflammatory and vascular diseases. 10Considering the favorable efficacy profile and minimal side effects associated with hormone injections and IPL therapy, respectively, we have implemented combination therapy utilizing both approaches in some patients and conducting a retrospective analysis to summarize our clinical findings.

| MATERIAL S AND ME THODS
From October 2021 to December 2022, nearly 100 patients presented or consult with nodules and papules following mesotherapy.Among them, 19 patients were diagnosed with granuloma through histopathological examination and were excluded for anaphylaxis and infection through blood routine tests, measurement of total IgE levels, assessment of infection indicators.Among the diagnosed granuloma patients, seven agreed to receive combination therapy and were followed up.The combination therapy involved IPL (intense pulsed light) treatment with intralesional corticosteroids and the treatment consisted of two steps (Figure 1).In step one, we used the M22 IPL device (Lumenis, Israel) with a 590 nm filter, the fluence was determined based on different Fitzpatrick skin types (16-20 J/cm 2 ), and the double pulse width ranged from 3.5 to 4.5 ms.The procedure was repeated twice until the lesion achieved moderate redness as an endpoint, and patients were instructed to apply local ice for 15 min after step one.In step two, compound betamethasone (1 mL: betamethasone sodium phosphate 5 mg and betamethasone dipropionate 2 mg) was diluted with Lidocaine solution to achieve a concentration of 0.5 to 1 mg/ mL.Then, 0.1-0.3mL of the mixture was injected at each lesion site using a 30-gauge needle based on the size and texture of the lesions.The combined therapy was repeated every 3-4 weeks depending on its effectiveness.During the treatment period, patients did not receive any other systemic or topical medications and refrained from undergoing any other cosmetic procedures.
Patients had weekly follow-up visits where their satisfaction level and clinical curative effects were evaluated using a 5-point scale at the end of the follow-up period (Table 1).

| Case 1
A 34-year-old woman received mesotherapy for freckle removal at a beauty salon.The material used was a whitening product named "INNO INNOAESTHETICS"; it contains silicone which has been reported to have a potential risk of causing granulomas. 11One week after injection, papules appeared at the injection site without other symptoms.Consequently, she sought further treatment at our clinic and histopathological examination confirmed foreign body granuloma as the final diagnosis.After two course of the combined treatment spaced 3 weeks apart, the lesions improved significantly (Figure 2).

F I G U R E 1
The combined treatment consisted of IPL (A) and intralesional corticosteroid administration (B).

| Case 2
A 32-year-old woman underwent mesotherapy at a private clinic for removing neck wrinkles.The injected ingredients included hyaluronic acid, nucleotide, and others.Five days post-injection, she noticed the gradual emergence of firm papules at neck.Allergy and infection were ruled out, and final diagnosis was granuloma annulare.After undergoing three treatment procedures spaced 3 weeks apart, the lesions almost completely disappeared (Figure 3).

| Case 3
A 30-year-old woman received mesotherapy for neck rejuvenation at a beauty salon.The injection products used were "Cytocare 532" and other unknown components, which may contain non-crosslinked hyaluronic acid, minerals, amino acids, and others.Erythematous papules gradually appeared at injection sites after 6 days of mesotherapy, with no response to oral corticosteroids.Histopathological diagnosis revealed foreign body granulomas.Finally, the papules almost disappeared after four treatments spaced 3 weeks apart, leaving some pigmentation (Figure 4).

| Case 4
A 32-year-old woman underwent mesotherapy in a private clinic for skin whitening.The name and composition of the product were unclear.Then, multiple firm and asymptomatic papules appeared at the injection site 4 days after injection.The histopathological diagnosis was foreign body granuloma.After one course of the combination treatment, the lesions subsided significantly.Only pigmentation remained (Figure 5).The patient used external whitening products to remove the pigmentation later and did not return to our clinic again.

| Case 5
A 31-year-old woman received mesotherapy in a beauty clinic for facial rejuvenation.The ingredients were hyaluronic acid mixed with tranexamic acid.Five days later, papules developed with mild pruritus at the injection site.Despite applying topical corticosteroids and taking oral antihistamines for 3 weeks, there was no significant the second treatment; however, during a telephone follow-up, she reported that the pigmentation had almost subsided (Figure 6).

| Case 6
A 29-year-old woman underwent mesotherapy in a beauty salon with unclear ingredients, and multiple firm papules were gradually formed 3 days after injection.The histopathological diagnosis was foreign body granuloma.After receiving one combination treatment (Figure 7), the patient was satisfied with the result and did not continue further treatment.

| Case 7
A 32-year-old woman received mesotherapy in a private hospital with mixed unknown ingredients.One week later, the patient found that papules gradually appeared at the injection site.Histopathological examination revealed formation of foreign body granulomas; she received two courses of combined therapy with only minimal pigmentation remaining (Figure 8).

| RE SULTS
Currently, there are no standards for evaluating the treatment effect of granulomas after mesotherapy.Evaluation is based on patient satisfaction and physician assessment (Table 2).Seven patients were diagnosed with noninfectious granulomas, including foreign body granuloma and granuloma annulare.On average, each patient received 2 ± 1 treatments.Five patients expressed high satisfaction with the outcome, while two reported moderate satisfaction due to pigmentation issues.According to the physicians, all patients demonstrated marked improvement.No adverse effects such as photoallergy, secondary infection, or skin atrophy were observed during the follow-up period, and there was no recurrence.

| DISCUSS ION
Mesotherapy is a nonsurgical technique for aesthetic injection which involves delivery of mixture or cocktail of different substances; the wrong choice of the products and techniques may raise security concerns.Noninfectious granuloma is specious and represents a physiological response of the host to foreign materials or other complicating factors; this reaction can occur with different types of clinical classification which includes granulomatous foreign body reaction, granuloma annulare, sarcoidosis, and so on. 12,13The appearance of foreign body granulomas caused by different substances varies, some exhibit distinct foreign body structures, while others display vacuole-like structures on a smaller scale. 14According to the literature review, some substances have been reported to have different incidence rate to cause foreign body reactions. 15,16Furthermore, factors such as physical and chemical properties, size, surface smoothness, degradation rate, impurities, and material composition ratios also can influence the development of granulomas. 17Currently, there is no standardized treatment for foreign body granulomas.In addition to pharmacotherapy, energy-based devices are also utilized in some cases.A clinical study was conducted using high intensity focused ultrasound combined with intralesional corticosteroids for the treatment of foreign body granulomas after "Polycaprolactone" filler injection.The post-treatment examination demonstrated a significant reduction in subcutaneous nodules.The author suggests that energy equipment can effectively ablate and degrade foreign materials while providing anti-inflammatory effects through thermal energy. 18Another report used IPL combined with intralesional corticosteroids to treat subcutaneous nodules following Artecoll injection, yielding excellent results.The author believed that IPL plays a role in sealing blood vessels and reducing inflammation. 19 this case series, the combination of IPL and low-dose intralesional corticosteroids injections was utilized.Firstly, intralesional corticosteroids exhibit a more rapid effect and a higher local concentration compared to systemic corticosteroids at the same dosage, and a significant reduction in nodules volume can be observed within a few days typically.However, due to the low dose used, repeated injections are necessary for optimal treatment efficacy while also better controlling adverse reactions.It is worth noting that patients who develop granulomas after mesotherapy may be further referred for severe epidermal atrophy due to the administration of local intralesional corticosteroids, which represents a secondary injury resulting from the utilization of high concentrations and doses of corticosteroids-a double-edged sword in the therapy.Secondly, we believe that IPL serves as an adjunct to the effectiveness of low-dose corticosteroids.
The photothermal effect not only exerts an anti-inflammatory role but also accelerates degradation and absorption of injected substances, thereby reducing the frequency of steroid injections required.Lastly, the IPL activates skin self-repair mechanisms, facilitating the production of healthy collagen to replace abnormal tissue. 20Additionally, in a limited number of cases during our clinical practice, it was discovered that IPL therapy alone effectively improved local erythema; however, it did not significantly impact the size of papules.This emphasizes the indispensable role of intralesional corticosteroids.Another patient underwent radiofrequency microneedling at lesions for treatment, a procedure that enables targeted delivery of energy to specific depths in the skin, resulting in good outcomes.The physician hypothesized that intradermal or subcutaneous radiofrequency energy could thermally ablate granuloma tissue, enhance skin metabolism, and stimulate collagen regeneration.
It is regrettable that our retrospective analysis still has several limitations.Given the limited number of cases and the diversity of injection substances, conducting rigorous controlled trials in clinical practice becomes challenging.Therefore, further analysis is required to determine the specific effectiveness and advantages of this combined treatment.However, based on observations and analysis, we believe that IPL combined with low-dose intralesional corticosteroids represents an effective treatment option with minimal side effects.Finally, we hope for more research advancements in the prevention and treatment of post-mesotherapy granulomas in the future.
improvement.The histopathological diagnosis was foreign body granuloma.Subsequently, she received two courses of combination therapy with a 3-week interval.After the first treatment, most of the lesions disappeared but some pigmentation remained.Due to the COVID-19 restrictions, the patient was unable to return after TA B L E 1 Patient satisfaction scale and evaluation of clinical curative effect.U R E 2 (H&E × 200) Transparent foreign bodies were scattered between inflammatory cells and epithelioid cells, multinucleate foreign body giant cells can be also observed (A).Multiple red papules on patient's face before treatment (B), 2 weeks after the first treatment the situation improved (C), and 2 weeks after the second treatment the papules were almost disappeared (D).

F
I G U R E 3 (H&E × 100) Palisaded granuloma (arrows) with necrobiotic center in deep dermis and necrobiotic collagen surrounded by palisading histiocytes and scattered lymphocytes (A).Multiple red papules on patient's neck before treatment (B), 2 weeks after the first treatment the situation improved (C), and 2 weeks after the third treatment the papules were almost disappeared (D).F I G U R E 4 (H&E × 200) Irregular foreign bodies were observed surrounded by inflammatory cells and epithelioid cell (A).Multiple red papules on patient's neck before treatment (B), 2 weeks after the first treatment the situation improved (C), and 2 weeks after the last treatment only some pigmentation were left (D).

F I G U R E 5 (
H&E × 200) The histocyte phagocytose injected material and form a lipogranuloma-like appearance with multilocular small vacuolar changes, surrounded by inflammatory cell infiltration.(A).Multiple red papules on patient's neck before treatment (B), 2 weeks after one treatment the situation improved (C).F I G U R E 6 (H&E × 200) Small vacuole-like changes, macrophages, and agminated lymphocytes were seen in the dermis (A).Multiple red papules on patient's face before treatment (B), 2 Weeks after the first treatment the situation improved obviously (C).

F I G U R E 7 (
H&E × 200) The dermis showed lymphocytes and epithelioid cells, with small vacuoles and macrophages were observed locally.(A).Multiple red papules on patient's face before treatment (B), after one combination treatment the lesions almost disappeared (C).F I G U R E 8 (H&E × 200) In the dermis, granuloma with foreign bodies, histiocytes, and multinuclear giant cells were seen clearly (A).Multiple red papules on patient's face before treatment (B), 2 weeks after the second combined treatments the lesions almost disappeared (C).TA B L E 2 Summary of patient information and assessments.