Consensus position statement on emerging treatments in dermatology by the Association of Cutaneous Surgeons of India Task Force

Background and objectives

Emerging treatments in dermatology gain immense traction due to their prominence on social media, robust marketing, and peer usage. Most of these treatments are unregulated, unapproved, with unknown long term-safety data. Many also have questionable efficacy with no standard protocols for use. Hence, it is imperative to present a position statement and consensus guidelines on some of these treatments so that dermatologists can adopt best clinical practices and foster quality and safety. This study consensus was thus conceived to find current clinical evidence, identify gaps, and provide a guideline to dermatologists while using these treatments.

Background

There is an emergent interest in exosomes as a new modality in the therapeutic field of dermatology. Dermatologists need to be aware of several aspects of this therapeutic modality and the available evidence of their use.

Exosomes are extracellular vesicles (EVs), measuring 30–150 nm in diameter, and are released by every cell in a physiological or pathological state. They carry coding and non-coding RNA, proteins, and lipids among other biomolecules.

Mechanism of action

Exosomes exert therapeutic effects by intercellular communication and gene regulation, thus modulating inflammation, modulating immunity, promoting angiogenesis, and stimulating fibroblasts via paracrine signaling.

However, exosomes are true to their parent cells and the therapeutic effects depend on the cargo they carry. The microRNA profiling of the vesicles is an important parameter to be deduced to know which proteins they will be translated into to bring about a particular therapeutic action.² They are hence not generic entities.

Ethical considerations

Exosome sources from animals carry ethical, regulatory, and safety issues. Plant-derived exosomes have been used experimentally, as cross-kingdom molecular communication has been established; they are a sustainable source and they are not subject to the scrutiny of animal sources.³ However, plant-derived exosomes may not be as effective as human-derived exosomes.⁴

The use of exosomes for clinical trials or in translational medicine requires the need to conform to Good Manufacturing Practice, involving production yield, purity, storage, the source, and biodistribution characteristics. However, accessing such information from manufacturers is challenging and not always forthcoming.⁵ Different methods of preparation and purification are used and these carry variable purity and levels of impurities. These need to be ascertained before clinical use, but these are not always easily available accessible. The Federal Drug Administration (FDA) in the USA has not approved any exosome product presently for any therapeutic condition and considers them as experimental therapy.⁶ The adverse effects related to exosome treatment are not fully established as there are no long-term studies available.^3,6

Regulatory guidelines in India

Exosomal products in India are overseen by the Central Drugs Standard Control Organization, which is the principal authority of approval and monitoring of clinical trials involving EVs. The Indian Council of Medical Research (ICMR) provides guidelines for the clinical trials of EVs. The Drugs Controller General of India authorizes the marketing of EV products. However, there is no explicit regulatory framework for the manufacturing and marketing of exosomes in India. They are presently partially regulated by the Drugs and Cosmetics Act of 1940.

Potential clinical uses

The following five main conditions for which they are under consideration for use in dermatology have been discussed with their level of evidence.

Position statement for the use of exosomes

Based on the nature of published studies, the field of exosomes is largely considered investigational and the level of evidence is 5. The strength of recommendation of use of exosomes as a therapeutic modality is Grade D. In view of this, the task force considers this modality with commercial products from any source to be experimental and does not recommend their routine use in practice.

Background

Polynucleotides (PNs) and PDRN are composed of a mixture of DNA fragments, weighing between 50 and 1500 kDa, extracted from purified DNA of salmon or trout gonads. PNs have the potential to regulate gene expression and promote tissue regeneration, cell proliferation, angiogenesis, cell differentiation, and survival as well as anti-inflammatory properties.^32,33 The therapeutic properties of PDRN are explained by two pathways: the A2 receptor stimulation pathway or the salvage pathway.³⁴

PNs and PDRN are sourced from the gonads of the salmon fish and the sperm cells, respectively, which also raises ethical concerns about fish being used. The PDRN and PN sourced from plants, phyto PDRN (derived from roots of Panax ginseng or the red alga of Porphyra spp.), may overcome this challenge.³⁵

PN and PDRN have been used for improvement in skin texture as skin boosters alone and in combination with platelet-rich plasma or hyaluronic acid (HA), showing improvement in various studies.^35,36 Periorbital rejuvenation with PN also showed significant improvement over HA in small RCTs.³⁷ PN has been used as a filler and to revitalize tissues to receive filler or other aesthetic treatments.^35,38 Both PN and PDRN have been used in androgenetic alopecia and Female Pattern Hair Loss, showcasing improvement in hair counts and hair thickness.^39-41 Pigmentary conditions such as melasma, post-inflammatory hyperpigmentation, and freckles have also been treated with favorable results in small case series.⁴² Several studies have reported the positive effects of PN and PDRN in scars (acne scars, burn scars, post thyroidectomy scars, burn scars, and traumatic scars) as monotherapy and in combination with other treatment modalities including fractional lasers.³⁵ The positive effects of PDRN on pressure sores and diabetic ulcers have been demonstrated in small RCTs.^42,43

Several concerns exist about their use. No standardized protocols for the administration of PN/PDRN have been formulated. Although studies assessing the safety profile of PDRN indicate that it is generally well-tolerated, safe, and non-toxic, with no reported complications, long-term evaluation data are lacking and theoretical concerns of mutagenic potential remain due to its nature as a biodrug that elevates vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1.⁴⁴ Studies are small and follow-up period is also small. Importantly, PN and PDRN are not FDA approved for any indications.

Position statement

Strength of recommendation: Most of the published data comes from case series and small RCTs, and there is variability in the study design, data collection, and small sample sizes. There is a need for high-quality research to draw firm conclusions. In view of this, the task force considers this modality to be experimental and does not recommend its routine use in practice. Dermatologists are advised follow precautions with their use.

Background

HFs are known to contain a well-characterized niche for adult SCs. The bulb has a rich population of epithelial, progenitor, and melanocytic SCs.⁴⁵ Numerous paracrine factors are involved in signaling between these during various hair cycle stages.^46-48

Autologous micrograft suspension technology is currently proposed as an interventional therapy in various conditions of skin and hair. The recipient zone on the treated area of scalp benefits from regenerative activity of the SVF, which is rich in progenitor cells and growth factors (GFs) and EVs extracted from biopsies from the donor site, which is the occipital area.⁴⁹

The technique is based on the principle demonstrating that there is a high concentration of the obtained SCs in the solid tissue. The samples of skin biopsy are processed in an FDA-approved, patented device.^49-51

Rigenera is based on the principle of the “Niche concept” of microenvironment around the progenitor cells. It is the physical place where extrinsic signals interact and integrate to influence cell behaviour.⁵⁰ The technique preserves the extracellular matrix environment, and the cells after desegregation still stand in their own physiological niche, which supports and gives them the chance to differentiate, and release GFs.⁵¹

Rigenera micro-grafts are 70–80 microns, viable cells, and they are made of SVF cells (CD90+/CD105+/CD73+), extracellular matrix, and GFs.

The mechanical disaggregation process preserves the viability of these cells, which can differentiate into various cell types.

Purported role of micrograft works in tissue regeneration: Increase of matrix production.

• Increase of GFs

• Increase in tissue neo-angiogenesis

• Modulation of Inflammation

• Activation of tissue remodeling through biological pathways

• This leads to stimulation of the bulge area SCs

• Regenerative role of this technology is applied for regeneration in burns wounds, chronic ulcers, chronic wound healing, post-surgical wounds, androgenetic alopecia, vitiligo, and stretch marks.^52-66 A few studies have been quoted in Table 3.

• The rigeneracons are surgical disposable medical devices CE certified with class 2A EU MDR and Rigenera N4SA machine as class 1 and FDA approved. FDA listing number D218368, D 218369, D260214.

Position statement

The Rigenera system and graft processing regeneracon are a patented device for obtaining an autologous micrograft suspension, which is FDA and CE approved.

• Recommendation in burns, chronic wound healing, Evidence Level 4 – Recommendation Grade C

• Efficacy for treatment of androgenetic alopecia in men and women by use of autologous micrograft suspension is supported by Evidence Level 4 – Recommendation grade C

• Rigenera for vitiligo is supported by Evidence Level 4 – Recommendation grade D

• Role in stretch marks and rejuvenation level of Evidence 5 – Recommendation Grade D

Most evidence comes from prospective, non-randomized clinical studies, small to moderate sample sizes, and limited long-term follow-up. RCTs with larger cohorts and standardized comparator arms are still sparse or pending. However, consistent positive clinical outcomes and regulatory approvals underpin a moderate recommendation.

Background

Nanofat and SVF therapies represent a growing trend in regenerative medicine. In hair restoration, these autologous adipose-derived products aim to stimulate follicular regeneration through paracrine effects and cellular regeneration. However, the evidence base remains limited, with small studies and the absence of large-scale RCTs.

Position statement

Keeping the above studies in mind, the following position statement is recommended. More RCTs are needed to establish the efficacy of the procedure with the development of standardization of protocols for the treatment. The long-term safety of the treatment needs to be established through systematic follow-up. It is prudent to restrict nanofat and SVF therapies to select patients under ethical oversight and with meticulous documentation until sufficient evidence is available.

Based on the studies, the Evidence Level is 4 for its use in androgenetic alopecia and the Recommendation Grade is D.

Background

IV drips have gained a lot of popularity in esthetic medicine practice. It involves the infusion of various supplements, antioxidants, minerals, and vitamins directly into the bloodstream, enhancing their bioavailability and aiming to deliver better outcomes. It is imperative to understand the actual use and effectiveness of these drips and be cautious of adverse effects. We aim to explore the key ingredients that are used in IV drips in dermatology, their effectiveness, adverse effects, and evidence in the present day esthetic practice.

Common indications for IV drips in esthetic practice

Common indications include hydration drips, skin brightening or fairness drips, anti-aging drips, immunobooster drips, skin, hair, nail, collagen boosting drips, etc. Some of the common ingredients in drips are discussed.

Vitamin C

Vitamin C is a potent antioxidant, promotes collagen synthesis, improves wound healing, and has a role in photoprotection and skin brightening. The absorption of vitamin C in the gut is limited by an active transport mechanism, and hence, a finite amount of the drug is absorbed despite high oral dosage.⁸² IV route bypasses the digestive system and allows for optimal absorption. In aesthetic practice, high doses of Vitamin C are administered intravenously, typically ranging from 500 mg to 5000 mg per session.⁸³ Sessions are spaced 1–2 weeks apart. It is usually infused along with IV glutathione (GSH). On testing the efficacy for other dermatological conditions, it was found that intravenously administered ascorbic acid did not relieve acute Herpes Zoster pain but was effective for reducing the incidence of Post Herpetic Neuralgia.⁸⁴

Higher doses are associated with the risk of hemolysis, kidney stones, allergic reactions, and gastrointestinal symptoms.

GSH

GSH is a powerful antioxidant, most commonly used for skin brightening. It also helps in detoxification and immune modulation. GSH helps in skin lightening by inhibiting the enzyme tyrosinase and shifting the melanin production from eumelanin to pheomelanin. IV administration of GSH has gained attention in dermatology and social media for its purported effects on skin pigmentation, aging, inflammation, and oxidative stress-related dermatoses. IV administration increases the bioavailability.

Nicotinamide adenine dinucleotide (NAD+)

NAD is a cofactor in the electron transport chain and is present in all the cells and is necessary for cell viability and optimum function. Accumulating evidence suggests that active maintenance of optimal levels of the essential pyridine nucleotide, NAD+, is beneficial in conditions of either increased NAD+ turnover or inadequate synthesis, including Alzheimer’s disease and other neurodegenerative disorders and the aging process.⁹¹

NAD is administered at a dose of 250–1000 mg, as a slow infusion over 3–4 h. It is infused along with Vitamin B, C, and GSH.

Adverse effects include nausea, light headedness, rarely, infusion reactions.

Safety considerations and medical risks of IV drips for aesthetic conditions

Many of these IV drips are given in salons, spas, in shopping malls, and even at home service. Medical risks include infections, allergic reactions, bruising, fluid overload, electrolyte imbalance, nutrient overdose, and can even be fatal. Infections from non-sterile technique or equipment can lead to site infections or systemic sepsis and phlebitis due to repeated cannulation. Fluid overload in older individuals can lead to cardiac and kidney compromise, and electrolyte imbalance can lead to cramps and arrhythmias. Allergic reactions can cause mild itching to life-threatening anaphylaxis.

Position statement

Strong scientific evidence is lacking in healthy individuals; much of the benefit may derive from hydration or placebo effects. There is a lack of randomized control trials and most of the evidence is low. No professional dermatology or esthetic medicine guidelines officially endorse IV vitamin drips, vitamin C, or GSH for cosmetic or anti-aging purposes – usage remains off-label and largely unregulated.

Available evidences emphasize limited efficacy potential risks, and variable results and is not sufficient to make a recommendation for their routine use in clinical practice. The patient should be thoroughly investigated for any underlying systemic disease, screen for allergies before administering these drips. IV drips, if administered, should be given in a clinical setting with all safety measures and an emergency crash cart ready, with full information to the patient as per guidelines mentioned in the next article on general guidelines for emerging treatments.

Level of Evidence 5, Strength of Recommendation D.

Position statement

Short-term face tissue lifting after thread lift is supported by moderate-quality evidence (RCTs and case series), but effects generally do not persist beyond 6–12 months.

Long-term rejuvenation claims are not supported by controlled trials or robust data – expectations for lasting results should be managed accordingly.

Increasing the thread quantity/numbers does not clearly improve outcomes.

Polydioxanone (PDO) threads may be associated with fewer complications than non-absorbable threads, but high-level comparative evidence is lacking. Monothreads have limited evidence for rejuvenation.

Safety is generally acceptable with a moderate rate of minor, transient complications, but data on rare or long-term risks are limited.

Overall, the level of evidence for thread lifts is Level 3 with Grade C strength of recommendation. However, thelevel of evidence for the use of threads for short-term lift is Level 2 with Grade B recommendation.

Guidelines on how to initiate an emerging treatment which is yet to achieve good evidence and is currently not approved by regulatory agencies