A newer approach in the treatment of seborrheic dermatitis with QR678® and QR678 Neo®—A prospective pilot study

Seborrheic dermatitis is a common chronic inflammatory skin disorder that affects the scalp and is characterized by erythema and oily scales. It could perhaps be difficult to control and could seriously degrade one's quality of life. The study's objective is to assess the effectiveness of intradermal administrations of QR678 Neo® hair growth factor therapy for the treatment of scalp seborrheic dermatitis in both men and women.


| INTRODUC TI ON
Seborrheic dermatitis (SD) is a common, chronic inflammatory skin disorder that affects areas with a lot of sebaceous glands and is characterized by erythema and greasy scales. 1 It appears as scaly, dark, itchy lesions on the head, face, and trunk where there are many sebaceous glands. 2 In the first 3 months of life, the condition affects about 70% of infants and 3%-5% of adolescents. 3,4Males are more likely to be inflicted by it, than females, presumably because androgens stimulate sebum production. 5A study in India by Banerjee et al. 6 recorded that 13.4% of kids aged <5 years had seborrheic dermatitis.
In a study by Pillai et al., 7 in Indian adults having scalp dermatoses, 18.7% of cases were recognized as seborrheic dermatitis.Its incidence is 1%-3% in the general population as compared to 34%-83% in immune-compromised people. 8It typically affects several areas of the body with face involvement in 88% of patients, the scalp in 70%, the chest in 27%, and the arms or legs in 1%-2%. 9Scalp is one of the frequently involved site; the prevalence of seborrheic dermatitis in the scalp was observed to be 10.16%-11.6% and as high as 20%-50% in a few trials. 10The scalp of infants with seborrheic dermatitis typically exhibits focal or generalized white or yellow, greasy scaling and crusting. 8Seborrheic dermatitis frequently manifests in teens and adults as severe dandruff or oily scaling of the scalp. 1 The patches vary from mild scaling to widespread thick adherent crusts. 11alp seborrheic dermatitis cases are classified into mild, moderate, and severe using 4-point grade scores that are used to rank the scalp in terms of erythema, dandruff, and lesional extent (Table 1).
On the basis of the calculation of these elements, it is classified into mild (1-3), moderate (4-6), and severe SD (7-9). 12The pathogenesis of seborrheic dermatitis to some extent has been ascribed to colonization of the stratum corneum by Malassezia spp., adding to chronic, localized inflammation of seborrheic areas. 13Malassezia yeast appears to cause a vague immune reaction that starts the surge of skin alteration that happens in seborrheic dermatitis. 14e clinical presentation of dandruff is assessed by size, adhesion, and the light refractive properties of flakes.Microbial colonization of Malassezia fungi, sebaceous lipids, and specific immunity are some of the reasons that contribute to inflamed lesions on the scalp. 15A possible etiopathological mechanism is attributed to the release of fatty acids by lipase action from the parent sebaceous triglycerides.Free fatty acids, particularly unsaturated acids, can lead to inflammation and hyperproliferation, manifesting as the frequently encountered symptoms and signs of seborrheic dermatitis. 16 has been observed that in comparison to the non-lesional skin or skin of healthy controls, there are elevated levels of Natural Killer cells (NK1+), CD16+ cells, and inflammatory interleukins among individuals with seborrheic dermatitis, suggesting augmented inflammatory response among these candidates. 17Also, there is a genetic predilection of enhanced rate of (human leukocyte antigen) HLA-A32, HLA-AW30, HLA-AW31, HLA-B12, and HLA-B18 in individuals with seborrheic dermatitis. 4,18lecular level records from the seborrheic dermatitis lesions, epidermis plane showed raised levels of IL-1α, IL-1β, IL-6, IL-10, IL-12, IL-2, IL-4, Tumor Necrosis Factor (TNFα), interferons (IFNγ), and histamine. 16Specifically, IL-1 and TNF stimulate time-and-dosedependent increase in the production of Complement Proteins Factor B (FB), C3, and Factor H (FH). 19 While scalp hair loss is not commonly associated with seborrheic dermatitis, there is a likely connection between long-term inflammation in scalp and increased telogen shedding hair phase.This may precipitate alopecia if scalp involvement is persistent and serious. 20,21Seborrheic dermatitis may possibly be resistant to management and can also have a significant detrimental effect on the quality of life of an individual.Hence, treatment should be targeted to recover skin symptoms as well as quality of life. 22,23The treatment for seborrheic dermatitis is the regulation of sebum secretion and delivery of antimicroorganisms, antioxidants, and anti-inflammatory treatments. 24Topical medications and shampoos containing antifungal, anti-inflammatory, keratolytic, and calcineurin inhibitors are used to treat scalp seborrheic dermatitis.These agents reduced cutaneous inflammation by inhibiting T lymphocyte cytokine assembly. 17though being used as a first-line treatment, external preparations have a number of restrictions like dense skin, high amount of scalp sebum which serves as a barrier.Low-power medications do not have adequate effectiveness, and regular usage of external products may interfere with grooming.Also, there may be adverse events and disease recurrence after termination of treatment. 24,25e formulation of the QR678 / QR678 Neo® is a patented formulation comprising of biomimetic polypeptides-targeted and focused to induce hair re growth on the scalp.It contains a precise Vitamin K were also added to the solution along with minerals such as calcium, sodium, potassium, and magnesium, nucleic acids, and essential and optional amino acids. 26 animal study was the first to demonstrate safety and effectiveness, and it revealed that they were largely free from negative effects. 27Additionally, a 1000-patient open-label, prospective, single-arm interventional pilot research using the QR678 Neo® revealed that the formulation of several growth factors in QR678® and QR678 Neo® is equally effective in treating both male and female pattern hair loss. 26e formulation QR678 Neo® contains hair growth factors, vitamins and minerals, which also have anti-inflammatory action.9][30][31] Owing to this fact, a study was conducted to evaluate the effect of QR678 Neo® hair growth factor intralesional administration therapy for scalp condition in men and women with seborrheic dermatitis.

| Scalp assessment and evaluation
1. Assessment of disease severity: Assessment of severity of flaking was carried out using the adherent scalp flaking score (ASFS) technique by two blinded qualified dermatologists at baseline, after four and eight sessions.The patient was seated on the stool, and the scalp region under inspection was highlighted by illumination that mirrored daytime situations.In order to grade the severity, the scalp was split into eight parts.Every segment was measured for the existence of adherent dandruff flakes on the scalp using a scale of 0-10 (increase of 2 units).Loose flakes in the hair were not included for scoring.The final or cumulative ASFS is the number of the scores for all eight parts of the scalp, resulting in a scale varying from 0 to 80 units. 32Results were analyzed with repeated measure ANOVA test.

Dermoscopic evaluation:
In addition to the above subjective steps, we have used a unique, noninvasive imaging method called dermoscopic assessment to quantitatively assess the clinical improvement in the patient with erythema, scaling, and arborizing vessels.Images of lesions on scalp were obtained using a dermoscope (Fotofinder Leviacam, 13 MP resolution) attached to a digital camera.
The assessment was done by a dermatologist with the severity of scalp lesions using the Seborrheic Dermatitis Scalp Severity Index (SDSSI).With this tool, we scored erythema, scaling, and arborizing vessels separately on a scale of 0-4 at baseline, after four sessions and eight sessions of treatment. 33Repeated-measured ANOVA test was applied to check whether the results were statistically significant or not.

Self-assessment score:
At the conclusion of the study, patients answered four items in section 1 of a validated hair-related questionnaire.After eight sessions, the treatment's effectiveness was scored between 0 and 5, with 5 being the highest level of satisfaction.Patients were asked to check the proper replies to questions in section 2 that dealt with the negative consequences (multiple ticks were also allowed; Tables 2,3).

| RE SULTS
From October 2021 to October 2022, the single-arm prospective clinical trial was conducted after receiving approval from the institutional ethics committee.Patients in the study ranged in age from 18 to 45 years and had seborrheic dermatitis of the scalp.They underwent intradermal administration therapy with QR678 Neo® for eight sessions.The table below shows the demographic breakdown of patients by age, gender, BMI, and severity score (Table 4).

| Assessment of disease severity: adherent scalp flaking score
Subjective evaluation of the flaking severity of each patient was performed by two blinded dermatologist reviewers.The scalp was divided into eight sections; reviewers rated each section to grade the severity.The assessment was done at baseline, after fourth and eighth session.The mean value at the baseline was 60.Marked improvement was seen after fourth session (mean = 36) which was further improved after eighth session (mean = 12) which was maintained for over 1 year.All the values were shown to be statistically significant.It was also noteworthy that only one individual (5%) showed no response with the therapy (Tables 5,6, Figure 1).

| Dermoscopic evaluation
Dermoscopic evaluation was done with a blinded dermatologist using a dermoscope (Fotofinder Leviacam, 13 MP resolution) attached to a digital camera with SDSSI tool.Total score of erythema, scaling, and arborizing vessels was counted separately on a scale of 0-4.Mean score at baseline was 11.Improvement was noticeable after fourth session (mean = 7) which further improved after the eighth session evaluation (mean = 2).The same was maintained at 1-year follow-up also.All the data showed statistically significant results.Only 5% of the participants did not respond with the maintenance therapy after 1 year and needed repeat therapy (Table 7, Figure 2).

| Self-assessment score
Patients were asked to rate the effectiveness of the treatment on a scale of 0-5 for each of the four questions in section A. Patients gave a higher satisfaction rating for the rate of erythema and pruritus reduction (mean = 5).For reduction in inflammation/itchiness, satisfaction score was (mean = 4.5) high, reduced in the visibility of flakes (mean = 4.5), and amount of noticeable improvement (mean = 4) also was significant.Ten percentage (N = 2) of patients in section 2 stated a feeling of discomfort during administration; however, only 5% (N = 1) of patients reported an itchy scalp post the procedure (Figures 3,4).

| DISCUSS ION
The scalp comprises of a large number of multiple follicular structures, including sebaceous glands, which corresponds to a higher degree of sebum development.This renders the scalp susceptible to inflammation due to changes in sebum quantities or consistency and to contamination with microorganisms. 24Scalp seborrheic dermatitis can be widespread and presents as a chronic inflammatory skin condition that appears to recur over time.While it is a reasonably common disease, the seborrheic dermatitis pathogenesis or dandruff is still questionable. 12Seborrheic dermatitis has been shown to have a substantial effect on the quality of life of the patient.The aim of seborrheic dermatitis therapy is to reduce the signs and symptoms of inflammatory conditions and to encourage normalization of skin structure and function and also quality of life. 16ltiple topical treatments, mainly shampoo and cream/lotion preparations, have been used to manage seborrheic dermatitis of the scalp and/or glabrous skin. 34The disease needs frequent care and daily prophylaxis since it follows a chronic pattern of reversal and relapse. 35single-blind study by Squire et al. 36 showed a shampoo with ciclopiroxolamine 1.5% and salicylic acid 3% to have a potency comparable to that of ketoconazole 2% shampoo for the management of dandruff/seborrheic dermatitis.For both types, progress was maintained only 14 days after the completion of therapy.When compared to the current study, the efficacy of both methods is comparable, though there is a significant difference in the patient satisfaction measure as the current study shows better scores, and the benefits are more long-lasting in the current study.
A study by Hosking et al. presented a case report of scalp dermatitis.In addition to intralesional corticosteroid administrations, three sessions of subdermal administrations of PRP have been done in the scalp over 18 weeks.The patient showed significant improvement after the second session of PRP.However, shortly before the third session, the patients experienced a mild flare-up, also increased pruritus accompanied by systemic fatigue.Six weeks after the last PRP treatment, improvement was significant as compared to pre-procedure status.PRP can also help in reducing the inflammatory reaction seen in scalp SD, ultimately encouraging healing of the lesions, but bears little risk of swelling and scalp tenderness seems to be the most frequently recorded adverse events. 37In addition, it is painful, time-consuming, and needs standardization in preparation and administration protocols.The use of 1-mL solution of QR678 Neo® in the current study showed no instances of flare-up or signs of side effects with the efficacy being comparatively higher than the PRP.It is also relatively painless, easy to administer, and is a standardized formulation.It also contains anti-inflammatory and hair growth stimulating agents in its composition.synthesis may result in regulation of the acute inflammatory system, even more advancement to tissue repair and remodeling processes. 19scular endothelial growth factor: It is a very specific mitogen for vascular epithelial cells.Following cellular injury, it triggers angiogenesis as well as vasculogenesis.It significantly affects blood artery permeability and functions as a powerful angiogenic protein in a variety of pathogenic neovascularization processes.In skin function, VEGF is an important modulator for both health and disease. 38,39sulin-like growth factor: IGF-I and KGF cDNA gene transfer helps independently to advance dermal and epidermal rejuvenation.

IGF-I with KGF in increased epidermal regeneration was found by
Jeschke & Herndon. 40The study also showed it to be superior to monotherapy in promoting wound healing.QR678 Neo® has proved its efficacy in male pattern baldness in a comparative study with Platelet Rich Plasma (PRP).The result showed that QR678 Neo® significantly improves hair growth and is relatively painless compared to PRP. 43 In a study of patients with female pattern androgenetic alopecia with Poly Cystic Ovarian Syndrome (PCOS), QR678 Neo® has proved its efficacy in terms of reduction in hair loss and new hair regrowth significantly. 44Also in chemotherapy-induced alopecia (pCIA), QR678 Neo® has proved its efficacy in both males and female with a history of lung and breast cancer. 45Apart from these, the growth factor formulation has also shown clinically significant results in higher grades of alopecia.F I G U R E 4 Adverse effects as evaluated at the end of the study.

Following
clearance from the Institutional Ethics Committee review board (ethical clearance number: IEC/TEC0013), a single-arm, prospective study was conducted.A total of 40 patients-20 men and 20 women-with scalp seborrheic dermatitis who were between the ages of 18 and 45 years were chosen.All participants provided their written, signed consent after being fully briefed.Following clinical examination, patients with moderate-tosevere seborrheic dermatitis of the scalp in the age range of 18-45 years, both male and female, were chosen.Patients were treated in a dedicated air-conditioned room with a temperature maintained at 25°C.Patients who were previously treated with standard current therapy recommended for seborrheic dermatitis(which comprises of varied combinations of oral antifungals, antifungal shampoo, topical antifungal, steroid lotion, and topical calcineurin inhibitors for at least 6 months) without significant clinical improvement or response were also included.Patients clinically diagnosed with any other scalp disease other than seborrheic dermatitis and ones with history of seborrheic dermatitis for less than 6 months were excluded from the study.Patients with history of skin cancer, suspected malignancy, autoimmune/hematologic disorders, connective vascular diseases and pregnant women were also excluded from the study.Participants were advised to avoid triggers (heat, humidity, sweat, and prolonged sun exposure) of seborrheic dermatitis symptoms to the extent possible and not to irritate the lesions by excessive scratching or use of potent keratolytic preparations.Participants were advised to continue with topical applications, as mentioned above, which they had already been using during the course of the treatment along with QR678 Neo® hair administrations.

2. 2 |
Administration technique used for scalp All the patients were evaluated at baseline, after four sessions and eight sessions with physician assessment of severity score, standard global photography, and scalp dermoscopy to assess the clinical endpoints.At each visit, 1-mL solution of QR678 Neo® was administered in the scalp skin of patients.Several tiny, and nearly painless administrations were made on the target scalp site using 31-G needle through nappage technique.Administrations were given covering the visible areas of erythema, scaling, and pruritus.Each administration was administered 1 cm apart with 0.02 mL of volume per administration.A total of eight sessions were performed at intervals of 3 weeks between sessions.

TA B L E 3 2
Patient self-assessment questionnaire: section 2adverse effects.Patient self-assessment questionnaire: section 1 patients satisfaction score.
Polypeptide growth factors are essential for mending tissue damage, regulating cell division, proliferation, and differentiation, and promoting tissue regeneration.Growth factors also have other effects that reduce inflammation, such as reducing cytokine production, stopping lymphocyte proliferative responses to IL-1 and IL-2, and reducing the expression of class II histocompatibility antigens that is boosted by interferon.Particular suppression of cytokineinduced growth factor rises in complement protein factor B (FB)

Vitamin C:
Vitamin C has been shown to have gained therapeutic importance in the treatment of efficacy in the reduction of highsensitivity C-reactive protein (hs-CRP), fasting blood glucose (FBG), interleukin 6 (IL-6), and triglyceride (TG).As a result, vitamin C has potential benefits in mitigating inflammatory status.41Vitamin B: Vitamin B complex (B1-B6 and B12) could efficiently prevent inflammatory reactions by decreasing pro-inflammatory expression and by increasing the control of anti-inflammatory cytokines, thus leading to inflammatory recovery.42Vitamin E: Vitamin E has been found to inhibit the growth and severity of the region of inflammation.Anti-inflammatory effect is attributed to its potential to protect the cell membrane, resulting in inhibition of the release of histamine and serotonin.12

5 |F I G U R E 3
46 A clinically significant hair growth was also seen when QR678 Neo® was administered in patients suffering from alopecia areata and post infection acute hairfall.47,48The efficacy of QR678 Neo® was investigated in conjunction with dermaroller application and its performance was evaluated in comparison to both intradermal and F I G U R E 1 Patient 1 clinical photographs: (A) pretreatment and (B) after eighth session.Value < 0.05 is showing statistically significant result.TA B L E 7 Dermoscopic evaluation with Seborrheic Dermatitis Scalp Severity Index tool by dermatologist.F I G U R E 2 (A) Dermoscopic image showing scaling, erythema, and arborizing vessels.(B) Dermoscopic image after eighth session.topical administrations.The outcomes demonstrated favorable results across these modalities.49,50As QR678 Neo® contains therapeutically acceptable ranges of growth factors, vitamins and minerals like IGF-1, VEGF, bFGF, KGF, thymosin β4, and copper tripeptide-1, Vitamin A, B complex, C, E, I, K, calcium, sodium, potassium, magnesium, 9 nucleic acids, essential and nonessential amino acids, this intricate composition collectively contributes to the discernible reduction in hairfall, as demonstrated by the results of the phase IV clinical trial.51Administration of QR678 Neo® in scalp skin of a patient with seborrheic dermatitis helped in reduction of signs of inflammatory lesions.Also, improvement was seen with a reduction in erythema, scaling, and arborizing vessels to a significant extent.Significant improvement was seen in the visibility of flakes and itchiness after eight sessions of treatment, thus helped to improve the quality of life of patients.It is important to note that none of the patients reported severe side effects and relapse at 1-year follow-up visit.Thus, QR678 Neo® seems to be efficacious in the treatment of seborrheic dermatitis of the scalp in both males and females.CON CLUS ION Our study proves that treatment with QR678 Neo® leads to an improvement in the overall scalp condition by the resolution of flaking and inflammatory biomarkers.As mentioned before, many other existing modalities of treatments fail to give improvement over time and have been found to have adverse effects in the long term.QR678 Patient self-assessment questionnaire.

Grade Elements of seborrheic dermatitis severity Erythema Dandruff Lesional extent
Demographic distribution of patients as per grading of severity, age, gender, and BMI.
TA B L E 4