Revolutionizing Pediatric Dermatology: Dupilumab’s Impact on Atopic Dermatitis in Kids

ABSTRACT


INTRODUCTION
Atopic dermatitis (AD), known as Eczema, is a common, chronic, non-communicable, immune-mediated inflammatory skin condition that mostly affects children.It ranks first among all skin illnesses and 15th among nonfatal diseases (Rusiñol & Puig, 2024).It typically manifests within the first six months of life.It harms general health and is linked to a higher occurrence of mental health conditions and symptoms, including anxiety, depression, hyperactivity, sleep problems, asthma, hay fever, cardiovascular disease, stroke, and obesity (Chovatiya & Silverberg, 2019;Nicholas et al., 2022;Xu et al., 2019).It is caused by changes in the skin microbiotaimmune system hyperactivity, sensitivity to immunoglobulin E, neuro-inflammation (Mandlik & Mandlik, 2021), environmental variables, and hereditary predisposition.(Grobe et al., 2019;Mehta & Fulmali, 2022).The intricate interactions between itch, inflammation, and barrier failure play a crucial role in this condition's onset, progression, and chronicity, even though the pathophysiological mechanisms are yet unknown.Skin inflammation that is aggravated by filaggrin abnormalities, intercellular lipids, and tight junctions is the hallmark of type 2 immune deviation.These abnormalities lead to barrier disruption in the skin, producing thymic stromal lymphopoietin, interleukin (IL)-25, and IL-33.Subsequently, this inflammation intensifies the breakdown of the epidermal barrier by suppressing filaggrin expression in keratinocytes.Moreover, various pruritogens and itch mediators generated during this inflammatory process can directly affect sensory nerves and induce itching (Kim et al., 2019;Nakahara et al., 2021).While in some children, food allergies are closely associated with AD, 30% of these children experience symptoms such as rash, itching, leaking, and dry, cracked skin.Smaller kids show intolerance to some foods.Red, weepy, crusty, itchy, and flaky skin patches that typically form in oval or circular forms are its defining feature (Rusiñol & Puig, 2024).Age-related symptom variations include red rash in infants, thickened rash in children, and scaly rash in teens and adults.Common  (Frazier & Bhardwaj, 2020;Soares et al., 2024).For patients with moderate to severe types of atopic dermatitis (AD), biological therapies are very important.These therapies concentrate on particular molecules involved in the inflammatory and immunological responses typical of AD.Compared to more conventional treatments like corticosteroids or immunosuppressive medications, biological therapies like monoclonal antibodies like Dupilumab and Tralokinumab provide a more tailored approach by concentrating on particular molecular targets (Deleanu & Nedelea, 2019).New insights into the immunopathology of AD have made it possible to identify therapeutic molecular targets for innovative biological therapies.By modifying the immune response and inflammatory pathways, these treatments; including "IL-4/IL-13" inhibitors, JAK inhibitors, and "IL-13 inhibitors" have demonstrated notable success in treating AD.Furthermore, the FDA has approved biologics like Dupilumab for treating moderate-to-severe AD, demonstrating their efficacy in enhancing patients' quality of life and symptom relief (Zhou et al., 2021).It provides a more focused and targeted approach.
Research has indicated that biological treatments are a useful means of alleviating symptoms.Furthermore, biologics have demonstrated a quick start of action, offering immediate relief to patients who have not responded well to traditional therapy.Clinical trials and real-world applications have provided strong evidence for the Safety and Effectiveness of biological therapy (Caffarelli et al., 2023;Montes-Torres et al., 2015).The present research paper aimed to evaluate and compare the efficacy, optimal dosage, and frequency of administration of biological treatment such as monoclonal antibody Dupilumab with standard treatment options, including antibiotics, corticosteroids, Immunosuppressants such as cyclosporine, mycophenolate, tacrolimus, and azathioprine, histamines, and Demards like Methotrexate in the management of atopic dermatitis in pediatric patients.

Methods and Clinical Trials
The research study on "Revolutionizing Pediatric Dermatology: Dupilumab's Impact on Atopic Dermatitis in Kids" was conducted by employing the approved clinical trials studies of "United States-Food & Drug Administration (FDA)" among individuals of different ages, ethnicity, genders and health status.

Efficiency of Biological Treatment
Systemic non-biological therapies, such as oral corticosteroids, cyclosporine, Methotrexate, azathioprine, and mycophenolic acid, effectively manage moderate to severe atopic dermatitis (Paolino et al., 2023).Nonbiological systemic therapy for atopic dermatitis may not be as effective at controlling symptoms and preventing exacerbations as biological treatments are (Ferrucci et al., 2023).Meanwhile, biological therapies, including Dupilumab, Omalizumab, and Ustekinumab, offer a more targeted approach focusing on molecules linked to the immune response and inflammatory processes in AD.These biologics have shown a significant improvement in symptoms and quality of life for those with moderate to severe AD (Chu et al., 2023) and disease control by targeting key pathways involved in AD pathogenesis, such as Th2, Th22, Th17/IL-23, and IgE.

Monoclonal Antibody Dupilumab
Dupilumab obstructs the signalling pathways for interleukin 13 (IL-13) and 4 (IL-4).Attaching to the alpha subunit of the interleukin-4 receptor (IL-4Rα), this method of action functions as a receptor antagonist.Dupilumab specifically targets two important cytokines involved in asthma and atopic dermatitis inflammation: "IL-4 and IL-13" intracellular signalling.The simultaneous inhibition of "IL-4 and IL-13" signaling enhances skin barrier function, reduces type 2 inflammation, reduces itching, and improves skin lesions in people with atopic dermatitis.(Kraft & Worm, 2017).Dupilumab significantly enhances clinical scores and symptoms in children with severe atopic dermatitis aged 6-11 years, improving their quality of life and smoother skin (Berna-Rico et al., 2023;Cork et al., 2024).The recommended dosages and frequency of dupilumab for children with atopic dermatitis are weight-based and range from 200 mg to 300 mg for children weighing 15 to 30 kg, 30 to 40 kg, and 40 kg or more (Berna-Rico et al., 2023;Cork et al., 2024;Kamal et al., 2021).

Comparison with Other Treatment Modalities Antibiotics for Atopic Dermatitis
Since secondary skin infections frequently arise in AD patients, antibiotics, including cephalexin, clindamycin, doxycycline, azithromycin and amoxicillin/clavulanic acid, are frequently used to manage AD.In eczematous lesions of atopic patients, Staphylococcus aureus colonization is common.It releases superantigens and exotoxins that prolong inflammatory reactions and worsen symptoms.Patients with AD are often offered topical antibiotics such as gentamicin, fusidic acid, and mupirocin for mild to moderate secondary infections (Neri, 2015).

Cephalexin
Is a first-generation cephalosporin used to treat Staphylococcus aureus-related skin infections in atopic dermatitis, particularly in those with colonized Staphylococcus aureus.Its bactericidal activity supports its use in treating atopic dermatitis, prophylaxis, and minor procedures (Class et al., 2022;Rist et al., 2002).

Clindamycin
A Lincosamide antibiotic, is used to treat severe skin and soft tissue infections caused by Staphylococcus aureus.It works well against aerobic and anaerobic bacteria, especially in those with S. aureus colonization due to atopic dermatitis (Coskey, 1978;Mose et al., 2022).

Doxycycline
A tetracycline antibiotic doxycycline, has been investigated for treating atopic dermatitis (AD).Doxycycline may be able to treat AD since research indicates that it may include anti-inflammatory qualities and antibacterial benefits.Doxycycline may have a role in regulating the immune response in allergy disorders such as AD.Its use has been widely demonstrated to reduce mast cell histamine release and asthmatic patients' levels of immunoglobulin E (IgE) for skin disorders such as rosacea, acne, and perioral dermatitis (Bohannon et al., 2020;Hulme, 2023); It also functions by destabilizing nitric oxide synthase (NOS), which can reduce inflammation and improve symptoms of atopic dermatitis by increasing degradation.It is frequently used to treat skin conditions such perioral dermatitis, acne, and rosacea.(Bohannon et al., 2020).

Effectiveness and Limitations
Children who were exposed to antibiotics in their early years had a higher chance of acquiring adverse events.Irrational and direct use of broad-spectrum antibiotics increases susceptibility to infections and resistance rates, potentially leading to fatal diseases.The relative efficacy of antibiotics and biological treatment for pediatric atopic dermatitis depends on the particular circumstances and degree of the ailment.Although they have a limited effect in treating the underlying inflammation of Atopic dermatitis, antibiotics are frequently used to treat infections that may worsen the symptoms of atopic dermatitis.According to research, antibiotics may not significantly help children with minor eczema infections, and they may even increase skin sensitivity and resistance (Choi et al., 2020;Li et al., 2021;Mubanga et al., 2021).

Corticosteroids in Atopic Dermatitis Management
Depending on the severity of the ailment, different dosages and potencies of corticosteroids, such as Hydrocortisone, fluticasone, betamethasone valerate, and tacrolimus, are frequently given to treat atopic dermatitis (Drucker et al., 2018;Stacey & McEleney, 2021).

Hydrocortisone
Hydrocortisone is frequently used for the treatment of atopic dermatitis in a variety of dosages and formulations.Hydrocortisone comes in various formulations for atopic dermatitis, with concentrations ranging from 0.1% to 2.5%.These formulations include creams, lotions, gels, solutions, and ointments.Lower potency hydrocortisone formulations "(class VI or VII), such as 1% cream" or ointment, are usually used for infants and children with atopic dermatitis.These formulations are administered twice a day to reduce inflammation and itch.Low-potency steroids should be used for maintenance in cases of mild atopic dermatitis after intermediatepotency steroids (class III, IV, and V) are taken for short periods to control flare-ups in severe atopic dermatitis cases in teenagers (Haeck et al., 2011), while their excessive strength may result in negative side effects such as folliculitis, dermatitis, acne, atrophy of the skin, itchiness, changes in pigmentation, and inhibition of the hypothalamic-pituitary-adrenal axis (Axon et al., 2021).

Fluticasone
A corticosteroid, is available in several formulations and doses ranging from 0.05% to 2.5%.It is used in atopic dermatitis to reduce inflammation and symptoms by suppressing the release of inflammatory mediators (Dhamija et al., 2024).On the other hand, a variety of negative side effects might occur, such as increased hair growth, dizziness, rash, itching, and redness of the treated area of skin.Hives, breathing difficulties, swelling of the lips, tongue, or throat, skin pain, tenderness, or swelling, wounds that do not heal, severe skin irritation, or signs of systemic absorption such as weight gain, thinning or discolored skin, increased body hair, nausea, diarrhoea, fatigue, mood swings, menstrual changes, and sexual changes, as well as severe headaches, confusion, muscle weakness, vision abnormalities, heart symptoms, or serious allergic reactions are examples of serious side effects that can occur.(Berth-Jones et al., 2003;Harvey et al., 2023).

Betamethasone Valerate
0.1% twice daily for three to five days.The corticosteroid betamethasone can efficiently manage Children's eczema flare-ups, which enhances skin barrier function and reduces skin inflammatory responses (Subramanian et al., 2018).

Topical & Oral Corticosteroids Effectiveness in
Comparison with Dupilumab-FDA It has been shown that Dupilumab (Dupixent) can be used with or without topical corticosteroids in the treatment of disorders like atopic dermatitis based on the information from the sources that have been presented, including the FDA clinical trials and reviews on the drug.Dupilumab is a useful therapeutic option for moderate-to-severe atopic dermatitis since clinical trials have demonstrated that adding it to topical corticosteroids has significantly improved patient-reported symptoms and quality of life.According to a study, dupilumab is far more effective than a placebo in relieving the condition of individuals with atopic dermatitis when used in conjunction with topical corticosteroids.These trial studies have demonstrated the advantages of using Dupilumab with topical corticosteroids, highlighting the drug's efficacy in treating atopic dermatitis and minimizing the need for corticosteroids alone.Consequently, dupilumab combined with topical corticosteroids is a beneficial therapeutic strategy for diseases like atopic dermatitis, providing patients with better results and a higher quality of life, according to data from FDA clinical trials and reviews (FDA, 2017).

Immunosuppressant's Cyclosporine
A calcineurin inhibitor, targets T cells specifically, inhibiting the transcription of the interleukin 2 gene, modifying the immune response, and lowering inflammation in diseases such as atopic dermatitis, typically administered at a dose of "5 mg/kg/day" and available in multiple forms, including intravenous formulations, oral solutions, and gelatin capsules (Amber & Tabassum, 2020;Antti et al., 2021;Megna et al., 2017;Rajagopalan et al., 2022).

Mycophenolate
Based on numerous investigations and clinical trials, Mycophenolate mofetil (MMF) has demonstrated promising outcomes in treating atopic dermatitis.Studies showed that MMF is useful in treating moderate to severe AD among individuals who did not respond to conventional treatments; there was a notable improvement in the severity of the illness.MMF significantly reduced the SCORAD index, a gauge of the severity of AD, within a few weeks of treatment; it may be a useful substitute for people with severe or refractory types of AD because of fewer risks of causing adverse effects than other longterm therapies for the disease (Phan & Smith, 2020).

Azathioprine
Immunosuppressive drugs like azathioprine prevent the manufacture of purines, which impacts lymphocytes and helps regulate the immune system in atopic dermatitis (AD) by lowering inflammation and managing symptoms.The recommended daily dose of azathioprine for AD is 1-2.5 mg/kg, with adjustments based on individual patient response and tolerance.It can cause myelosuppression, increased risk of infection, and gastrointestinal problems.

Safety profile & Clinical trials of Immunosuppressants in Comparison with Dupilumab
According to the information provided by the sources, including the FDA approvals and clinical trials on the drug, Dupilumab, also known as Dupixent, has been the subject of substantial research spanning over "60 clinical trials" involving over "10,000" patients with various chronic conditions.For the treatment of disorders such as asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyposis, and eosinophilic esophagitis, Dupilumab, a completely human monoclonal antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling has demonstrated noteworthy clinical advantages.Dupilumab's Effectiveness in lowering type 2 inflammation, a major factor in many illnesses, has been demonstrated by these trials.Specifically, the FDA has approved Dupilumab for kids with eosinophilic esophagitis aged one year and older, as well as kids with moderate-to-severe atopic dermatitis aged six months to five years.(FDA, 2019).

Demards (Disease-Modifying Anti-Rheumatic Drugs) Methotrexate
Inhibits the immune system by inhibiting DNA synthesis and cell division by blocking dihydrofolate reductase.For AD, Methotrexate is administered at a starting dose of 10.3-2.6 mg/week, which can be changed according to the patient's tolerance and reaction.Weekly increases are possible, with maintenance dosages of about "11.7 mg" (Lee et al., 2020;Shah et al., 2018).

Comparison with Biological Agents Like Dupilumab on Based on Clinical Trials
In individuals with moderate to severe atopic dermatitis, Dupilumab has been demonstrated to be more successful than Methotrexate in reducing symptoms and quality of life.This conclusion is based on FDA clinical trials and real-world analysis comparing the two medications.When compared to Methotrexate, the trials showed that Dupilumab improved atopic dermatitis symptoms and signs more, and there were fewer side effects and treatment discontinuations.For treating atopic dermatitis, Dupilumab is therefore thought to be more effective and tolerable than Methotrexate, according to data from FDA clinical studies and real-world research (FDA, 2017).

Histamine Antagonist's Comparison with Dupilumab-FDA Clinical Trials
According to FDA clinical trials, Dupilumab is superior to histamine antagonists in treating disorders like atopic dermatitis and chronic spontaneous urticaria.Atopic dermatitis patients with moderate-to-severe AD have shown notable improvements in their quality of life and a reduction in the severity of their condition after using Dupilumab, an interleukin-4 receptor alpha antagonist.Dupilumab, on the other hand, may provide a more thorough treatment of the disease's underlying inflammatory processes than histamine antagonists, which target histamine receptors to relieve symptoms like pruritus.Dupilumab is a better therapy choice than histamine antagonists for disorders including atopic dermatitis and chronic spontaneous urticaria because of its demonstrated ability to relieve signs and symptoms of AD with a tolerable safety profile (Hon et al., 2021;Clinical trials 2017).

Tacrolimus as an Immunosuppressant
Atopic dermatitis (AD) has found a valuable new therapy option in tacrolimus, a macrolide calcineurin inhibitor.It achieves its therapeutic effects through immune response modulation and inhibition of inflammatory processes linked to AD progression.In the treatment of moderate to severe AD, topical tacrolimus has demonstrated efficacy and safety, providing a non-corticosteroid option.
Research has shown that tacrolimus ointment (available in 0.03% and 0.1% concentrations) is more effective in treating AD than pimecrolimus and moderate corticosteroids.Tacrolimus works by attaching itself to particular T cell receptors, which raises intracellular calcium levels and inhibits the transcription of cytokines such as "IL-2, IL-4, and IL-5".Clinical studies have demonstrated topical tacrolimus's Effectiveness in lowering AD severity ratings and improving safety profiles with less systemic absorption (Martins et al., 2015;Umar et al., 2022).

Dupilumab
Compared to tacrolimus, the FDA clinical trials have yielded strong evidence for the safety and Effectiveness of dupilumab in treating ailments such as atopic dermatitis.Atopic dermatitis patients with moderate-to-severe AD have shown notable improvements in their quality of life and a reduction in the severity of their condition after using Dupilumab, an interleukin-4 receptor alpha antagonist.Dupilumab is a better therapy option than tacrolimus for AD patients due to its great efficacy in reducing symptoms and enhancing quality of life, as demonstrated by clinical trials.Dupilumab is a better therapy choice than tacrolimus because of its focused mechanism of action and excellent safety profile (FDA, 2019).

Summary of FDA-approved Clinical Studies
According to FDA clinical trials, Dupilumab has proven to be a highly effective and safe treatment for moderateto-severe atopic dermatitis in children.In children with atopic dermatitis, aged "6 to 11 years", who are not sufficiently managed by traditional therapy such as topical corticosteroids and emollients, these trials have assessed the real-world Effectiveness of dupilumab.Research has indicated that Dupilumab significantly improves overall quality of life, pruritus, sleep quality, and disease severity in young AD patients.More specifically, at week sixteen of treatment, a large percentage of patients showed statistically significant improvements in the "Children's Dermatology Life Quality Index (c-DLQI), Sleep NRS (S-NRS), Pruritus Numerical Rating Scale (P-NRS), and Eczema Area Severity Index (EASI) scores".Based on these results, young patients with moderate-to-severe atopic dermatitis can benefit from using dupilumab as a treatment option.It is a viable therapeutic alternative beyond topical medications (FDA, 2019;Kamphuis et al., 2022;Napolitano et al., 2022).

DISCUSSION
Eczema, or atopic dermatitis, is a chronic, noncommunicable, inflammatory skin ailment mainly affecting children.It ranks first among skin conditions and fifteenth among non-fatal diseases, and it can cause mental health problems.Biological therapies like Dupilumab, Omalizumab, and Ustekinumab target immune response and inflammatory processes in atopic dermatitis, improving symptoms, quality of life, and disease control.In contrast, Nonbiological systemic therapy for atopic dermatitis may not be as effective in controlling symptoms and preventing exacerbations as biological treatments.Early exposure to antibiotics can raise a child's vulnerability to infections and resistance rates, which can result in life-threatening illnesses.The severity of the condition determines how well biological therapy and antibiotics work for pediatric atopic dermatitis.Dupilumab and other biological agents are suggested for children with mild eczema infections.Topical corticosteroids can be used alone or with dupilumab, a medication used to treat atopic dermatitis.Clinical investigations demonstrate that augmenting corticosteroids with dupilumab greatly improves patients' symptoms and quality of life.According to studies, dupilumab is a better treatment option for atopic dermatitis than a placebo, especially when used with topical corticosteroids.According to FDA guidelines, biological agents are preferred in paediatrics over Immunosuppressant including cyclosporine, mycophenolate, azathioprine and antimetabolite methotrexate because of their Effectiveness in enhancing immune results rather than inhibiting the body's immune system.It was evident from FDA clinical trials that dupilumab is a safe and effective treatment for children with moderateto-severe atopic dermatitis, ages 6 to 11.Studies reveal that in young AD patients, it considerably reduces the severity of the disease, pruritus, and general quality of life.In addition to conventional topical drugs, this treatment provides a good therapeutic alternative.

Challenges and Considerations Cost-effectiveness of Dupilumab in Comparison with Non-biological Treatments
The analysis revealed that although the costs of Dupilumab may be higher than those of non-biological treatments like topical medicines, it is related to more "Quality-Adjusted Life Years (QALYs)" and good cost-effectiveness ratios.It suggests that compared to more affordable standard treatments like moisturizers and emollients, Dupilumab adds value by significantly increasing health outcomes.According to the research, dupilumab presents a novel and efficacious therapeutic option for patients with moderate-to-severe atopic dermatitis, particularly when the Effectiveness of conventional treatments is compromised.The severity of the ailment affects how cost-effective Dupilumab is compared to non-biological treatments; more severe patients are likely to benefit more from Dupilumab in terms of better health and quality of life (Anderson III & Szefler, 2019;Sonya Kahn et al., 2018).

Adherence to Treatment Regimens in Pediatric Patients
In comparison to non-biological therapy, pediatric children with atopic dermatitis seem to adhere better to Dupilumab treatment regimens.Research has indicated that children with moderate-to-severe atopic dermatitis can experience improvements in disease severity, pruritus, sleep quality, and overall quality of life while using the completely human monoclonal antibody Dupilumab.Based on actual data from clinical trials, Dupilumab significantly improves pediatric patients' scores on the "Eczema Area Severity Index (EASI), Pruritus Numerical Rating Scale (P-NRS), Sleep NRS (S-NRS), and Children's Dermatology Life Quality Index (c-DLQI)".Dupilumab is well-tolerated and efficacious in juvenile populations, as evidenced by the high percentage of patients achieving "EASI75" and the significant mean percentage reduction in P-NRS, S-NRS, and c-DLQI scores (Napolitano et al., 2022;Papp et al., 2021).

CONCLUSION Potential Advancements in Biological Therapies for Atopic Dermatitis
Targeted biological therapy dupilumab addresses treatment resistance and lowers the likelihood of relapse in patients with atopic dermatitis, improving treatment results and quality of life.This development in biological treatments is immensely beneficial in treating chronic inflammatory diseases like atopic dermatitis.

Importance of Personalized Treatment Approaches
Optimizing results for children with disorders such as atopic dermatitis requires the use of personalized therapy techniques utilizing monoclonal antibodies, such as Dupilumab.Personalized treatment is a helpful therapeutic option for inadequately controlled atopic dermatitis, as studies in children aged 6-11 reveal significant improvements in disease severity, pruritus, sleep quality, and quality of life.

RECOMMENDATIONS
➢ Real-world data on Dupilumab's Effectiveness in diverse pediatric populations is needed to validate clinical trials and provide insights into its wider patient cohorts.➢ Examine the long-term safety and efficacy of dupilumab in treating pediatric patients with atopic dermatitis, as well as any possible negative effects and overall disease control.➢ Evaluate the Effectiveness, safety, and tolerability of Dupilumab compared to other biologic drugs in pediatric atopic dermatitis therapy, such as Tralokinumab or Omalizumab.

LIMITATIONS
➢ The severity of atopic dermatitis in children significantly influenced the response to Dupilumab treatment, making it challenging to draw definitive conclusions.➢ Dupilumab treatment's high cost and accessibility issues in certain healthcare settings caused hindrances in its widespread adoption and data availability in research studies.

Figure 1 :
Figure 1: Conditions related to atopic dermatitis