|Year : 2021 | Volume
| Issue : 2 | Page : 107-117
Biologics in pediatric dermatology
Manjyot Gautam1, Ratnakar Shukla2
1 Department of Dermatology, Dr. DY Patil Medical College, Navi Mumbai, Maharashtra, India
2 Senior Resident, Department of Dermatology, AIIMS, Patna, Bihar, India
|Date of Submission||21-Jan-2021|
|Date of Decision||27-Jan-2021|
|Date of Acceptance||16-Feb-2021|
|Date of Web Publication||31-Mar-2021|
Department of Dermatology, Mayo Institute of Medical Sciences, Barabanki, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Biologics are the molecules of protein, produced by recombinant DNA technology that are used in various diseases to target the specific points in the immunopathogenesis of the diseases without interfering with rest of the pathogenetic pathways and thereby expected to have a lesser side effects profile when compared to conventional immunosuppressant. With the advent of biologic therapy, the treatment of various systemic and cutaneous diseases, especially autoimmune diseases, has been revolutionized; biologicals are goal-directed lethal weapons in treatment armamentarium of a dermatologist; they are a major breakthrough and game changer in the field of dermatology therapeutics or you can say in general as a therapeutic option. While adults have been enjoying the benefits of biologics in treating skin conditions such as psoriasis, eczema, and hidradenitis suppurativa for last few years, but the use of biologics in the pediatric population is still limited because of unknown long-term safety profile and absence of large-scale studies. Thankfully, times are changing, and Biologics are slowly being approved for pediatric use too, in coming future dermatologists will be able to assess which pathways, in particular, are overactive and then prescribing the exact biological as per the need of the patient. In this review, a brief description is given of different biologic agents that are known currently. An extensive literature search was done; all clinical trials, randomized double-blind or single-blind controlled trials, open-label studies, retrospective studies, reviews, case series, and case reports concerned with the use of biologics in various pediatrics dermatoses were screened. The selected articles were retrieved; the final manuscript was prepared, analyzed, and presented in a narrative fashion.
Keywords: Autoimmune diseases, biologics, immunosuppressant, paediatric, recombinant DNA technology
|How to cite this article:|
Gautam M, Shukla R. Biologics in pediatric dermatology. Indian J Paediatr Dermatol 2021;22:107-17
| Introduction|| |
The advent of biologics has revolutionized the treatment of many chronic, inflammatory, and autoimmune dermatoses, especially in the adult population. The biologics are target specific, and therefore, less immunosuppressive as compared to the conventional immunosuppressants which have a broader impact on the immune system. Biologics are the new-age medicine because of their convenient dosing regimens, high efficacy, fewer side effects, low frequency of laboratory monitoring, and better tolerability.
Dermatologic diseases common in the pediatric age group such as atopic dermatitis (AD) and psoriasis (Ps) have a significant impact on the child's quality of life, and thus, early recognition and prompt management is warranted to decrease the associated psychological morbidity; biologic options available for pediatric patients are still very few and limited. Therapeutic guidelines are missing, and further research is needed to evaluate the efficacy, safety, and precise dosing of these agents in the pediatric population. Nevertheless, slowly but steadily, biologics are gaining approval for the use in pediatric dermatoses. It is therefore essential for dermatologists to have a thorough knowledge of the various biologics being used in pediatric dermatoses, their indications, efficacy, and safety in this population.
| Method of Acquiring Data|| |
An extensive literature search included key words such as “biologics,” “pediatric,” “psoriasis,” “atopic dermatitis,” “alopecia totalis,” “alopecia universalis,” “pemphigus,” “ bullous pemphigoid,” “vitiligo,” “lupus erythematosus,” “Stevens–Johnson syndrome,” “toxic epidermal necrolysis,” “TNF alpha inhibitors,” “etanercept,” “adalimumab,” “infliximab,” “secukinumab,” “ustekinumab,” “dupilumab,” “omalizumab,” “apremilast,” “rituximab,” “JAK inhibitors,” “tofacitinib,” “ruxolitinib,” “baricitinib,” “crisaborole,” and “belilumab.” All clinical trials, randomized double-blind or single-blind controlled trials, open-label studies, retrospective studies, reviews, case series, and case reports concerned with the use of biologics in various pediatrics dermatoses were screened. The articles which did not have relevant information were excluded. The selected articles were retrieved; the final manuscript was prepared, analyzed, and presented in a narrative fashion.
The various biologic agents used in pediatric dermatoses are listed in [Table 1].
Etanercept is a recombinant fully human dimeric fusion protein consisting of the Fc portion of IgG1 fused with a recombinant human tumor necrosis factor (TNF) receptor protein. It has the capacity to bind with both membrane-bound and soluble forms of TNF.
Among all the biologics available, Etanercept is the most extensively studied biologic in children including infants. The European Medicines Agency (EMA) (2009) approved the use of Etanercept in children aged 6 years and above and Food and Drug Administration (FDA) (2016) approved its use in children 4 years and above for the treatment of severe, chronic plaque psoriasis refractory or intolerant to conventional systemic therapies or phototherapy. It has also been successfully used in children and infants with other variants of psoriasis including erythroderma, generalized pustular psoriasis (GPP), palmoplantar psoriasis, and psoriatic arthritis (PsA). There is a significant improvement in the quality of life of children with psoriasis Etanercept can be combined with other immunosuppressant such as methotrexate (MTX).
Other off-label indications
Etanercept can be used as off label in many dermatological conditions:
Commonly observed adverse effects (AEs) include upper respiratory tract infection (URI) (37.6%), nasopharyngitis (26%), headache (21.5%), injection site reactions (6.1%), and cellulitis (<1%). There have been no cases of opportunistic infections or malignancy reported, but an increased risk of lymphoma and other malignancies in pediatric populations have been expected.
Adalimumab is a fully-humanized, recombinant, IgG1 monoclonal anti-TNF-α antibody having the capacity to bind with both soluble and membrane-bound TNF, thereby preventing attachment and binding with the p55 and p75 cell surface receptors.
Adalimumab is FDA approved for Crohn's disease in children 6 years and above and juvenile idiopathic arthritis in children 2 years and above, but its use in pediatric psoriasis is off-label. In 2015, the EMA approved its use in children 4 years and above for chronic plaque psoriasis with poor response to topical treatments and phototherapy. Adalimumab has superior efficacy compared to MTX while having a similar safety profile.
Although there are no clinical trials of Adalimumab use in HS in the pediatric age group, the FDA and European Union approved its use in moderate-to-severe HS in patients aged 12 years and older. Dosing in adolescents is same as in adults 0.8 mg/kg.
Adalimumab is efficacious, well-tolerated, and safe in children. AEs are mild and include nasopharyngitis and URI. Serious adverse events (SAEs) are rare.
Infliximab is a chimeric monoclonal antibody protein which works by competitively blocking TNF-α by binding to its soluble as well as the bound transmembrane form irreversibly.
Infliximab is an FDA-approved for children 6 years or older with Crohn's disease since 2006, but for psoriasis it is not an approved drug, whereas in few cases it can paradoxically induce psoriasis as well, however there are few case reports of “off-label use” of Infliximab in children with GPP. Infliximab can be used as a rescue treatment in GPP because of its rapid onset of action.
There are anecdotal case reports of its use in atopic eczema, TEN, and HS.
The common AEs include headache and mild infections, and serious AEs can be infusion-related reactions, cytopenias, hepatotoxicity, and malignancies. Higher rates of malignancies have been reported in children treated with infliximab, but the association remains unconfirmed. Sporadic use of infliximab can induce neutralizing antibodies, thereby reducing its efficacy and increasing the risk of infusion reactions.
Other tumor necrosis factor alpha inhibitors
Certolizumab pegol is FDA approved for Ps and PsA in adults but not in children. Similarly, Golimumab is also FDA approved for the treatment of adults with moderate-to-severe RA and active PsA.
Ustekinumab is an IgG1 monoclonal antibody and acts by targeting p40 subunit of both Interleukin (IL)-12 and IL-23. It prevents these cytokines from binding to the IL-12 receptor, found on the surface of immune cells thus inhibiting both Th1 and Th17 pathways.
| Psoriasis|| |
Ustekinumab is FDA-approved and EMA-approved in adolescents (12 years and older) for the treatment of moderate-to-severe psoriasis with inadequate response or intolerance to conventional systemic therapies or phototherapy; the onset of action is rapid. Given the efficacy, safety data, and convenient dosing schedule, Ustekinumab should be considered a first-line treatment for adolescent patients with moderate-to-severe psoriasis. The gain of function mutation in caspase recruitment domain family member 14 (card 14) was found to be associated with plaque psoriasis and PRP. Ustekinumab is proposed to be currently the treatment of choice for pediatric patients with CARD14 mutations. There are anecdotal case reports of its use in children younger than 12 years.
| Atopic dermatitis|| |
There are few case reports of its use in adolescents with recalcitrant AD with significant improvement. Whereas some have shown the lack of response, and hence, larger studies are needed to evaluate its safety and efficacy in AD.
| Adverse effects|| |
The commonly observed AEs were nasopharyngitis (34.5%) followed by URI (12.7%). No case of opportunistic infections or malignancy was reported.
Secukinumab is a fully human monoclonal antibody which selectively targets pro-inflammatory cytokine IL-17 A.
| Psoriasis|| |
FDA has approved Secukinumab as the first-line biologic therapy for moderate-to-severe plaque psoriasis and PsA in adults. The onset of action is rapid within a few days. Its efficacy is superior to etanercept and ustekinumab.
Although it is not licensed for use in children, there are case reports showing efficacy of secukinumab in pediatric psoriasis due to IL-36 receptor antagonist deficiency. An 8-year-old female with severe and recalcitrant nail psoriasis, arthritis, and mild psoriatic plaques on the scalp, ears, and genitals was successfully treated with Secukinumab A 4-year-old boy with GPP achieved complete clearance with Secukinumab 75 mg/week. An adolescent boy with generalized erythrodermic Ps showed complete clearance of lesions with Secukinumab and remained disease free at 1-year follow-up. Clinical trials are currently evaluating the safety and efficacy of Secukinumab in pediatric patients with Ps.
| Adverse effects|| |
Nasopharyngitis, headache, and URI were the most commonly reported AEs. Other AEs included arthralgia, hypertension, diarrhea, back pain, pruritus, and cough. SAEs were rare. There was one reported death due to hemorrhagic stroke.
Omalizumab is a recombinant, humanized, monoclonal antibody that targets free serum human immunoglobulin E (IgE). The reduced free IgE levels ultimately cause dissociation of IgE from basophils with subsequent receptor down-regulation which may lead to a reduction in allergen presentation to T-cells and attenuation in the Th2-mediated allergic pathway, thus reducing allergic inflammation and proinflammatory mediator release. Omalizumab also has the capacity to decrease mast-cell activation and sensitivity as well as eosinophil infiltration and activation.
| Chronic spontaneous urticaria|| |
In 2014, both FDA and the EMA approved Omalizumab for the treatment of antihistamine-resistant chronic spontaneous urticaria (CSU) in adults and children 12 years and older., It is administered subcutaneously in the dose of 300 mg 4 weekly. There have been reports of low dose Omalizumab with variable success rates. Doses were 75, 150, or 300 mg or placebo administered subcutaneously every 4 weeks during the 24-week treatment period. Although it is not approved for CSU in children below 12 years of age, there are case reports and case series demonstrating its efficacy and safety in children younger than 12 years.
| Atopic dermatitis|| |
Omalizumab has been used off-label for the treatment of moderate-to-severe AD, recalcitrant to conventional systemic therapies in the pediatric population with variable response. Chan et al. have demonstrated the safety and efficacy of this drug in severe pediatric AD through a double blind, randomized placebo-control trial. However, a few studies have shown poor response to Omalizumab., Patients who lack filaggrin mutation and have the lower elevation of total serum IgE are most likely to respond to Omalizumab therapy.
| Adverse effects|| |
The most common AEs include nasopharyngitis, URI, headache erythema, and urticaria. The serious AEs include appendicitis, pneumonia, and bronchitis.
Dupilumab is a fully-humanized monoclonal antibody which targets α subunit of IL-4 and IL-13 receptors and inhibits their downstream signaling. It blocks the pathways of IL-4 and IL-13 which is effective in reducing Th2 response.
| Atopic dermatitis|| |
It is the first biologic agent approved by FDA for children 6 years and above with moderate-to-severe AD not responding to conventional modalities of treatments. The onset of action is rapid with improvement in itch and disease severity within 2 weeks after the first dose.
Dupilumab, as monotherapy or with concomitant use of topical corticosteroids, can significantly improve the clinical outcomes and quality of life in these patients.
There is an industry-sponsored clinical trial in process to study the efficacy, tolerability, and long-term safety of dupilumab in moderate-to-severe AD in children 6 months–6 years at the time of writing this manuscript.
| Adverse effects|| |
Most common adverse effects of dupilumab include nasopharyngitis, URI, skin infections, conjunctivitis, and injection site reactions.
Apremilast is an orally administered small molecule which acts by inhibiting Type 4 Phosphodiesterase (PDE 4).
| Psoriasis|| |
It is the first oral biologic approved for the treatment of PsA and moderate-to-severe plaque psoriasis in adults. According to a clinical trial conducted in the pediatric population, it seems safe and effective in children too.
| Atopic dermatitis|| |
Recently, Apremilast has completed the phase 2 clinical trial for the treatment of AD in adults. Significant improvements were noted in Eczema Area and Severity Index with Apremilast. Saporito and Cohen published a case report of 8-year-old boy with severe AD who failed traditional therapy but had a favorable response to Apremilast.
Apremilast has also been used as off-label in the treatment of LP, psoriasis of nails and scalp and palmoplantar psoriasis, Behcets disease, HS, and AA.
The adverse events were found to be more in pediatrics populations when compared to adults. The most frequently reported AEs were nausea (52.4%), headache (45.2%), abdominal pain (42.9%), nasopharyngitis (38.1%), diarrhea (35.7%), and vomiting (31.0%).
Crisaborole, a topical PDE inhibitor, is FDA approved for AD in children 2 years and older. It reduces the skin inflammation and pruritus in these patients. It is, however, less effective than topical steroids of low potency., The AEs are usually mild and include stinging, infection, and discoloration at the application site.
Rituximab (RTX) is a chimeric monoclonal antibody which binds with very high affinity to all pre-B and mature antibody-producing B-cells expressing CD20.
| Pemphigus vulgaris|| |
RTX is the first FDA approved biologic for the treatment of adults with moderate-to-severe pemphigus vulgaris (PV). Although it is not licensed for the use in childhood PV (CPV), there are several case reports and case series of off-label use of RTX in severe and/or refractory PV in children and adolescents with successful outcome. Vinay et al. reported a positive clinical and immunologic outcome in a series of 10 cases of childhood/juvenile pemphigus treated with RTX. Clinical outcomes varied from partial remission requiring ongoing systemic immunosuppression to complete remission off all therapy. Kincaid and Weinstein successfully treated CPV in a 4-year-old girl with RTX. The youngest case report is of a 5 months old boy with severe BP, unresponsive to systemic corticosteroids, IV immunoglobulins, dapsone, and cyclosporine A who was successfully treated with RTX.
There are anecdotal case reports of successful use of RTX in various dermatological conditions in children as follows:
- In autoimmune disorders, i.e., PV Pemphigus foliaceus, Bullous pemphigoid, mucous membrane pemphigoid, and epidermolysis bullosa acquisita
- In neoplastic disorders,
- Connective tissue disorders, i.e., Juvenile Dermatomyositis, antiphospholipid antibody syndrome with cutaneous necrosis, and systemic lupus erythematosus (SLE)
- Vasculitis disorders, i.e., cutaneous polyarteritis nodosa, granulomatosis with polyangiitis, and microscopic polyangiitis.
| Adverse effects|| |
- Infusion-related reaction, flu-like symptoms (fever and chills), hematologic toxicity, lymphocytopenia, neutropenia, and thrombocytopenia
- Hypotension, headache, and dizziness
- Local pain at the injection site, hypersensitivity reaction, Angioedema, and anaphylaxis
- Peripheral B-cell depletion, increased risk of infection, and possible septicemia.,
Janus kinase inhibitors
Janus kinase inhibitors (JAK inhibitors) work by inhibiting the activity of a particular family of enzymes called as JAK (JAK-1, 2, 3, and Tyrosine kinase-2). JAK inhibitors block the cytokine signaling and cause a broad, relatively nonspecific anti-inflammatory effect. They can be used as oral drugs or locally as topical formulations. The currently available JAK inhibitors include Tofacitinib (JAK 1 and JAK 3 inhibitor), Ruxolitinib (JAK 1 and JAK 2 inhibitor), and Baricitinib (JAK 1 and JAK 2 inhibitor). Oral JAK inhibitors are more promising than topical ones.
| Psoriasis|| |
Tofacitinib is the most extensively studied JAK inhibitor in psoriasis. Tofacitinib is FDA approved for refractory PsA in adults in the dose of 5 mg twice daily.
It is also effective in patients with moderate-to-severe plaque psoriasis. However, discontinuation of treatment was associated with a risk of relapse. The lesions resolved rapidly on the re-initiation of treatment. The efficacy of Tofacitinib 10 mg twice daily is comparable to that of Etanercept 50 mg twice weekly in psoriasis. Tofacitinib has been found to be effective in nail psoriasis. However, the topical 2% ointment has failed to show good results in psoriatic plaques.
Baricitinib has shown promising results in the treatment of moderate-to-severe psoriasis.
A double-blinded randomized controlled trial (RCT) has shown that Ruxolitinib cream (1% and 1.5%) is comparable to calcipotriene ointment (0.005%) or betamethasone dipropionate cream (0.05%) in clearing the plaques of psoriasis.
| Alopecia areata and alopecia universalis|| |
JAK inhibitors have shown promising results in the treatment of Alopecia Areata (AA) and Alopecia Universalis (AU) in case reports and small clinical trials. Regrowth of hair is reported with both oral and topical formulations of Tofacitinib in adult patients with AA and AU which may be long standing and refractory to conventional therapies. Similarly, treatment with oral Ruxolitinib showed hair regrowth in 9 out of 12 patients of AA. However, the hair loss recurs within months of discontinuation of therapy., The response to treatment is better with the oral agents as compared to the topical ones.
There are case reports of the use of JAK inhibitors including oral or topical tofacitinib, ruxolitinib cream, and oral baricitinib in children with AA and AU with significant regrowth of hair. The topical agents were well tolerated. Clinical trials (NCT02812342 and NCT02553330) are currently exploring the use of topical JAK inhibitors for AA.,
| Other indications|| |
Although JAK inhibitors are being used in various dermatological conditions in adults like AD (Tofacitinib and baricitinib),, vitiligo (Tofacitinib), recalcitrant DMS (Ruxolitinib, Tofacitinib), SLE (baricitinib), and recalcitrant lichen planopilaris (Tofacitinib). Their use in the pediatric population is in the nascent stage, and only few case reports are available. Further, studies are needed for efficacy and safety profile of JAK inhibitors in this population.
Since JAK inhibitors block several signaling pathways used by type I and type II cytokines, this broad activity explains the wide range of potential AEs associated with them.
Oral JAK inhibitors have been associated with AEs including serious infections in up to 2%–6% of patients.,
- Risk of urinary tract infection, nasopharyngitis, and URIs
- Varicella-zoster virus reactivation
- Gastrointestinal disorders: nausea and diarrhea
- Blood/serum changes
- Elevation of liver enzymes (aspartate aminotransferase alanine aminotransferase)
- Hyperlipidemia (increase in cholesterol and triglycerides)
- Increase in bilirubin
- Increase in creatine phosphokinase.
- Impaired response to vaccination
- Blood cell count alteration
- Anemia, leucopenia, and thrombocytopenia
- Fatigue, dizziness, and headache
- Increased risk of malignancies.
It is a fully-humanized IgG1 γ monoclonal antibody directed against soluble B-lymphocyte stimulator; currently, it is the only approved biological for the treatment of SLE.
| Lupus erythematosus|| |
Intravenous belimumab (Benlysta) is the first biologic approved by the FDA to treat SLE in children 5 years and older. It is effective in moderately active, autoantibody-positive lupus erythematosus (LE) with predominantly mucocutaneous and/or musculoskeletal manifestations. A RCT-PLUTO study (pediatric lupus trial of belimumab and background standard therapy) evaluated the efficacy, safety, and pharmacokinetics of intravenous belimumab in 93 patients aged 5–17 years with active LE. The present study concluded that the drug was safe and efficacious for childhood LE and supported its use in children. Belimumab reduced the overall disease activity and the incidence and severity of flares.
| Adverse effects|| |
Belimumab is generally well-tolerated. The most common AEs include infections, infusion reactions, hypersensitivity, headache, nausea, and fatigue. Other AEs include psychiatric events including insomnia, anxiety, depression, and suicidal ideation. Two cases of progressive multifocal leukoencephalopathy have also been reported. The most common malignancies were skin cancers (squamous cell carcinoma and basal cell carcinomas).
Other new biological currently under trial
Currently clinical trials are in process for various new biologics such as ixekizumab, guselkumab (IL-23 inhibitor), brodalumab (IL-17 inhibitor) and tildrakizumab (IL-23 inhibitor) for psoriasis, and risankizumab (IL-23 inhibitor) for AD and Il-15 in vitiligo.
Biologics and vaccination
The vaccination schedule of the children should be considered before administering biologics. It is better to finish the vaccination schedule before starting biologics. Live vaccines should be given 4 weeks before and inactivated vaccines 2 weeks before starting biologics. Live vaccines should generally be avoided during therapy, but if they need to be given then the biologics should be discontinued for at least 3 half-lives of that particular biologic. Inactivated vaccines are safe to administer concurrently with biologics, but the response may be inadequate.
| Conclusions|| |
While biologics are highly effective and well-tolerated for the treatment of various dermatological disorders in the adult population, these data are lacking in the pediatric population. Furthermore, there is no published consensus on the dose and duration of various biologics in children. As these and other biological agents will continuously be used to treat children with immune-mediated dermatologic conditions, collaborative research is important to optimize efficacy, safety, and access to these medications for children.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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