Indian Journal of Paediatric Dermatology

REVIEW ARTICLE
Year
: 2021  |  Volume : 22  |  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

Correspondence Address:
Ratnakar Shukla
Department of Dermatology, Mayo Institute of Medical Sciences, Barabanki, Uttar Pradesh
India

Abstract

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.



How to cite this article:
Gautam M, Shukla R. Biologics in pediatric dermatology.Indian J Paediatr Dermatol 2021;22:107-117


How to cite this URL:
Gautam M, Shukla R. Biologics in pediatric dermatology. Indian J Paediatr Dermatol [serial online] 2021 [cited 2021 Apr 22 ];22:107-117
Available from: https://www.ijpd.in/text.asp?2021/22/2/107/312836


Full Text



 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].{Table 1}

Etanercept

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.

Indications

Psoriasis

Among all the biologics available, Etanercept is the most extensively studied biologic in children including infants. The European Medicines Agency (EMA) (2009)[1] approved the use of Etanercept in children aged 6 years and above and Food and Drug Administration (FDA) (2016)[2] 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[3] Etanercept can be combined with other immunosuppressant such as methotrexate (MTX).[4]

Other off-label indications[5]

Etanercept can be used as off label in many dermatological conditions:

Hidradenitis suppurativa[7]AD[8]Pyoderma gangrenosum[9]SJS/TEN[10]Kawasaki disease[11]Juvenile PRP.[12]

Adverse effects

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%).[13] 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.[14]

Adalimumab

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.

Indications

Psoriasis

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.[15]

Hidradenitis suppurativa

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.[16]

Adverse effects

Adalimumab is efficacious, well-tolerated, and safe in children. AEs are mild and include nasopharyngitis and URI. Serious adverse events (SAEs) are rare.[17]

Infliximab

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.

Indications

Psoriasis

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,[18] whereas in few cases it can paradoxically induce psoriasis as well,[19] however there are few case reports of “off-label use” of Infliximab in children with GPP.[20] Infliximab can be used as a rescue treatment in GPP because of its rapid onset of action.

Other indications

There are anecdotal case reports of its use in atopic eczema,[21] TEN,[22] and HS.[23]

Adverse effects

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.[24] 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.[25] Similarly, Golimumab is also FDA approved for the treatment of adults with moderate-to-severe RA and active PsA.[26]

Ustekinumab

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.[27]

Indications

 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;[28] 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.[29] There are anecdotal case reports of its use in children younger than 12 years.[30]

 Atopic dermatitis



There are few case reports of its use in adolescents with recalcitrant AD with significant improvement.[31] Whereas some have shown the lack of response,[32] 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.[28]

Secukinumab

Secukinumab is a fully human monoclonal antibody which selectively targets pro-inflammatory cytokine IL-17 A.

Indications

 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.[33]

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.[34] 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[35] A 4-year-old boy with GPP achieved complete clearance with Secukinumab 75 mg/week.[34] An adolescent boy with generalized erythrodermic Ps showed complete clearance of lesions with Secukinumab and remained disease free at 1-year follow-up.[35] Clinical trials are currently evaluating the safety and efficacy of Secukinumab in pediatric patients with Ps.[36]

 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.[33]

Omalizumab

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,[37] thus reducing allergic inflammation and proinflammatory mediator release.[38] Omalizumab also has the capacity to decrease mast-cell activation and sensitivity as well as eosinophil infiltration and activation.[38]

Indications

 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.[39],[40] It is administered subcutaneously in the dose of 300 mg 4 weekly. There have been reports of low dose Omalizumab with variable success rates.[41] Doses were 75, 150, or 300 mg or placebo administered subcutaneously every 4 weeks during the 24-week treatment period.[42] 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.[43]

 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.[44] However, a few studies have shown poor response to Omalizumab.[45],[46] Patients who lack filaggrin mutation and have the lower elevation of total serum IgE are most likely to respond to Omalizumab therapy.[46]

 Adverse effects



The most common AEs include nasopharyngitis, URI, headache erythema, and urticaria. The serious AEs include appendicitis, pneumonia, and bronchitis.[47]

Dupilumab

Dupilumab is a fully-humanized monoclonal antibody which targets α subunit of IL-4 and IL-13 receptors and inhibits their downstream signaling.[48] It blocks the pathways of IL-4 and IL-13 which is effective in reducing Th2 response.

Indications

 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.[49] 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.[50]

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.[49]

 Adverse effects



Most common adverse effects of dupilumab include nasopharyngitis, URI, skin infections, conjunctivitis, and injection site reactions.[51]

Apremilast

Apremilast is an orally administered small molecule which acts by inhibiting Type 4 Phosphodiesterase (PDE 4).[52]

Indications

 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.[53]

 Atopic dermatitis



Recently, Apremilast has completed the phase 2 clinical trial for the treatment of AD in adults.[54] 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.[55]

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.[56]

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%).[57]

Crisaborole

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.[58],[59] The AEs are usually mild and include stinging, infection, and discoloration at the application site.[60]

Rituximab

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.

Indications

 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.[61] 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.[62] Kincaid and Weinstein successfully treated CPV in a 4-year-old girl with RTX.[63] 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.[64]

 Other indications[65]



There are anecdotal case reports of successful use of RTX in various dermatological conditions in children as follows:

AD[66]In autoimmune disorders, i.e., PV[61] Pemphigus foliaceus,[67] Bullous pemphigoid,[68] mucous membrane pemphigoid,[64] and epidermolysis bullosa acquisita[69]In neoplastic disorders[70],[71]Connective tissue disorders, i.e., Juvenile Dermatomyositis,[72] antiphospholipid antibody syndrome with cutaneous necrosis,[73] and systemic lupus erythematosus (SLE)[74]Vasculitis disorders, i.e., cutaneous polyarteritis nodosa,[75] granulomatosis with polyangiitis,[75] and microscopic polyangiitis.[76]

 Adverse effects



Infusion-related reaction, flu-like symptoms (fever and chills), hematologic toxicity, lymphocytopenia, neutropenia, and thrombocytopenia[77]Hypotension, headache, and dizziness[78]Local pain at the injection site, hypersensitivity reaction, Angioedema, and anaphylaxis[79]Peripheral B-cell depletion, increased risk of infection, and possible septicemia.[72],[78]

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.

Indications

 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.[80] The efficacy of Tofacitinib 10 mg twice daily is comparable to that of Etanercept 50 mg twice weekly in psoriasis.[81] Tofacitinib has been found to be effective in nail psoriasis.[82] However, the topical 2% ointment has failed to show good results in psoriatic plaques.[83]

Baricitinib has shown promising results in the treatment of moderate-to-severe psoriasis.[84]

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.[85]

 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.[86],[87] The response to treatment is better with the oral agents as compared to the topical ones.[88]

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.[89],[90]

 Other indications



Although JAK inhibitors are being used in various dermatological conditions in adults like AD (Tofacitinib and baricitinib),[91],[92] vitiligo (Tofacitinib),[93] recalcitrant DMS (Ruxolitinib, Tofacitinib),[94] SLE (baricitinib),[95] and recalcitrant lichen planopilaris (Tofacitinib).[96] 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.[97]

Adverse effects

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.[98],[99]

Risk of urinary tract infection, nasopharyngitis, and URIsVaricella-zoster virus reactivationGastrointestinal disorders: nausea and diarrheaBlood/serum changes

Elevation of liver enzymes (aspartate aminotransferase alanine aminotransferase)Hyperlipidemia (increase in cholesterol and triglycerides)Increase in bilirubinIncrease in creatine phosphokinase.

Impaired response to vaccinationBlood cell count alteration

Anemia, leucopenia, and thrombocytopenia,

Fatigue, dizziness, and headacheIncreased risk of malignancies.

Belimumab

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.[100]

Indications

 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.[101]

 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.[102] Two cases of progressive multifocal leukoencephalopathy have also been reported.[103] The most common malignancies were skin cancers (squamous cell carcinoma and basal cell carcinomas).[104]

Other new biological currently under trial

Currently clinical trials are in process for various new biologics such as ixekizumab,[105] guselkumab (IL-23 inhibitor),[106] brodalumab (IL-17 inhibitor)[107] and tildrakizumab (IL-23 inhibitor)[108] for psoriasis, and risankizumab (IL-23 inhibitor)[109] for AD and Il-15 in vitiligo.[110]

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.[111]

 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

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Fortina AB, Bardazzi F, Berti S, Carnevale C, Di Lernia V, El Hachem M, et al. Treatment of severe psoriasis in children: Recommendations of an Italian expert group. Eur J Pediatr 2017;176:1339-54.
2Available from: https://www.drugs.com/newdrugs/fda-approves-expanded-enbrel-etanercept-children chronic-moderate-severe-plaque-psoriasis-4451.html. [Last accessed on 2020 Oct 12].
3Dogra S, Bishnoi A. Childhood psoriasis: What is new and what is news. Indian J Paediatr Dermatol 2018;19:308-14
4Zhang J, Xie F, Delzell E, Yun H, Lewis JD, Haynes K, et al. Impact of biologic agents with and without concomitant methotrexate and at reduced doses in older rheumatoid arthritis patients. Arthritis Care Res (Hoboken) 2015;67:624-32.
5Nguyen QD, Starling CT, Hebert AA. The use of TNFα inhibitors in treating pediatric skin disorders. Pediatr Drugs 2020;22:311-9.
6Guedes R, Leite L. Therapeutic hotline. Treatment of pitiriasis rubra pilaris with etanercept. Dermatol Ther 2011;24:285-6.
7Haslund P, Lee RA, Jemec G. Treatment of hidradenitis suppurativa with tumour necrosis factor-alpha inhibitors. Acta Derm Venereol 2009;89:595-600.
8Rullan P, Murase J. Two cases of chronic atopic dermatitis treated with soluble tumor necrosis factor receptor therapy. J Drugs Dermatol 2009;8:873-6.
9McGowan JW 4th, Johnson CA, Lynn A. Treatment of pyoderma gangrenosum with etanercept. J Drugs Dermatol 2004;3:441-4.
10Gavigan GM, Kanigsberg ND, Ramien ML. Pediatric Stevens-Johnson Syndrome/Toxic epidermal necrolysis halted by etanercept. J Cutan Med Surg 2018;22:514-5.
11Lin SC, Wan-Lin T, Guo MM, Kuo HC. Etanercept as rescue therapy for refractory Kawasaki disease. Austin J Pediatr 2014;1:1010.
12Zhong Z, Li J, Xue R, Liang Y, Chen Y. Refractory classic juvenile pityriasis rubra pilaris successfully treated with a combination of etanercept and methotrexate. Dermatol Ther 2020;33:e13431.
13Paller AS, Siegfried EC, Pariser DM, Rice KC, Trivedi M, Iles J, et al. Long-term safety and efficacy of etanercept in children and adolescents with plaque psoriasis. J Am Acad Dermatol 2016;74:280-70.
14Diak P, Siegel J, La Grenade L, Choi L, Lemery S, McMahon A. Tumor necrosis factor alpha blockers and malignancy in children: Forty-eight cases reported to the Food and Drug Administration. Arthritis Rheum 2010;62:2517-24.
15Saurat JH, Stingl G, Louis D, Papp K, Langley RG, Ortonne JP, et al. Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br J Dermatol 2008;158:558-66.
16Oranges T, Chiricozzi A, Iannone M, Romanelli M, Dini V. Long-term outcome of adalimumab in a young girl with hidradenitis suppurativa. Skin Appendage Disord 2018;5:38-41.
17Papp K, Thaçi D, Marcoux D, Weibel L, Philipp S, Ghislain PD, et al. Efficacy and safety of adalimumab every other week versus methotrexate once weekly in children and adolescents with severe chronic plaque psoriasis: A randomised, double-blind, phase 3 trial. Lancet 2017;390:40-9.
18Official Healthcare Professional Website for REMICADE® (Infliximab). Available from: https://remicade.com. [Last accessed on 2020 Oct 12].
19Broge T, Nguyen N, Sacks A, Davis M. Infliximab associated psoriasis in children with Crohn's disease may require withdrawal of anti-tumor necrosis factor therapy. Inflamm Bowel Dis 2013;19:E75-7.
20Tsang V, Dvorakova V, Enright F, Murphy M, Gleeson C. Successful use of infliximab as first line treatment for severe childhood generalized pustular psoriasis. J Eur Acad Dermatol Venereol 2016;30:e117-e119.
21Jacobi A, Antoni C, Manger B, Schuler G, Hertl M. Infliximab in the treatment of moderate to severe atopic dermatitis. J Am Acad Dermatol 2005;52:522-6.
22Chafranska L, Saunte DM, Behrendt N, Nygaard U, Christensen RJ, Sand C, et al. Pediatric toxic epidermal necrolysis treated successfully with infliximab. Pediatr Dermatol 2019;36:342-5.
23Adams DR, Gordon KB, Devenyi AG, Ioffreda MD. Severe hidradenitis suppurativa treated with infliximab infusion. Arch Dermatol 2003;139:1540-2.
24Bellodi Schmidt F, Shah KN. Biologic response modifiers and pediatric psoriasis. Pediatric Dermatol 2015;32:303-20.
25Cline A, Bartos GJ, Strowd LC, Feldman SR. Biologic treatment options for pediatric psoriasis and atopic dermatitis. Children (Basel) 2019;6:103.
26Mazumdar S, Greenwald D. Golimumab. MAbs 2009;1:422-31.
27Goldminz AM, Gottlieb AB. Ustekinumab for psoriasis and psoriatic arthritis. J Rheumatol Suppl 2012;89:86-9.
28Landells I, Marano C, Hsu MC, Li S, Zhu Y, Eichenfield LF, et al. Ustekinumab in adolescent patients age 12 to 17 years with moderate-to-severe plaque psoriasis: Results of the randomized phase 3 CADMUS study. J Am Acad Dermatol 2015;73:594-603.
29Signa S, Campione E, Rusmini M, Chiesa S, Grossi A, Omenetti A, et al. Whole exome sequencing approach to childhood onset familial erythrodermic psoriasis unravels a novel mutation of CARD14 requiring unusual high doses of ustekinumab. Pediatr Rheumatol Online J 2019;17:38.
30Min MS, Shroff A, Rose S, Lebwohl M, Guttman-Yassky E. Ustekinumab as therapy for psoriasis in a 2-year-old girl. J Eur Acad Dermatol Venereol 2016;30:e109-10.
31Wlodek C, Hewitt H, Kennedy CT. Use of ustekinumab for severe refractory atopic dermatitis in a young teenager. Clin Exp Dermatol 2016;41:625-7.
32Samorano LP, Hanifin JM, Simpson EL, Leshem YA. Inadequate response to ustekinumab in atopic dermatitis – A report of two patients. J Eur Acad Dermatol Venereol 2016;30:522-3.
33Frieder J, Kivelevitch D, Menter A. Secukinumab: A review of the anti-IL-17A biologic for the treatment of psoriasis. Ther Adv Chronic Dis 2018;9:5-21.
34Kostner K, Prelog M, Almanzar G, Fesq H, Haas JP, Hugle B. Successful use of secukinumab in a 4-year-old patient with deficiency of interleukin-36 antagonist. Rheumatology 2018;57:936-8.
35Wells LE, Evans T, Hilton R, Wine Lee L, Ruth N. Use of secukinumab in a pediatric patient leads to significant improvement in nail psoriasis and psoriatic arthritis. Pediatr Dermatol 2019;36:384-5.
36Novartis Pharmaceuticals. Study to Assess the Long-term Safety, Tolerability, Efficacy of Secukinumab in Pediatric Patients of Age 6 to <18 Years, with Moderate to Severe Plaque Psoriasis. Available from: https://clinicaltrials.gov/ct2/show/NCT03668613. [Last accessed on 2020 Oct 14].
37Prussin C, Griffith DT, Boesel KM, Lin H, Foster B, Casale TB. Omalizumab treatment downregulates dendritic cell FcepsilonRI expression. J Allergy Clin Immunol 2003;112:1147-54.
38Holgate S, Smith N, Massanari M, Jimenez P. Effects of omalizumab on markers of inflammation in patients with allergic asthma. Allergy 2009;64:1728-36.
39Food and Drug Administration. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/-2014/103976s5211lbl.pdf. [Last accessed on 2020 Oct 14].
40European Medicines Agency. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/-medicines(human/medicines/000606/human_med_001162.jsp&mid=WC0b01ac058001d124. [Last accessed on 2020 Oct 15].
41Godse K. Omalizumab in the treatment of chronic urticaria. Indian J Drugs Dermatol 2018;4:1-2
42Bernstein JA, Sarbjit SS, Maurer R, Hsin-JU H, Chen H, Canvin J, et al. Efficacy of omalizumab in patients with chronic idiopathic/spontaneous urticaria with different background therapy: Post hoc analysis of Asteria I, Asteria II, and Glacial studies. J Allergy Clin Immunol 2014;133 Suppl 2:AB117.
43Al-Shaikhly T, Rosenthal JA, Ayars AG, Petroni DH. Omalizumab for chronic urticaria in children younger than 12 years. Ann Allergy Asthma Immunol 2019;123:208-1000.
44Chan S, Cornelius V, Cro S, Harper JI, Lack G. Treatment effect of omalizumab on severe pediatric atopic dermatitis: The ADAPT randomized clinical trial. JAMA Pediatr 2019;174:29-37.
45Krathen RA, Hsu S. Failure of omalizumab for treatment of severe adult atopic dermatitis. J Am Acad Dermatol 2005;53:338-40.
46Wang HH, Li YC, Huang YC. Efficacy of omalizumab in patients with atopic dermatitis: A systematic review and meta-analysis. J Allergy Clin Immunol 2016;138:1719-220.
47Licari A, Marseglia A, Caimmi S, Castagnoli R, Foiadelli T, Barberi S, et al. Omalizumab in children. Paediatr Drugs 2014;16:491-502.
48Tsianakas A, Stander S. Dupilumab: A milestone in the treatment of atopic dermatitis. Lancet 2016;387:4-5.
49Available from: https://www.sanofi.com/en/media-room/press-releases/2020/2020-05-26-17-40-00. [Last accessed on 2020 Oct 15].
50Gooderham MJ, Hong HC, Eshtiaghi P, Papp KA. Dupilumab: A review of its use in the treatment of atopic dermatitis. J Am Acad Dermatol 2018;78:S28-36.
51Simpson E, Paller AS, Siegfried E, Boguniewicz M, Pariser D, Blauvelt A, et al. Dupilumab, Efficacy and Safety in Adolescents with Moderate-to-Severe Atopic Dermatitis: Results from a Multicenter, Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Phase 3 Study. In Proceedings of the European Academy of Dermatology and Venereology, Paris, France; 12–16 September, 2018.
52Bubna AK. Apremilast: A dermatologic perspective. Indian J Drugs Dermatol 2016;2:75-82.
53Relvas M, Torres T. Pediatric psoriasis. Am J Clin Dermatol 2017;18:797-811.
54Simpson EL, Imafuku S, Poulin Y, Ungar B, Zhou L, Malik K, et al. A phase 2 randomized trial of apremilast in patients with atopic dermatitis. J Invest Dermatol 2019;139:1063-72.
55Saporito RC, Cohen DJ. Apremilast use for moderate-to-severe atopic dermatitis in pediatric patients. Case Rep Dermatol 2016;8:179-84.
56Maloney NJ, Zhao J, Tegtmeyer K, Lee EY, Cheng K. Off-label studies on apremilast in dermatology: A review. J Dermatolog Treat 2020;31:131-40.
57Paller AS, Hong Y, Becker EM, de Lucas R, Paris M, Zhang W, et al. Pharmacokinetics and safety of apremilast in pediatric patients with moderate to severe plaque psoriasis: Results from a phase 2 open-label study. J Am Acad Dermatol 2020;82:389-97.
58Zane LT, Kircik L, Call R, Tschen E, Draelos ZD, Chanda S, et al. Crisaborole topical ointment, 2% in patients ages 2 to 17 years with atopic dermatitis: A Phase 1b, open-label, maximal-use systemic exposure study. Pediatr Dermatol 2016;33:380-7.
59Eichenfield LF, Call RS, Forsha DW, Fowler J Jr., Hebert AA, Spellman M, et al. Long-term safety of crisaborole ointment 2% in children and adults with mild to moderate atopic dermatitis. J Am Acad Dermatol 2017;77:641-9.e5.
60Callender VD, Alexis AF, Stein Gold LF, Lebwohl MG, Paller AS, Desai SR, et al. Efficacy and safety of crisaborole ointment, 2%, for the treatment of mild-to-moderate atopic dermatitis across racial and ethnic groups. Am J Clin Dermatol 2019;20:711-23.
61Kanwar AJ, Sawatkar GU, Vinay K, Hashimoto T. Childhood pemphigus vulgaris successfully treated with rituximab. Indian J Dermatol Venereol Leprol 2012;78:632-4.
62Vinay K, Kanwar AJ, Sawatkar GU, Dogra S, Ishii N, Hashimoto T. Successful use of rituximab in the treatment of childhood and juvenile pemphigus. J Am Acad Dermatol 2014;71:669-75.
63Kincaid L, Weinstein M. Rituximab therapy for childhood pemphigus vulgaris. Pediatr Dermatol 2016;33:e61-4.
64Schulze J, Bader P, Henke U, Rose MA, Zielen S. Severe bullous pemphigoid in an infant – successful treatment with rituximab. Pediatr Dermatol 2008;25:462-5.
65Bellodi-Schmidt F, Shah K. Beyond psoriasis: Novel uses for biologic response modifiers in pediatric dermatology. Pediatr Dermatol 2016;33:18-27.
66Simon D, Hösli S, Kostylina G, Yawalkar N, Simon HU. Anti-CD20 (rituximab) treatment improves atopic eczema. J Allergy Clin Immunol 2008;121:122-8.
67Connelly EA, Aber C, Kleiner G, Nousari C, Charles C, Schachner LA. Gen- eralized erythrodermic pemphigus foliaceus in a child and its successful re- Sponse to rituximab treatment. Pediatr Dermatol 2007;24:172-6.
68Le Roux-Villet C, Prost-Squarcioni C, Alexandre M, Caux F, Pascal F, Doan S, et al. Rituximab for patients with refractory mucous membrane pemphigoid. Arch Dermatol 2011;147:843-9.
69McKinley SK, Huang JT, Tan J, Kroshinsky D, Gellis S. A case of recalcitrant epidermolysis bullosa acquisita responsive to rituximab therapy. Pediatr Dermatol 2014;31:241-4.
70Park MY, Jung HJ, Park JE, Kim YC. Pediatric primary cutaneous marginal zone B-cell lymphoma treated with intralesional rituximab. Eur J Dermatol 2010;20:533-4.
71Wallet-Faber N, Bodemer C, Blanche S, Delabesse E, Eschard C, Brousse N, et al. Primary cutaneous Epstein-Barr virus-related lymphoproliferative disorders in 4 immunosuppressed children. J Am Acad Dermatol 2008;58:74-80.
72Bader-Meunier B, Decaluwe H, Barnerias C, Gherardi R, Quartier P, Faye A, et al. Club Rhumatismes et Inflammation. Safety and efficacy of rituximab in severe juvenile dermatomyositis: results from 9 patients from the French Autoimmunity and Rituximab registry. J Rheumatol 2011;38:1436-40.
73Iglesias-Jiménez E, Camacho-Lovillo M, Falcón-Neyra D, Lirola-Cruz J, Neth O. Infant with probable catastrophic antiphospholipid syndrome successfully managed with rituximab. Pediatrics 2010;125:e1523-8.
74Willems M, Haddad E, Niaudet P, Koné-Paut I, Bensman A, Cochat P, et al. Rituximab therapy for childhood-onset systemic lupus erythematosus. J Pediatr 2006;148:623-7.
75Eleftheriou D, Melo M, Marks SD, Tullus K, Sills J, Cleary G, et al. Biologic therapy in primary systemic vasculitis of the young. Rheumatology (Oxford) 2009;48:978-86.
76Brunner J, Freund M, Prelog M, Binder E, Sailer-Hoeck M, Jungraithmayr T, et al. Successful treatment of severe juvenile microscopic polyangiitis with rituximab. Clin Rheumatol 2009;28:997-9.
77Kimby E. Tolerability and safety of rituximab (MabThera). Cancer Treat Rev 2005;31:456-73.
78El-Hallak M, Binstadt BA, Leichtner AM, Bennett CM, Neufeld EJ, Fuhlbrigge RC, et al. Clinical effects and safety of rituximab for treatment of refractory pediatric autoimmune diseases. J Pediatr 2007;150:376-82.
79Hoffman MB, Bhandari RA, Sinha AA. Rituximab use in pediatric dermatology. J Drugs Dermatol 2016;15:821-9.
80Papp KA, Krueger JG, Feldman SR, Langley RG, Thaci D, Torii H, et al. Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: Long-term efficacy and safety results from 2 randomized phase-III studies and 1 open-label long-term extension study. J Am Acad Dermatol 2016;74:841-50.
81Valenzuela F, Paul C, Mallbris L, Tan H, Papacharalambous J, Valdez H, et al. Tofacitinib versus etanercept or placebo in patients with moderate to severe chronic plaque psoriasis: Patient-reported outcomes from a Phase 3 study. J Eur Acad Dermatol Venereol 2016;30:1753-9.
82Merola JF, Elewski B, Tatulych S, Lan S, Tallman A, Kaur M. Efficacy of tofacitinib for the treatment of nail psoriasis: Two 52-week, randomized, controlled phase 3 studies in patients with moderate-to-severe plaque psoriasis. J Am Acad Dermatol 2017;77:79-870.
83Papp KA, Bissonnette R, Gooderham M, Feldman SR, Iversen L, Soung J, et al. Treatment of plaque psoriasis with an ointment formulation of the Janus kinase inhibitor, tofacitinib: A Phase 2b randomized clinical trial. BMC Dermatol 2016;16:15.
84Papp KA, Menter MA, Raman M, Disch D, Schlichting DE, Gaich C, et al. A randomized phase 2b trial of baricitinib, an oral Janus kinase (JAK) 1/JAK2 inhibitor, in patients with moderate-to-severe psoriasis. Br J Dermatol 2016;174:1266-76.
85Kivelevitch DN, Hebeler KR, Patel M, Menter A. Emerging topical treatments for psoriasis. Expert Opin Emerg Drugs 2013;18:523-32.
86Craiglow BG, King BA. Killing two birds with one stone: Oral tofacitinib reverses alopecia universalis in a patient with plaque psoriasis. J Invest Dermatol 2014;134:2988-90.
87Kennedy Crispin M, Ko JM, Craiglow BG, Li S, Shankar G, Urban JR, et al. Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata. JCI Insight 2016;1:e89776.
88Phan K, Sebaratnam DF. JAK inhibitors for alopecia areata: A systematic review and meta-analysis. J Eur Acad Dermatol Venereol 2019;33:850-6.
89Topical Tofacitinib for the Treatment of Alopecia Areata and Its Variants ClinicalTrials.gov Identifier: NCT02812342.
90A Study With Ruxolitinib Phosphate Cream Applied Topically to Subjects With Alopecia Areata (AA) ClinicalTrials.gov Identifier: NCT02553330.
91Napolitano M, Fabbrocini G, Cinelli E, Stingeni L, Patruno C. Profile of baricitinib and its potential in the treatment of moderate to severe atopic dermatitis: A short review on the emerging clinical evidence. J Asthma Allergy 2020;13:89-94.
92Purohit VS, Ports WC, Wang C, Riley S. Systemic tofacitinib concentrations in adult patients with atopic dermatitis treated with 2% tofacitinib ointment and application to pediatric study planning. J Clin Pharmacol 2019;59:811-20.
93Liu LY, Strassner JP, Refat MA, Harris JE, King BA. Repigmentation in vitiligo using the Janus kinase inhibitor tofacitinib may require concomitant light exposure. J Am Acad Dermatol 2017;77:675-820.
94Kurtzman DJ, Wright NA, Lin J, Femia AN, Merola JF, Patel M, et al. Tofacitinib citrate for refractory cutaneous dermatomyositis: An alternative treatment. JAMA Dermatol 2016;152:944-5.
95Werth VP, Merrill JT. A double-blind, randomized, placebo-controlled, phase II trial of baricitinib for systemic lupus erythematosus: How to optimize lupus trials to examine effects on cutaneous lupus erythematosus. Br J Dermatol 2019;180:964-5.
96Yang CC, Khanna T, Sallee B, Christiano AM, Bordone LA. Tofacitinib for the treatment of lichen planopilaris: A case series. Dermatol Ther 2018;31:e12656.
97Ciechanowicz P, Rakowska A, Sikora M, Rudnicka L. JAK-inhibitors in dermatology: Current evidence and future applications. J Dermatolog Treat 2019;30:648-58.
98Kavanaugh AF, Geier J, Bingham C III, Chen C, Reed GW, Saunders KC, et al. Real World Results from a Post-Approval Safety Surveillance of Tofacitinib (Xeljanz): Over 3 Year Results from an Ongoing US-Based Rheumatoid Arthritis Registry [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/real-world-results-from-a-post-approval-safety-surveillance-of-tofacitinib-xeljanz-over-3-year-results-from-an-ongoing-us-based-rheumatoid-arthritis-registry/. [Last accessed on 2020 Oct 16].
99Bubna AK. Janus kinase inhibitors in dermatology. Indian J Drugs Dermatol 2019;5:6-13
100Dubey AK, Handu SS, Dubey S, Sharma P, Sharma KK, Ahmed QM. Belimumab: First targeted biological treatment for systemic lupus erythematosus. J Pharmacol Pharmacother 2011;2:317-9.
101ClinicalTrials.gov Identifier: NCT04179032, Study of Subcutaneous (SC) Belimumab in Pediatric Participants with Systemic Lupus Erythematosus (SLE). Available from: https://clinicaltrials.gov/ct2/show/NCT04179032. [Last accessed on 2020 Oct 14].
102Wallace D, Navarra S, Petri M, Gallacher A, Thomas M, Furie R, et al. Safety profile of belimumab: Pooled data from placebo-controlled phase 2 and 3 studies in patients with systemic lupus erythematosus. Lupus 2013;22:144-54.
103Fredericks CA, Kvam KA, Bear J, Crabtree GS, Josephson SA. A case of progressive multifocal leukoencephalopathy in a lupus patient treated with belimumab. Lupus 2014;23:711-3.
104Ginzler E, Wallace D, Merrill J, Furie R, Stohl W, Chatham W, et al. Disease control and safety of belimumab plus standard therapy over 7 years in patients with systemic lupus erythematosus. J Rheumatol 2014;41:300-9.
105Eli Lilly and Company. Study of Ixekizumab (LY2439821) in Children 6 to Less Than 18 Years with Moderate-to-Severe Plaque Psoriasis. Available from: https://clinicaltrials.gov/ct2/show/NCT03073200. [Last accessed on 2020 Oct 16].
106Janssen Research & Development, LLC. A Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Subcutaneously Administered Guselkumab for the Treatment of Chronic Plaque Psoriasis in Pediatric Participants. Available from: https://clinicaltrials.gov/ct2/show/NCT03451851. [Last accessed on 2020 Oct 16].
107Bausch Health Americas, Inc. An Open-label, Single-dose Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Brodalumab in Pediatric Subjects. Available from: https://clinicaltrials.gov/ct2/show/NCT03240809. [Last accessed on 2020 Oct 17].
108A Study to Evaluate Risankizumab in Adult and Adolescent Subjects with Moderate to Severe Atopic Dermatitis. Available from: https://clinicaltrials.gov/-ct2/show/NCT03706040. [Last accessed on 2020 Oct 17].
109A Study of Tildrakizumab in Pediatric Subjects with Chronic Plaque Psoriasis. Available from: https://clinicaltrials.gov/ct2/show/NCT03997786. [Last accessed on 2020 Oct 17].
110Richmond JM, Strassner JP, Zapata L Jr, et al. Antibody blockade of IL-15 signaling has the potential to durably reverse vitiligo. Sci Transl Med 2018;10.
111Dudam R, Gumdal N. Checklist prior to biologics: Indian perspective. Indian J Rheumatol 2016;11:126-8.