Biologics in Dermatology: Off-Label Indications

Abstract

Skin and subcutaneous diseases affect millions of people worldwide, causing significant morbidity. Biologics are becoming increasingly useful for the treatment of many skin diseases, particularly as alternatives for patients who have failed to tolerate or respond to conventional systemic therapies. Biological therapies provide a targeted approach to treatment through interaction with specific components of the underlying immune and inflammatory disease processes. Advances in the understanding of disease pathophysiology for inflammatory skin diseases and in drug development have ushered in biologic therapies in dermatology. Biologic therapies are molecules that target specific proteins implicated in immune-mediated disease. This review article highlights the increasing evidence base for biologics in dermatology for off-label use.

Introduction

Off-label use of pharmaceutical drugs for an indication, age group, dosage, or route of administration refers to the use of the drug that is not approved by the regulatory agencies or is not declared in the prescribing information for the product. Regulatory agencies based on clinical trials and available literature evidence approves a drug for a particular indication, dose, formula and route of administration.[1] Off-label use of drug is not illegal, unless it is within ethical guidelines and other safety regulations. Based on the reliable data and perfect evidence drug can be used in for off-label indication to patients who have drained all other approved therapeutic options.[2]

Biopharmaceuticals also known as Biologic drug, or biological medicinal product are genetically engineered proteins produced in living organisms such as bacteria, yeast, or human cell lines or derived from recombinant DNA and/or controlled gene expression methods. Examples include biological proteins (cytokines, clotting factors, and hormones), vaccines, monoclonal antibodies (mABS), cell, and tissue-based therapies.[3]

Biologics are proving their worth as treatment modalities for many skin diseases, particularly as alternatives for patients who have failed respond to approved therapeutic options. Biologic therapy has shown its efficacy in the treatment of inflammatory diseases and their use in the effective treatment of Psoriasis (PsO) and other skin diseases is well established.[4] Biologics or biologicals are large complex molecules produced in living organisms. They cover a range of molecules including peptide (human insulin), small protein (Erythropoietin) and large proteins like mABS. Biologics have transformed several areas of medical therapeutics, mainly chronic inflammatory diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), inflammatory bowel disease (IBD), PsO and more recently, Pemphigus group of diseases.[5] The European Medicines Agency (EMA) defines biologics as medical products which contain one or more active substances produced by the living organism or originated in a living organism. Unlike for synthesized medicines, due to the very nature of the biological process it is not possible to produce identical copies of biological medicine batch to batch, and variability is an inherent feature of biological medicines.[6]

The number of currently available biological agents in dermatology is growing with new developments every passing day. Most of the biologic drugs target PsO but several other dermatologic diseases seem to respond to biologic therapy. Common biologic therapies encountered include tumor necrosis factor (TNF) α inhibitors, interleukin (IL)-12/IL-23 inhibition, IL-17 inhibitors, rituximab, immunoglobulin E (IgE) antagonists, and intravenous immunoglobulin.[7]

The introduction of new biological treatment in recent years has dramatically altered the practice of dermatology.[8] The interest of clinicians in exploring biological therapy in various skin conditions has fundamentally increased over the years. This article discusses the off-label indication of biologics in dermatology. List of the different biologics commonly prescribed along with their specifications is shown in Table 1. Common off-label indications of various biologics are listed in Table 2.

Table 1.

Characteristics of the different biologic agents available in India

	Infliximab	Etanercept	Adalimumab	Golimumab	Rituximab	Secukinumab
Type	Monoclonal antibody against TNF-α	TNF soluble receptor	Monoclonal antibody against TNF-α	Monoclonal antibody against TNF-α	Anti-CD20 Monoclonal antibody	Interleukin-17A monoclonal antibody
Composition	Chimeric antibody	Recombinant fusion protein	Recombinant mnoclonalantibodyo	Monoclonal antibody	Chimeric antibody	Monoclonal antibody
Dose	3-5 mg/kg at weeks 0, 2, and 6; then, every 4-8 weeks	25-50 mg once or twice a week	40 mg every other week	50 mg once monthly	500 mg every other week weekly for 4-8 consecutive weeks The off-label protocol in the literature is a 375-mg/m2 IV infusion once weekly for 2-4 consecutive weeks	Initial: 300 mg SC at weeks 0, 1, 2, 3, and 4 Monthly maintenance: Beginning at week 8, give 300 mg SC once monthly
Route of administration	Intravenous	Subcutaneous	Subcutaneous	Subcutaneous	Intravenous	Subcutaneous
Indications	AS, CD, PsA, PsO, RA, UC	AS, JIA, PsA, PsO, RA	AS, CD, JIA, PsA, PsO, RA, UC, HS, NIU	AS, PsA, RA, UC	CLL, NHL, RA, GPA, MPA, PV	PsO, PsA, AS
Biosimilar	Yes	Yes	Yes	No	Yes	No
Available

AS: Ankylosing Spondylitis; RA: Rheumatoid Arthritis; JIA: Juvenile idiopathic Arthritis; PsA: Psoriatic Arthritis; PsO: Psoriasis; IBD: Inflammatory Bowel Disease; HS: Hidradenitis Suppurativa; UC: Ulcerative Colitis; CD: Crohn’s Disease; NIU; Non Infectious Uvetits; CLL: Chronic Lymphocytic Leukemia; NHL: Non Hodgkins Lymphoma; GPA: Granulomatosis with polyanglitis; MPA: Microscopic Polyangitis; PV: Pemphigus Vulgaris

Table 2.

List of off-label indications of biologics

Biologic	Off-label Use
Etanercept	Pyodrma gangrenosum
	Sarcoidosis
	Necrobiosis lipoidica diabeticorum
	Hidradenitis suppurativa
	Sweet’s syndrome
	Vasculitis
	Behcet Disease
	Atopic Dermatitis
	Pityriasis Rubra Pilaris
	Lichen Planus
	SAPHO syndrome
	Toxic Epidermal Necrolysis
	Pruritus
	Keloid
Infliximab	Sarcoidosis
	Hidradenitis suppurativa
	Pyodrma gangrenosum
	Necrobiosis lipoidica diabeticorum
	Giant Cell Arteritis
	Vasculitis
	Behcet Disease
	Atopic Dermatitis
	Toxic Epidermal Necrolysis
Adalimumab	Sarcoidosis
	Pyodrma gangrenosum
	Behcet Disease
	Pityriasis Rubra Pilaris
	Lichen Planus
	Alopecia Areata
	SAPHO syndrome
Rituximab	Chronic graft-versus-host disease
	Dermatomyositis
Secukinumab	Pityriasis rubra pilaris
	Hidradenitis suppurativa
Omalizumab	Churg-Strauss Syndrome
	Bullous pemphigoid
	Atopic dermatitis
	Angioedema
Anakinra	Pyoderma gangraenosum
	PAPA syndrome
	Hidradenitis suppurativa

Off-Label Use of Tumor Necrosis Factor (TNF) Inhibitors

TNF-α is a pleiotropic cytokine which plays a key role in chronic inflammatory diseases such as PsO and PsA. Biologic agents that inhibit TNF include a fusion protein, etanercept, and mABS such as infliximab and adalimumab. Levels of TNF- α are increased in many inflammatory diseases of the skin and are supposed to be a key player in the entire immune pathogenesis. The TNF-α inhibitors have been prescribed as an off-label indication for several dermatologic conditions.[9] Review of several case reports and case series in the literature show that the TNF-α inhibitors can be used in the management of a growing number of inflammatory skin conditions.

Following are amongst the ever-growing list of inflammatory dermatoses where TNF-α inhibitors have been successfully used but are awaiting relevant clearances to be the first line therapeutic options.

Off-Label Uses of TNF-α Inhibitors

Sarcoidosis

It is an idiopathic granulomatous inflammatory disease with multisystem involvement.[10] TNF-α is thought to play an important role in the pathogenesis of sarcoidosis.[11] The TNF gene, which is in the class III region of the major histocompatibility complex (MHC) on chromosome 6 suggested that the several genes in this region are useful in defining the disease susceptibility and prognosis in sarcoidosis. In particular, a biallelic functional polymorphism in the TNF-α promoter leads to variations in TNF-α production, which shows an association with distinct sarcoidosis subtypes.[12,13,14,15] Various reports describe the off-label use of TNF-α inhibitors in the treatment of sarcoidosis. Use of Infliximab[16,17,18] and Etanercept[19] has been described in various case reports. There have been two reports of the successful use of adalimumab for the treatment of cutaneous sarcoidosis.[20,21]

Pyoderma Gangrenosum (PG)

It is a rare ulcerative disorder of the skin in association with systemic involvement such as IBD, polyarthritis, monoclonal gammopathy, and hematological malignancy. Due to the complexity and wide variety of clinical appearance, it can be challenging to treat.[22] The pathogenesis of PG remains unclear, but may be related to TNF-α.[23] Use of Infliximab,[24,25,26,27] Etanercept[28] and Adalimumab,[24] are described in a considerable number of reports in the treatment of PG.1

Necrobiosis lipoidica diabeticorum (NLD)

A rare chronic and granulomatous skin disorder with unknown etiology. Legs are the most commonly affected site of NLD.[29] Raised levels of TNF-α have been found in the NLD patient's sera and skin. Promising results were observed with TNF-α inhibitors treatment.[30] Few cases of necrobiosis lipoidica diabeticorum have been reported to be cured with infliximab[31] and etanercept.[32]

Hidradenitis suppurativa (HS)

It is characterised by chronic inflammation of the skin, affecting apocrine gland-rich areas of the body with the presence of painful nodules, abscesses, sinus tracts, and scarring.[33] Adalimumab is the only approved biologic in the treatment for HS. Off label, moderate improvement with infliximab[34] has been reported in one case study. There is another report of six patients with refractory HS treated with etanercept, 25 mg twice weekly.[35] TNF-α antagonists may lead to an improvement in HS by inhibiting the effects of TNF- α.[36] which has been described as the key inflammatory marker in the disease's pathophysiology.

Sweet's syndrome

Cytokines play an etiological role, directly or indirectly in the development of Sweet's syndrome.[37] In particular, serum Granulocyte colony-stimulating factor (G-CSF) levels have been reported much higher in patients with active Sweet's syndrome.[38] One published report with two patients with Sweet's syndrome and RA achieved complete skin clearance after etanercept administration.[39]

Vasculitis

TNF-α is having an important role in inducing the membrane expression of proteinase-3 or myeloperoxidase, which could be recognized by ANCA later in ANCA-associated vasculitis (AAV).[40]

Infliximab provided remission in 88% of the patients in a prospective trial of patients suffering from small vessel vasculitis with systemic complications.[41] Etanercept has also been evaluated for the possible treatment of vasculitis. However, results have not been remarkable.[42]

Giant cell arteritis (GCA)

The raised tissue concentraions of TNF-α led to hypothesis that anti-TNF-α agents will be a promising treatment in GCA.[43] In a study where 44 patients with GCA were treated with placebo or glucocorticoids plus infliximab have shown a significant difference in the therapeutic effect.[44]

Behcet disease (BD)

It is an idiopathic inflammatory disorder affecting multiple organ systems with a chronic-relapsing course. TNF-α is a central inflammatory mediator in BD with the involvement of Human Leukocyte Antigens (HLA)-51 gene.[45] Etanercept in a trial with 40 patients with BD has shown significant improvement in oral ulcers, papulopustular lesions, and nodular lesions, but has not shown significant resolution of the genital lesions.[46] In another case study, infliximab (3 mg/kg) and methotrexate provided remission to patients resistant to etanercept with RA and Behcet disease.[47] Adalimumab in its randomized, prospective study with a large number of patents has proven its efficacy in the treatment of BD.[48]

Atopic dermatitis (AD)

In AD, the TNF-α production has been found to be up-regulated by keratinocytes, mast cells, monocytes, and dendritic cells. However, some conflicting results have been observed regarding the efficacy of TNF-α inhibitors in treatment in AD.[49] Use of infliximab in nine patients with AD showed 53% clinical improvement at week 2 of the treatment.[50] Etanercept has also been reported to be used in the management of chronic AD in two patients who achieved remission after 11 months of therapy.[51]

Pityriasis rubra pilaris (PRP)

It is an uncommon inflammatory papulosquamous skin disorder which is often refractory to conventional therapies. The off-label use of Infliximab has shown significant improvement in two weeks of therapy,[52] Etanercept has proved its efficacy in both type I and type II PRP.[53] Adalimumab mono-therapy has also been reported in the successful treatment of PRP.[54] A PRP type I patient who was treated with adalimumab, achieved clinical remission after four months. An increased level of mRNA of TNF-alpha was found in the lesional and perilesional skin at the time of active disease but was found to be normal after remission. This finding was consistent with the observed clinical remission and supported the use of anti-TNF-alpha for the treatment of PRP. It may be possible that although biologics are effective in a subset of PRP cases, their success is over-represented in the literature.[55]

Lichen planus (LP)

Genetic polymorphisms of several cytokines associated with the clinical presentation of LP, an increase in the frequency of 308A (TNF-α) allele may contribute to the development of more skin involvement.[56] Several case reports mention that severe erosive LP has improved with Etanercept. Adalimumab also has been reported in the treatment of LP.[57]

Alopecia areata (AA)

TNF-α inhibitors have been shown to induce AA/worsen symptoms.[58,59] TNF-α inhibitors are believed to regulate the production of interferon (IFN), which has been implicated in AA.[60] Adalimumab has been reported in the successful treatment of a patient with alopecia universalis which was unresponsive to multiple treatments.[61]

Synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome (SAPHO syndrome)

It is an autoimmune disorder characterized by the association of neutrophilic cutaneous involvement and chronic osteomyelitis.[62] TNF-α plays an important role in the occurrence and development of SAPHO syndrome. High expression of TNF-α in mandibular biopsy specimens of SAPHO syndrome patients have been demonstrated in a study. Several clinical reports have also established the definite efficacy of TNF-α inhibitors in management of SAPHO syndrome.[63] Palmoplantar pustulosis and HS which can be associated with SAPHO syndrome have also been treated with TNF inhibitors.[64,65,66] In a report, SAPHO syndrome associated with acne conglobata was effectively treated with a combination of etanercept and isotretinoin.[67] In a report, Adalimumab in combination with isotretinoin has led to remission of most of the features of SAPHO syndrome; however the osteoarticular manifestation continued to remain progressive.[68]

Toxic epidermal necrolysis (TEN)

TNF-α and IFN-gamma drive and perpetuate the pathogenesis of TEN. In a reported case series with ten participants with TEN, the use of single dose of Etanercept has shown complete healing.[69] Infliximab also has been reported to induce successful healing of TEN in one patient.[70]

Pruritus

In a 51-year-old man with Grover's disease who was non-responsive to conventional therapy, a reduction in pruritus by 98% was observed with use of Etanercept and the response was maintained for four months.[71]

Keloid

Etanercept has been shown to be associated with favorable therapeutic effect in the treatment of Keloid in a single case report.[72]

Erythema nodosum leprosum (ENL)

In Leprosy, the clinical spectrum is associated with the immunity of the patient. Around 30–50% of the patients develop acute inflammatory episodes known as type I reaction or reverse reaction and type II reaction ENL. This reaction may remain recurrent after being released from the hospital, requiring long-term use of thalidomide and or prednisone, thus increasing the risk of side effects. Two reports of infliximab and etanercept with a good response was found in the literature.[73]

Infliximab (5 mg/kg) was used successfully refractory ENL to conventional drugs including prednisone, pentoxifylline, and thalidomide in a patient with dimorphic lepromatous leprosy The symptoms of ENL were significantly reduced after 24 h. No further episodes of ENL were described after two infliximab administrations during weeks 2 and 6 and a follow-up of one year.[74]

Off-Label Uses of Rituximab

Rituximab is an anti-CD20 monoclonal antibody and currently approved for the treatment of relapsed or refractory, low-grade or CD20 positive follicular B-cell lymphoma.[75] Rituximab can be useful for dermatologic diseases where B cells play a major role in pathogenesis.[76] Chronic graft-versus-host disease and dermatomyositis (DM) are two of the most reported indications for off-label use of rituximab.[77]

Pemphigus

Rituximab has finally been approved as the first drug in the last 60 years in the management of moderate to severe Pemphigus vulgaris. This approval has finally been obtained in June 2018 after years of off label and successful use in this clinical condition. Rituximab however still continues to be an off-label indication for other pemphigus variants and bullous pemphigoid (BP). This approval is a landmark shift in the spectrum of off-label and approved indication for biologics wherein a drug was approved after evidence of its off-label use. The previous practice of labeling a biologic for a particular indication and then obtaining its long term patient response was reversed in this case and an off-label indication was finally approved.[77]

Chronic graft-versus-host-disease

GVHD is the most promising indication reported in dermatology with Rituximab.[78,79] More than four case series have reported the successful use of Rituximab at a dose of 375 mg/m² in GVHD, wherein 70% of the patients achieved clinical response with the therapy.[80]

Dermatomyositis (DM): Since B cell plays a vital role in the pathogenesis of DM, Rituximab can be a promising treatment option.[79] Rituximab has shown therapeutic improvement in several cases.[77,79,81]

Off-Label Uses of Secukinumab

Secukinumab is an interleukin-17A monoclonal antibody approved for the treatment of Psoriasis, PsA, and AS. Secukinumab can be useful for the dermatological disease where IL-17 plays a key role,[82]

Hidradenitis suppurativa (HS)

Therapeutic response to secukinumab in a case of HS refractory to conventional local, systemic therapies as well as biolohgics including anti-TNF and anti-IL12/23 antagonists has been reported. However, the role of IL-17 in HS pathogenesis is lacking.[83] In other two case reports, it was reported that secukinumab may be beneficial in HS for the short term.[84,85] A patient suffering from both PsO and HS, was successfully treated with secukinumab in a single case report.[86] Contemporary research confirms the presence of increased IL-17 levels in patients with HS.[87]

Pityriasis rubra pilaris (PRP)

In a recent study, the gene expression analysis revealed an increase in T-helper (Th) 1 cytokines levels in PRP. In particular, Th17 cytokines, such as IL-17A, IL-22, and IL-23 were found to be increased.[88] High levels of IL-17 have been found in a previous PRP patient providing a rationale for targeting IL-17 in some PRP patients.[89] In a case report of two patients with refractory PRP, it has been effectively treated with secukinumab. In both cases, the patients' erythematous plaques resolved or had a near complete resolution by week 4 of the treatment.[90]

Off-label use of Omalizumab

Omalizumab is a recombinant DNA-derived humanized IgG1 monoclonal antibody that selectively binds to free and membrane-bound IgE. It has been licensed for use in severe allergic asthma and chronic urticaria. Patients are required to have a baseline serum IgE between 30 and 700 IU/ml and body weight not more than 150 kg. Diseases in which IgE maybe or certainly has an important role such as bullous pemphigoid, angioedema, atopic dermatitis, Churg-Strauss syndrome (CSS) are reported off-label indications for Omalizumab.[91]

Churg-Strauss syndrome (CSS)

Eosinophilic granulomatosis with polyangitis (EGPA) also termed as Churg-Strauss syndrome is an extremely rare autoimmune allergic granulomatosis that causes inflammation of small- and medium-sized blood vessels. Omalizumab has been used to successfully treat this condition, and it has also been shown to aggravate this syndrome. A poorly understood link between Omalizumab and CSS has been hypothesized. Various case studies have been published about the association of Omalizumab with CSS. Omalizumab treatment may unmask CSS due to the weaning of corticosteroids in some asthma patients or may delay corticosteroid treatment allowing for CSS to manifest.[92,93]

Bullous pemphigoid (BP)

Bullous pemphigoid is an acquired, autoimmune, bullous disease presenting with subepidermal blistering, eosinophilia, and severe itch that is characterized by autoantibodies against bullous pemphigoid antigen within basal keratinocytes.[94] IgE antibodies specific for the BP180 autoantigens are detected in sera and biopsy samples from the majority of BP patients. A successful treatment of BP with Omalizumab was observed in a case report.[95] In another study with six patients followed up for 42 weeks reported therapeutic benefit with Omalizumab.[96]

Angioedema

A case reported by Ozturk and Kocaturk in a 47-year-old male patient with severe idiopathic recurrent attacks of angioedema was controlled by Omalizumab treatment.[97]

Atopic dermatitis

Various studies have been published on the effective treatment of AD with Omalizumab. A case series on 11 patients with severe AD treated with Omalizumab showed improvement in SCORing Atopic Dermatitis (SCORAD) scores.[98]

Anakinra

It is approved for the treatment of RA and cryopyrin-associated periodic syndromes. Anakinra is currently reported in case reports as an option for the treatment of skin conditions such as psoriasis, atopic dermatitis, photo-ageing, melanoma, Schnitzler syndrome, pyoderma gangraenosum, PAPA syndrome, HS, lamellar ichthyosis, Sweet's syndrome, panniculitis, Muckle-Wells syndrome, familial Mediterranean fever, SAPHO syndrome, and other disorders.[99] However, the use of Anakinra due to its availability and cost is very limited.

Pyoderma gangraenosum (PG)

Abnormal immune cells identified in PG lesions including neutrophils, T cells, the inflammatory mediators IL-1β, IL-8, IL-17, and TNF-α lend themselves to new therapeutic approaches.[22] A successful treatment of PG with anakinra in a patient with Wiskott–Aldrich syndrome has been reported.[100]

PAPA syndome

PAPA syndrome is characterized by the triad of sterile pyogenic arthritis, PG, and acne. Due to the genetic backgro und of PAPA syndrome resulting in permanent elevation of IL-1b levels, the IL-1 receptor antagonist anakinra seems to be the choice of treatment. A quick and effective response of Anakinra in a patient with PAPA syndrome was reported.[100]

Hidradenitis suppurativa

In a study on cases with PG and HS, one patient was successfully treated with Anakinra and responded with good therapeutic effect.[101]

Safety profile of biologics

Immunogenicity is an important safety concern for biologics, which may induce immune responses, including mild hypersensitivity, infusion reactions, or cross-reactions to endogenous molecules. This could result in a loss of efficacy or deficiency syndromes (e.g., thrombocytopenia as a result of neutralizing antibodies blocking endogenous thrombopoietin after treatment with recombinant thrombopoietin or neutralizing antibodies with human growth hormone).[102]

Biologic-related immunologic reactions include systemic inflammatory reactions such as cytokine release syndrome (CRS) or cytokine storms, and TGN1412, a humanized anti-CD28 monoclonal antibody. During pre-clinical studies, no proinflammatory reactions were detected. But in phase I clinical trial, the enrolled patients developed multi-organ failure, lymphopenia, thrombocytopenia, and elevations in cytokine levels. These outlined the clinical picture of a CRS.[103,104] Such reactions were also documented for infliximab, rituximab, and alemtuzumab.[105] Severe or life-threatening CRS induced by chimeric antigen receptor T cells was reported with tocilizumab.[106]

Adverse drug reactions associated with individual biologics due to their mechanism of action. Biologics associated with serious infections including tuberculosis reactivation, malignancies (e.g., anti-TNF-α agents), and progressive multifocal leukoencephalopathy (e.g., natalizumab and rituximab). Wound-healing complications or arterial thromboembolic events observed for angiogenesis inhibitors (e.g., bevacizumab). Dermatologic toxicities observed for epidermal growth factor receptor inhibitors (cetuximab and panitumumab) and B-cell lymphocyte depletion from anti-CD20 antibodies (rituximab).[107,108,109,110,111,112]

Ongoing Trials and Future Perspective

Dupilumab (Dupixent®) a monoclonal antibody against the IL-4 receptor is the first biologic approved to treat AD.[113] 52 weeks phase III randomized clinical trial (RCT) demonstrated the long-term efficacy of dupilumab in combination with topical corticosteroids. This displayed an acceptable safety profile with only injection site reactions and conjunctivitis more commonly occurred in dupilumab-treated subjects. Results from the preliminary phase II trials on lebrikizumab and tralokinumab were promising with eczema area and severity index (EASI), 50 improvements in 82.4% (n = 51), and 73.4 (n = 52) at week 12.[114]

Currently, several new biological preparations MABp1, CJM112, and bimekizumab are under investigation for the management of HS.[115]

Conclusion

Development of biological therapy has a remarkable impact on several dermatologic diseases. TNF blocker has widely been reported in several off-label indications without any trial-based evidence except data provided by case reports and case series. Due to limited and unsatisfactory therapeutic options, many dermatological diseases have been successfully managed with biologics, although the indication may not have been approved by the regulatory authorities. A large number of potential targets for the treatment of these chronic inflammatory skin conditions show the complexity and knowledge gaps in the pathogeneses of these diseases. This depicts the need for future larger scale studies. Further research in this field is needed to support the development of new treatments option. We expect that the off-label use of biologics will continue to grow in the field of dermatology. With the addition to new literature in off-label indication, we will acquire more knowledge about the rational use of these agents for other dermatological disorders.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.