Off-Label-Use in der Dermatologie

When making therapeutic decisions, doctors often find themselves faced with a dilemma regarding ethical, professional, legal liability, social and service aspects of their duties. These conflicts may be enhanced when medications have to be prescribed for non-approved usages, known as off-label prescribing, because existing therapy options have been exhausted. This option become considerably more difficult since the German Federal Social Court decision of March 2002 which limited off-label use to a number of very strictly defined circumstances. In order to clarify the basis for taking decisions in a given situation, an oncology expert commission has been formed under the coordination of the Department of Health and Social Security. However, this is no solution for the great variety of uncommon dermatological diseases which often require off-label medication usage.     

Off-label use of biologic agents in the treatment of dermatosis, part 2: etanercept, efalizumab, alefacept, rituximab, daclizumab, basiliximab, omalizumab, and cetuximab

In recent years, a series of new drugs have been developed through the application of molecular biology. These drugs act by blocking specific molecules of the immune system and have been developed to act on specific targets that play an important role in the pathophysiology of the diseases in which their therapeutic use has now been approved. Over time, experience has been accumulated in the use of these drugs in the treatment of skin diseases for which they have not been approved but in which the pathophysiology suggests that they could also be effective. The use of these drugs is increasing in difficult-to-treat cases of skin diseases for which the drugs are not approved. The second part of this review of off-label use of biologic agents in dermatology considers the use of etanercept, efalizumab, alefacept, rituximab, basiliximab, omalizumab, and cetuximab.     

Off-Label Dermatologic Uses of Anti-TNF-a Therapies

Background

Tumor necrosis factor-alpha (TNF-a) is a proinflammatory cytokine that plays an immunomodulatory role in a variety of systemic and dermatologic diseases. Currently, three anti-TNF-a drugs are available in North America— infliximab (approved in the U.S. for the treatment of rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis, ulcerative colitis, and psoriatic arthritis), etanercept (approved in the U.S. for the treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and psoriasis), and adalimumab (approved for the treatment of rheumatoid arthritis and psoriatic arthritis).

Objective

To review the current literature supporting alternative (and currently off-label) dermatologic uses of TNF-a antagonists.

Methods

A MEDLINE search (1966–March 2005) was conducted using the keywords “infliximab,” “etanercept,” “adalimumab,” “TNF inhibitors,” and “off-label” to identify published reports of off-label dermatologic uses of TNF-a inhibitors.

Results

Anti-TNF-a therapies have been reported in the following dermatologic diseases: sarcoidosis, hidradenitis suppuritiva, cicatricial pemphigoid, Behçet’s disease, pyoderma gangrenosum, multicentric reticulohistiocytosis, apthous stomatitis, Sneddon–Wilkinson disease, SAPHO syndrome, pityriasis rubra pilaris, eosinophilic fasciitis, panniculitis, Crohn’s disease, necrobiosis lipoidica diabeticorum, dermatomyositis, and scleroderma. The vast majority of these reports are in the form of individual case reports and small case series. Only two published randomized controlled trials involving the off-label use of a TNF inhibitor were found.

Conclusions

A growing number of published reports suggest that anti-TNF-a therapies may be effective in the treatment of numerous inflammatory skin diseases outside their currently approved indications.     

The use of infliximab in dermatology

Autoimmune diseases like Crohn's disease, rheumatoid arthritis (RA) and psoriasis are often difficult to treat due to complex underlying immunologic pathways. Tumor necrosis factor (TNFα) is an important proinflammatory cytokine that seems to play an important role in the pathogenesis of these diseases. After the approval of a variety of drugs which block the biological activity of TNFα, new therapeutic options were available and especially infliximab became widely used. TNFα, as a member of the proinflammatory cytokine family, is a major cytokine in different inflammatory dermatological diseases such as cutaneous vasculitis, lupus erythematosus, eczema or psoriasis. Therefore infliximab has been used in a variety of inflammatory dermatoses lately, sometimes with great success. Several case reports showing new indications for a successful use of TNFα‐inhibitors in dermatology have been published and will be reviewed in the following article. Nevertheless, infliximab is not approved for these indications at the moment and has to be considered as off‐label use.     

Biologics in Dermatology: An Integrated Review

The advent of biologics in dermatologic treatment armentarium has added refreshing dimensions, for it is a major breakthrough. Several agents are now available for use. It is therefore imperative to succinctly comprehend their pharmacokinetics for their apt use. A concerted endeavor has been made to delve on this subject. The major groups of biologics have been covered and include: Drugs acting against TNF-α, Alefacept, Ustekinumab, Rituximab, IVIG and Omalizumab. The relevant pharmacokinetic characteristics have been detailed. Their respective label (approved) and off-label (unapproved) indications have been defined, highlighting their dosage protocol, availability and mode of administration. The evidence level of each indication has also been discussed to apprise the clinician of their current and prospective uses. Individual anti-TNF drugs are not identical in their actions and often one is superior to the other in a particular disease. Hence, the section on anti-TNF agents mentions the literature on each drug separately, and not as a group. The limitations for their use have also been clearly brought out.     

Methotrexate for inflammatory skin disease in pediatric patients: Consensus treatment guidelines

Methotrexate (MTX) is a readily accessible drug, first used in 1948 and employed for a wide variety of indications since then. However, despite widespread off-label use, FDA labeling does not include approved indications for the use of MTX for many inflammatory skin diseases in pediatric patients, including morphea, psoriasis, atopic dermatitis, and alopecia areata, among others. Without published treatment guidelines, some clinicians may be hesitant to use MTX off-label, or uncomfortable prescribing MTX in this population. To address this unmet need, an expert consensus committee was convened to develop evidence- and consensus-based guidelines for use of MTX to treat pediatric inflammatory skin disease. Clinicians with experience and expertise in clinical research, drug development, and treating inflammatory skin disease in pediatric patients with MTX were recruited. Five committees were created based on major topic areas: (1) indications and contraindications, (2) dosing, (3) interactions with immunizations and medications, (4) adverse effects (potential for and management of), and (5) monitoring needs. Pertinent questions were generated and addressed by the relevant committee. The entire group participated in a modified Delphi process to establish agreement on recommendations for each question. The committee developed 46 evidence- and consensus-based recommendations, each with >70% agreement among members, across all five topics. These are presented in tables and text, along with a discussion of supporting literature, and level of evidence. These evidence- and consensus-based recommendations will support safe and effective use of MTX for the underserved population of pediatric patients who may benefit from this valuable, time-honored medication.     

Can we teach old drugs new tricks?—Repurposing of neuropharmacological drugs for inflammatory skin diseases

Despite the “hype” for monoclonal antibodies, the so‐called biologics, which added significant value to the therapeutic armamentarium of dermatologists and improved the life of many patients, but may exhibit significant adverse effects, the vast majority of dermatological patients suffering from atopic dermatitis or psoriasis is still treated topically. Thus, there is a huge need for locally applied, locally acting drugs for inflammatory skin diseases with better risk‐benefit profiles compared to topical corticosteroids or calcineurin inhibitors. Drug repositioning is a complex process, but offers advantages, in particular for indications with lower revenues. In this viewpoint, the neuroendocrine system of the skin is described as an attractive drug target because it contributes significantly to neutralizing external noxious agents prior to inducing immune or vascular changes leading to the clinical signs of skin inflammation, for example, itch and erythema. In addition, epidermis and dermis are accessible for topically applied products which may act locally without pharmacodynamically relevant systemic exposure limiting adverse events. Moreover, since numerous drugs have been evaluated for various CNS diseases, some failed and some approved, this resource should be exploited for repurposing as anti‐inflammatory drugs for topical application, for example, cannabidiol, fingolimod or asimadoline. Finally, a screening algorithm is shared which gives direct evidence of links between drug and inflammatory skin diseases.     

2020年中国皮肤病药物临床试验分析

【摘要】 目的 了解2020年中国皮肤病药物临床试验开展及上市情况。方法 从中国国家药品监督管理局药物临床试验登记与信息公示平台登记数据库和国产及进口药品数据查询系统，收集2020年皮肤病药物注册临床试验信息，包括试验数量、分期和受试药物主要适应证、类型等信息以及上市皮肤病药物情况。结果 2020年共有157项皮肤病药物注册临床试验在中国药物临床试验登记与信息公示平台登记，占同期全部药物临床试验（2 548项）的6.16%。其中，中国制药企业发起127项（80.9%），国际多中心试验25项（15.9%）。生物等效性临床试验在国制药企业发起的临床试验中占比最高（55.9%，71/127）。国内制药企业发起的国际多中心临床试验占比低于国际制药企业［1.9%（3/157）比14.0%（22/157），P < 0.001］，Ⅰ期临床试验和生物等效性试验占比［24.4%（31/127）和55.9%（71/127）］高于国际制药企业［10.0%（3/30）和0，均P < 0.001］。共涉及90种试验药物，银屑病、特应性皮炎、皮肤黑素瘤是常见适应证，创新药占53.3%（48/90）；国内制药企业创新药比例低于国际制药企业［43.2%（32/74）比16/16，P < 0.001］。2020年，共有22家制药企业研发的28种皮肤病治疗药物在中国获准上市，其中21种来自国内制药企业。结论 国内制药企业开展的药物临床试验多集中于仿制药，需进一步提高创新能力。     

Legal ramifications of off-label filler use

Dermal fillers are often used in an off-label manner. Most off-label use is not only legal, but represents an appropriate physician standard of care. This chapter will first explore what is and what is not considered off-label. Then the chapter will explore manufacturer promotion of off-label use of both drugs and devices. Finally, the legal ramifications of off-label dermal filler use will be discussed.     

Aktuelle Trends in der Berufsdermatologie

In clinical practice occupational skin diseases usually present as hand dermatitis. Occupationally acquired contact allergies are of eminent relevance in many work place products e.g. skin care products, dyes and paints, epoxy resins or protective gloves. However, not infrequently, a range of other dermatoses of different etiology and localization can be occupationally induced and, at least in Germany, thus be medically treated and—if necessary—compensated for with full coverage by the statutory employers’ liability insurance. Examples regarding non-eczematous skin diseases triggered by external factors are psoriatic lesions, cutaneous type-1-allergies, occupationally acquired infections, and dermatoses in other localizations which are occupationally exposed to irritant influences (e.g. feet in workers wearing occlusive safety boots). Moreover, outdoor workers deserve specific attention by the dermatologist if squamous cell carcinomas including precursor lesions like actinic keratoses or Bowen disease have occurred. In Germany, recently the scientific advisory committee to the Ministry of Labor has recommended including these skin cancers caused by occupational solar UV exposure in the national list of occupational diseases. The framework for dermatological preventive care of occupationally-induced inflammatory dermatoses has been continuously improved in the last years. The aim is to reach a similar level of care and preventive measures for patients with occupational skin cancer, including primary preventive workers’ education.     

Non‐cosmetic dermatological uses of botulinum neurotoxin

Botulinum neurotoxin (BoNT) is renowned for its inhibitory effects on the neuromuscular junction. The evidence for its use in cosmetic dermatology and in non‐dermatological indications is well established. We have systemically analysed the evidence for the non‐cosmetic dermatological uses of BoNT. This review presents the many small studies showing promising results for the use of BoNT in a multitude of dermatological diseases, including (but not limited to) hyperhidrosis, Darier's disease, Hailey–Hailey disease, pompholyx and hidradenitis suppurativa. There is, however, the need for larger, double‐blinded randomized control trials against established treatments to cement the evidence base underlying the use of BoNT in dermatology.     

Intravenous immunoglobulin treatment: Where do dermatologists stand?

Intravenous immunoglobulins (IVIG) are therapeutic products, comprising polyclonal IgGs, which are obtained from human plasma pool of healthy blood donors. Despite the lack of Food and Drug Administration (FDA) approval, the experience of using IVIG in various dermatological diseases increases day by day and exciting results are reported. However, experience with the use of IVIG in dermatological indications are mostly case reports whereas randomized, controlled, double‐blind, multicentric studies have not been performed. Dermatological diseases treated with IVIG are autoimmune bullous skin diseases, Stevens‐Johnson syndrome and toxic epidermal necrolysis, connective tissue diseases, pyoderma gangrenosum, severe atopic dermatitis, chronic urticaria, Kawasaki disease, pretibial myxoedema, scleredema, and graft‐versus‐host disease.     

Biosimilars in Dermatology – theory becomes reality

Biosimilars are biological medicines that are analogues of a specific reference product. Biosimilars of the tumor necrosis factor alpha inhibitors infliximab and etanercept are already approved and available for dermatological indications. Regulatory agencies require in‐depth analysis of physicochemical and functional properties of these highly complex molecules as well as clinical data on their similarity regarding efficacy and safety in at least one clinical trial in a sensitive and homogeneous population. Thus, it must be shown that biosimilars are essentially the same as the originator product if they are to be licensed in regulated drug markets. As a consequence, these data are extrapolated from one molecule (the originator) to another (biosimilar) resulting in an approval that includes the same indications as the originator product. While extrapolation is well accepted and regulated, clear recommendations regarding the interchangeability of originators and biosimilars as well as data on multiple consecutive switching are missing. Current scientific knowledge does not argue against the use of biosimilars for dermatological indications, but sequential switching of biosimilars should be considered carefully. To increase confidence and enhance evidence for biosimilars, accurate documentation of the specific products given to each patient is essential and should preferably be included in patient registries.     

Botulinum Toxin for Glabellar Lines

Facial rhytides represent a widespread aesthetic concern. In particular, glabellar lines are perceived as a sign of aging and may give an erroneous impression of negative emotions. The onset of glabellar lines is closely related to the movements of the underlying muscles. Botulinum toxins inhibit the release of acetylcholine into the synaptic cleft and therefore result in temporary muscle paralysis. The observation that botulinum toxin (BTX) smoothed facial lines when used therapeutically led researchers to study the toxin effect on glabellar lines. Nowadays, the use of BTX to smooth glabellar frown lines represents the leading procedure in aesthetic facial treatments and an increasing number of BTX formulations are becoming available. This article provides a comparative evaluation of currently available BTX options for the treatment of glabellar lines. Toxins have been divided into three groups, based on whether they have obtained approval for cosmetic use (approved treatments) or not (off-label treatments), or whether they are still under investigation (experimental treatments). We examine the basic similarities and differences between available botulinum toxins, and summarize the pharmacokinetics and dosing. All approved treatments consist of BTX type A (BTX-A) and differ in their molecular weight, as some formulations are made of a BTX-A complex of 900 kDa while the latest option on the market is a 150 kDa BTX-A that is free from complexing proteins. As for the dosage, the important aspect that emerges from this comparison is that even within a given serotype, such as BTX-A, formulations are not interchangeable as each possesses distinctive characteristics that are attributed to the unique toxin purification and manufacturing processes. There is a substantial body of published evidence on the use of these approved treatments for facial enhancement, proving efficacy and safety. We investigate the methods of evaluation used for each toxin and review the safety and efficacy data reported in the literature. Minor adverse effects, such as headache, blepharoptosis, and injection-site reactions, are relatively frequent but transient, whilst major adverse effects are rare. Some botulinum toxins, i.e. BTX type B, that are approved for therapeutic applications are used off-label for cosmetic indications, thus without the approval of the health regulatory committees and without sufficient published evidence on safety and efficacy. As for experimental treatments, a number of BTX products are currently in development or have been recently launched for aesthetic applications. These products have been specifically designed to overcome some of the limitations present in the older generation of products. However, some of these toxins may be easily purchased via the Internet, without having any license or approval for cosmetic or therapeutic indications; these products must be considered unsafe and are potentially a severe health risk for patients.