Off-label use of biologic agents in the treatment of dermatosis, Part 1: infliximab and adalimumab

In recent years, the therapeutic armamentarium available to dermatologists has been extended thanks to the development of numerous biologic agents. In our field, immunomodulators--although currently only approved for psoriasis--have given rise to new therapeutic possibilities in a number of inflammatory skin diseases. Since these new agents have more specific immunologic mechanisms of action, their efficacy and safety is an improvement on traditional immunosuppressants. Consequently, it is very likely that they will play an important role in dermatology in the next few years. This article, the first part of a review of off-label use of biologic agents in dermatology, describes the anti-tumor necrosis factor-alpha antibodies, infliximab and adalimumab.     

Mycophenolate mofetil and leflunomide: promising compounds for the treatment of skin diseases

In the past decade, there has been enormous progress in the understanding of the pathomechanisms of immune-mediated diseases, which has led to major advances in immunotherapeutic strategies. As a consequence, the armamentarium of specific and nonspecific immune-modulating and immunosuppressive drugs for the treatment of skin diseases has been widely extended. Among the nonspecific immunomodulators, mycophenolate mofetil and leflunomide show promising effects in a variety of autoimmune and inflammatory skin disorders. Both compounds inhibit a key enzyme in nucleotide biosynthesis, a step that is pivotal for the production of cytotoxic T cells and antibody formation. They do not act in the nucleus, which may explain their advantageous side-effect profile.     

Photodynamic therapy: update 2006 Part 2: Clinical results

In several randomized, controlled studies, the application of a standard preparation containing methyl-aminolevulinate (MAL; Metvix, Galderma, F), followed by red light irradiation proved effective and well tolerated in the treatment of actinic keratosis and basal cell carcinoma, and has now been approved for clinical use in European countries. A brand name aminolevulinic acid (ALA) solution (Levulan Kerastick, Dusa Pharmaceuticals Inc., Wilmington, MA) plus blue light exposure has been approved for the treatment of actinic keratosis in the USA. Randomized and controlled studies have shown that MAL as well as ALA are also effective in the treatment of Bowen's disease. In addition, a large and growing number of open studies or case reports have evaluated its use in the treatment of a broad range of other neoplastic, inflammatory and infectious skin diseases. However, efficacy and definite advantages over standard therapies remain to be clarified because the experimental design of these studies was often poor, the number of enrolled patients was generally low, and the follow-up was shorter than 12 months. However, these studies have suggested a few possible clinical applications worthy of further investigation. A growing number of laboratory and clinical findings suggest that several new synthetic sensitizers, besides ALA and MAL, may be helpful in the treatment of non-melanoma skin cancers, melanoma metastasis, and selected inflammatory and infective skin diseases. These compounds are deliverable intravenously, have short half-lives both in the blood and skin, and are highly efficient. However, they are as of yet not approved for clinical use.     

Current and emerging treatments targeting the neuroendocrine system for disorders of the skin and its appendages

The skin as a neuroendocrine organ and the role of neuroendocrine signalling in the development of disorders affecting the skin and its appendages has received increasing attention in the last years. Different neuroendocrine systems have been described in the barrier organ skin, including the thyroid system, the hypothalamic-pituitary-adrenal axis, the opioid, the endocannabinoid, the cholinergic, the secosteroidogenic and the serotonergic systems. All of these systems have been implicated in the development of skin diseases, which often have an inflammatory origin. These discoveries have led to an increase in the development of new drugs targeting components of neuroendocrine signalling pathways. Additionally, attempts have been made to repurpose already approved drugs targeting neuroendocrine signalling pathways in other organs for the treatment of skin diseases. Recently published results from preclinical and clinical studies look promising and may offer improved therapies to patients suffering from skin diseases in the near future. In this review, from a pharmaceutical point of view, we focus on recent progress in synthetic drug development of compounds targeting neuroendocrine signalling in the skin and its appendages to treat skin diseases such as atopic dermatitis, psoriasis, acne, alopecia areata and hyperhidrosis.     

Off-label-Use und G-BA

Off-label use of medicinal products, i.e. beyond their submitted, tested and approved indications, lies between 30 and 90%—depending on the indication. In dermatology, off-label use is of special importance, for even guideline-endorsed standard therapeutic approaches for common dermatological diseases like atopic eczema, psoriasis, or malignant melanoma are to some extent not licensed for these indications. In addition, many of the approximately 5000 dermatological diseases have a low prevalence. For many such orphan diseases, there are no approved drugs, and it is not feasible that licensing studies will be performed for these indications within a foreseeable time. A reliable legal framework for the reimbursement of medicinal products that are used off-label is essential both for patients and to allow physicians to choose the most adequate therapy. Therefore, off-label use expert groups have been convened by the Federal Ministry of Health (BMG) in order to improve patient care. So far this new and innovative approach has not provided any reasonable improvement for many patients with dermatological diseases whose treatment can only be off-label since a comprehensive evaluation of all off-label indications is not possible. The following statement of the former Federal Minister of Health, U. Schmidt, is particularly true for dermatological therapy: “Good oncologic care also requires a good drug treatment—especially in the outpatient setting. The use of drugs which are not or not yet approved for this indication is often required here”. Federal Minister of Health, Ulla Schmidt, 25th German Cancer Congress, 10 March 2002, Berlin.     

Mycophenolatmofetil und Leflunomid: viel versprechende Immunmodulatoren zur Therapie von Hauterkrankungen

Summary: In the past decade, there has been enormous progress in the understanding of the pathomechanisms of immune‐mediated diseases, which has led to major advances in immunotherapeutic strategies. As a consequence, the armamentarjum of specific and nonspeciflc immune‐modulating and immunosuppressive drugs for the treatment of skin diseases has been widely extended. Among the nonspeciflc immunomodulators, mycophenolate mofetil and leflunomide show promising effects in a variety of autoimmune and inflammatory skin disorders. Both compounds inhibit a key enzyme in nucleotide biosynthesis, a step that is pivotal for the production of cytotoxic T cells and antibody formation. They do not act in the nucleus, wbich may explaln their advantageous side‐effect profile.     

Imatinib,dasatinib and nilotinib: a review of adverse cutaneous reactions with emphasis on our clinical experience

In the last years, several tyrosine kinase inhibitors (TKIs) have been developed and approved for human cancer treatment. Imatinib mesylate was the first of this novel family of drugs that target cancer‐specific molecules and signalling pathways. The appearance of imatinib resistances led to the introduction of second‐generation TKIs with higher potency and selectivity, such as dasatinib and nilotinib. However, the range of activity of these agents is not simply directed at tumour cells. Patients and their clinicians are indeed frequently confronted with the cutaneous side‐effects associated with the employ of these drugs, which represent the most common non‐hematological adverse reactions. For this reason, a systematic dermatological survey of patients receiving these therapies is highly important, and an early and appropriate dermatological treatment is required. In this review, we analyse the clinical and pathological characteristics of the most commonly reported adverse skin events associated with first‐ and second‐generation tyrosine kinase inhibitors, with a particular emphasis on our clinical experience.     

Reacciones paradójicas de los tratamientos biológicos utilizados en psoriasis: revisión de la literatura

Biologic drugs, which are molecules designed to act on specific immune system targets, have been shown to be very effective in treating various dermatological, rheumatological, and systemic diseases. As a group, they have an acceptable safety profile, but their use has been associated with the onset of both systemic and organ-specific inflammatory conditions. True paradoxical reactions are immune-mediated disorders that would usually respond to the biologic agent that causes them. There is still debate about whether certain other adverse reactions can be said to be paradoxical. The hypotheses proposed to explain the pathogenesis of such reactions include an imbalance in cytokine production, with an overproduction of IFN-α and altered lymphocyte recruitment and migration (mediated in part by CXCR3), and the production of autoantibodies. Some biologic therapies favor granulomatous reactions. While most of the paradoxical reactions reported have been associated with the use of TNF-α inhibitors, cases associated with more recently introduced biologic therapies —such as ustekinumab, secukinumab, and ixekizumab— are increasingly common. The study of paradoxical adverse events not only favors better management of these reactions in patients receiving biologic therapy, but also improves our knowledge of the pathogenesis of chronic inflammatory diseases and helps to identify potential therapeutic targets.     

Novel systemic antibiotics in dermatology

The treatment of bacterial skin infections has become challenging with the evolution of resistant species. As common antibiotics are losing efficacy, there is a pressing need for the discovery of new antibacterial agents. Only several systemic antibiotics have been approved for the treatment of skin infections in recent years. The expanding repertoire includes novel compounds structurally based on existing antibiotic classes, such as the glycopeptides, cephalosporins, and glycylcyclines. Antibiotics with completely unique mechanisms of action are being developed as members of the lipoprotein, oxazolidonone, and streptogramin classes. Most of these drugs require intravenous administration that limits their use. Future development should focus on more accessible routes of antibiotic administration, including oral, inhaled, or transdermal formulations.     

Cutaneous lymphomas

Cutaneous lymphomas are rare skin diseases. They must be differentiated from secondary skin infiltrates by primary nodal lymphomas. Primary cutaneous lymphomas can be classified into B‐ and T‐cell lymphomas and hematodermic neoplasms; they usually possess a favorable prognosis and run a chronic course. Treatment is dependent on stage. As complete cure is not possible, it is essential to control the disease and alleviate symptoms. In recent years numerous new drugs have been developed to treat these diseases.     

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.     

Adverse cutaneous reactions secondary to tyrosine kinase inhibitors including imatinib mesylate, nilotinib, and dasatinib

Imatinib mesylate is the first of a novel group of drugs that specifically target protein tyrosine kinases, which are central to the pathogenesis of human cancer. It has been approved for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumor and has been found efficacious in other neoplastic diseases. Nilotinib and dasatinib, a second-generation of tyrosine kinase inhibitors (TKIs), were developed in response to findings of emerging imatinib resistance or intolerance to the drug. Cutaneous reactions are the most common nonhematologic side effect of these drugs, and their management is challenging especially in the absence of alternative anticancer agents. The present review focuses on the clinical characteristics and the hypothesized molecular pathogenesis of these first- and second-generation TKIs' cutaneous side effects, and approaches to their treatment. The wide range of adverse effects clarifies the difficulty in designing a truly antitumoral TKI.     

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.     

Beyond Psoriasis: Novel Uses for Biologic Response Modifiers in Pediatric Dermatology

Dermatologists have witnessed the increasing availability of novel biologic response modifiers for the treatment of inflammatory and autoimmune diseases in recent years. The most common dermatologic indication for the use of biologic response modifiers in adults is psoriasis, but the U.S. Food and Drug Administration has not approved any of these agents for use in any dermatologic disease in children with the exception of omalizumab, and as such, use in this population is considered off‐label. In this review, we focus on the use of these agents in children to treat inflammatory skin diseases other than psoriasis, including atopic dermatitis, hidradenitis suppurativa, pemphigus vulgaris, bullous pemphigoid, and toxic epidermal necrolysis, with an emphasis on the use of etanercept, infliximab, rituximab, omalizumab, and ustekinumab. By highlighting novel uses of these agents, particularly for the treatment of dermatologic conditions for which optimal therapies are yet to be established, we hope to raise awareness of the potential use of this class of medications to treat inflammatory skin diseases in children.     

Topische Immunmodulation in der Dermatologie

Summary: Immunomodulators include both immunostimulatory and immunosuppressive agents.
If successful, topical immunotherapy may represent an important improvement in the therapy of inflammatory dermatoses, viral infections and cancers of the skin and genital mucosa. This rather old concept
has emerged some 100 years ago, but only recently have its basic mechanisms been elucidated. Topical immunotherapy using obligate contact sensitizers such
as diphencyprone or dinitrochlorobenzene elicit hapten‐mediated immune responses, which involve specific antigens or act merely by the induction of an inflammatory infiltrate. They have been used against viral (e. g. common warts) and autoimmune diseases (e. g. alopecia areata). Newer agents such as imidazoquinolines (imiquimod and resiquimod) act by cytokine secretion from monocytes/macrophages (interferon‐α, interleukin‐12, tumour‐necrosis factor‐α). The locally generated immune milieu leads to a
Th₁‐dominance and cell‐mediated immunity that have been clinically used to treat viral infections such as HPV, HSV and mollusca and cancerous lesions including initial squamous cell and basal cell carcinoma in immunocompetent and immunosuppressed patients. While these agents improve antigen‐presentation by dendritic cells, they also act on B‐cells leading to the synthesis of antibodies such as IgG_2a much
like the recently discovered immunostimulatory CpG sequences that stimulate innate immunity. These sequences act as ?danger signals” as they occur in bacterial and viral DNA but are selectively methylated and inactivated in the mammalian genome. They share the induction of the same cytokines like imidazoquinolines, while they display different magnitudes and kinetics of the response. On the other hand, the topical immunosuppressive tacrolimus has been used with great success in the treatment of chronic inflammatory diseases such as atopic dermatitis in children and adults. Topical immunotherapy with both immunostimulatory and immunosuppressive agents bears potential for effective and patient‐friendly treatment of inflammatory, infectious and cancerous skin diseases. Due to their adjuvant properties immunoenhancers may also improve conventional (protein) and DNA vaccination against cancer, atopy and allergies.     

Disseminated granuloma annulare: a cutaneous adverse effect of anti-tnf agents

Tumor necrosis factor-alpha (TNF-α) inhibitors, such as etanercept, infliximab, and adalimumab, bind to TNF-α and thereby act as anti-inflammatory agents. This group of drugs has been approved for the treatment of rheumatoid arthritis, psoriatic arthritis, moderate to severe plaque psoriasis, ankylosing spodylitis, Crohn disease, and juvenile idiopathic arthritis. We describe a 56-year-old woman who developed an erythematous pruritic rash on both arms-diagnosed as granuloma annulare by skin biopsy-approximately 22 months after initiating adalimumab for treatment of rheumatoid arthritis. On stopping adalimumab there was total clearance of the skin lesions, but a similar rash developed again when her treatment was switched to another anti-TNF agent (etanercept). This clinical observation supports a link between TNF inhibition and the development of granuloma annulare.     

Mites,caterpillars and moths

Besides conditions such as scabies and hypersensitivity to house dust mites, other diseases caused by mites and caterpillars tend to be more uncommon in everyday practice. Nevertheless, there is a broad spectrum of medically relevant disorders associated with these arthropods. Mites may act as parasites that infect or colonize the skin (e.g., scabies, pseudoscabies, demodicosis) or they may pierce the host’s skin and feed on tissue fluid and blood (trombiculosis). In the latter case, they also play a role as vectors transmitting Orientia tsutsugamushi, the pathogen that causes Tsutsugamushi fever. In addition to house dust mites, storage mites, too, are characterized by their allergenic potential. The terms erucism and lepidopterism are used for the various diseases caused by caterpillars and moths. Both terms are not used consistently. With respect to pathogenesis, various mechanisms have been described, including type I and type IV hypersensitivity as well as irritant and toxin‐induced reactions. In Germany, skin reactions following exposure to the hairs of oak processionary caterpillars are particularly common. Extracutaneous manifestations including nausea, vomiting, hemorrhage, arthropathy or even life‐threatening reactions have been reported in association with certain exotic species. Some species act as parasites by feeding on blood or tears. As natural silk can cause immediate and delayed‐type hypersensitivity reactions, workers in the silk industry may develop allergic asthma, rhinitis, or conjunctivitis. Consumption of silkworm pupae is associated with the risk of food allergy.     

Immunosuppressive therapy in collagen vascular diseases.

Over the past ten to fifteen years cytotoxic drugs have gradually been added to the therapeutic armamentarium of physicians other than oncologists, particularly dermatologists. They are being used to treat nonmalignant cutaneous diseases such as pemphigus vulgaris, bullous pemphigoid, and psoriasis. The rationale for their use in these diseases is conjectural, yet those dermatologists who use them feel strongly not only that cytotoxic drugs are effective, but that when used properly, they are relatively safe. The immunosuppressive activity of cytotoxic drugs has been accepted and widely acclaimed in immunology, renology, and transplant medicine. However, their usefulness in two autoimmune diseases frequently managed by dermatologists is widely disputed. In this short discussion the rationale for the use of cytotoxic agents and evidence for their effectiveness when used appropriately in progressive systemic sclerosis and systemic lupus erythematosus is presented.