Using Biologic Agents Off-Label

O ff-label use of medications provides new sources for effective therapeutic alternatives when all other treatment modalities have been exhausted. Off-label use not only encompasses traditional medications but biologic agents as well. The use of biologics in dermatology, both FDA indicated and off-label, has increased recently with the advent of new agents entering the market. Several of these agents have found their way into the normal therapeutic rotation in certain conditions, and some agents have been an effective “last resort” for others. In this article, we will briefly review some agents utilized in dermatology and discuss their off-label uses. (See the accompanying tables.) (We will not cover biologic agents used in cosmetic dermatology, such as botulinum toxin or collagen.) The varied uses of these biologics presents the possibility of offering your patients an effective treatment where none was previously available. EXPLORING THE DIFFERENT AGENTS Adalimumab (Humira) New to the market, adalimumab (Humira) is a human recombinant IgG1 fully human monoclonal antibody against tumor necrosis factor alpha (TNFa).1 Its mechanism of action is similar to that of infliximab (Remicade), which binds membrane and receptor-bound TNFa. Indications. Rheumatoid arthritis is the only FDA-approved indication. Contraindications. Because this agent can reactivate tuberculosis, it is important to check a PPD and chest X-ray prior to a patient using it. In addition to tuberculosis, other contraindications include malignancy, infection/sepsis, antibody formation to this product, and demyelinating neurologic disorders. Reactions can occur and most commonly include injection site reactions, fevers, chills, nausea, headaches, upper respiratory symptoms, dizziness and rashes. Rarely, antibody formation can arise. Off-Label Uses. Adalimumab has been used effectively in psoriasis as an off-label indication.2 Since adalimumab’s mechanism of action is similar to infliximab’s, it is a biologic that we will be seeing more of in the near future regarding its use for other diseases. Alefacept (Amevive) Alefacept is a human dimeric fusion protein. Alefacept has binding sites from LFA3 and Fc portion of IgG1, which binds to the CD2 receptor on T cells and inhibits co-stimulatory functions, leading to apoptosis of memory T cells.3 Indications. It is FDA approved for use in psoriasis. Contraindications. It is contraindicated for use in patients who have active infections and malignancy. Because alefacept depletes memory T cells, it is important to check patients’ baseline and weekly CD4 counts. If a patient’s CD4 falls below 250, he or she will need to forego injections either temporarily or permanently. Common side effects include injection site reactions, fevers, chills, nausea, headaches and dizziness. Off-Label Uses. No off-label uses have been reported yet in the literature.2 Alemtuzumab (Campath) Alemtuzumab (Campath) is a recombinant human monoclonal antibody against cell surface glycoprotein CD52, which is found in normal and malignant T and B cells, NK cells, macrophages, and tissue from male reproductive tracts.4 It contains human variable and constant regions, and murine complementarity determining regions. Indications. The FDA has approved its use in patients with B-cell leukemias. Contraindications. Patients who are immunosuppressed or have active infections should not receive this medication. A complete blood cell count, platelets, and CD4 count must be checked at baseline and weekly. Patients may report common side effects, such as fevers, chills, nausea, vomiting, infections and bone marrow suppression. Off-Label Uses. Several off-label uses for alemtuzumab in dermatology consist of malignancies (cutaneous T-cell lymphoma and hypereosinophilic syndrome) and inflammatory conditions (Behcet’s disease, scleroderma and graft versus host disease).2 Becaplermin (Regranex) Becaplermin (Regranex) is recombinant platelet-derived growth factor (PDGF), which stimulates chemotactic recruitment and proliferation of cells needed for wound repair and granulation tissue formation.5 Indications. It is FDA approved for use in diabetic foot ulcers and is applied topically to wounds. Patients have rarely complained of side effects such as erythema or a burning sensation. Contraindications. Becaplermin is contraindicated for use in neoplastic wounds. Off-Label Uses. Numerous off-label uses have been found for becaplermin, many of which are for the treatment of ulcers from inflammatory conditions (pyoderma gangrenosum, scleroderma and necrobiosis lipoidica diabeticorum) as well as for pressure ulcers and venous leg ulcers.2 Denileukin Diftitox (Ontak) Denileukin diftitox (Ontak) is a dimeric fusion protein consisting of the diphtheria toxin and interleukin 2 (IL-2), which directs the cytotoxic activity of the diphtheria toxin to cells containing IL-2 receptor (CD25).6 Indications. This agent is FDA approved for use in tumor stage cutaneous T-cell lymphoma. Contraindications. This drug is contraindicated for use in patients with albumin less than 3, due to increased risk of capillary leak syndrome, and those who have had hypersensitivity reaction to diphtheria toxin or any of the components of denileukin diftitox. In addition to albumin, complete blood count, liver function tests and renal function should be checked at baseline and before each infusion session. Common side effects include fevers, chills, hypotension, vasodilation, tachycardia, injection site reactions and flu-like symptoms. Off-Label Uses. The only off-label use reported in the literature for this drug is psoriasis, for which it was effective.2 Its widespread use has been limited because of the potentially serious adverse side effects it can cause. Efalizumab (Raptiva) Efalizumab (Raptiva) is a recombinant human monoclonal antibody that binds to CD11, a portion of LFA1 on T cells, and inhibits the binding of LFA1 to ICAM1 on keratinocytes.7 This prevents the activation, adhesion and migration of T cells. Indications. It is FDA approved for use in psoriasis. Contraindications. Contraindications for use include thrombocytopenia, infection and malignancy. Patients receiving this therapy should have their platelets checked at baseline and monthly thereafter. Common side effects include headaches, infections, fevers, chills, flu-like symptoms, pharyngitis, rhinitis and rashes. Off-Label Uses. Granuloma annulare is the only off-label use reported for this agent.2 Etanercept (Enbrel) Etanercept (Enbrel) is a recombinant TNFa fusion protein consisting of two TNFa receptors and the Fc portion of IgG1, which inhibits soluble and membrane-bound TNFa.8 Indications. The FDA has approved its use in patients with psoriasis, psoriatic arthritis, adult and juvenile rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. Contraindications. Contraindications for use are congestive heart failure, infection/sepsis, malignancy, and demyelinating neurologic disorders. There are minimal side effects associated with etanercept use, such as injection site reactions, headaches, and upper respiratory symptoms. No labs need to be monitored; however, some physicians obtain PPD and chest X-ray prior to using this medication. Off-Label Uses. The off-label uses for etanercept are numerous, including inflammatory conditions (pyoderma gangrenosum, hidradenitis suppurativa, and Behcet’s disease), vasculitides (Churg Strauss vasculitis, Taykayasu’s, and giant cell arteritis), and autoimmune processes (dermatomyositis, antiphospholipid antibody syndrome, pemphigus and pemphigoid).2 Granulocyte Colony Stimulating Factor (GCSF)/Filgrastim (Neupogen) Granulocyte colony stimulating factor (GCSF)/Filgrastim (Neupogen) is recombinant GCSF, which stimulates granulocyte and macrophage proliferation and differentiation.9 Indications. It is FDA approved for use in patients with AIDS neutropenia, bone marrow transplant neutropenia, post-chemotherapy neutropenia, and progenitor mobilization. Complete blood cell count and absolute neutrophil count should be checked at baseline and periodically throughout treatment. Patients may report side effects such as bone pain, thrombocytopenia, injection site reactions, headaches and nausea. Contraindications. Contraindications include hypersensitivity to Escherichia coli, sickle cell disease, myelodysplasias and myeloid malignancies. Off-Label Uses. These include topical treatment for diabetic foot ulcers and prophylaxis in graft versus host disease.2 Granulocyte Monocyte Colony Stimulating Factor (GMCSF)/Sargramostim (Leukine) Granulocyte monocyte colony stimulating factor (GMCSF)/Sargramostim (Leukine) is a recombinant GMCSF, which stimulates proliferation and differentiation of hematopoetic progenitor cells.10 Indications. FDA approved indications are acute myelogenous leukemia, bone marrow transplants, and patients who have progenitor cell mobilization. Contraindications. Its use is contraindicated in patients with excessive leukemic myeloid blasts, hypersensitivity to GMCSF or yeast products, and concomitant use with chemotherapy or radiotherapy. Complete blood cell count and absolute neutrophil count should be checked at baseline and bi-weekly. If patients have renal or liver insufficiency, then renal and liver function should be checked at baseline and bi-weekly as well. Patients may complain of headaches, fevers, myalgias and arthralgias. Off-Label Uses. These consist of the topical treatment of cutaneous ulcerations of various etiologies (venous, sickle cell, pyoderma gangrenosum, and pressure) and systemic treatment of oral erosions of various etiologies (candidiasis, chemotherapy induced and aphthous stomatitis).11 Immunoglobulins (Gammagard, Gamimune, Many Others) Immunoglobulins (Gammagard, Gamimune, many others) are freeze-dried preparations of highly purified immunoglobulin G and some A from the human serum of more than 1,000 donors.12 These preparations serve to block Fc antibody receptors, prevent complement mediated damage, decrease circulating pathogens and antibodies, alter cytokine profiles, cause anti-idiotype actions, act as long lasting colloid, and decrease Fas-FasL mediated apoptosis. Indications. They are FDA approved for use in primary immunodeficiencies, chronic B-cell leukemia, idiopathic thrombocytopenic purpura, graft versus host disease, hepatitis A, Kawasaki’s disease, measles, rubella, varicella, pediatric HIV patients, and bone marrow transplant patients. Contraindications. Contraindications include IgA deficiency, hypersensitivity to thiomerosal and renal dysfunction. It is advised to check liver and renal function as well as complete blood cell count and IgA levels prior to use and periodically throughout therapy. Common side effects include headaches, tachycardia, myalgias, nausea, fevers and chills. Rare instances of aseptic meningitis and thrombosis have been noted. Off-Label Uses. These include autoimmune blistering diseases (pemphigus and pemphigoid), atopic dermatitis, and toxic epidermal necrolysis.2 Infliximab (Remicade) Infliximab (Remicade) is a chimeric monoclonal IgG antibody to TNFa with human constant regions and mouse variable regions, which inhibit soluble, membrane-bound and receptor-bound TNFa.13 Indications. Crohn’s disease and rheumatoid arthritis are the only FDA- approved indications. This medication is delivered through intravenous infusion. Contraindications. Because it binds membrane and receptor-bound TNFa, infliximab is contraindicated in patients who have latent tuberculosis because this drug can reactivate tuberculosis. It is recommended to check the patient’s PPD and take a chest X-ray prior to use. Other contraindications include the following: infections/sepsis, malignancies, congestive heart failure, antibody formation/hypersensitivity to infliximab, demyelinating neurologic disorders and sensitivity to murine products. Similar to adalimumab, common side effects are injection site reactions, fevers, chills, nausea, headaches, upper respiratory symptoms, dizziness, and rashes. Off-Label Uses. Numerous off-label uses for infliximab have been reported in the literature. These include inflammatory conditions (hidradenitis suppurativa, pyoderma gangrenosum and Behcet’s disease) and vasculitides (Wegener’s granulomatosis, Churg Strauss vasculitis and giant cell arteritis).2 Interferon Alpha (IFNa) (Roferon, Intron) Interferon alpha (IFNa) (Roferon, Intron) is recombinant IFNa (2a and 2b), which binds to its receptor and induces anti-proliferative effects against tumor cells, inhibits viral replication and modulates host immune response.14 Indications. They are FDA approved for use in patients with chronic myelogenous leukemia, Kaposi’s sarcoma, hairy cell leukemia, and chronic hepatitis C. Contraindications. Contraindications to their use include myelosuppression, autoimmune hepatitis, seizures, cardiac/liver/renal/CNS/thyroid disorders, diabetes mellitus, autoimmune disorders, and concomitant use of nephrotoxic or cardiotoxic agents. Common side effects reported are flu-like symptoms, rashes, anorexia, dizziness, depression, headaches and injection site reactions. Off-Label Uses. Several off-label uses consist of malignancies (cutaneous T-cell lymphoma, keratoacanthomas and basal cell carcinomas) and infections (acyclovir-resistant HSV, genital herpes, and herpes zoster).2 Interferon Gamma (IFNg) (Actimmune) A recombinant IFNg, interferon gamma stimulates increased phagocytic activity and superoxide production, suppresses IgE and modulates cytokines.15 Indications. The FDA has approved its use in chronic granulomatous disease and malignant osteopetrosis. Contraindications. It is contraindicated for use in patients with known hypersensitivity to E. coli products. Common side effects include fevers, chills, headaches, rashes, injection site reactions, nausea, myalgias and lethargy. Off-Label Uses. These include malignancies (basal cell carcinoma and Bowenoid papulosis), infections (condyloma acuminate and visceral leischmania), and atopic dermatitis.2 Rituximab (Rituxan) Rituximab (Rituxan) is recombinant chimeric monoclonal IgG1 antibody to CD20, which is found on normal and malignant B cells.16 It consists of murine variable regions and human constant regions. Indications. This drug is FDA approved for use in patients with relapsed or refractory, low-grade or follicular, CD20+ B-cell non-Hodgkin’s lymphomas. Contraindications. Patients with known hypersensitivity to murine products should not receive rituximab. Common side effects include fevers, chills, nausea, myalgias and infections. Complete blood cell count and platelets should be checked at baseline and periodically throughout treatment. Off-Label Uses. Rituximab has been used off-label for the treatment of a number of conditions such as malignancies (Castleman’s disease and paraneoplastic pemphigus) and autoimmune bullous diseases (pemphigus and pemphigoid).17,18 Familiarizing Yourself with Off-Label Uses With the significant investments of time and money put forth by drug companies seeking initial FDA approval for their new drugs, it is less likely that they will spend even more money and time after achieving approval, to seek new indications on already approved medications.19 Also, many dermatologic conditions are rare, and drug companies are reluctant to invest their time and money in rare conditions. Therefore, since off-label use of biologics will not cease pending supplemental FDA approvals, physicians will need to become well versed in the mechanism of action, uses, side effects and dosage regimens of these biologic agents. Off label-use does not imply incorrect, improper or unsuitable use.20 Off-label use, in fact, seems to be standard of care in many conditions. As long as we disclose to patients that the drug they’re receiving is being used off-label and keep our patients’ best interests in mind, off-label uses of biologics will likely remain potential, viable treatments options for a growing number of conditions. Disclosure:The authors have no relevant disclosures with regard to the subject matter of this article. BIOLOGIC AGENTS USED IN DERMATOLOGY • Adalimumab (Humira) • Alefacept (Amevive) • Alemtuzumab (Campath) • Becaplermin (Regranex) • Denileukin Diftitox (Ontak) • Efalizumab (Raptiva) • Etanercept (Enbrel) • Granulocyte Colony Stimulating Factor/Filgrastim (Neupogen) • Granulocyte Monocyte Colony Stimulating Factor/Sargramostim (Leukine) • Immunoglobulins (Gammagard, Gamimune, Many Others) • Infliximab (Remicade) • Interferon Alpha (Roferon, Intron) • Interferon Gamma (Actimmune) • Rituximab (Rituxan) OFF-LABEL USES ADALIMUMAB (HUMIRA) • Psoriasis ALEMTUZUMAB (CAMPATH) • Behcet’s Disease • Cutaneous T-Cell Lymphoma • Graft Versus Host Disease • Hypereosinophilic Syndrome • Scleroderma BECAPLERMIN (REGRANEX) • Abdominal Wound Dehiscence • Klippel Trenauney, Ulcers • Lichen Planus, Ulcers • Necrobiosis Lipoidica Diabeticorum, Ulcers • Perineal Hemangioma, Ulcers • Pyoderma Gangrenosum • Recalcitrant Lower Extremity Ulcers • Sarcoidosis, Ulcers • Scleroderma, Ulcers • Sickele Cell Disease, Ulcers • Thrombotic Thrombocytopenic Purpura, Ulcers • Venous Leg Ulcers DENILEUKIN DIFTITOX (ONTAK) • Psoriasis EFALIZUMAB (RAPTIVA) • Granuloma Annulare ETANERCEPT (ENBREL) • Amyloidosis • Antiphospholipid Antibody Syndrome • Aphthous Stomatitis • Behcet’s Disease • Churg Strauss Vasculitis • Cicatricial Pemphigoid • Cutaneous T-Cell Lymphoma • Dermatomyositis • Erythroderma • Giant Cell Arteritis • Graft Versus Host Disease • Langerhan Cell Histiocytosis • Multicentric Reticulohistiocytosis • PAPA Syndrome • Pemphigus Vulgaris • Pyoderma Gangrenosum • SAPHO Syndrome • Sarcoidosis • Scleroderma • Taykayasu’s Arteritis • Wegener’s Granulomatosis GRANULOCYTE COLONY STIMULATING FACTOR/FILGRASTIM (NEUPOGEN) • Chronic Granulomatous Disease • Cutaneous T-Cell Lymphoma, Subcutaneous • Diabetic Foot Ulcers • Graft Versus Host Disease, Prophylaxis • Toxic Epidermal Necrolysis, with Cyclosporine GRANULOCYTE MONOCYTE COLONY STIMULATING FACTOR/SARGRAMOSTIM (LEUKINE) • Aphthous Stomatitis in AIDS and Behcet’s Disease • Herpes Simplex Virus • Hydroxyurea-Induced Ulcers • Hyper IgE Syndrome • Langerhan’s Cell Histiocytosis • Leischmania, Ulcers • Melanoma • Necrobiosis Lipoidica Diabeticorum, Ulcers • Oral Candidiasis in AIDS • Oral Mucositis Secondary to Chemotherapy • Pressure Ulcers • Pyoderma Gangrenosum • Sickle Cell Disease, Ulcers • Venous Leg Ulcers IMMUNOGLOBULINS (GAMMAGARD, GAMIMUNE, Many Others) • Atopic Dermatitis • Bullous Pemphigoid • Chronic Urticaria • Polyarteritis Nodosa • Dermatomyositis • Epidermolysis Bullosa Acquisita • Erythema Multiforme • Herpes Gestationis • Hypereosinophilic Syndrome • Leukocytoclastic Vasculitis • Livedoid Vasculitis • Mixed Connective Tissue Disease • Oral Pemphigoid • Pemphigus Foliaceus • Pemphigus Vulgaris • Psoriasis • Pyoderma Gangrenosum • Stevens Johnson Syndrome • Toxic Epidermal Necrolysis INFLIXIMAB (REMICADE) • Acrodermatitis Continua of Hallopeau • Behcet’s Disease • Churg Strauss Vasculitis • Cryoglobulinemia • Dermatomyositis • Giant Cell Arteritis • Graft Versus Host Disease • Hidradenitis Suppurativa • Kawasaki’s • Necrotizing Vasculitis • Psoriasis • Pyoderma Gangrenosum • Reiter’s Disease • Relapsing Polychondritis • SAPHO Syndrome • Sarcoidosis • Scleroderma • Sjogren’s • Sneddon Wilkinson • Toxic Epidermal Necrolysis • Ulcerative Necrobiosis Lipoidica Diabeticorum • Wegener’s Granluomatosis INTERFERON ALPHA (ROFERON, INTRON) • Acylcovir-Resistant Herpes Simplex Virus • Angiosarcoma of Scalp • Atopic Dermatitis • Basal Cell Carcinoma • Behcet’s Disease • Chronic Urticaria/Mastocytosis • Cryoglobulinemia • Cutaneous T Cell Lymphoma • Discoid Lupus • Eosinophilic Cellulitis • Hemangiomas • Herpes Zoster • Hypereosinophilic Syndrome • Keratoacanthoma • Langerhan’s Cell Histiocytosis • Necrobiotic Xanthogranuloma • POEMS Syndrome • Recurrent Genital Herpes • Subacute Cutaneous Lupus • Systemic Lupus Erythematosus INTERFERON GAMMA (ACTIMMUNE) • Atopic Dermatitis • Basal Cell Carcinoma • Bowenoid Papulosis • Condyloma Accuminata • Keloids • Morphea • Psoriasis • Scleroderma • Visceral Leischmania RITUXIMAB (RITUXAN) • Bullous Pemphigoid • Castleman’s Disease • Cryoglobulinemia • Graft Versus Host Disease • Paraneoplastic Pemphigus • Pemphigus Foliaceus • Pemphigus Vulgaris • Thrombotic Thrombocytopenic Purpura • Urticarial Vasculitis • Waldenstrom’s Macroglobulinemia • Wegener’s Granulomatosis