More Clinical Updates

Gonorrhea and syphilis are common sexually transmitted diseases (STDs) that share many characteristics.

Read more

Oral lichen planus (OLP) is as common as psoriasis and affects approximately 1-2% of the population. The disease develops in women more than twice as often as in men and most commonly occurs in the fifth to sixth decade of life, although the disease can sometimes affect children.

Read more

Recalcitrant cutaneous lupus erythematosus (CLE) causes patients considerable discomfort and often leads to disfigurement. Although the majority of CLE responds to the combination of sun protection, local glucocorticoids, and antimalarials, some cases require more aggressive therapy.

Read more

Solar ultraviolet (UV) radiation is the most important environmental factor involved in the pathogenesis of skin cancers.

Read more

Clinical Updates

David S. Rubenstein, MD, PhD

Unconventional Uses of Biologics

David Rubenstein

Tuesday, June 07, 2005

Along with the pulmonary and gastrointestinal epithelium, the skin is the major interface between the environment and us. Skin provides protection both against infectious agents such as fungi, bacteria, and viruses as well as toxins and other nonliving noxious agents. As such, the immune system has evolved both to protect against infection and to regulate responses to toxic agents from the environment.

Inflammatory skin disease occurs when this system breaks down, either by disruption of the barrier or by the inappropriate activation of the immunity in response to a "perceived" pathogen.

To establish an immune response, several key steps must occur. The immune system must first sense the presence of an antigen. Typically, this occurs when an antigen-presenting cell, such as a macrophage or a Langerhans cell, presents an antigen to a selected lymphocyte, across a macromolecular interface referred to as the immunologic synapse. Stimulated lymphocytes then migrate from lymph nodes to the skin (and other organs) via the vascular system.

Major Biologic Agents Currently Used in Dermatology

As a class of drugs, biologic agents are macromolecules, typically proteins, that are synthesized using bacterial or mammalian expression systems. Once purified to provide homogenous, pure reagents, they are injected via a vein or the percutaneous route, ultimately reaching the systemic circulation. Over the past decade, an increasing number of such biologics have been introduced. Currently available biologics have several mechanisms of action, including:

  • disruption of antigen presentation
  • removal or destruction of activated immune cells
  • disruption of lymphocyte migration
  • inhibition of cytokine function

Efalizumab (Raptiva®) is a humanized monoclonal antibody that binds to CD11a, a subunit of lymphocyte-function-associated antigen 1 (LFA1), an integrin expressed on T-lymphocytes. LFA1 binds to:

  1. the intercellular adhesion molecule (ICAM), expressed on antigen-presenting cells
  2. vascular endothelium
  3. keratinocytes

By inhibiting the binding of LFA1 and ICAM, efalizumab suppresses inflammatory skin diseases by disrupting antigen presentation, inhibiting margination of lymphocytes and exit from the circulatory system, and disrupting direct interaction between T-cells and keratinocytes. Approved for the treatment of psoriasis, efalizumab therapy begins with an induction dose of 0.7 mg/kg, with subsequent weekly doses of 1 mg/kg. Efalizumab is self-administered by subcutaneous injection and is generally well tolerated.

Alefacept (Amevive®) also suppresses inflammation by targeting T-lymphocytes. It is a recombinant LFA3/lgG fusion protein that binds to CD2, which is found on T-lymphocytes. Alefacept has two potential mechanisms of action:

  • interference with CD2-LFA3 costimulatory signals for CD45RO+ memory effector T-cell activation
  • natural-killer-cell-mediated depletion of CD45RO+ memory effector T-cells via the binding of the Ig constant region of the fusion protein

Alefacept is delivered in a series of 12 weekly 15-mg intramuscular injections. Alefacept depletes T-cells, requiring monitoring of CD4 counts. Alefacept is approved for the treatment of psoriasis in the United States but not in Europe.

Because of its role as a major mediator of inflammation, a number of biologic agents have been produced that bind and inhibit the proinflammatory activity of TNF-α. Anti-TNF-α biologic agents include etanercept (Enbrel®), infliximab (Remicade®), and adalimumab (Humira®):

  • Etanercept is a TNF receptor 2 Ig fusion protein approved for rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and psoriasis. It is a self-administered subcutaneous injection. For psoriasis, it is prescribed at an induction dose of 50 mg twice weekly for 3 months and subsequently decreased to 50 mg once weekly or 25 mg twice weekly for maintenance.
  • Infliximab is a chimeric monoclonal antibody to TNF-α and is given by the intravenous route at 5 mg/kg on an induction schedule at weeks 0, 2, and 6, and subsequently every 8 weeks for maintenance. It is approved for rheumatoid arthritis and Crohn's disease, and its use in psoriasis is currently under investigation.
  • Adalimumab is a fully human monoclonal anti-TNF-α monoclonal antibody approved for use in rheumatoid arthritis; its use in psoriasis and psoriatic arthritis is under investigation. Adalimumab is a self-administered subcutaneous injection that is administered at a dose of 40 mg every other week.

The humoral immune response can also be targeted. Rituximab (Rituxan®) is a murine-human chimeric monoclonal antibody directed against the CD20 antigen expressed by pre-B- and mature B-lymphocytes. It rapidly depletes B-cells by inducing B-cell lysis through antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. It is given by intravenous administration and is approved for use in CD20+ B-cell non-Hodgkin's lymphoma.

Physicians should consult the Physicians' Desk Reference or other authoritative source for full prescribing, monitoring, and safety information before using these agents.

Autoimmune Blistering Disease

In the passive transfer mouse model of experimental bullous pemphigoid (BP), administration of anti-BP180 antibodies reproduces the major clinical and histological features of the human disease. TNF-α knockout mice, animals genetically engineered not to express TNF-α, do not develop blisters or other features of BP, demonstrating a critical role for TNF-α in the immunopathogenesis of this autoimmune blistering disease.1 This suggests a role for anti-TNF-α biologics in treating BP. Sacher and colleagues reported the use of etanercept to treat a patient with cicatricial pemphigoid recalcitrant to prior immunosuppressive therapies. Their patient, flaring despite treatment with 70 mg daily of prednisone, came under rapid control with the addition of etanercept, allowing subsequent tapering of the prednisone.2

Pemphigus vulgaris (PV) is another autoimmune blistering disease in which a biologic therapy has shown promise. Like BP, the passive transfer mouse model has been used to demonstrate a pathogenic role in blister formation for anti-DSG3 autoantibodies produced by patients with this life-threatening disease. Standard treatments for PV include:

  • immunosuppression with agents such as systemic corticosteroids, cyclosporine, azathioprine, cyclophosphomide, or mycophenolate mofetil
  • IVIG
  • plasmapheresis

Rituximab, approved for the treatment of CD20+ B-cell non-Hodgkin's lymphoma, has found recent application in the treatment of PV. The autoantibody-producing population of B-cells is depleted by the action of this cytolytic antibody. B-cells are rapidly depleted. Salopek and colleagues reported a case of PV with an extended hospital course, complicated by recurrent sepsis and poor disease control despite treatment that included (at various times) combinations of high-dose steroids, azathioprine, cyclophosphamide, IVIG, plasmapheresis, and mycophenolate mofetil. At hospital day 282, the patient received the first dose of rituximab, while continuing prednisone at 1 mg/kg/d. This regimen resulted in gradual arrest of blister formation and subsequent re-epithelialization.3 Additional descriptions of using this anti-CD20 antibody in pemphigus have been reported.4,5,6,7 The response of PV patients to rituximab suggests that this biologic may be useful in other humoral-mediated autoimmune disorders in which autoantibodies may have a pathogenic role, such as lupus erythematosus.

T-Cell-Mediated Inflammatory Dermatoses

T-cell-mediated skin diseases, such as alopecia areata, graft versus host disease, lichen planus, lupus, and mycoses fungoides, may be potential targets for treatment with T-cell-directed biologics such as efalizumab and alefacept. Histologically, lichen planus is characterized by a dense, predominantly T-cell inflammatory infiltrate hugging the dermal-epidermal junction. In our practice, we have used efalizumab to effectively treat lichen planus. A 34-year-old man with longstanding pruritic, widespread, well-demarcated violaceous keratotic plaques on his extremities and trunk was treated weekly with efalizumab 1 mg/kg subcutaneously. Within 1 month, he experienced marked diminution of his pruritus and thinning of his plaques. On discontinuation of efalizumab, both the pruritus and the plaques recurred.

The presence of elevated levels of TNF-α in polymyositis and dermatomyositis prompted the use of etanercept for polymyositis in a patient who had failed conventional therapies.8 The addition of etanercept 25 mg BIW to prednisone resulted in rapid improvement and facilitated tapering of the prednisone. The success of etanercept in this patient with polymyositis suggests a role for anti-TNF-α therapy in dermatomyositis. Etanercept, at 25 mg SQ BIW, was tested for safety, efficacy, and toxicity in a small pilot study in cutaneous T-cell lymphoma (CTCL). Although patients with advanced disease showed no response, patients with early-stage disease showed a partial response, suggesting that higher doses and/or longer treatment times might be effective for early-stage CTCL.9 Querfeld and colleagues reported 2 patients with erythroderma-associated pruritus, clinically felt to be evolving into CTCL, who responded to etanercept.10

Granulomatous Disease

Efalizumab has also been reported effective in the treatment of granuloma annulare (GA). A recent case report describes a 52-year-old man with biopsy-proven GA and severe plaque psoriasis. As a participant in the Phase III clinical trials, he received efalizumab at 1 mg/kg subcutaneously each week for his psoriasis. His GA had improved at 4 weeks and was completely resolved at 12 weeks of therapy.11 Anti-TNF-α therapy may also have a role in the treatment of granulomatous inflammatory skin disease. Both etanercept12 and infliximab have been reported to benefit the cutaneous manifestations of sarcoidosis.13

Kovach and colleagues described a 46-year-old man who, after a 1-year history of an ill-defined acral eruption, developed reddish brown papules and nodules and progressive inflammatory arthritis manifested by severe stiffness, pain, and swelling. A diagnosis of multicentric reticulohistiocytosis was made based upon (i) the clinical findings and (ii) the presence of DIP erosions on hand films and multinucleated giant cells with characteristic ground glass cytoplasm on skin biopsy. After failing treatment with combination therapy, including (i) methotrexate, prednisone, and Plaquenil®; (ii) prednisone and chlorambucil; and (iii) developing gross hematuria when cyclophosphamide was added to prednisone and methotrexate, the patient was started on a regimen in which etanercept was added to prednisone and leflunomide. The patient responded with clearing of his skin lesions and improvement in his arthritis, enabling tapering of both the prednisone and the leflunomide.14

Pasternack and colleagues recently reported treating silicone granulomas with etanercept.15 Their 2 patients developed painful tender erythematous nodules after receiving silicone injections. Biopsies confirmed the diagnosis of silicone granulomas, and both patients' pain and erythema dramatically improved after starting etanercept 25 mg twice weekly by the subcutaneous route.

Behcet's Disease and Vasculitis

Anti-TNF-α therapy is effective in treating the mucocutaneous manifestations of Behcet's disease.16 In our practice, we have used etanercept in Behcet's. A 53-year-old woman with an 11-year history of mucocutaneous ulcers, arthralgias, and pustules was continuing to experience oral ulcerations causing severe discomfort despite combination therapy with prednisone, colchicine, and dapsone. Subcutaneous Etanercept 25 mg twice wekly was added. She responded rapidly, with no new oral ulcers after 4 weeks. Prednisone, colchicine, and dapsone were subsequently tapered and discontinued. She has remained disease-free for the past 8 months on etanercept, including the past 2 months on etanercept monotherapy. TNF-α blockade with infliximab and adalimumab has also been reported to be effective in treating Behcet's disease in patients who had previously failed traditional therapies.17 Other vasculitic ulcerations have been reported to respond to anti-TNF therapy. Infliximab has been used to effectively treat cutaneous ulcerations in patients with rheumatoid vasculitis18 and Wegener's granulomatosis.19

Aphthous Stomatitis

Robinson and Guitart reported effective treatment of recurrent, recalcitrant aphthous ulcers with etanercept.20 The 50-year-old patient had a 24-year history of recurrent aphthous ulcers, experiencing 9-12 ulcers each week that caused severe pain. After just 1 month of etanercept 25 mg twice weekly, the patient experienced a markedly decreased frequency of oral ulcers (1 per month).

Hidradenitis Suppurativa and Pyoderma Gangrenosum

Suppurative noninfectious inflammatory processes may be amenable to treatment with TNF-α blockade. Lebwohl and Sapadin reported the use of infliximab in the treatment of hidradenitis suppurativa.21 Regueiro and colleagues reported the use of infliximab in the treatment of pyoderma gangrenosum.22 The link between Crohn's disease and pyoderma gangrenosum is well established, and the reported responsiveness of both diseases to TNF-α blockade supports that concept.23

The past few years of experience using biologic agents for psoriasis has demonstrated the value of these drugs for treating inflammatory skin diseases. Their off-label use in nonpsoriatic skin disease is beginning to be explored. These agents hold promise for the effective treatment of some of the more difficult and nonresponsive conditions encountered in the practice of dermatology.

References

  1. Gleason DM, Chen R, Fairley JA, Liu Z. Tumor necrosis factor and TNF receptor-1, but not TNF receptor-2-deficient mice are resistant to experimental bullous pemphigoid. J Invest Dermatol. 2000;114:769A.
  2. Sacher C, Rubbert A, Konig C, Scharffetter-Kochanek K, Krieg T, Hunzelmann N. Treatment of recalcitrant cicatricial pemphigoid with the tumor necrosis factor alpha antagonist etanercept. J Am Acad Dermatol. 2002;46:113-115.
  3. Salopek TG, Logsetty S, Tredget EE. Anti-CD20 chimeric monoclonal antibody (rituximab) for the treatment of recalcitrant, life-threatening pemphigus vulgaris with implications in the pathogenesis of the disorder. J Am Acad Dermatol. 2002;47:785-788.
  4. Cooper HL, Healy E, Theaker JM, Friedmann PS. Treatment of resistant pemphigus vulgaris with an anti-CD20 monoclonal antibody (Rituximab). Clin Exp Dermatol. 2003;28:366-368.
  5. Dupuy A, Viguier M, Bedane C, et al. Treatment of refractory pemphigus vulgaris with rituximab (anti-CD20 monoclonal antibody). Arch Dermatol. 2004;140:91-96.
  6. Morrison LH. Therapy of refractory pemphigus vulgaris with monoclonal anti-CD20 antibody (rituximab). J Am Acad Dermatol. 2004;51:817-981.
  7. Schadlow MB, Anhalt GJ, Sinha AA. Using rituximab (anti-CD20 antibody) in a patient with paraneoplastic pemphigus. J Drugs Dermatol. 2003;2:564-756.
  8. Sprott H, Glatzel M, Michel BA. Treatment of myositis with etanercept (Enbrel), a recombinant human soluble fusion protein of TNF-alpha type II receptor and IgG1. Rheumatology (Oxford). 2004;43:524-526.
  9. Tsimberidou AM, Giles FJ, Duvic M, Kurzrock R. Pilot study of etanercept in patients with relapsed cutaneous T-cell lymphomas. J Am Acad Dermatol. 2004;51:200-204.
  10. Querfeld C, Guitart J, Kuzel TM, Rosen S. Successful treatment of recalcitrant, erythroderma-associated pruritus with etanercept. Arch Dermatol. 2004;140:1539-1540.
  11. Goffe BS. Disseminated granuloma annulare resolved with the T-cell modulator efalizumab. Arch Dermatol. 2004;140:1287-1288.
  12. Khanna D, Liebling MR, Louie JS. Etanercept ameliorates sarcoidosis arthritis and skin disease. J Rheumatol. 2003;30:1864-1867.
  13. Baughman RP, Lower EE. Infliximab for refractory sarcoidosis. Sarcoidosis Vasculitis Diffuse Lung Dis. 2001;18:70-74.
  14. Kovach BT, Calamia KT, Walsh JS, Ginsburg WW. Treatment of multicentric reticulohistiocytosis with etanercept. Arch Dermatol. 2004;140:919-921.
  15. Pasternack FR, Fox LP, Engler DE. Silicone granulomas treated with etanercept. Arch Dermatol. 2005;141:13-15.
  16. Melikoglu M, Fresko I, Mat C, et al. Short-term trial of etanercept in Behcet's disease: a double blind, placebo controlled study. J Rheumatol. 2005;32:98-105.
  17. Estrach C, Mpofu S, Moots RJ. Efficacy and safety of infliximab and adalimumab in behcet's syndrome. In: abstract presented at the 2003 American College of Rheumatology. 2003.
  18. Unger L, Kayser M, Nusslein HG. Successful treatment of severe rheumatoid vasculitis by infliximab. Ann Rheum Dis. 2003;62:587-588.
  19. Bartolucci P, Ramanoelina J, Cohen P, et al. Efficacy of the anti-TNF-alpha antibody infliximab against refractory systemic vasculitides: an open pilot study on 10 patients. Rheumatology (Oxford). 2002;41:1126-1132.
  20. Robinson ND, Guitart J. Recalcitrant, recurrent aphthous stomatitis treated with etanercept. Arch Dermatol. 2003;139:1259-1262.
  21. Lebwohl B, Sapadin AN. Infliximab for the treatment of hidradenitis suppurativa. J Am Acad Dermatol. 2003;49:S275-S276.
  22. Regueiro M, Valentine J, Plevy S, Fleisher MR, Lichtenstein GR. Infliximab for treatment of pyoderma gangrenosum associated with inflammatory bowel disease. Am J Gastroenterol. 2003;98:1821-1826.
  23. Sapienza MS, Cohen S, Dimarino AJ. Treatment of pyoderma gangrenosum with infliximab in Crohn's disease. Dig Dis Sci. 2004 Sep;49(9):1454-1457.

 

Back