Unconventional Uses of Biologics
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
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"
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:
- the intercellular adhesion molecule (ICAM), expressed on
- vascular endothelium
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
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
- 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
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
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
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
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
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
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
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
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
- 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
- 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.
- 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.
- 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.
- 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.
- Morrison LH. Therapy of refractory pemphigus vulgaris with
monoclonal anti-CD20 antibody (rituximab). J Am Acad
- Schadlow MB, Anhalt GJ, Sinha AA. Using rituximab (anti-CD20
antibody) in a patient with paraneoplastic pemphigus. J Drugs
- 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
- 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.
- Querfeld C, Guitart J, Kuzel TM, Rosen S. Successful treatment
of recalcitrant, erythroderma-associated pruritus with etanercept.
Arch Dermatol. 2004;140:1539-1540.
- Goffe BS. Disseminated granuloma annulare resolved with the
T-cell modulator efalizumab. Arch Dermatol.
- Khanna D, Liebling MR, Louie JS. Etanercept ameliorates
sarcoidosis arthritis and skin disease. J Rheumatol.
- Baughman RP, Lower EE. Infliximab for refractory sarcoidosis.
Sarcoidosis Vasculitis Diffuse Lung Dis.
- Kovach BT, Calamia KT, Walsh JS, Ginsburg WW. Treatment of
multicentric reticulohistiocytosis with etanercept. Arch
- Pasternack FR, Fox LP, Engler DE. Silicone granulomas treated
with etanercept. Arch Dermatol. 2005;141:13-15.
- 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.
- 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.
- Unger L, Kayser M, Nusslein HG. Successful treatment of severe
rheumatoid vasculitis by infliximab. Ann Rheum Dis.
- 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.
- Robinson ND, Guitart J. Recalcitrant, recurrent aphthous
stomatitis treated with etanercept. Arch Dermatol.
- Lebwohl B, Sapadin AN. Infliximab for the treatment of
hidradenitis suppurativa. J Am Acad Dermatol.
- Regueiro M, Valentine J, Plevy S, Fleisher MR, Lichtenstein GR.
Infliximab for treatment of pyoderma gangrenosum associated with
inflammatory bowel disease. Am J Gastroenterol.
- 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.