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The Effectiveness of Tumor Necrosis Factor  Antibody (Infliximab) in Treating Recalcitrant Psoriasis
A Report of 2 Cases
Ryan P. O'Quinn, MD;
Jami L. Miller, MD
Arch Dermatol. 2002;138:644-648.
ABSTRACT
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Background Psoriasis is being recognized as an autoimmune disease in which immunocyte-derived
cytokines are thought to drive the development of the altered keratinocyte
phenotype. Although the role of tumor necrosis factor  (TNF-)
in psoriasis is not completely understood, it may underlie many of the key
steps that lead to induction and maintenance of the disease. Infliximab is
an immunoglobulin monoclonal antibody that binds and inactivates TNF-
and has been successfully used in the management of TNF-–mediated
diseases, such as Crohn disease and rheumatoid arthritis.
Observations Two patients with recalcitrant psoriasis that was unresponsive to multiple
skin-directed and systemic therapies were treated with a single infusion of
infliximab. The treatments resulted in rapid and complete clearing of psoriatic
erythroderma and resolution of symptoms of arthritis in one case and complete
clearing of widespread psoriatic plaques and improvement of symptoms of arthritis
and inflammatory bowel disease in the other. The single treatments with infliximab
were well tolerated with no immediate or long-term adverse effects noted.
Conclusion A single infusion of infliximab at 5 to 10 mg/kg resulted in the rapid
and complete clearing of recalcitrant psoriatic plaques and erythroderma with
a disease-free interval of 3 to 4 months in these 2 patients and improved
the symptoms of psoriatic arthritis.
INTRODUCTION
INHIBITION OF tumor necrosis factor (TNF-) has been shown
to improve psoriasis and psoriatic arthritis. The following case reports detail
our experience using the TNF- antibody infliximab.
REPORT OF CASES
CASE 1
A 52-year-old white man presented with a 17-year history of widespread
recalcitrant psoriasis vulgaris. He initially had well-defined psoriatic plaques
with adherent silvery scale that slowly spread despite treatment and coalesced
to cover most of the skin surface. Except for sparing of the face and dorsal
aspects of the hands, he had had erythroderma for the past 7 years. In addition,
the patient complained of nail involvement and psoriatic arthritis of the
distal interphalangeal and sacroiliac joints.
Multiple topical and systemic therapies failed to arrest the development
of erythroderma. Topical steroids and calcipotriene were used without effect.
Treatment with oral etretinate, 50 mg/d, combined with psoralen–UV-A
initially showed significant clearing but had to be discontinued owing to
unmanageable hypertriglyceridemia. Acetretin use also was discontinued because
of high serum triglyceride levels. Treatment with 6-thioguanine resulted in
lowered hematocrit and white blood cell count and was stopped. Other treatments
that failed to clear the psoriasis included up to 25 mg/wk of methotrexate
administered by both the oral and intramuscular routes, up to 6 mg/kg daily
of cyclosporine, 150 mg/d of azathioprine, and 200 mg/d of hydroxyurea.
The patient was seen in March 2000 with worsening arthritis in the back
and fingers and psoriatic erythroderma. At this time, the patient was using
only topical triamcinolone acetonide ointment. He complained of intense itching
and occasional chills, but denied fever or sweats. On physical examination,
the patient had thick erythematous plaques with scale covering more than 85%
of the skin surface (Figure 1).
There were islands of sparing on the face and dorsal aspects of the hands.
The nails were pitted with subungual hyperkeratosis. The distal interphalangeal
joints showed some edema and pain with active motion.
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Figure 1. Patient 1 before infusion of infliximab.
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After informed consent was obtained, 10 mg/kg of infliximab (Remicade;
Centocor, Malvern, Pa) was administered intravenously over 3 hours after premedication
with acetaminophen and diphenhydramine hydrochloride. No adverse effects were
associated with the infusion. Within 2 days the patient noted a decrease in
pruritus and erythema of the skin and resolution of his chills and cold intolerance.
A follow-up examination 10 days after the infusion showed that the plaques
were noticeably thinner to palpation. Significant improvement in the erythema
with persistence of scaling was noted. The patient reported resolution of
pain associated in the distal interphalangeal and sacroiliac joints, and the
results of the clinical examination of the fingers were clinically normal,
with no pain on active motion.
A 4-week follow-up examination showed complete resolution of all psoriatic
plaques, erythema, and scaling (Figure 2).
The patient's skin was clinically normal for the first time in 7 years.
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Figure 2. Patient 1 eight weeks after a
single infusion of infliximab.
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A biopsy specimen of the left forearm was taken before treatment with
infliximab, which showed psoriasiform acanthosis of the epidermis with parakeratosis
of the stratum corneum, infiltrating neutrophils forming Munro microabscesses,
thinning of the suprapapillary plates, and dilated blood vessels in the dermal
papillae (Figure 3). A follow-up
biopsy specimen of the left forearm 10 days after treatment with infliximab
revealed a resolution of psoriasiform epidermal changes. The stratum corneum
showed an orthokeratotic basket weave pattern, whereas the epidermis showed
spongiosis with a mild perivascular lymphocytic infiltrate and occasional
eosinophils (Figure 4).
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Figure 3. Skin biopsy results from the arm
of patient 1 before infliximab treatment. Note typical histological findings
for psoriasis (hematoxylin-eosin, original magnification x200).
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Figure 4. Skin biopsy results from the arm
of patient 1, eight weeks after a single infusion of infliximab. Note normalization
of histologic findings (hematoxylin-eosin, original magnification x200).
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The patient noted the onset of slight pruritus beginning 4 weeks after
treatment, which he thought heralded the onset of new psoriatic skin involvement.
Follow-up after 8 weeks showed a few small erythematous plaques on the legs,
but the patient's trunk, arms, and scalp remained clear. Ongoing treatment
with sunlight exposure and topical triamcinolone was instituted. The patient
relapsed with development of psoriatic plaques 3 months following treatment.
CASE 2
A 33-year-old white woman presented with an 8-year history of psoriasis
vulgaris and psoriatic arthritis. She initially presented with confluent scale
over the entire scalp and generalized erythematous plaques with adherent silvery
scale measuring 0.5 to 6.0 cm2 over the chest, abdomen, back, buttocks,
gluteal crease, and upper and lower extremities. She also had edema, warmth,
and nearly incapacitating pain in the phalangeal joints. Her medical history
was also notable for diarrhea, hematochezia, and crampy abdominal pain diagnosed
by upper and lower gastrointestinal tract endoscopy as unspecified inflammatory
bowel disease.
Multiple therapeutic regimens were administered that ultimately failed
to produce significant clearing and control of the patient's psoriatic plaques
and arthritis. A previous trial of psoralen–UV-A had been terminated
because of psoralen intolerance. Treatment with high-potency topical steroids,
topical calcipotriene, and methotrexate was begun. The methotrexate dose was
increased up to 15 mg/wk to a total dose of 290 mg. Despite some improvement
of both skin and joint disease, its use was discontinued because of the onset
of diarrhea. A trial of topical tazarotene was ineffective. Broad-band UV-B
for 12 treatments followed by narrow-band UV-B for 43 treatments was given.
Many plaques decreased in size but were still present, and the psoriatic arthritis
worsened. Treatment with cyclosporine, 4 mg/kg, showed improvement in both
skin and joint symptoms, but its use was soon discontinued because of intractable
headaches. Azathioprine therapy was begun concurrently with cyclosporine therapy
and titrated up to 100 mg/d. After 3 months, no response was noted.
In January 2000, the patient presented with low-grade fever (temperature,
37.8°C) and complaints of worsening joint pain and swelling, increased
numbers of psoriatic plaques, and bloody diarrhea accompanied by crampy abdominal
pain. Physical examination findings were notable for erythematous, thin, guttate
plaques and papules over the arms, legs, back, chest, and abdomen. There were
scaling patches on the scalp. The distal and proximal interphalangeal joints
were erythematous, edematous, and tender. The patient, although motivated
and compliant with therapy, had had a poor response to conventional topical
treatment, phototherapy, and systemic immunosuppressive agents. In addition,
intolerance to multiple agents and the potential to exacerbate the inflammatory
bowel disease limited treatment options. An alternate treatment to address
both the refractory psoriasis and inflammatory bowel disease was needed.
After informed consent was obtained, infliximab was administered intravenously
at a dosage of 5 mg/kg for 3 hours. The patient was premedicated with acetaminophen
and diphenhydramine, and the infusion was tolerated well. The patient reported
decreased erythema in the psoriatic plaques within 24 hours. She also noted
a rapid resolution of diarrhea and abdominal symptoms. Complete clearing of
the plaques occurred within 2 weeks, and arthritis symptoms improved significantly.
A follow-up examination after 2 weeks was remarkable for complete clearing
of all plaques with residual macules and patches of hyperpigmentation with
minimal overlying scale (Figure 5).
Examination of the interphalangeal joints showed no erythema and minimal discomfort
on active motion. Biweekly etanercept, 25 mg subcutaneously, was initiated.
The patient discontinued the etanercept therapy after 2 weeks. She maintained
a 4-month disease-free interval before relapsing with psoriatic plaques and
arthritis.
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Figure 5. Patient 2 one month after a single
dose of infliximab. Note flat, mostly hyperpigmented lesions.
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COMMENT
Tumor necrosis factor is a cytokine that induces proinflammatory
effects by binding to specific TNF receptors and activating the NF- B
signal transduction pathway.1 As a primary
cytokine, it can evoke all the steps required to produce immunocyte infiltration
in tissues, including the up-regulation of cell adhesion molecule expression
and the induction of secondary cytokines and chemokines.2
Primarily secreted by macrophages, monocytes, and T cells, newly synthesized
TNF- is a cell surface transmembrane protein before its release as
a soluble protein homotrimer.3
Psoriasis is being recognized as an autoimmune disease. Immunocyte-derived
cytokines are thought to mediate the altered keratinocyte phenotype.4 The cytokine profile derives from the TH1
subset.5-6 Accordingly, TNF-
has been shown to be overexpressed in psoriatic skin lesions and in the synovium
and synovial fluid in patients with psoriatic arthritis.7-9
The role of the cytokine TNF- in psoriasis is incompletely understood,
but it may underlie many of the steps that lead to induction and progression
of the disease. The most important function of TNF- may be the initiation
of a proinflammatory cytokine cascade that leads to the recruitment of leukocytes
to lesional epidermis. Several observations point to such a role. In psoriasis,
endothelial cells express TNF-–regulated adhesion molecules,
such as intercellular adhesion molecule 1 and E-selectin, that are critical
for the migration of activated leukocytes into areas of inflammation.10 Adhesion molecules have also been noted on psoriatic
keratinocytes.11-13
In addition, increased concentrations of TNF- have been found in the
serum in generalized pustular psoriasis.14-15
Attention has recently been focused on promoter region polymorphisms of the TNF- gene in patients with psoriasis.16-17
Inhibition of TNF- has been shown to improve psoriasis and psoriatic
arthritis. A recent randomized controlled study18
showed that a 25-mg twice-weekly dose of the TNF- inhibitor etanercept
provided a statistically significant clinical benefit in disease activity
of psoriatic skin lesions and psoriatic arthritis.
Infliximab is a chimeric (murine-human) immunoglobulin monoclonal antibody
that was developed to treat TNF-–mediated diseases.19
It binds soluble TNF- with high affinity and specificity and neutralizes
its effects by preventing it from binding with the TNF receptors. It has been
shown in vitro that infliximab also interacts with membrane-bound TNF-,
leading to lysis of the cell.20
Infliximab has been used with success in multiple trials in the treatment
of Crohn disease and rheumatoid arthritis; both are diseases in which TNF-
plays a central role in the pathogenesis.21-23
Treatment with infliximab has led to observations of profound down-regulation
of inflammation in Crohn disease and rheumatoid arthritis. In Crohn disease,
a regression of the inflammatory infiltrate, especially neutrophils, is noted,
as well as a reduction or disappearance of activation markers and adhesion
molecules such as aberrant HLA-DR expression, intercellular adhesion molecule
1, and leukocyte function–associated antigen 1.24
Similar findings have been observed in patients with rheumatoid arthritis
treated with the antibody.25-26
Infliximab also suppresses serum markers of inflammation, such as C-reactive
protein and the erythrocyte sedimentation rate, and down-regulates the production
of numerous cytokines in vivo.26-27
In addition, some actions of infliximab may be due to an inhibition of angiogenesis
that has been observed with its use.26
Infliximab has a half-life of approximately 10 days when administered
as a single 5-mg/kg dose.28 Its metabolism
and excretion are not known, but as a protein, infliximab is not metabolized
by cytochrome P-450 enzymes, decreasing the concern for complex drug interactions.
The most commonly reported adverse effects are headache, diarrhea, rash, rhinitis,
and coughing. The incidence of mild infections is increased, with upper respiratory
tract infection occurring in 4.6% and urinary tract infection occurring in
4.6%, and serious infections resulting in death, although rare, have been
reported.29 Chimeric antibodies are less immunogenic
than murine antibodies, but immediate hypersensitivity reactions have been
reported with the administration of infliximab, similar to those seen with
other immunoglobulin preparations.30 For this
reason, it is recommended that antihistamines, corticosteroids, and epinephrine
should be available during the infusion.31
The development of lymphomas in patients treated with infliximab has been
a theoretical concern. In several trials, 3 of 555 patients with rheumatoid
arthritis treated with infliximab developed lymphoma during 3 years of follow-up.23 Cause and effect have been difficult to determine
because patients with rheumatoid arthritis and other autoimmune diseases,
especially when treated with immunosuppressive medications, have higher incidences
of lymphoma.32
Because of the concern for potential exacerbation of a concurrent infection
secondary to infliximab use, both of our patients underwent complete physical
examinations and chest radiography before administration.
Infliximab has been observed to improve psoriatic skin lesions in a
single case of a patient undergoing treatment for Crohn disease.33
We present a case significant for complete clearing of psoriatic erythroderma
and another in which the plaques of psoriasis vulgaris, arthritis, and inflammatory
bowel disease cleared rapidly after treatment with anti–TNF-
antibodies. Psoriasis has been shown to be more prevalent in patients with
inflammatory bowel disease and may be of use in patients in whom these diseases
coexist.34 Use of infliximab should be reserved
for those patients who are acutely ill and in whom more conventional therapies
have failed. It may be a useful agent in such patients to rapidly clear widespread
psoriasis before other systemic and skin-directed therapies begin to mediate
their effects. The role of infliximab in TNF-–mediated diseases
seems very promising. The efficacy of a treatment suggested by a single report
may serve to provide clues about the pathogenesis of a disease, but will need
to be subjected to trials before its widespread use.
AUTHOR INFORMATION
Accepted for publication August 20, 2001.
Corresponding author and reprints: Jami L. Miller, MD, 3900 The Vanderbilt
Clinic, Nashville, TN 37232 (e-mail: jami.miller{at}mcmail.vanderbilt.edu).
From the Department of Medicine, Division of Dermatology, Vanderbilt
University, Nashville, Tenn.
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