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Clinical and Immunologic Assessment of Patients With Psoriasis in a Randomized, Double-blind, Placebo-Controlled Trial Using Recombinant Human Interleukin 10
Alexa B. Kimball, MD, MPH;
Tatsuyoshi Kawamura, MD, PhD;
Krupali Tejura;
Carol Boss;
Ana R. Hancox, RN;
Jonathan C. Vogel, MD;
Seth M. Steinberg, PhD;
Maria L. Turner, MD;
Andrew Blauvelt, MD
Arch Dermatol. 2002;138:1341-1346.
ABSTRACT
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Background In several open-label studies, recombinant human interleukin 10 (rhIL-10),
a type 2 anti-inflammatory cytokine, has been reported to improve psoriasis,
a disease characterized by type 1 cytokine inflammation.
Objective To evaluate the safety, efficacy, and immunologic parameters in individuals
with psoriasis treated with rhIL-10.
Design and Intervention Patients received rhIL-10 (20 µg/kg) or placebo subcutaneously
3 times weekly for 12 weeks in a randomized, double-blind manner.
Setting and Patients National Institutes of Health Clinical Center in Bethesda. Twenty-eight
patients with moderate-to-severe psoriasis as defined by a Psoriasis Area
Severity Index (PASI) score of 10 or higher.
Main Outcome Measure The primary clinical end point was the mean percentage change in the
PASI score comparing baseline and week 12 scores. Intracellular cytokine production
by peripheral blood mononuclear cells (PBMCs) was measured by flow cytometry.
Results There was no significant difference in the mean percentage change in
the PASI score from baseline to week 12 between the rhIL-10–treated
group and control patients (17% vs 13% improvement, respectively; P = .69), although a modest trend toward improvement in patients receiving
rhIL-10 was documented at both the 6- and 8-week points. Interestingly, proinflammatory
and type 1 cytokine production by PBMCs progressively declined in the rhIL-10–treated
patients during the entire 12-week study period.
Conclusions Treatment with rhIL-10 resulted in only temporary clinical improvement
in psoriasis, despite sustained systemic decreases in proinflammatory and
type 1 cytokine production. These data suggest that immunotherapy that decreases
the ratio of systemic type 1 and type 2 cytokine production does not necessarily
lead to improvement of type 1 cytokine–mediated disease.
INTRODUCTION
AN IMPORTANT role for T cells in the pathogenesis of psoriasis is supported
by both the clinical benefits of treatments that specifically target T cells
and the documentation of clonal T-cell proliferation within lesions.1-3 The T-cell–driven
inflammatory response in psoriasis is dominated by type 1 cytokines, with
high levels of interleukin 2 (IL-2), interferon  (IFN-), and
other proinflammatory cytokines detected within lesions.4-6 By
contrast, IL-10, a type 2 cytokine with a broad spectrum of immunosuppressive
and anti-inflammatory effects in vitro and in vivo,7-9 is
absent or markedly diminished in psoriatic skin when compared with normal
skin.10-12 Because
of these findings, recombinant human IL-10 (rhIL-10) has been tested as a
possible treatment for psoriasis. In several small studies, patients with
psoriasis were treated with varying doses of rhIL-10 for relatively short
periods ( 6 weeks) with reported efficacy.13-17 Given
this background, we designed a randomized, double-blind, placebo-controlled
trial to evaluate safety, efficacy, and immunologic parameters of rhIL-10
treatment in patients with moderate-to-severe psoriasis.
SUBJECTS AND METHODS
PATIENTS
Eligibility criteria included stable classic psoriatic skin lesions,
a Psoriasis Area and Severity Index (PASI) score of 10 or higher, an affected
total body surface area of more than 10%, weight less than 110 kg, and cessation
of systemic psoriasis medications for 4 weeks and topical psoriasis medications
for 2 weeks before study entry. Patients were permitted to use emollients
as needed throughout the study.
STUDY DESIGN
The protocol was approved by the Institutional Review Board of the National
Cancer Institute of the National Institutes of Health in Bethesda. An accrual
goal of 36 patients was established to provide 90% power to detect a 20% difference
(1.3 SDs) between a placebo group of 10 patients and a treatment group of
20 patients with a 2-tailed  of .05 and a dropout rate of 15%. Patients
who met eligibility criteria and who consented to participate in the study
were randomized to receive placebo or rhIL-10 (20 µg/kg) by self-administered
subcutaneous injection 3 times weekly for 12 weeks. Randomization was done
in a blinded fashion by telephoning an off-site intramural clinical trials
statistical center. The center created a computer-generated random allocation
list with fixed blocks of 3 patients each that was used to assign patients
to treatment without disclosure to the caller. Once a patient was so randomized,
a central pharmacy with a secure copy of the randomization list was notified
by the statistical center that a patient with a particular sequence number
had been accepted, and the pharmacy then dispensed a blinded agent for use
with the patient with that sequence number. Patients were examined at an initial
screening visit, at day 0, and at weeks 1, 2, 4, 6, 8, and 12, with a final
follow-up visit 1 month after cessation of rhIL-10 treatment.
EFFICACY AND SAFETY MONITORING
The principal evaluation criterion for this study was the comparison
between baseline and 12-week PASI scores; however, skin disease activity and
drug toxicities were monitored and recorded throughout the study. Specifically,
photographs, physician-assessed PASI scores, self-assessed PASI (SAPASI) scores,
and routine laboratory screening were performed. Skin biopsies were also performed
at the screening visit, week 4, and week 12 from the same target lesion, and
samples were processed for routine histologic analysis.
ASSESSMENT OF INTRACELLULAR CYTOKINE PRODUCTION BY PERIPHERAL BLOOD
MONONUCLEAR CELLS
Heparinized blood was collected at weeks 0, 6, and 12 from 14 patients
(4 placebo-treated patients and 10 rhIL-10–treated patients), peripheral
blood mononuclear cells (PBMCs) were isolated by density centrifugation, and
cells were frozen in 90% fetal bovine serum (Biofluids, Rockville, Md) and
10% dimethyl sulfoxide (Sigma Aldrich Corp, St Louis, Mo) at -70°C.
All PBMCs gathered from individual patients were thawed and assayed for intracellular
cytokine staining on the same day using monoclonal antibody (mAb) staining
(PharMingen, San Diego, Calif) and flow cytometry. Briefly, thawed PBMCs were
restimulated for 6 hours with 4--phorbol 12-myristate 13-acetate, 25
ng/mL (Sigma Aldrich Corp) and ionomycin, 1 µg/mL (Sigma Aldrich Corp).
Two hours before harvesting, brefeldin A, 5 µg/mL (Sigma Aldrich Corp),
was added to cultures to prevent cytokine secretion. Following stimulation,
cells were incubated with Cy-chrome–conjugated anti-CD4 mAbs, fixed
and permeabilized with Cytofix/Cytoperm (PharMingen), incubated with fluorescein
isothiocyanate–conjugated anti–IFN- mAbs, 10 µg/mL,
and phycoerythrin-conjugated anti–IL-4 mAbs or phycoerythrin-conjugated
anti–tumor necrosis factor (TNF-) mAbs, and examined
by flow cytometry (FACScan; Becton Dickinson, Mountain View, Calif) using
Lysis II software (Becton Dickinson).
STATISTICAL ANALYSIS
The 2-sample t test was used to determine the
statistical significance of differences from baseline for PASI scores, SAPASI
scores, and laboratory parameters between groups of patients randomized to
placebo or rhIL-10. If the variances were not equal, then the standard Satterthwaite
method for modifying the t test was used. Otherwise,
if the data were not normally distributed, a Wilcoxon rank sum test was performed.
Categorical demographic and prior treatment variables were compared between
the 2 groups using the  2 or Fisher exact test as appropriate.
All P values are reported without correction for
multiple comparisons, but only the 12-week PASI score difference should be
interpreted without any caveats. All other test results are exploratory and
should be considered in the context of the number of evaluations performed
and the likelihood of identifying a small P value
by chance when many are calculated. All P values
are 2-tailed.
RESULTS
DEMOGRAPHICS AND COMPLIANCE
Twenty-eight patients with moderate-to-severe psoriasis enrolled in
this study, with 10 randomly assigned to receive placebo and 18 randomly assigned
to receive rhIL-10 (Figure 1). Baseline
PASI scores ranged from 9.3 (in a patient subsequently determined to be ineligible)
to 45.0, with an overall mean PASI score of 19.3. The mean PASI scores were
19.9 for rhIL-10–treated patients and 19.2 for placebo-treated patients.
The mean age was 44.9 years, and the overall ratio of men to women was 1.8:1.
Randomization resulted in 2 groups that differed somewhat in several aspects;
the rhIL-10–treated group was significantly older, had a slightly greater
proportion of men, and reported more alcohol use (Table 1). Most patients had been undergoing some form of systemic
psoriasis treatment in the past.
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Figure 1. Patient disposition. rhIL-10 indicates
recombinant human interleukin 10; FDA, US Food and Drug Administration.
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Table 1. Baseline Characteristics of Patients*
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Of the 28 patients who enrolled in the trial, 21 were able to complete
all 12 weeks of therapy (Figure 1).
Two patients in the placebo arm withdrew from the study at 6 weeks because
of worsening skin disease (an increase of PASI score of >30%), 2 left the
study early because of adverse events (one case each of anemia and pancreatitis,
details follow), and 2 discontinued the trial because of early study termination
by the US Food and Drug Administration. Two patients were considered statistically
unevaluable because they both received fewer than 3 doses of rhIL-10 or placebo
(Figure 1).
Compliance throughout the study was excellent. Because of noncompliance
and not medical reasons, 5 patients in the rhIL-10 group missed a total of
9 doses and 2 patients in the placebo group missed 2 doses. No patient missed
more than 3 doses while enrolled in the study.
rhIL-10 LEADS TO TRANSIENT CLINICAL IMPROVEMENT IN PATIENTS WITH PSORIASIS
All patients, whether they were receiving placebo or rhIL-10, improved
slightly during the initial weeks of treatment (Table 2). The rhIL-10–treated patients but not the placebo-treated
patients continued to improve during the second month of treatment (Table 2 and Figure 2). However, most patients receiving rhIL-10 experienced
rebound flares in their psoriasis following 8 weeks of therapy. This was reflected
in their 12-week PASI scores (Table 2).
At this point, there was no statistically significant difference between the
rhIL-10 and placebo groups (P = .69). Although the
SAPASI scores tended to be higher than the investigator scores, the SAPASI
scores showed similar trends to PASI scores (data not shown).
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Table 2. Mean Percentage Improvement in PASI Scores Over Time*
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Figure 2. Recombinant human interleukin
10 (rhIL-10) leads to transient clinical improvement. Representative clinical
photographs of an rhIL-10–treated patient showing significant improvement
at week 6 (Psoriasis Area Severity Index [PASI] score = 6.6) compared with
baseline (PASI score = 31.8) and disease flare at week 12 (PASI score = 19.1).
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Histologic review of target lesions at weeks 0, 4, and 12 revealed changes
consistent with classic psoriasis or partially treated psoriasis (data not
shown) and were consistent with the clinical score at the time of the biopsy.
rhIL-10 IS RELATIVELY WELL TOLERATED
Overall, there were no differences in the type or frequency of adverse
events between the 2 study groups, including headaches, fever, and gastrointestinal
symptoms (data not shown). Serious adverse events observed in this study included
gallstone pancreatitis in an rhIL-10–treated patient and cellulitis
in a placebo-treated patient. The former patient underwent laparoscopic cholecystectomy,
and the latter received 2 days of intravenous antibiotics and both recovered
completely.
rhIL-10 LEADS TO ANEMIA, THROMBOCYTOPENIA, AND REDUCTIONS IN SERUM
CHOLESTEROL LEVELS
Statistically significant changes in hemoglobin levels, reticulocyte
counts, platelet counts, and cholesterol levels were observed during the study
between the rhIL-10 and placebo groups (Figure
3). Changes in hemoglobin levels were statistically lower in the
rhIL-10–treated group during weeks 2 to 8 compared with baseline (range
in P values: .001 to .02, unadjusted for multiple
comparisons) but returned to levels similar to placebo-treated patients by
week 12. One patient demonstrated a gradual decline in hemoglobin levels throughout
8 weeks of rhIL-10 therapy (to a nadir of 9.9 g/dL), was discontinued from
the study for this reason, and had return of his hemoglobin levels to baseline
values 1 month after stopping use of the drug. No other patient demonstrated
laboratory-defined anemia (hemoglobin levels <12 g/dL). Perhaps in compensation
for mild drug-associated anemia, changes in reticulocyte counts were statistically
higher in the rhIL-10–treated group from weeks 6 to 12 (range in P values: .001 to .13, unadjusted for multiple comparisons),
but only rarely exceeded the upper limit of normal. As has been previously
observed, platelet levels dropped in the first week of rhIL-10 therapy (P<.001) but returned to normal by week 2.
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Figure 3. Recombinant human interleukin
10 (rhIL-10) leads to decreases in platelet counts, hemoglobin levels, and
cholesterol levels and increases in serum IgE levels. Absolute mean values
± SEMs for either rhIL-10–treated (closed diamonds or closed
bars) or placebo-treated (open circles or open bars) patients during the study
are shown. To convert cholesterol to millimoles per liter, multiply by 0.0259.
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One of the most unexpected laboratory findings of this study was a marked
decline in cholesterol levels seen in the rhIL-10–treated group (mean
change, 50-67 mg/dL [1.30-1.74 mmol/L]; <.001 P.01) at every point in the study (Figure 3C). Mean triglyceride levels were unaffected by rhIL-10.
No other statistically significant differences were found in other routine
laboratory tests, or if statistically significant changes were seen, they
were not clinically relevant because the values all remained within normal
limits. These laboratory evaluations included chemistry panels, liver function
tests, and urinalyses.
rhIL-10 LEADS TO INCREASED SERUM IgE LEVELS AND DECREASED PRODUCTION
OF TYPE 1 CYTOKINES
Serum IgE levels doubled in the rhIL-10 group by 12 weeks (from a mean
of 104.3 mg/dL at baseline to 208.78 mg/dL at week 12; mean difference of
96.0 mg/dL for those with paired observations; P =
.002 by Wilcoxon signed rank test) (Figure
3D). Furthermore, consistent with this, intracellular cytokine staining
of PBMCs from the rhIL-10–treated patients revealed progressive declines
in the IFN-/IL-4 ratio and TNF- production in CD4+ T
cells and decreases in TNF- production in monocytes during the 12-week
period (Figure 4). The combination
of these immunologic findings indicates that rhIL-10 therapy induced a decrease
in the ratio of systemic type 1 and type 2 cytokine production.
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Figure 4. Recombinant human interleukin
10 (rhIL-10) leads to decreased production of type 1 and proinflammatory cytokines
by peripheral blood CD4+ T cells and monocytes. Peripheral blood
mononuclear cells were collected at 0 (baseline), 6, and 12 weeks in the study,
frozen, thawed, and restimulated with 4--phorbol 12-myristate 13-acetate
and ionomycin. Intracellular cytokine production was quantified using monoclonal
antibody staining and flow cytometry. A, Representative dot plots from a single
patient receiving rhIL-10 showing decreased interferon (IFN-)
and increased IL-4 production by CD4+ T cells throughout 12 weeks.
B, Mean IFN-/IL-4 production ratio in CD4+ T cells throughout
12 weeks, using the ratio at week 0 (baseline) as 100% (left panel). Mean
percentage of CD4+ T cells or monocytes producing tumor necrosis
factor (TNF-) throughout 12 weeks, using the percentage of
cells at week 0 (baseline) as 100%. T cells and monocytes were identified
and gated based on CD4 expression and forward scatter–side scatter profile.
Closed diamonds indicate rhIL-10–treated patients; open diamonds, placebo-treated
patients; asterisk, P<.05; and dagger, P<.005.
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COMMENT
Because of its anti-inflammatory and immunomodulatory properties, rhIL-10
has been tested as a treatment for a variety of inflammatory disease states,18 including Crohn disease19-20 and
rheumatoid arthritis.21-22 These
have been relatively small open-label studies. To date, significant clinical
utility has not been established in either of these conditions. In the first
report on the use of rhIL-10 in psoriasis, 3 patients received subcutaneous
rhIL-10, 8 µg/kg per day, for 24 days and were described as experiencing
clinical efficacy without major adverse effects.13 In
a subsequent open-label study, 10 patients with psoriasis14 received
subcutaneous rhIL-10, 4 µg/kg per day, for 42 days with clinical improvement.14, 16 In the largest reported study to
date, 10 patients with psoriasis received subcutaneous rhIL-10 during a 7-week
period at a dose of 8 µg/kg daily (n = 5) or 20 µg/kg 3 times
per week (n = 5).15 Again, substantial improvement
in PASI scores was reported. The authors of these studies have posited that
a defect in the production of IL-10 within lesions may cause or contribute
to psoriasis. Others have suggested that rhIL-10 may be working by decreasing
proinflammatory cytokine production by PBMCs. Whether local skin or systemic
cytokine production is more important in the pathogenesis of psoriasis remains
subject to debate.10-12,23
Herein, we report the first (to our knowledge) randomized, double-blind,
placebo-controlled study to evaluate the effects of rhIL-10 as a treatment
option for a human disease. In patients with moderate to severe psoriasis,
use of rhIL-10 for 12 weeks did not lead to sustained clinical efficacy, although
there were favorable differences between placebo- and rhIL-10–treated
patients at both the 6- and 8-week points. Our 6- and 8-week data are consistent
with the reported efficacy of rhIL-10 in several smaller studies, since patients
were only treated for 6 weeks or less in these studies.13-17 The
findings that rhIL-10–treated patients experience flares in psoriasis
despite continued use of the drug and despite persistent suppression of type
1 and proinflammatory cytokine production are novel. Our study also emphasizes
the importance of blinded controlled studies in evaluating the clinical efficacy
and immunologic effects of new therapeutic agents for psoriasis.
In general, the subcutaneous injections of rhIL-10 were well tolerated.
No patients withdrew because they disliked the treatment; instead, patients
withdrew because of worsening skin disease or adverse events that precluded
continuing with the study. As with previous experience with this medication,
predictable declines in hemoglobin levels and platelet counts were seen soon
after the initiation of treatment (Figure
3). However, the declines in cholesterol levels were surprising
and striking (Figure 3), especially
considering that current cholesterol-lowering agents decreased levels by approximately
25% on average.24 In our study, an average
decrease of 30% (59 points) was noted in rhIL-10–treated patients throughout
12 weeks (P = .004). This finding may be worth exploring
in future clinical and experimental studies.
With a few notable exceptions, cytokine therapy has been somewhat disappointing
in the treatment of immune-mediated diseases. In our study, rhIL-10 demonstrated
significant antipsoriatic effects for 6 to 8 weeks of treatment (Table 2, Figure 2) and induced distinct immunologic changes (Figure 3 and Figure 4).
However, clinical responses were not maintained with continued use of the
drug, despite persistent reduction of proinflammatory and type 1 cytokine
production by PBMCs. This is one of the more interesting findings of our study,
yet we are unsure why cytokine production did not correlate with clinical
disease severity at the 12-week point. This may reflect compensatory mechanisms
and/or redundancy in cytokine pathways within the skin. Regardless, our data
suggest that immunotherapy that decreases the ratio of systemic type 1 and
type 2 cytokine production does not necessarily correlate with improvement
of type 1 cytokine–mediated skin disease.
AUTHOR INFORMATION
Accepted for publication March 23, 2002.
This study was supported by the intramural research program of the National
Cancer Institute. The rhIL-10 was supplied free of charge by Schering-Plough
Corporation, Kenilworth, NJ.
We thank Debra L. Borris, MS, for technical assistance, Harry Schaefer,
BA, for helping prepare the figures, and R. Todd Plott, MD, and Stephen I.
Katz, MD, PhD, for support and helpful suggestions.
Corresponding author and reprints: Andrew Blauvelt, MD, Dermatology
Branch, National Cancer Institute, Building 10/Room 12N238, 10 Center Dr MSC
1908, Bethesda, MD 20892-1908 (e-mail: blauvelt{at}mail.nih.gov).
From the Dermatology Branch (Drs Kimball, Kawamura, Vogel, Turner,
and Blauvelt and Mss Tejura, Boss, and Hancox) and the Biostatistics and Data
Management Section (Dr Steinberg), National Cancer Institute, Bethesda, Md.
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