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TitleBiologics in General Medicine - W. Boehncke, H. Radeke (Springer, 2007) WW
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W.-H. Boehncke • H.H. Radeke (Eds.) Biologics in General Medicine

Page 101

long-term treatment reduces the numbers of TNF- [
and IL-1 producing cells to the numbers seen in healthy
controls. Gottlieb and colleagues studied histological
response, inflammatory gene expression, and cellular
infiltration in psoriatic plaques of patients receiving
etanercept, 25 mg subcutaneously twice weekly for
6 months. After 6 months of treatment with etanercept,
nine out of the ten patients treated had thinning of the
epidermis and normalization of keratinocyte differenti-
ation, and eight of the ten displayed an absence of kera-
tin 10 (K 16), indicating normalization of keratinocyte
differentiation and proliferation. A rapid and complete
reduction of both IL-1 and IL-8 were observed, with
maximal suppression seen by 1 month of treatment.
Unlike IL-1 and IL-8, which are early TNF- [ induced
genes, most other inflammatory genes, such as STAT-1,
inducible nitric oxide synthase (iNOS), IL-23, and IP-10
(IFN- * -inducible protein-10, CXCL 10), showed a more
gradual response and generally were most suppressed at
6 months. Slower reductions in infiltrating myeloid cells
(CD11c+ cells) and T lymphocytes were also observed.
In another study, NF-κB, a nuclear transcription factor
central in the cell stress response and keratinocyte dif-
ferentiation, was found to be upregulated in the epider-
mis of normal epidermis of psoriasis patients, and even
more so in the plaques of these patients. Treatment with
etanercept correlated with downregulation of phos-
phorylated NF-κB as well as decreases in epidermal
thickness, return of normal markers of keratinocyte
differentiation, and lastly clinical outcomes.

9.2.3
Efficacy

The efficacy of etanercept for the treatment of plaque
psoriasis has been evaluated in four placebo-controlled
studies, one of which evaluated psoriasis in the setting of
psoriatic arthritis. This study by Mease and colleagues
which evaluated etanercept in the treatment of psoriatic
arthritis also examined a subset of 38 patients who had
more than 3% of their body surface area (BSA) covered
with plaque psoriasis. Of the 38 patients, 19 received eta-
nercept, 25 mg subcutaneous twice weekly, while the
remaining 19 received placebo. After 12 weeks of thera-
py, 26% of those subjects receiving etanercept achieved
PASI-75 compared to 0% of those receiving placebo.

A larger, phase 2, randomized, double-blind and
placebo controlled study by Gottlieb and colleagues
(Gottlieb, Chaudhari, et al. 2003) examined the efficacy

and safety of etanercept, 25 mg subcutaneously twice a
week compared to placebo, as monotherapy for moder-
ate to severe plaque psoriasis. After 12 weeks of thera-
py, 30% of patients achieved a PASI-75 compared to 2%
in the placebo group. After 24 weeks of continuous
therapy, 56% of patients receiving etanercept achieved
PASI-75 compared to 5% in the control group. In addi-
tion, by 24 weeks, psoriasis was clear or minimal by the
physician’s global assessment in more than 50% of
patients who received etanercept.

Leonardi and colleagues later conducted a phase 3,
placebo-controlled, double blind study that evaluated
etanercept for psoriasis. Patients with moderate to
severe psoriasis who were not receiving any other ther-
apies including systemic, phototherapy or topical treat-
ments, were enrolled. Six hundred and seventy-two
patients underwent randomization and 652 received
either placebo or received etanercept subcutaneously at
low dose (25 mg once weekly), medium dose (25 mg
twice weekly), or high dose (50 mg twice weekly). After
12 weeks, patients who were in the placebo group
began twice weekly treatment with 25 mg of etanercept.
After 12 weeks of therapy, 4%, 14%, 32%, and 47% of
patients achieved a PASI-75 on placebo, 25 mg once
weekly, 25 mg twice weekly, and 50 mg twice weekly,
respectively. After 24 weeks of continuous therapy, the
PASI-75 score in the low dose group was 21%, 41% in
those receiving 25 mg twice weekly, and 54% in those
receiving the high dose of 50 mg twice weekly.

A second large, phase 3, double-blind study evaluat-
ing etanercept for moderate to severe plaque psoriasis
was conducted in the US, Europe, and Canada by Papp
and colleagues. The study involved three groups of
patients, each receiving placebo twice weekly, etaner-
cept 25 mg twice weekly, or etanercept 50 mg twice
weekly, for the first 12 weeks. After 12 weeks, all three
groups were continued on etanercept 25 mg twice
weekly for 12 weeks. After the first 12 weeks of therapy,
3%, 34%, and 49% of patients receiving placebo, 25 mg
twice weekly, and 50 mg twice weekly, achieved PASI-75
respectively, findings consistent with those results seen
in the US studies. During the second 12-week period
during which all patients received 25 mg, those patients
who were previously receiving 25 mg twice weekly con-
tinued to improve, with 45% achieving PASI-75 at
week 24. The high dose group (50 mg twice weekly)
who were then placed on 25 mg twice weekly main-
tained their previous improvements, with 54% achiev-
ing PASI-75 at week 24, and of those patients who were

9.2 Etanercept 87

Page 102

previously receiving placebo, 28% achieved a PASI-75.
These finds suggested that induction with high-dose
etanercept can then be maintained with a lower dose
and still preserve PASI-75 scores.

9.2.4
Safety

In psoriasis clinical trial experience, etanercept has
been well tolerated. The most common adverse event in
patients receiving placebo or any dose of etanercept
was injection site reaction, where rates in the previous-
ly mentioned two phase 3 trials ranged from 6% to
18%. These reactions typically occur 2–3 weeks into
treatment and consist of erythema, pain, itching, and/
or swelling, and typically resolve in 3–5 days. In addi-
tion, upper respiratory tract infections (5–11%) and
headache (3–12%) were also seen. In the study by Leo-
nardi and colleagues, serious infectious adverse events
were infrequent and were not more frequent in the high
dose etanercept groups when compared to the placebo-
crossover group of lower dose groups. In placebo-con-
trolled trials for all uses of etanercept, the most com-
mon type of adverse event was an upper respiratory
tract infection, which occurred in between 12% and
20% of patients, but not at an increased frequency
when compared with placebo groups.

9.2.4.1
Serious Infections

In rheumatoid arthritis patients in whom there is more
long-term data, it appears that etanercept may increase
the risk of serious infection. In clinical trials, the rates
of infection that required hospitalization or parental
antibiotic therapy were 0.04 per patient-year in etaner-
cept treated groups, which is very similar to the total
population. In post marketing data on the use of eta-
nercept, serious infections and sepsis were reported in
patients using etanercept, but most of these cases were
in patients receiving concomitant immunosuppressive
therapies. Great care should be practiced when placing
a patient on multiple immunosuppressive therapies,
and they should be monitored closely. Rare cases of
reactivation of tuberculosis have been noted in patients
receiving etanercept, and consideration should be giv-
en to performing a purified protein derivative (PPD)
skin test prior to initiation of treatment, especially if
geographic location makes a patient more at risk.

9.2.4.2
Malignancy

The rates of malignancy in patients with psoriasis do
not appear to be increased in those receiving etaner-
cept. In placebo-controlled, randomized studies, 8 of
933 etanercept treated patients were diagnosed with
malignancy whereas 1 in 414 patients receiving placebo
were diagnosed with malignancy. The rate of lympho-
ma was threefold greater in patients receiving etaner-
cept than in the general population. A cohort study by
Gelfand though found that both rheumatoid arthritis
and psoriasis patients are at a threefold increased risk
of developing lymphoma. Taking this into account,
analysis of the effects of etanercept or any other immu-
nosuppressive therapy must consider the inherited risk
of lymphoma to that specific disease population.

9.2.4.3
Demyelinating Disease

TNF- [ inhibition should not be initiated in patients
with a history of demyelinating disorders such as mul-
tiple sclerosis (MS). Post-marketing surveillance has
reported rare incidences of demyelinating disorders or
exacerbations of pre-existing multiple sclerosis in
patients receiving etanercept. In addition, early studies
examining the use of a TNF- [ inhibitor, lenercept, in
the treatment of multiple sclerosis found increased
numbers of MS exacerbations compared to placebo as
well as MS exacerbations that occurred earlier com-
pared to placebo. Physicians should be wary of new-
onset neurological symptoms in patients receiving eta-
nercept treatment, and a good neurological history
should be obtained before commencing therapy.

9.2.4.4
Autoimmunity

Approximately 6% of patients with RA, psoriatic
arthritis, ankylosing spondylitis, or plaque psoriasis
developed non-neutralizing antibodies to the TNF
receptor (package insert). Antinuclear antibodies
develop in some patients receiving etanercept, but
most typically this finding has no clinical significance.
There have been rare cases of systemic and cutaneous
lupus associated with etanercept use.

88 9 Biologics in Psoriasis

Page 201

hyperproliferation 46

IBD, see inflammatory bowel disease
IBDQ, see Inflammatory Bowel Disease

Questionnaire
90Y-ibritumomab tiuxetan 151
ICAM, see intercellular adhesion

molecule
IgG 1 κ immunoglobulin 5
IHC, see immunohistochemistry
IMID, see immune-mediated inflam-

matory disease
immune
– cell migration 141
– system 1
immune-mediated inflammatory

disease (IMID) 1
immunoconjugate 155
immunohistochemistry (IHC) 56
immunosuppressive therapy 79
immunotoxin 157
IMPACT trial 103
indomethacin 151
inducible nitric oxide synthase

(iNOS) 87
infectious disease 60
inflammatory
– arthritis 102
– bowel disease (IBD) 124
Inflammatory Bowel Disease Question-

naire (IBDQ) 139
infliximab 5–12, 14, 16, 17, 74, 77, 78,

82, 86, 89, 95, 103, 104, 111–117, 124,
127, 128, 130, 131, 133, 134, 137,
168–170, 184

– ankylosing spondylitis 7
– antibody 10
– Crohn’s disease 6, 7, 128, 130
– failures 132
– pharmacokinetics 8
– plaque psoriasis 7
– psoriasis 7
– psoriatic arthritis 7
– rheumatoid arthritis 6, 7, 10, 11
– ulcerative colitis 6, 7
intercellular adhesion molecule

(ICAM) 42
– ICAM-1 45, 46, 77, 86, 89, 98
– – keratinocyte level 47
[ 4 q 1 integrin molecule 170

interferon
– IFN- [ 59, 65
– IFN- q 144
– IFN- * 42, 85, 126
interleukin
– IL-1 15, 37, 112
– – blockade 118, 119
– IL-2 45, 85
– – DAB389 149

– IL-6 15, 37, 86, 112, 136
– IL-8 112
– IL-9 137
– IL-12 135
– IL-23 135
iodine isotope 53

JunB 98
Jurkat cell 5, 44

keratinocyte 98
Koebner phenomenon 81

lactate level 61
LacZ 178
Langerhans cell 45
lenercept 88, 116, 142
LET, see linear energy transfer
LFA-1, see lymphocyte function-associ-

ated antigen
linear energy transfer (LET) 52
listeriosis 115
lymphocyte
– count 48
– function-associated antigen (LFA-1)

42, 45, 46, 86, 89
lymphoma 27, 88, 116
lymphotoxin 78
– LT- [ 15, 159

macrophage 98
MAK195 14
manufacturing 62
marginal zone lymphoma (MZL) 149
Master Cell Bank (MCB) 62
matrix metalloproteinase (MMP) 16,

37, 86, 118
MCB, see Master Cell Bank
melanoma 158
memory effector cell 92
messenger RNA 161
metastatic melanoma 159
methotrexate (MTX) 7, 11, 19, 35, 39,

95, 112, 113, 119, 131
MHM24 43
mixed lymphocyte response assay

(MLR) 44
MLN-02 135
MLR, see mixed lymphocyte response

assay
monomeric FAB fragment 5
monomethyl auristatin E 156
mouse myeloma 61
MPIF-1 176
MTX, see methotrexate
multiple sclerosis (MS) 88, 116, 141,

178
murine collagen-induced arthritis

111

Mycobacterium
– pneumonia 150
– tuberculosis 115
mycophenolate mofetil 71, 78, 79
mycosis fungoides 148
mylolarg 50, 156
MZL, see marginal zone lymphoma

natalizumab 127, 129, 135, 143, 170
neuritis 145
neuroblastoma 158
neuromyelitis optica 145
NF-κB 87, 98
NHL, see non-Hodgkin’s lymphoma
NNT, see number needed to treat
non-Hodgkin’s lymphoma (NHL) 50,

73, 116, 148, 151
nonsteroidal anti-inflammatory drug

(NSAID) 102
number needed to treat (NNT) 184

OLE study 22, 24
onercept 134
onycholysis 84
OPG, see osteoprotegerin
osteoclast 38
osteoprotegerin (OPG) 118

paclitaxel 56
palmoplantar
– psoriasis 84
– pustulosis 84
paracetamol 150
parakeratosis 44
PASI, see Psoriasis Area and Severity

Index
Pautrier microabscess 148
PBMC, see peripheral blood mononu-

clear cell
pemphigoid 70
pemphigus 69
– foliaceus 69
– rituximab 73
– vulgaris 69, 74
– – TNF- [ 78
peptide hormone 59
peripheral blood mononuclear cell

(PBMC) 44
p-glycoprotein 161
phage display technology 14
Physician’s Global Assessment (PGA)

93, 94
Pichia pastoris 61
pioglitazone 106
plaque psoriasis 44, 81, 87, 93
– infliximab 7
Pneumocystis carinii 75, 115

polyarthritis 112
polymorphonuclear leukocyte

(PMN) 98

Subject Index 189

Page 202

PRECISE 133
prednisolone 75
prednisone 79
PREMIER study 22, 28, 113, 114
primary cutaneous lymphoma (PCL)

147
progressive multifocal leukoencephalo-

pathy (PML) 143, 170
pro-matrix metalloproteinase 113
protein vehicle 56
pruritus 71, 94
PSA, see Psoriasis Symptom Assess-

ment
PsA, see psoriatic arthritis
Pseudomonas 156

psoralen 39
psoriasis 38, 81, 92
– adalimumab 17, 25
– clinical features 83
– efalizumab 44
– etanercept 33, 38, 86
– flare 92
– infliximab 7
– – pharmacokinetics 9
– vulgaris 44
Psoriasis Area and Severity Index

(PASI) 24, 48, 91, 84, 87, 90, 93
Psoriasis Symptom Assessment (PSA)
psoriatic
– arthritis (PsA) 23, 38, 95, 97
– – etanercept 38
– – infliximab 7
– nail changes 100
Psoriatic Arthritis Response Criteria

(PsARC) 102
purified protein derivative (PPD) 88
pustular psoriasis 84

quality
– assurance (QA) 64
– control (QC) 64

radioimmunotherapy (RIT) 53
radioisotope 51
radionuclide 51, 52
RANTES 179
Raptiva, see efalizumab
REACH 131
recombinant
– DNA molecule 59
– therapy 1
renal insufficiency 34

– etanercept 34
respiratory tract infection 27, 114
rheumatoid arthritis 111, 116, 119,

169, 179
– adalimumab 17, 18, 20, 26
– etanercept 33, 37, 86
– infliximab 6, 7, 10, 11, 73
rheumatoid factor 99
rhinitis 27
ribozyme 161
RIT, see radioimmunotherapy
Rituxan, see rituximab
rituximab 50, 56, 72–77, 78, 144, 145,

147, 150, 171
– autoimmune bullous skin disorder

72
– epidermolysis bullosa acquisita 75
– pemphigus 73
– rheumatoid arthritis 73
– toxicity 75

SAHA, see suberoylanilide hydroxamic
acid

sargramostim 129, 137
secretome 176, 180
Sézary syndrome 148, 152
Short Form-36 (SF-36) 19
signal sequence trapping 176
single nucleotide polymorphism

(SNP) 177, 180
SLE, see systemic lupus erythematosus
soluble receptor activator of nuclear

factor κB ligands (sRANKL) 118
somatropin 137
SONIC study 131
SPECT 53
spine inflammation 99
spondyloarthropathy 37
– etanercept 37
STAR trial 22
STAT-1 87
static Physician’s Global Assessment

(sPGA) 90
suberoylanilide hydroxamic acid

(SAHA) 152
sulfasalazine 35
systemic lupus erythematosus (SLE)

179

T cell 44, 92, 105
– proliferation 47
– surveillance 171

TAA, see tumor-associated antigen
targeted monoclonal antibody 168
T-cell receptor (TCR) 42
TCR, see T-cell receptor
TEMPO study 113
tetanus toxoid 94
thrombocytopenia 92, 152
tissue plasminogen activator 59
Total Sharp Score (TSS) 19
toxin 157
trastuzumab 56, 60, 168, 171
TSS, see Total Sharp Score
tuberculosis 27, 94, 115, 169
tumor necrosis factor
– TNF- [ 5, 32, 37, 77, 98, 111, 126, 142
– – blockade 118, 119
– – inhibition 88
– – pemphigus vulgaris 78
– TNF- * 65
tumor-associated antigen (TAA) 50

ulcerative colitis 124, 137
– infliximab 6, 7
ultraviolet A phototherapy 39
urinary tract infection 27

varicella zoster 78
vascular
– cell adhesion molecule (VCAM) 86
– – VCAM-1 117
– endothelial growth factor (VEGF)

118
– leak syndrome 157
VCAM, see vascular cell adhesion

molecule
vinca alkaloid 154
visilizumab 127, 137
Visual Analogue Score (VAS) 90
VLA-4 143
von Zumbusch pustular psoriasis 84

warfarin 35
WCB, see working cell bank
white blood cell (WBC) count 47
WHO-EORTC classification 147
working cell bank (WCB) 62

xenograft tumor 161

Yttrium-90 151

Zevalin 50, 53

190 Subject Index

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