Antiinfliximab antibody status and its relation to clinical response in psoriatic patients: a pilot study
Journal of Dermatology 2010; 37: 708–713
Anti-infliximab antibody status and its relation toclinical response in psoriatic patients: A pilot study
Esra ADIS¸EN,1 Arzu ARAL,2 Cemalettin AYBAY,2 Mehmet Ali GU
Departments of 1Dermatology and 2Immunology, Gazi University, Faculty of Medicine, Ankara, Turkey
Although the mechanisms underlying the loss of response to infliximab are not completely understood, the forma-tion of antibodies to infliximab (ATI) are thought to play a role. The aim of this study was to investigate the presenceof ATI in psoriatic patients and to evaluate its relationship to the clinical response. Fifteen patients with psoriasiswere treated with infliximab (5 mg ⁄ kg) every 8 weeks after an initial three-dose induction treatment. An enzymelinked immunosorbent assay kit was used for analyzing the presence of ATI in sera. Effectiveness assessmentsincluded the change in Psoriasis Area and Severity Index (PASI) compared with study entry. Five (33.3%) patientsdeveloped ATI. While 5.9 ± 3.2 infliximab infusions achieved a fall in the PASI score from a mean of 20.4 ± 8.3to 5.3 ± 2.4 in ATI-negative patients, these values changed from 23.3 ± 11 to 10 ± 4.9 after 9 ± 5.2 infusions inATI-positive patients. Our results suggested that ATI measured in psoriatic patients are of clinical importance. Therefore, monitoring for the induction of ATI and rescue strategies should be developed to avoid or to maintain adelay in ATI development.
antibodies to infliximab, clinical response, infliximab, loss of efficacy.
Severity Index (PASI 75) and PASI 90 was achievedby 54.5% and 34.3%, respectively, of patients receiv-
Infliximab is a recombinant immunoglobulin G1-j,
ing 5 mg ⁄ kg on an every 8-week regimen, compared
human-murine chimeric monoclonal antibody that
with 38.1% and 10.4%, respectively, by patients
specifically binds to both soluble and membrane-
receiving 5 mg ⁄ kg on an as-needed regimen.2 There-
bound tumor necrosis factor (TNF)-a and neutralizes
fore, currently, continuous infliximab therapy is
its biological activity. It has been shown to be highly
recommended in psoriatic patients. However, many
effective for the treatment of psoriasis in several pre-
clinical studies have reported that some patients trea-
vious clinical studies. The recommended dose for
ted with infliximab experienced a loss of efficacy over
psoriasis is 5 mg ⁄ kg given as an i.v. infusion lasting
time. Although the mechanisms underlying the loss of
2 h followed by similar doses at weeks 2 and 6, then
response to infliximab are not completely under-
stood, antibody formation against infliximab may play
Several studies investigated the effects of varying
a role. In addition to loss of efficacy, the development
dosing regimens on the clinical responses and
of antibodies to infliximab (ATI) are thought to be
showed that responses in every 8-week maintenance
related to the occurrence of acute and delayed
dosing regimens were significantly better when com-
type reactions. These reactions and loss of efficacy
pared to on-demand therapy groups. In one study, at
are the current problems encountered during the
week 50, a 75% reduction in Psoriasis Area and
Correspondence: Esra Adis¸en, M.D., Department of Dermatology, Gazi University Faculty of Medicine, 11.kat, 06500 Besevler, Ankara, Turkey. Email: [email protected] authors have contributed significantly, and all authors are in agreement with the content of the manuscript. Received 27 August 2009; accepted 24 November 2009.
Ó 2010 Japanese Dermatological Association
Anti-infliximab antibodies in psoriasis patients
Monoclonal antibodies, like any other immunoglob-
If patients had chest radiographs indicative of prior
ulin, may elicit side-effects. For infliximab, it is the
TB infection or a positive purified protein derivative
murine binding portion which comprises 25% of
(PPD) tuberculin skin test, appropriate prophylactic
the antibody that is antigenic and is responsible for
anti-TB therapy was to be initiated before entering
the study. A total of six (40%) patients received isoni-
Infliximab has been approved for treatment of
azid prophylaxis for TB based on baseline chest
psoriasis after approval of the agent in rheumatoid
radiograph indicative of latent TB, positive PPD skin
arthritis (RA), ankylosing spondylitis (AS) and Crohn’s
disease (CD); therefore, much of the data on the safety
Demographic data of our patients are presented in
and efficacy of infliximab has been conducted with
Table 1. Patients were assessed at screening, and
these patients.10–19 In RA, CD and AS, the presence
then at baseline, weeks 2, 8 and 16, and every
of ATI and their relationship to clinical response and
8 weeks thereafter through the treatment period.
allergic reactions have been previously shown.10–19
At each visit, the presence of infections, side-effects
This issue and the clear-cut demonstration of the
or infusion reactions were recorded. Effectiveness
presence of ATI in psoriasis have been examined in
assessments included the change in PASI compared
few studies to date. In this pilot study, we investigated
the presence of ATI in psoriatic patients and evaluatedits relationship to the clinical response to infliximab
In the study, peripheral blood samples of 5–10 mLwere collected from patients at the beginning of thestudy and thereafter just before infliximab infusions.
Venous blood samples were collected and centri-
fuged at 3000 g for 10 min, aspirated and stored
Fifteen patients (seven female and eight male) with
at )80°C until analysis. A commercially available
moderately severe to severe plaque-type psoriasis
enzyme linked immunosorbent assay (ELISA) kit
vulgaris, generalized pustular psoriasis or erythroder-
(Matriks Biotek Laboratories, Ankara, Turkey) was
mic psoriasis were consecutively recruited into the
used for analyzing the presence of ATI in sera. The
study. Inclusion criteria were patients who had a PASI
assay was based on a highly specific double antigen
score of more than 10 with at least 10% total body
binding assay principle. In this procedure, the specific
surface area (BSA) involvement, and had not
antibody in serum, namely ATI, binds to the inflix-
responded to other systemic therapies including
imab-coated well with one of its Fab arms and also
methotrexate, oral retinoids, cyclosporine or psoralen
binds to the biotinylated infliximab with the aid of its
plus ultraviolet A therapy (PUVA), or had not tolerated
other Fab arm. The ELISA kit demonstrates the pres-
these agents, and had no history of serious infection,
ence of antibodies to infliximab, and the intensity of
lymphoproliferative disease or active tuberculosis
the color developed is proportional to the amount of
(TB). Following the introduction of infliximab for clini-
specific antibodies. Results were expressed as posi-
cal use at our department, blood samples were
routinely collected just before every infliximab admin-istration. The age and sex of the patients, duration of
psoriasis, previous treatments, concomitant thera-
Data analysis was carried out using the SPSS
pies, baseline PASI and PASI follow-up values and
ver. 11.00 statistical package software. Data were
summarized descriptively. Comparisons between
The dose of infliximab was adjusted for body-
ATI-positive and ATI-negative groups were per-
weight. A single dose of 5 mg ⁄ kg was administrated
formed using a Mann–Whitney U-test for continuous
at weeks 0, 2 and 6 and thereafter regularly every
data and v2-test for categorical data. Statistical signif-
8 weeks. Generally, in erythrodermic patients, inflix-
icance was defined as P < 0.05. A Wilcoxon signed
imab was started in combination with systemic corti-
rank test was used to assess changes in PASI
costeroids that were gradually tapered over 2 weeks.
Ó 2010 Japanese Dermatological Association
Table 1. Features of antibodies to infliximab (ATI)-positive and -negative patients
Duration of psoriasis, years, mean ± SD (min–max)
Mean of baseline PASI, mean ± SD (min–max)
Infliximab infusion number, mean ± SD (min–max)
Concomitant immunosuppressive therapy, n (%)
*Mann–Whitney U-test, **v2-test, ***P = 0.01; comparison of the mean of baseline Psoriasis Area and Severity Index (PASI) with last PASI score,Wilcoxon signed rank, ****P = 0.1; comparison of the mean of baseline PASI with last PASI score, Wilcoxon signed rank. SD, standard deviation.
(P = 0.01), in the current study. In addition, thoughthe mean of baseline PASI scores were not showing
Table 1 shows the characteristics of the study
difference between the groups (P = 0.63), the mean
population. All patients received 3–16 infliximab
of last PASI scores were higher in ATI-positive
infusions during the study. Five (5 ⁄ 15, 33.3%)
patients when compared to ATI-negative patients
patients developed ATI at the time of the 5th,
6th, 7th, 10th and 13th infusion of infliximab ther-
All five patients with ATI presented with either new
lesion development or a loss of efficacy which was
reaction requiring infliximab discontinuation after
reflected by an increase in PASI in these patients
the third infusion. All other patients were contin-
uing infliximab therapy without any problem at the
Because the numbers of the patients receiving
time of the study. Four patients received concom-
concomitant corticosteroid treatment were low, the
itant corticosteroid treatment. Three patients had
effect of corticosteroids on ATI positivity could not be
subjected to any statistical analysis.
Clinical characteristics of patients who developed
When all the ATI-positive patients receiving inflix-
ATI (n = 5) and those who did not (n = 10) were
imab were treated with additional methotrexate with
shown in Table 1. Statistical analysis revealed no dif-
doses ranging 5–15 mg ⁄ week, the disappearance of
ference according to age (P = 0.58) and sex (P =
ATI was observed only after 8 weeks of methotrexate
0.95) characteristics, the duration of the disease
(P = 0.79) or types (plaque-type psoriasis vulgaris,generalized pustular psoriasis or erythrodermic pso-
riasis) of psoriasis (P = 0.38, P = 0.13, P = 0.67,respectively) between the ATI-positive and -negative
Our study, which aimed to document the frequency
patients. In ATI-negative patients, 5.9 ± 3.2 (3–14) of
of ATI formation in psoriatic patients receiving inflix-
infliximab infusions achieved a fall in the PASI score
imab monotherapy on a regularly scheduled basis,
from a mean of 20.4 ± 8.3 (11–34) to 5.3 ± 2.4 (1–9)
showed that one-third of patients receiving infliximab
(P = 0.01). However, in ATI-positive patients, inflix-
for psoriasis developed ATI during their therapy. More
imab treatment achieved a fall in the PASI score from
importantly, we were able to show that the forma-
a mean of 23.3 ± 11 (16–36) to 10 ± 4.9 (5–16) after
tion of ATI reflected the loss of efficacy of inflixi-
9 ± 5.2 (3–16) infusions (P = 0.01). This finding
mab in these patients. Interestingly, our results were
showed that the similar numbers of infusions of inflix-
in agreement with a previous study that reported
imab (P = 0.16) failed to satisfactorily reduce the
that 35.8% of the psoriatic patients developed ATI
mean PASI scores of ATI-positive patients (P = 0.1)
after 60 weeks of 5 mg ⁄ kg infliximab applied every
when compared to that of ATI-negative patients
Ó 2010 Japanese Dermatological Association
Anti-infliximab antibodies in psoriasis patients
Table 2. Antibodies to infliximab (ATI)-positive patients and their characteristics
infusion number(no. at the time of ATIpositivity)Last PASI before
MTX, methotrexate; PASI, Psoriasis Area and Severity Index.
reported in other psoriasis clinical trials4,20 and in
However, these findings need to be clarified by long-
other indications of the drug.9–11,13,19,21 The develop-
ment of ATI up to 61%, 43% and 64% have been
Hypersensitivity reactions are among other prob-
reported in patients with CD,22,23 RA,11 and AS,12
lems encountered during infliximab use. One impor-
respectively. In RA, AS and CD, it has been shown
tant consequence of the formation of ATI is the
that ATI was among the determinants of the thera-
increased risk for hypersensitivity reactions.6,19 A cor-
peutic response11,19,22 on the other hand, in contrast
relation between antibody level and increased likeli-
to our observations, some authors have proposed
hood of reaction was not observed in some studies.14
that this does not hold true for psoriasis.2 In our study,
We observed only one infusion reaction in one patient
five out of 15 patients (33.3%) developed ATI at 5th
that occurred in the third infusion. However, this
to 13th infusions. These patients experienced new
patient was observed to be ATI negative.
lesion development or an increase in erythema and
Most of the hummanized monoclonal antibodies
an increase in induration in the previous lesions
are immunogenic to a greater or lesser extent. The
reflecting an increase in PASI suggesting that ATI
incidence of immunogenicity of therapeutic proteins
measured in our patients are of clinical importance.
is variable; though not totally understood, patient-
Moreover, the similar numbers of infusions of inflix-
related and treatment-related factors may have an
imab failed to satisfactorily reduce the mean PASI
affect.6–8,24,25 The half-life elimination of infliximab is
scores in ATI-positive patients when compared to
also related to other substantial inter-subject variabili-
that of ATI-negative patients, in the current study.
ties.9 Possibly because of this, the frequency and the
Ó 2010 Japanese Dermatological Association
timing of the development of ATI varied among stud-
approaches will have obvious financial implications.
In RA, AS and CD patients, the loss of response could
Several strategies such as continuous therapy on a
be prevented by the increase in infliximab dosage.7,18
regularly scheduled basis, concomitant use of metho-
In the case of psoriasis, however, current knowledge
trexate, slowing infusion rate, shortening the infusion
does not support that this approach may work in pso-
interval, switching to another anti-TNF agent such as
riasis treatment. In contrast to other indications of the
adalimumab, and premedication with systemic ste-
infliximab, the response of psoriasis to infliximab
roids have been developed to prevent ATI forma-
does not appear to be dose dependent. Two studies
tion.5,6,26 However, these strategies fail especially in
investigated the efficacy of infliximab, 3, 5 or 10
patients who are intolerant to methotrexate or who
mg ⁄ kg, in psoriasis. A dose of 3 or 5 mg ⁄ kg provided
have developed severe infusion reactions. Also, in
a PASI 75 in 72% and 88% of the patients, respec-
psoriatic patients, administration of prophylactic sys-
tively, and a PASI 90 in 45.5% or 57.6% of the
temic steroids before every infliximab infusion does
patients, respectively, whereas infliximab in doses of
10 mg ⁄ kg did not produce an increase in efficacy.3,20
An induction regimen followed by regularly sched-
A further increase in the efficacy was not observed
uled maintenance infusions decreases the likelihood
with 10 mg ⁄ kg when compared to the lesser doses of
of antibody formation possibly by generating immuno-
the drug. Therefore, the recommended dose of inflix-
logical tolerance.10,15,16 It has been suggested that
imab is 5 mg ⁄ kg for psoriasis.3 This is the optimum
with the extended intervals between the infusions, the
dose of the drug to achieve a sustained response,
probability of the formation of infliximab antibodies
and it is not known how much increase in infliximab
increases.5 In accordance with that suggestion,
doses in ATI-positive patients will provide a simi-
Menter et al.2 have shown that the probability of
lar response that was previously achieved in a ATI-
development of ATI was higher in as-needed
regimens (41.5%) when compared to every 8-week
At the moment, infliximab in psoriasis appears to
infliximab regimens (35.8%), and favored use of every
offer the advantage of rapid healing, reduced mor-
8-week therapy. Moreover, induction regimen and
bidity and hospital stay, and freedom from the
maintenance therapy with 8-week intervals have
common side-effects of other immunosuppressives.
been found better than the addition of an immuno-
However, prolonged use of infliximab is generally
modulator for preventing antibody formation.7
recommended to achieve a sustained response. On
It has been shown that the use of concomitant
the other hand, prolonged use of infliximab has
immunomodulators prior to starting infliximab is
been associated with loss of efficacy which is gen-
effective in reducing antibody production in indica-
erally but not totally2 believed to be related to the
tions other than psoriasis.7,10,26 When it comes to
formation of anti-neutralizing antibodies. Therefore,
psoriasis, there is no study that investigated the effect
monitoring for the induction of ATI and rescue strat-
of concomitant use of immunosuppressants on the
egies should be developed to avoid or to maintain
formation of antibodies. Even with a limited number
a delay in ATI development. Although our patient
of subjects, the present study demonstrated that in
number is low, our results showed that the forma-
psoriasis adding methotrexate (5–15 mg ⁄ week) to inf-
tion of ATI development may be responsible for the
liximab provided a negative ATI status and achieved
loss of efficacy of infliximab in long-term use, espe-
a sustained clinical efficacy in previously ATI-positive
cially in patients whose clinical benefit wanes over
patients. At present, it is not known for how long
immunosuppressive therapy with methotrexate incombination with infliximab should be continued inany of the indications of the drug.6,26
In ATI-positive patients, the infliximab levels will
1 Gottlieb AB, Chaudhari U, Mulcahy LD, Li S, Dooley LT,
be decreased. Therefore, patients with ATI may
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Ó 2010 Japanese Dermatological Association
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Ó 2010 Japanese Dermatological Association
Diagnosis and therapy of tuberculous meningitis in childrenDepartment of Maternal and Pediatric Sciences, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico,Via Commenda 9, 20122 Milan, ItalyChildren are among the subjects most frequently affected by tuberculous meningitis (TBM) due to theirrelative inability to contain primary Mycobacterium tuber
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