Download Efficacy of Tocilizumab in Conventional TreatmentRefractory

ARTHRITIS & RHEUMATOLOGY
Vol. 66, No. 6, June 2014, pp 1659–1665
DOI 10.1002/art.38398
© 2014, American College of Rheumatology
Efficacy of Tocilizumab in Conventional Treatment–Refractory
Adult-Onset Still’s Disease
Multicenter Retrospective Open-Label Study of Thirty-Four Patients
Francisco Ortiz-Sanjuán,1 Ricardo Blanco,1 Vanesa Calvo-Rio,1 Javier Narvaez,2
Esteban Rubio Romero,3 Alejandro Olivé,4 Santos Castañeda,5 Adela Gallego Flores,6
M. Victoria Hernández,7 Cristina Mata,1 Inmaculada Ros Vilamajo,8
Walter Alberto Sifuentes Giraldo,9 Miguel A. Caracuel,10 Mercedes Freire,11
Catalina Gómez Arango,12 José Llobet,13 Sara Manrique Arija,14 Carlos Marras,15
Concepción Moll-Tuduri,16 Chamaida Plasencia-Rodriguez,17 Rosa Roselló,18
Ana Urruticoechea,19 Maria L. Velloso-Feijoo,20 Jordi del Blanco,21
M. Carmen González-Vela,1 Javier Rueda-Gotor,1 Trinitario Pina,1
Javier Loricera,1 and Miguel A. González-Gay1
Objective. Adult-onset Still’s disease (AOSD) is
frequently refractory to standard therapy. Tocilizumab
(TCZ) has demonstrated efficacy in single cases and in
small series of patients with AOSD. The aim of this
multicenter study was to assess the efficacy of TCZ in
patients with AOSD refractory to conventional treatment.
Methods. This was a retrospective open-label
study of TCZ treatment in 34 patients with AOSD who
had experienced an inadequate response to corticosteroids and at least 1 standard synthetic immunosuppressive drug and also, in many cases, biologic agents.
Results. The mean ! SD age of the patients (8
men and 26 women) was 38.7 ! 16.1 years. The median
duration of AOSD before TCZ was initiated was 4.2
years (interquartile range [IQR] 1–9 years). The initial
dosages of intravenous TCZ were 8 mg/kg every 4 weeks
in 22 patients, 4 mg/kg every 4 weeks in 2 patients, and
8 mg/kg every 2 weeks in 10 patients. TCZ treatment
Supported in part by the Instituto de Salud Carlos III, Spain
(RETICS Programs; RD08/0075 [RIER] and RD12/0009/0013).
Presented in part at the 77th Annual Scientific Meeting of the
American College of Rheumatology, San Diego, CA, October 2013.
1
Francisco Ortiz-Sanjuán, MD, Ricardo Blanco, MD, PhD,
Vanesa Calvo-Rio, MD, Cristina Mata, MD, M. Carmen GonzálezVela, MD, Javier Rueda-Gotor, MD, Trinitario Pina, MD, Javier
Loricera, MD, Miguel A. González-Gay, MD, PhD: Hospital Universitario Marqués de Valdecilla and Instituto de Investigación Marqués
de Valdecilla (IDIVAL), Santander, Spain; 2Javier Narváez, MD,
PhD: Hospital Universitario de Bellvitge, Hospitalet, Barcelona,
Spain; 3Esteban Rubio Romero, MD: Hospital Universitario Virgen
del Rocı́o, Seville, Spain; 4Alejandro Olivé, MD, PhD: Hospital
Universitario Germans Trias i Pujol, Badalona, Spain; 5Santos
Castañeda, MD, PhD: Hospital Universitario de La Princesa, IIS
Princesa Madrid, Madrid, Spain; 6Adela Gallego Flores, MD: Hospital
de Mérida, Mérida, Spain; 7M. Victoria Hernández, MD, PhD:
Hospital Clinic of Barcelona, Barcelona, Spain; 8Inmaculada Ros
Vilamajo, MD: Hospital Son Llàtzer, Palma de Mallorca, Spain;
9
Walter Alberto Sifuentes Giraldo, MD: Hospital Ramón y Cajal,
Madrid, Spain; 10Miguel A. Caracuel, MD: Hospital Reina Sofı́a,
Córdoba, Spain; 11Mercedes Freire, MD: Hospital Universitario Juan
Canalejo, La Coruña, Spain; 12Catalina Gómez-Arango, MD: Hospital
Universitario Basurto, Bilbao, Spain; 13José Llobet, MD: Hospital
Sant Pau, Barcelona, Spain; 14Sara Manrique-Arija, MD: Urgencias
Hospital Regional Universitario Carlos Haya, Málaga, Spain; 15Carlos
Marras, MD: Hospital Universitario Virgen de la Arrixaca, Murcia,
Spain; 16Concepción Moll-Tuduri, MD: Hospital Mateu Orfila,
Mahón, Spain; 17Chamaida Plasencia-Rodriguez, MD: Hospital Universitario La Paz, Madrid, Spain; 18Rosa Roselló, MD: Hospital San
Jorge, Huesca, Spain; 19Ana Urruticoechea, MD: Hospital Can Misses,
Ibiza, Spain; 20Maria Luisa Velloso Feijoo, MD: Hospital Valme,
Seville, Spain; 21Jordi del Blanco, MD: Hospital Sant Jaume, Calella,
Spain.
Drs. Ortiz-Sanjuán, R. Blanco, and Calvo-Rio contributed
equally to this work.
Address correspondence to Miguel A. González-Gay, MD,
PhD, or Ricardo Blanco, MD, PhD, Rheumatology Division, Hospital
Universitario Marqués de Valdecilla, IDIVAL, Avenida Valdecilla s/n,
39008 Santander, Spain. E-mail: [email protected] or
[email protected].
Submitted for publication November 8, 2013; accepted in
revised form February 4, 2014.
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resulted in rapid and maintained improvement in both
clinical and laboratory parameters. After 1 year of TCZ
therapy, the incidence of joint manifestations had decreased from 97.1% at baseline to 32.4%, the incidence
of both cutaneous manifestations and fever had decreased from 58.8% to 5.9%, and the incidence of
lymphadenopathy had decreased from 29.4% to 0%. A
dramatic reduction in laboratory markers of inflammation, including the C-reactive protein level, the erythrocyte sedimentation rate, and the ferritin level, was
achieved. The median dosage of prednisone was also
reduced, from 13.8 mg/day (IQR 5–45) at the initiation
of TCZ to 2.5 mg/day (IQR 0–30) at 12 months. After a
median followup of 19 months (IQR 12–31 months),
only 2 patients required permanent discontinuation of
TCZ therapy because of severe infections.
Conclusion. TCZ treatment was associated with
rapid and maintained clinical and laboratory improvement in patients with AOSD refractory to standard
treatment. However, joint manifestations seem to be
more refractory to treatment compared with systemic
manifestations.
Adult-onset Still’s disease (AOSD) is a systemic
inflammatory disease of unknown etiology characterized by high fever spikes, arthritis and/or arthralgia, and
evanescent maculopapular salmon-pink rash that appears predominantly on the trunk and proximal limbs.
Other features are sore throat or pharyngitis, myalgia,
lymphadenopathy, hepatosplenomegaly, and serositis.
Laboratory tests show increased concentrations of
acute-phase reactants, leukocytosis with neutrophil predominance, elevated levels of liver enzymes, and high
serum levels of ferritin (1,2).
The pathogenesis of AOSD remains unknown.
Several studies have suggested a genetic predisposition,
while others have identified different infectious agents
as potential triggers of the disease. A number of studies
have demonstrated abnormal production of proinflammatory cytokines, such as interleukin-1 (IL-1), IL-6,
IL-18, tumor necrosis factor ! (TNF!), or interferon-",
by T lymphocytes and macrophages (3,4). These findings
may explain the intermittent course of AOSD and the
clinical and laboratory features that resemble those of
genetic autoinflammatory syndromes. Increased levels
of IL-6 and/or IL-18 have been associated with clinical
and laboratory features such as fever, rash, elevated liver
enzyme levels, hyperferritinemia, and increased
C-reactive protein (CRP) levels (5).
First-line treatment in AOSD includes the use
of nonsteroidal antiinflammatory drugs, although only
ORTIZ-SANJUÁN ET AL
15–20% of patients respond to this treatment; in most
cases, treatment with corticosteroids is required. Other
therapies, such as methotrexate, azathioprine, leflunomide, intravenous immunoglobulin, anakinra, antiTNF! drugs, rituximab, and abatacept, are often needed
to achieve adequate control of the disease and reduce
the dose of corticosteroids. However, the efficacy of
these drugs in the control of disease activity is variable,
and in some cases, they are associated with potential
severe side effects.
Tocilizumab (TCZ) is a humanized monoclonal
antibody against the IL-6 receptor; it is approved for the
treatment of rheumatoid arthritis (RA) (6) and systemic
juvenile idiopathic arthritis (JIA) (7). Because IL-6 has
been implicated in the pathogenesis of AOSD (3),
several studies have assessed the potential effect of TCZ
in patients with AOSD refractory to multiple therapies
(8–10). However, in most cases, information related to
this issue is based on small series or case reports.
Therefore, the aim of the current study was to evaluate
the efficacy of TCZ in a large series of patients with
AOSD refractory to other treatments.
PATIENTS AND METHODS
Patients and study protocol. We conducted a retrospective, open-label, multicenter study that included 34 patients with AOSD. All patients had previously received standard synthetic immunosuppressive drugs and in some cases
other biologic agents. TCZ treatment was prescribed due to
lack of efficacy and/or adverse events associated with previous
treatments. AOSD was diagnosed at the rheumatology units of
21 Spanish referral centers according to the criteria described
by Yamaguchi et al (11). Other diseases were excluded.
Before the initiation of TCZ treatment, the presence
of infections, including hepatitis B or hepatitis C virus infections, was excluded using clinical examination and serologic
tests. In all patients, latent tuberculosis was also ruled out by
tuberculin (purified protein derivative) skin testing and/or
QuantiFeron assay and chest radiography. Because AOSD is
an off-label indication for TCZ, a written informed consent
form approved for each hospital was requested and obtained
from each patient prior to the onset of TCZ treatment. Data
registered by each investigator were reviewed according to a
protocol agreed upon beforehand that included the collection
of relevant information on the patients.
Clinical definitions. The medical records were reviewed according to a previously established protocol. According to that protocol, fever was defined as a body temperature
of #38°C in the previous week of the assessment period.
Joint symptoms included arthralgia and/or arthritis. Cutaneous
rash was considered to be present if patients had a salmon-pink
macular or maculopapular eruption predominantly on the
trunk and extremities. Hepatomegaly and splenomegaly were
confirmed by ultrasonography or computed tomography.
Lymphadenopathy was defined as the presence of enlarged
TOCILIZUMAB IN AOSD REFRACTORY TO STANDARD TREATMENT
lymph nodes at #2 different sites. A diagnosis of pericarditis
was made if the patient presented with chest pain and had
pericardial rub or an effusion documented by echocardiography. Pleuritis was identified by the presence of pleuritic pain
and pleural effusion. Clinical manifestations were considered
to be improved if resolution of these manifestations occurred
during the extended followup period.
Laboratory data. According to the study protocol,
information on routine laboratory markers of disease activity,
including complete blood cell count, erythrocyte sedimentation rate (ESR), CRP level, serum levels of ferritin and
creatinine, liver enzymes, proteinuria, and hematuria, was
collected. Anemia was defined as a hemoglobin level of $11
gm/dl. Leukocytosis was defined as a white blood cell count of
#11,000/mm3. The ESR was considered to be increased when
it was !20 mm/hour in men or !25 mm/hour in women. An
elevated CRP level was defined as !0.5 mg/dl, and a high
serum level of ferritin was defined as #200 ng/ml. The effect of
TCZ on variables other than clinical manifestations, such as
the leukocyte count and hemoglobin level, the ESR, CRP and
ferritin levels, and the daily prednisone dose, was also assessed.
Values for these variables at baseline were compared with
those at 1 month, 3 months, 6 months, and 12 months. In
addition, clinical and laboratory data from the last visit were
assessed.
Data collection. Data were first reviewed and then
analyzed in an attempt to assess the following: clinical and
laboratory data, therapies used in the management of AOSD
(including those given to patients before the onset of TCZ
treatment), response to previous biologic therapy, and adverse
events. This information was extracted from the patients’
clinical records, reviewed for confirmation of the diagnosis,
and stored in a computerized file according to a protocol
established beforehand and agreed upon by researchers. To
minimize entry error, all of the data were double-checked.
Statistical analysis. Statistical analysis was performed
using StatSoft Statistica software. Results are expressed as the
mean " SD for variables with a normal distribution or as the
median (range) or interquartile range (IQR) for variables with
a non-normal distribution. Continuous variables were compared using Wilcoxon’s signed rank test.
RESULTS
Thirty-four patients (26 women and 8 men) with
AOSD who received TCZ therapy were studied. The
mean age of the patients at the onset of TCZ treatment
was 38.7 " 16.1 years (range 16–74 years), and the
median duration of AOSD before the initiation of TCZ
treatment was 4.2 years (IQR 1–9 years). Prior to
receiving TCZ, in addition to receiving corticosteroids,
all of the patients had been treated with traditional
synthetic immunosuppressive drugs, and 17 (50%) of
them had received other biologic therapies (Table 1).
TCZ was prescribed as monotherapy (15 cases)
or in combination with other traditional synthetic immunosuppressive drugs (19 cases), usually methotrex-
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Table 1. Main features of the 34 patients with conventional
treatment–refractory adult-onset Still’s disease treated with tocilizumab (TCZ)*
Age, mean " SD (range) years
No. men/no. women
Disease duration before TCZ, median (IQR)
years
Immunosuppressive treatment before TCZ
Nonbiologic
Methotrexate
Leflunomide
Cyclosporin A
Sulfasalazine
Cyclophosphamide
Mycophenolate mophetil
Biologic
Anakinra
Etanercept
Adalimumab
Rituximab
Infliximab
Abatacept
Concomitant treatment with TCZ at baseline
Corticosteroids
Methotrexate
Hydroxychloroquine
TCZ dosage
Baseline
8 mg/kg every 4 weeks
6 mg/kg every 4 weeks
4 mg/kg every 4 weeks
8 mg/kg every 2 weeks
After 1 year
8 mg/kg every 4 weeks
6 mg/kg every 4 weeks
4 mg/kg every 4 weeks
8 mg/kg every 2 weeks
38.7 " 16.1 (16–74)
8/26
4.2 (1–9)
31 (91.2)
5 (14.7)
2 (5.9)
2 (5.9)
1 (2.9)
1 (2.9)
14 (41.2)
7 (20.6)
7 (20.6)
6 (17.6)
4 (11.8)
2 (5.9)
22 (64.7)
18 (52.9)
1 (2.9)
22 (64.7)
0 (0)
2 (5.9)
10 (29.4)
17 (50.0)
4 (11.8)
3 (8.8)
10 (29.4)
* Except where indicated otherwise, values are the number (%).
IQR # interquartile range.
ate (Table 1). The initial intravenous TCZ dosage was
8 mg/kg every 4 weeks (22 cases), 8 mg/kg every 2 weeks
(10 cases), and 4 mg/kg every 4 weeks (2 cases). The
maintenance dosage of TCZ was 4–8 mg/kg every 2
weeks or every 4 weeks (Table 1).
At the onset of TCZ treatment, the most frequent clinical features were joint manifestations (33
cases), fever (20 cases), cutaneous rash (18 cases),
lymphadenopathy (10 cases), splenomegaly (2 cases),
hepatomegaly (3 cases), pleuritis (1 case), and pericarditis (2 cases). Most patients had abnormal laboratory
values at baseline, including anemia (15 cases), leukocytosis (19 cases), a high CRP level (28 cases), and an
increased ESR (27 cases) (Table 2). Nevertheless, most
patients experienced improvement in both clinical manifestations and laboratory abnormalities following TCZ
therapy; such improvement was already clinically evident
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ORTIZ-SANJUÁN ET AL
Table 2. Clinical manifestations and laboratory parameters at baseline and following tocilizumab therapy in the patients with adult-onset Still’s
disease refractory to previous immunosuppressive drugs*
Clinical manifestations
Joint manifestations
Fever
Cutaneous manifestations
Lymphadenopathy
Splenomegaly and/or hepatomegaly
Pleuritis and/or pericarditis
Laboratory parameters
Hemoglobin, mean " SD gm/dl
Anemia
Leukocyte count, mean " SD mm3
Leukocytosis
CRP, median (IQR) mg/dl
High CRP level
ESR, median (IQR) mm/hour
High ESR
Ferritin, median (IQR) ng/ml
High serum ferritin level
Baseline
(n # 34)
Month 1
(n # 34)
Month 3
(n # 34)
Month 6
(n # 34)
Month 12
(n # 32)
97.1
58.8
58.8
29.4
11.8
8.8
67.6
5.9
5.9
11.8
6.25
0
44.1
5.9
5.9
0
0
0
26.5
5.9
5.9
0
0
0
32.4
5.9
5.9
0
0
0
11.9 " 1.4
44.1
13,534.2 " 6,022.8
55.9
8.9 (3.9–23.2)
82.4
52 (45–69)
79.4
480 (200–808)
47.1
12.9 " 1.2
14.7
8,983.1 " 4,549.6
26.5
0.2 (0.1–1.6)
29.4
4 (2–12)
8.8
239 (39–358)
17.7
13.3 " 1.1
11.8
8,044.2 " 4,359.9
17.6
0.1 (0.01–0.7)
8.8
4 (2–9)
0
100 (73–132)
2.9
13.3 " 1.3
8.9
7,579.2 " 3,587.8
11.8
0.2 (0.01–0.9)
20.6
4 (2–8)
2.9
107 (53–187)
5.9
14 " 1.3
2.9
8,682.9 " 3,658.2
17.6
0.2 (0.03–1.1)
23.5
2 (2–12)
2.9
90 (63–115)
2.9
* Except where indicated otherwise, values are the percent of patients. CRP # C-reactive protein; IQR # interquartile range; ESR # erythrocyte
sedimentation rate.
at month 1. This good response to TCZ was maintained
over time (Table 2 and Figure 1).
After 1 year of TCZ therapy, the incidence of
joint manifestations had decreased from 97.1% at base-
Figure 1. Rapid improvement following the initiation of tocilizumab therapy and maintenance of improvement over 12 months. A, Leukocyte counts
(black line) and hemoglobin levels (shaded line). B, C-reactive protein (CRP) levels (black line) and erythrocyte sedimentation rates (ESRs) (shaded
line). C, Ferritin levels. D, Corticosteroid-sparing effects. Values in A are the mean " SD; values in B–D are the median (interquartile range).
! # P $ 0.05 versus basal.
TOCILIZUMAB IN AOSD REFRACTORY TO STANDARD TREATMENT
line to 32.4%, the incidence of both cutaneous manifestations and fever had decreased from 58.8% to 5.9%,
and the incidence of lymphadenopathy had decreased
from 29.4% to 0%. The frequency of abnormally elevated CRP levels and ESRs decreased from 82.4% to
23.5% and from 79.4% to 2.9%, respectively. The incidence of leukocytosis also decreased, from 55.9% at
baseline to 17.6% at 1 year, the incidence of anemia
decreased from 44.1% to 2.9%, and the incidence of
high serum levels of ferritin decreased from 47.1% to
2.9% (Table 2). Interestingly, after 1 year of TCZ
therapy, the median dosage of prednisone had decreased from 13.8 mg/day (IQR 5–45) at the onset of
TCZ treatment to 2.5 mg/day (IQR 0–30). There was
also a significant corticosteroid-sparing effect when the
basal dose of prednisone was compared with the doses
administered at 1 month (P # 0.01), 3 months (P $
0.01), 6 months (P $ 0.01), and 12 months (P # 0.01),
respectively (Figure 1).
After a median followup of 19 months (IQR
12–31 months), infections were the most common complications related to TCZ therapy. Nevertheless, TCZ
had to be permanently discontinued in only 2 patients,
both of whom had severe infections. One of these
patients had pyelonephritis and acute enterocolitis, and
the other had bacterial spondylodiscitis with an abscess
in the psoas muscle caused by Staphylococcus aureus.
Nevertheless, full recovery following antibiotic treatment was achieved in both patients. Other infections
attributed to TCZ were pneumonia (1 case), upper
respiratory tract infection (3 cases), dental infection
(1 case), urinary infection (1 case), Epstein-Barr virus
infection (1 case), and herpes zoster virus infection
(1 case). Other minor side effects were mild leukopenia
or neutropenia (4 cases), elevated hepatic enzyme levels
during TCZ treatment (4 cases), hypercholesterolemia
that required statin therapy in 1 patient who had normal
cholesterol levels before the initiation of TCZ treatment, and headache associated with TCZ infusion in
another patient.
DISCUSSION
In this multicenter observational study, we observed that TCZ treatment resulted in rapid clinical and
laboratory improvement that was maintained over time,
even in patients with AOSD refractory to treatment with
other biologic agents. First-line therapy in AOSD is
based on corticosteroids, which often requires high
doses for a long period of time, with the subsequent risk
of side effects. In an attempt to provide a corticosteroidsparing effect, different medications such as metho-
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trexate, azathioprine, intravenous immunoglobulin, anakinra, and anti-TNF! agents have been used in patients
with AOSD. All of them have shown variable results
without being exempt from side effects.
The rationale for the use of the anti–IL-6 receptor antibody TCZ in AOSD is based on our understanding of the role of IL-6 in this disease and experience with
TCZ in the treatment of RA (6,12). IL-6 is a pleiotropic
cytokine involved in production of immunoglobulins,
B cell differentiation, T cell growth and cytotoxic T cell
differentiation, macrophage differentiation, modulation
of hematopoiesis, and stimulation of hepatocytes to
produce acute-phase proteins such as CRP. Overproduction of IL-6 can explain major symptoms of AOSD,
inducing fever, leukocytosis, thrombocytosis, acutephase reactant production, and bone resorption. Furthermore, high levels of IL-6 have been observed in the
blood of patients with AOSD and have been shown to
correlate with disease activity (3).
TCZ is a humanized monoclonal antibody that
binds to the cell receptor for IL-6 and has demonstrated
efficacy in patients with RA (13). Additionally, randomized placebo-controlled trials also demonstrated the
efficacy of TCZ in systemic JIA, an entity that shows
some similarities with AOSD (7).
TCZ has been used in cases of treatmentrefractory AOSD, with promising results; however, the
number of cases reported is still small (8–10). To the
best of our knowledge, 2 small series of patients with
conventional treatment–refractory AOSD who received
therapy with TCZ have been reported. One of these
studies assessed 14 patients (8), and the other assessed
11 patients (14). In both series, the patients were
followed up for 6 months.
In the current report, we present data on 34
patients with AOSD who were followed up for a median
of 19 months. In keeping with previous series (8,14), a
high number of our patients had received other synthetic
immunosuppressive agents (Table 1). Moreover, in
many of these patients, AOSD had also been refractory
to treatment with biologic agents such as anakinra or
anti-TNF! (Table 1). As in our series, the patients
described by Puechal et al (8) and Elkayam et al (14)
received variable dosages of TCZ (4–8 mg/kg every 2, 4,
or 8 weeks). In this regard, although the dosage of TCZ
in RA or systemic JIA is well established (6,7), there is
no consensus on the dosage of TCZ that should be given
to patients with AOSD.
We believe that patients with AOSD in whom
disease is very active, as manifested by a high inflammatory burden, may need a higher dosage of TCZ. In our
series, two-thirds of the patients (n # 22) received an
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initial TCZ dosage of 8 mg/kg every 4 weeks, but 10
patients received an initial dosage of 8 mg/kg every 2
weeks. This higher dosage (8 mg/kg every 2 weeks)
is used in systemic JIA. Thus, even in children with
JIA who weigh $30 kg, the recommended dosage is
12 mg/kg every 2 weeks (7).
During the followup period in our series, some
patients required an increase in the dosage, while the
dosage was reduced in others depending on efficacy and
side effects (Table 1). Regardless of whether TCZ was
combined with methotrexate, we observed a nonsignificant trend toward greater improvement in patients who
received a higher or more frequent dose of TCZ compared with the remaining patients. However, the difference was not statistically significant (data not shown).
In most cases, improvement in clinical and laboratory parameters was observed at the time of the first
available analysis of data (1 month after the onset of
TCZ therapy). Of note, improvement was also observed
at 3, 6, and 12 months. The significant reductions in the
CRP level and the ESR following the initiation of TCZ
treatment were especially remarkable. This finding was
consistent with previous reports that also described a
reduction of these acute-phase reactants after 3 months
or 6 months of TCZ treatment (8,14). Rapid improvement in systemic symptoms such as fever and cutaneous
manifestations was also observed in our series. This was
also described in a review article by de Boysson et al
(15), which showed clinical and laboratory improvement
in 27 of 28 patients (96%). However, it is well known
that joint manifestations in patients with AOSD may be
more refractory to treatment compared with systemic
manifestations. This was also the case in our series,
because 32.4% of patients had persistent joint involvement after 1 year of TCZ therapy. In accordance with
our results, Puechal et al (8) reported improvement in
joint manifestations (European League Against Rheumatism Response Criteria [Disease Activity Score in 28
joints of $2.6]) (16) in only 36% and 57% of patients
after 3 months and 6 months of TCZ therapy, respectively.
In our series, TCZ also had a significant corticosteroid-sparing effect. The prednisone dosage was reduced significantly during TCZ therapy (Figure 1). This
is especially important in patients with chronic AOSD
and those whose disease is refractory to conventional
drugs, because these patients receive an inappropriately
high cumulative dose of corticosteroids, leading to a
high risk of side effects. TCZ was relatively safe in our
series, with only 2 patients having to discontinue treatment due to severe infection. Other minor side effects
ORTIZ-SANJUÁN ET AL
such as mild leukopenia and neutropenia and increased
levels of hepatic enzymes were transient, and discontinuation of TCZ was not required.
To the best of our knowledge, this is the largest
series of TCZ-treated patients with AOSD refractory to
conventional immunosuppressive drugs and, in some
cases, to other biologic therapies. TCZ treatment resulted in rapid and maintained clinical and laboratory
improvement in these patients. Although TCZ showed
global efficacy, joint manifestations were more refractory to treatment than were systemic manifestations.
The efficacy and safety of TCZ in AOSD should be
assessed in prospective controlled clinical trials.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved
the final version to be published. Drs. Blanco and González-Gay had
full access to all of the data in the study and take responsibility for the
integrity of the data and the accuracy of the data analysis.
Study conception and design. Ortiz-Sanjuán, Blanco, Calvo-Rio,
Narvaez, Romero, Olivé, Castañeda, Flores, Hernández, Mata,
Vilamajo, Giraldo, Caracuel, Freire, Arango, Llobet, Arija, Marras,
Moll-Tuduri, Plasencia-Rodriguez, Roselló, Urruticoechea, VellosoFeijoo, del Blanco, González-Vela, Rueda-Gotor, Pina, Loricera,
González-Gay.
Acquisition of data. Ortiz-Sanjuán, Blanco, Calvo-Rio, Narvaez,
Romero, Olivé, Castañeda, Flores, Hernández, Mata, Vilamajo,
Giraldo, Caracuel, Freire, Arango, Llobet, Arija, Marras, Moll-Tuduri,
Plasencia-Rodriguez, Roselló, Urruticoechea, Velloso-Feijoo, del
Blanco, González-Vela, Rueda-Gotor, Pina, Loricera, González-Gay.
Analysis and interpretation of data. Ortiz-Sanjuán, Blanco, Calvo-Rio,
Castañeda, González-Gay.
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