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Efficacy and safety of anakinra therapy in pediatric and adult patients with the autoinflammatory Muckle-Wells syndrome.

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Vol. 63, No. 3, March 2011, pp 840–849
DOI 10.1002/art.30149
© 2011, American College of Rheumatology
Efficacy and Safety of Anakinra Therapy in Pediatric and Adult
Patients With the Autoinflammatory Muckle-Wells Syndrome
Jasmin B. Kuemmerle-Deschner,1 Pascal N. Tyrrell,2 Ina Koetter,1 Helmut Wittkowski,3
Anja Bialkowski,1 Nicolai Tzaribachev,1 Peter Lohse,4 Assen Koitchev,1 Christoph Deuter,1
Dirk Foell,3 and Susanne M. Benseler2
activity were investigated using descriptive statistics
and paired comparative analysis.
Results. A total of 12 patients with severe MWS
(5 children and 7 adults) received anakinra for a
median of 11 months (range 5–14 months). The median
followup was 11 months (range 5–14 months). Disease
activity was significantly lower in all patients at 2 weeks
(P ⴝ 0.0005). Organ manifestations of MWS improved,
as did all patient-derived measures of health status,
markers of inflammation, and hearing loss in 2 of the
patients. Levels of the novel neutrophil activation biomarker S100A12 followed clinical disease activity.
Treatment was well tolerated, and no serious adverse
events were observed.
Conclusion. Anakinra was found to be a safe and
effective treatment of severe MWS, leading to a significant improvement in disease activity at 2 weeks as well
as long-term. Anakinra therapy should therefore be
considered in children and adults with severe MWS
disease requiring IL-1 blockade.
Objective. Muckle-Wells syndrome (MWS) is an
inherited autoinflammatory disease caused by mutations in the NLRP3 gene that result in excessive
interleukin-1 (IL-1) release. It is characterized by severe
fevers, rashes, arthralgia, and conjunctivitis, leading to
sensorineural deafness and amyloidosis. The recombinant IL-1 receptor antagonist anakinra blocks the biologic activity of IL-1. The aim of this study was to
determine the short- and long-term efficacy and safety
of anakinra therapy in children and adults with severe
Methods. A single-center observational study was
performed. Standardized assessments included clinical
features, the Disease Activity Score (DAS) for MWS,
classic and novel markers of inflammation, and patientderived measures of health status. The primary outcome
was a score of <10 on the DAS for MWS at 2 weeks and
at the last followup visit. Measures of MWS disease
Dr. Foell’s work was supported by the IKZF at the University
of Muenster (project Foe 2/005/06) and by the DFG (project FO
Jasmin B. Kuemmerle-Deschner, MD, Ina Koetter, MD,
Anja Bialkowski, MD, Nicolai Tzaribachev, MD, Assen Koitchev, MD,
PhD, Christoph Deuter, MD: University Hospital Tübingen, Tübingen, Germany; 2Pascal N. Tyrrell, MSc, Susanne M. Benseler, MD:
The Hospital for Sick Children, and University of Toronto, Toronto,
Ontario, Canada; 3Helmut Wittkowski, MD, Dirk Foell, MD: University of Muenster, Muenster, Germany; 4Peter Lohse, MD: University
of Munich, Munich, Germany.
Dr. Koetter has received consulting fees, speaking fees,
and/or honoraria from Abbott, Roche, Chugai, Wyeth, Essex, UCB,
Bristol-Myers Squibb, and Pfizer (less than $10,000 each). Dr. Tzaribachev has received consulting fees, speaking fees, and/or honoraria
from Pfizer and MSD (less than $10,000).
Address correspondence to Jasmin B. Kuemmerle-Deschner,
MD, Division of Pediatric Rheumatology, Department of Pediatrics,
University Children’s Hospital Tübingen, Hoppe-Seyler Strasse 1,
72076 Tübingen, Germany. E-mail:
Submitted for publication February 19, 2010; accepted in
revised form November 4, 2010.
Muckle-Wells syndrome (MWS) is an inherited
autoinflammatory disease that belongs to the group of
cryopyrin-associated periodic syndromes (CAPS). At
the molecular level, CAPS are characterized by mutations in the NLRP3/CIAS1 gene, which encodes the
protein cryopyrin (1). The clinical phenotype of CAPS
encompasses the mild familial cold autoinflammatory
syndrome (FCAS), the moderately severe MWS, and the
devastatingly severe neonatal-onset multisystem inflammatory disease (NOMID), which is also known as
chronic infantile neurologic, cutaneous, articular
(CINCA) syndrome (2,3).
Patients with MWS commonly present with acute
attacks of fever, rash, musculoskeletal symptoms, and
conjunctivitis. These characteristic features occur episodically and can last between 1 day and 2 weeks. The
MWS-associated rash can be cold-induced, urticarial, or
erythematous. Musculoskeletal symptoms include arthralgia, arthritis, and myalgia. Conjunctivitis and progressive sensorineural hearing loss are the pathognomonic clinical findings that support the diagnosis of
MWS (4). Constitutional features of severe, persistent
fatigue are commonly found and have a significant
impact on the quality of life. Sequelae of MWS may
include deafness and amyloidosis, requiring renal transplantation. Markers of inflammation are commonly elevated, particularly during fever episodes (5).
The NLRP3 mutations underlying MWS result in
an altered function of the gene product cryopyrin, which
is essential for the activation of intracellular caspase 1
and the processing of interleukin-1␤ (IL-1␤) (6–9).
Macrophages from MWS patients show a constitutively
increased production of IL-1␤ (3,10,11). Excessive
amounts of IL-1␤ lead periodically to the characteristic
inflammatory features of MWS. Case reports and small
case series have demonstrated the efficacy of IL-1
inhibition with the IL-1 receptor antagonist (IL-1Ra)
anakinra (5). Anakinra is a recombinant, nonglycosylated form of the human IL-1Ra. It blocks the biologic
activity of IL-1 by competitively binding to the IL-1
receptor type I (IL-1RI), which is expressed on a wide
variety of tissues (12). However, no standardized assessment of the long-term efficacy, safety, and use of
anakinra in pediatric patients has been reported so far.
The aims of this study were therefore 1) to
describe a cohort of MWS patients with a severe disease
course requiring IL-1 blockade, 2) to report the shortterm efficacy of treatment with the IL-1Ra anakinra in
MWS patients, and 3) to determine the long-term
response, including the effect on disease sequelae such
as hearing loss and amyloidosis, and the safety of
anakinra therapy in MWS.
Study design. A single-center open-label observational
study of anakinra therapy for consecutive patients diagnosed as
having active MWS between April 1, 2004 and December 31,
2007 was performed. Informed individual consent was obtained from all patients for DNA sequence analysis of their
NLRP3 gene. The study was approved by the Local Ethics
Committee (REB no. 326/2007B01).
Patients. Consecutive patients with MWS were eligible
for study if they met the following criteria: 1) clinical features
of active MWS requiring medical intervention and 2) carriage
of an NLRP3 mutation. Patients were excluded if they were
concurrently treated with immunomodulatory agents such as
methotrexate or had evidence of a preexisting underlying
infection or a significant medical condition(s) not related to
MWS. Female patients of child-bearing age were required to
start an effective method of contraception.
All MWS patients were followed up according to a
standardized protocol at the institutional interdisciplinary Hereditary Periodic Fevers Clinic in a tertiary care center led by
an experienced pediatric and adult rheumatologist (JBK-D
and IK). Clinical and laboratory features and disease scores
were recorded from standardized assessments obtained for all
patients at baseline, after 2 weeks and 4 weeks, and then
monthly thereafter.
Demographics and family history. Demographic information included sex, ethnicity, age at diagnosis and at start of
anakinra therapy, and duration of followup. Family history
assessment determined parental consanguinity and identified
family members diagnosed as having autoinflammatory syndromes and a history of possible organ involvement, such as
hearing loss.
Clinical characteristics. Review of systems included
constitutional symptoms of fever (pattern and duration) and
fatigue. Organ-specific clinical characteristics, such as headache, ocular symptoms (conjunctivitis, uveitis, optic disk
edema, etc.), sensorineural hearing loss, oral ulcers, abdominal
pain, arthralgia, arthritis, myalgia, and skin symptoms, including erythematous and cold-induced rashes, were evaluated.
Associated conditions, disease complications, and sequelae,
including hearing impairment or loss, renal impairment, or
delayed puberty, also were recorded.
Disease Activity Score (DAS) for MWS. The previously
developed DAS for MWS captures active disease in 10 domains: 9 domains reflect the organ involvement in MWS
(fever, headache, eye involvement, hearing impairment, oral
ulcers, abdominal pain, renal disease, musculoskeletal disease,
and rash), and the tenth is the patient’s global assessment score
(13). The DAS for MWS assigns 0, 1, or 2 points to each level
of disease activity: 2 points for severe symptoms, 1 point for
mild symptoms, and 0 points for absence of symptoms in each
domain (maximum possible score 20). As previously determined, a score of ⬍10 points reflects overall mild activity,
whereas a score of ⱖ10 points reflects severe activity of the
Global measures of disease activity. Three patientderived measures of health were determined at each visit: 1)
patient’s global assessment, which was scored using a 10-cm
visual analog scale (VAS), where 0 represents no disease
activity and 10 represents maximum disease activity; 2) patient’s mood score, which was recorded on a 3-point Likert
scale, where 1 represents excellent mood and 3 represents the
lowest mood possible; and 3) patient’s performance score,
which was scored using a 10-cm VAS, where 0 represents
inability to perform and 10 represents the best possible performance level. The physician’s global assessment, which was
scored using a 10-cm VAS, where 0 represents no disease
activity and 10 represents maximum disease activity, was also
recorded at each visit.
Laboratory measures and additional tests. Standardized laboratory testing of blood, serum, and urine was conducted at each visit. Classic markers of inflammation assessed
were the erythrocyte sedimentation rate (ESR) and C-reactive
protein (CRP). Hematologic assessments included a complete
blood cell count with differential cell count, neutrophil count,
hemoglobin value, and platelet count. Novel MWS biomarkers
assessed were serum amyloid A (SAA), IL-1␤, IL-6, and tumor
necrosis factor ␣ (TNF␣), as well as the serum concentration
S100A12, as determined by enzyme-linked immunosorbent
assay (14). Assessments of renal function included serum levels
of creatinine, urea, and uric acid, a standard urinalysis, a urine
dipstick test for blood and albumin levels, a spot urine
collection for protein levels (␣1-microglobulin and ␤2microglobulin), and a 24-hour urine collection for creatinine
and protein levels. In addition, creatinine clearance and the
protein-to-creatinine ratio were calculated.
Audiologic assessment. A clinical examination and an
audiogram were performed prior to initiation of anakinra and
every 6 months thereafter to evaluate hearing status. The
audiologic examination included an air-conduction threshold
for pure tone frequencies of 250–8,000 Hz, bone conduction
threshold, and tympanometry. Hearing was graded on a scale
of 0–4, where 0 ⫽ normal (ⱕ20% hearing loss), 1 ⫽ mild
impairment (⬎20–40% hearing loss), 2 ⫽ moderate impairment (⬎40–60% hearing loss), 3 ⫽ severe impairment (⬎60–
80% hearing loss), and 4 ⫽ profound deafness (⬎80% hearing
loss). Percentages of hearing loss were calculated from the
measurements of pure tone audiologic threshold (15).
Ophthalmologic examination. A standardized ophthalmologic evaluation was performed prior to initiation of anakinra, at 2 weeks, and every 6 months thereafter. Emphasis was
on visual changes as sensitive indicators of optic nerve function, conjunctivitis, and uveitis.
Magnetic resonance imaging (MRI). A gadoliniumenhanced MRI of the brain and inner ear was performed prior
to the start of anakinra therapy and then every 12 months
thereafter. Inflammatory changes affecting the meninges and
the inner ear were the primary focus of the MRI.
Scintigraphic scan for amyloidosis. In all patients with
amyloidosis diagnosed by renal biopsy, a scintigraphic scan for
amyloidosis was performed with 123I-labeled serum amyloid P
component (16).
Treatment. All MWS patients were treated with the
chimeric monoclonal IL-1Ra anakinra (Kineret; Amgen).
Anakinra was administered at doses of 1–2 mg/kg in patients
weighing ⬍40 kg and 100 mg for patients weighing ⱖ40 kg. The
drug was self-administered by subcutaneous injection once a
day. In children with persistent disease activity, the anakinra
dose was increased stepwise to a maximum of 8 mg/kg.
Concurrent treatment with a nonsteroidal antiinflammatory
drug was added if required.
Outcomes. The primary study outcome was response
to anakinra therapy at 2 weeks of treatment. A good response
was defined as control of the MWS disease activity, with a
DAS for MWS of ⬍10 at 2 weeks.
Secondary outcomes included efficacy at the primary
study end point (2 weeks) and long-term efficacy. To determine efficacy at the primary study end point, the following
parameters were assessed: the disease activity in all single
domains of the DAS for MWS, the patient-derived and
physician-derived global measures of disease activity and overall health, the classic markers of inflammation, and the novel
biomarkers at 2 weeks. To determine long-term efficacy, the
following parameters were assessed: the overall response, as
Table 1. Baseline characteristics, disease activity, and followup of the patients with MWS*
No. male/female
Age, median (range) years
At diagnosis of MWS
At start of anakinra therapy
Pediatric MWS patients
No. of pediatric patients receiving anakinra therapy
No. male/female
Age at start of anakinra therapy, median (range) years
Adult MWS patients
No. of patients ⱖ18 years old at start of anakinra therapy
No. male/female
Age at start of anakinra therapy, median (range) years
Ethnicity, no. (%) Caucasian
NALP3 mutation, no. (%) of patients
Patients with confirmed mutation
Mutation subtype
MWS disease activity at diagnosis, no. (%)
Mild (⬍10 on the DAS for MWS)
Severe (ⱖ10 on the DAS for MWS)
Followup, median (range) months
Total followup
Followup after start of anakinra therapy
Total MWS population at
study center (n ⫽ 21)
Anakinra-treated MWS inception
cohort (n ⫽ 12)
33.5 (3.0–72)
19.1 (3.0–65.5)
21.0 (3.0–66.9)
6.4 (3.0–15.3)
21 (100)
39.0 (20.6–66.9)
12 (100)
21 (100)
12 (100)
13 (62)
3 (14)
5 (24)
7 (58)
3 (25)
2 (17)
5 (24)
16 (76)
0 (0)
12 (100)
51 (22–114)
51 (22–114)
11 (5–14)
* MWS ⫽ Muckle-Wells syndrome; NA ⫽ not applicable; DAS ⫽ Disease Activity Score.
Table 2. Clinical efficacy of anakinra therapy in the patients with MWS*
Last followup
(n ⫽ 12)
Baseline vs. study
end point
Baseline vs. last
6 (50)
0 (0)
1 (8)
10 (83)
12 (100)
11 (92)
2 (17)
0 (0)
10 (83)
10 (83)
6 (50)
9 (75)
7 (58)
2 (17)
1 (8)
12 (100)
12 (100)
8 (67)
6 (50)
8 (67)
8 (67)
1 (8)
2 (17)
1 (8)
1 (8)
0 (0)
0 (0)
10 (83)
1 (8)
3 (25)
4 (33)
4 (33)
0 (0)
1 (8)
0 (0)
0 (0)
0 (0)
0 (0)
1 (8)
1 (8)
0 (0)
1 (8)
4 (33)
4 (33)
1 (8)
0 (0)
9 (75)
1 (8)
1 (8)
3 (25)
2 (17)
0 (0)
1 (8)
3 (25)
3 (25)
0 (0)
0 (0)
2 (17)
2 (17)
0 (0)
12.8 ⫾ 2.2
3.2 ⫾ 1.0
3.9 ⫾ 3.2
6.3 ⫾ 2.0
2.2 ⫾ 0.5
5.9 ⫾ 2.1
7.3 ⫾ 1.1
2.8 ⫾ 1.6
1.8 ⫾ 0.6
8.2 ⫾ 1.6
1.9 ⫾ 1.3
2.5 ⫾ 0.8
1.4 ⫾ 0.5
8.3 ⫾ 1.2
1.9 ⫾ 1.1
2 (17)
1 (8)
1 (8)
1 (8)
1 (8)
(n ⫽ 12)
Constitutional symptoms, no. (%)
MWS symptoms by organ system, no. (%)
Ocular symptoms
Optic disk edema
Sensorineural hearing loss
Oral ulcers
Abdominal pain
Renal disease
Renal failure
Musculoskeletal symptoms
Skin symptoms
Erythematous rash
Cold-induced rash
Disease activity, mean ⫾ SD
Global measures of health status, mean ⫾ SD
Patient-derived global measures
Patient’s global assessment, by 10-cm VAS
Patient’s mood score, by 3-point Likert scale
Patient’s performance score, by 10-cm VAS
Physician’s global assessment, by 10-cm VAS
Sequelae, no. (%)
Delay of puberty
Study end
(n ⫽ 12)
* The primary study end point was 2 weeks. The median followup was 11 months (range 5–14 months). P values less than 0.05 were considered
significant. MWS ⫽ Muckle-Wells syndrome; NS ⫽ not significant; NA ⫽ not applicable; DAS ⫽ Disease Activity Score; VAS ⫽ visual analog scale;
ND ⫽ not done.
determined by the DAS for MWS and its single domains, the
patient-derived and physician-derived global measures, and
the classic and novel markers of inflammation at the last
followup visit at a median of 11 months (range 5–14 months).
In addition, MWS sequelae, including delayed puberty and
amyloidosis, were evaluated. Treatment safety assessments
included adverse events and severe adverse events. Adverse
events captured signs of local injection reaction, local and
systemic infections, and organ disease. Severe adverse events
were defined as signs and symptoms requiring hospitalization
or as death.
Statistical analysis. Demographic characteristics, clinical and laboratory measures, scores for the different domains
of the DAS for MWS, and patient-derived and physicianderived measures of health (by VAS) were collected in a
designated Arthritis and Rheumatology Documentation and
Information System (ARDIS) research database. Summary
statistics were determined. Comparisons were made for each
variable at baseline and at the primary study end point using
paired analysis: McNemar’s exact test for categorical variables
and Student’s paired t-test or Wilcoxon’s signed rank test,
when appropriate, for continuous variables. P values less than
0.05 were considered significant. All analyses were performed
with SAS for Windows software, version 9.3 (SAS Institute).
Patient characteristics. A total of 21 Caucasian
patients (9 males and 12 females) with the clinical
diagnosis of MWS and an underlying NLRP3 exon 3
mutation were included in the study. The patients came
from 4 different families; all had a family history of
MWS. The median age at diagnosis was 33.5 years
(range 3.0–72 years) (Table 1).
Study inception cohort. Of the 21 MWS patients,
16 (76%) had severe disease activity, and 4 of these 16
patients were excluded from the study: 1 required dia-
Table 3. Laboratory findings in MWS patients treated with anakinra*
Classic markers of inflammation
No. (%) with elevated ESR
Mean ⫾ SD ESR, mm/hour (normal ⬍22)
No. (%) with elevated CRP
Mean ⫾ SD CRP, mg/dl (normal ⬍0.5)
Hematologic abnormalities
No. (%) with leukocytosis
Mean ⫾ SD leukocytes/␮l (normal 4-10)
No. (%) with neutrophilia
Mean ⫾ SD neutrophils/␮l (normal 2.5–7.5)
No. (%) with anemia
Mean ⫾ SD hemoglobin, gm/dl (age/sex-adj.)
Novel biomarkers of inflammation
No. with elevated SAA/no. evaluated (%)
Mean ⫾ SD SAA, mg/liter (normal ⬍10)
No. with elevated IL-1␤/no. evaluated (%)
Mean ⫾ SD IL-1␤, pg/ml (normal ⬍0.5)
No. with elevated IL-6/no. evaluated (%)
Mean ⫾ SD IL-6, pg/ml (normal ⬍5)
No. with elevated TNF␣/no. evaluated (%)
Mean ⫾ SD TNF␣, pg/ml (normal ⬍8)
No. with elevated S100A12/no. evaluated (%)
Mean ⫾ SD S100A12, ng/ml (normal ⬍130)
(n ⫽ 12)
Study end
(n ⫽ 12)
Last followup
(n ⫽ 12)
9 (75)
32 ⫾ 17
1 (8)
13 ⫾ 16
2 (17)
13 ⫾ 8
11 (92)
2.11 ⫾ 1.33
5 (42)
0.87 ⫾ 1.86
3 (25)
0.44 ⫾ 0.7
5 (42)
9,906 ⫾ 2,814
1 (8)
6,949 ⫾ 1,708
0 (0)
6,016 ⫾ 1,409
1 (8)
6,918 ⫾ 3,209
0 (0)
3,930 ⫾ 1,745
0 (0)
3,506 ⫾ 1,572
3 (25)
12.7 ⫾ 2
0 (0)
13.6 ⫾ 1.4
11/12 (92)
36.5 ⫾ 26.1
4/12 (33)
27.5 ⫾ 70.5
3/12 (25)
6.6 ⫾ 5.2
7/11 (64)
1.4 ⫾ 2.4
5/7 (72)
0.8 ⫾ 0.5
7/12 (58)
15.0 ⫾ 16.0
1/12 (8)
3.2 ⫾ 3.9
5/12 (42)
9.42 ⫾ 5.1
6/12 (50)
8.8 ⫾ 4.3
6/11 (55)
240 ⫾ 172
5/11 (42)
142 ⫾ 57
5/11 (42)
273 ⫾ 330
0 (0)
13.7 ⫾ 2
Baseline vs.
study end
Baseline vs.
* The primary study end point was 2 weeks. The median followup was 11 months (range 5–14 months). P values less than 0.05 were considered
significant. MWS ⫽ Muckle-Wells syndrome; ESR ⫽ erythrocyte sedimentation rate; CRP ⫽ C-reactive protein; NS ⫽ not significant; age/sex-adj.
⫽ adjusted for age and sex; SAA ⫽ serum amyloid A; IL-1␤ ⫽ interleukin-1␤; ND ⫽ not done; TNF␣ ⫽ tumor necrosis factor ␣.
lysis, 1 had multiple sclerosis, and 2 refused the daily
subcutaneous injections. Thus, 12 patients (3 males and
9 females) were included in the inception cohort. Five
patients (42%) were children under 18 years of age, with
a median age of 6.4 years (range 3.0–15.3 years),
whereas 7 patients were adults, with a median age of
39.0 years (range 20.6–66.9 years). The median age at
diagnosis of MWS was 19.1 years (range 3.0–65.5 years).
The median age at the start of anakinra therapy was 21.0
years (range 3.0–66.5 years).
Three different NLRP3 gene mutations were
found: 7 of the 12 patients carried the E311K mutation
(17). The remaining mutations were T348M in 3 of the
12 patients (25%) and V198M in 2 (17%). The median
followup time was 51 months (range 22–114 months)
(Table 1).
Baseline characteristics. Clinical features. All patients had clinically active MWS. Severe fatigue was seen
in all patients. The most common organ system features
were musculoskeletal and ocular manifestations (Table
2). Arthralgias were present in all 12 of the patients
(100%), arthritis in 8 (67%), and myalgia in 6 (50%).
Ocular symptoms were seen in 12 patients (100%), with
conjunctivitis in 11 (92%) and anterior uveitis in 2
(17%). No optic disk edema was found in the cohort. At
baseline, hearing loss was present in 10 patients (83%).
Recurrent episodes of headache and oral ulcers were
found in 10 patients (83%). Erythematous rash independent of cold exposure was described by 8 patients (67%).
Only 1 patient had cold-induced rash (8%). Febrile
episodes were reported by 6 patients (50%), lasting an
average of 3–5 days. The maximum temperature per
episode ranged between 39°C and 40°C. A total of 6
patients (50%) experienced abdominal pain during a
disease flare. Disease sequelae were present in 3 patients: amyloidosis in 2 patients and delay of puberty in
1 female patient.
Scores on the DAS for MWS. The mean DAS for
MWS was 12.8 (maximum possible score 20) and was
therefore in the range of severe disease activity (ⱖ10
points) in all patients at baseline. All patient-derived
scores confirmed the presence of active disease. The
mean score on the patient’s global assessment was high
at 6.3 (on a 10-cm VAS). The patient’s mood score was
2.2 (on a 3-point Likert scale), reflecting poor mood, and
the patient’s performance score was low at 5.92 (on a
10-cm VAS), indicating a decreased performance level.
The physician’s global assessment score mirrored that of
the patient’s global assessment, with a high mean score
of 7.25 (on a 10-cm VAS), confirming high levels of
disease activity.
Markers of inflammation. The majority of patients
had elevated levels of the classic markers of inflammation at baseline (Table 3). ESR elevation was seen in 9
patients (75%), and the CRP was raised in 11 (92%).
Five patients had leukocytosis (42%), 3 were anemic
(25%), and 1 had neutrophilia. Levels of novel biomarkers of MWS were raised in all patients at baseline. High
serum levels of SAA were seen in 11 of the 12 patients
(92%). There were marked increases in proinflammatory cytokine levels, with increased IL-6 in 7 of the 12
patients (58%), TNF␣ in 5 of the 12 patients (42%), and
IL-1␤ in 7 of the 11 patients tested (64%). S100A12 was
elevated above the upper limit of normal (⬎120 ng/ml)
in 6 of the 11 patients tested (55%).
Efficacy of anakinra therapy. Primary outcome.
All 12 patients reached the primary study end point of 2
weeks of anakinra therapy. A good response, defined as
control of disease activity (score of ⬍10 on the DAS for
MWS), was noted in all patients. The mean DAS for
MWS at 2 weeks was 3.2, which was a statistically
significant improvement compared to baseline (P ⫽
0.0005) (Table 2).
Secondary outcomes at 2 weeks of therapy. Disease
activity in the domains of the DAS for MWS. Treatment
with anakinra led to a complete resolution of constitutional symptoms, such as fatigue and fever, in all patients
at 2 weeks. Musculoskeletal manifestations, including
arthralgias, arthritis, and myalgia, also completely resolved in all patients. Ocular symptoms in general (P ⬍
0.0001) and conjunctivitis in particular (P ⫽ 0.002) were
significantly reduced. Uveitis, which was present in only
2 patients, resolved in both. Skin manifestations of MWS
resolved in the majority of patients (P ⫽ 0.02). In
addition, there was a significant reduction of headaches
and oral ulcers. There was also a decrease in the number
of patients reporting abdominal pain. Proteinuria improved and hematuria resolved in all affected patients
(Table 2).
Patient-derived and physician-derived global
measures. All patient- and physician-derived measures
of health status significantly improved in all patients.
Scores for the patient’s global assessment of overall
disease activity decreased from 6.3 to 2.8 (P ⫽ 0.0005).
Simultaneously, the patient’s performance score increased from 5.9 to 8.2 (P ⫽ 0.05). The patient’s mood
score also decreased from 2.2 to 1.8 (P ⫽ 0.03), indicating better mood. The physician’s global assessment score
was reduced from 7.3 to 1.9 (P ⫽ 0.0005) (Table 2).
Classic markers of inflammation. Classic markers
of inflammation improved in all but 1 patient. The ESR
normalized in 11 of the 12 patients (P ⫽ 0.02). CRP
levels normalized in 5 of the 11 individuals with CRP
elevation at baseline. Only 1 patient became worse.
Hematologic abnormalities resolved in all but 1 patient
(Table 3).
Novel biomarkers of MWS. At 2 weeks of anakinra therapy, the mean levels of the novel neutrophil
activation marker S100A12 significantly decreased (P ⫽
0.05). In contrast, SAA levels improved overall but the
difference was not statistically significant (Table 3).
Long-term efficacy. Overall disease control at the
last followup visit. Ninety-two percent of the patients
experienced sustained disease control, with a score of
⬍10 on the DAS for MWS. However, there was a slight
increase from 3.2 to 3.9. One patient experienced a
disease flare, with a score of 13 on the DAS for MWS at
the last followup visit. Two children age 3.0 years and 6.4
years, respectively, required a dosage adjustment of
anakinra in order to maintain disease control. The
dosage had to be increased stepwise to 8 mg/kg/day.
Both children were found to carry the V198M mutation.
The highest score on the DAS for MWS at the last
followup was 13 and was measured in the second
youngest patient. No adjustment of the anakinra dosage
was needed in adult patients with MWS.
Disease activity in the domains of the DAS for
MWS. At the last followup visit, all but 1 patient
remained afebrile. Musculoskeletal manifestations also
remained well controlled in all but 3 patients, who
reported a recurrence of arthralgia. Ocular symptoms
were present in 5 of the 12 patients. Conjunctivitis had
recurred in 4 of the 11 patients who had this manifestation at baseline. Skin manifestations flared in 1 patient
Figure 1. Improvement in hearing loss in a 15-year-old patient with Muckle-Wells syndrome
following treatment with anakinra. Serial bilateral audiograms demonstrate a 10–30-dB improvement in the 250–4,000-Hz frequency range. Air-conducted sounds at baseline (E) and the last
followup (F) and bone-conducted sounds at baseline (䊐) and the last followup (■) were recorded.
who did not have skin manifestations at baseline. Sustained disease control was seen for headache, oral
ulcers, and renal disease, including proteinuria and
hematuria. There was a further increase in the number
of patients reporting resolution of abdominal pain.
Hearing loss subjectively resolved in 1 patient who
previously had significant hearing loss. The audiogram
demonstrated persistent, but nevertheless improved,
mild impairment in this patient (Figure 1).
Patient-derived and physician-derived global
measures. All global measures of health status further
improved at the last followup visit in all patients. The
score on the patient’s global assessment of overall
disease activity decreased from 2.8 at 2 weeks to 2.5 at
last followup. The patient’s mood score also decreased,
from 1.8 to 1.4, indicating improved mood. The patient’s
performance score remained stable at 8.2. The physician’s global assessment confirmed stable disease control (Table 2).
Classic markers of inflammation. Values for the
classic markers of inflammation remained stable at the
last followup visit. There was a slight increase in
the number of patients with an elevated ESR; however,
the mean value for the ESR was stable at 13 mm/hour.
CRP levels further improved compared to the 2-week
primary end point and normalized in the majority of
patients. Hematologic abnormalities completely resolved in all patients (Table 3).
Novel biomarkers of MWS. Mean SAA levels
further decreased from 27.5 mg/liter to 6.6 mg/liter.
Simultaneously, the proinflammatory cytokine levels significantly decreased. The S100A12 concentration, in
contrast, increased compared to the 2-week assessment,
reaching and exceeding baseline levels (Table 3).
Sequelae of MWS. Amyloidosis, which was confirmed by kidney biopsy in 2 patients at baseline, resolved in one and improved in the other, as documented
by repeat scintigraphic scans (data not shown). Delayed
puberty in 1 patient had resolved at the time of the last
followup visit. Sensorineural hearing loss was documented in 10 of the 12 patients at baseline, and improved in 2 patients with treatment. It completely resolved in one patient and significantly improved in the
other. In the latter individual, initial hearing impairment
was found to be the most severe (grade 4). Subsequent
testing revealed only grade 3 impairment. Hearing loss
became worse during anakinra treatment in 2 patients:
from grade 1 to grade 2 in one and from grade 2 to grade
3 in the other.
Safety. Overall, anakinra therapy was well tolerated. There were no serious adverse events during the
study period. Adverse events included mild injection site
reactions in 5 patients (42%), mild infections in 5 (42%),
and hyperactivity and weight gain in 4 patients each
Our study determined the short- and long-term
efficacy and safety of anakinra therapy in children and
adults with genetically confirmed MWS. All 12 patients
included in this observational cohort had severe MWS
requiring IL-1 blockade. Patients were followed up in a
designated periodic fever clinic according to a standard-
ized protocol. Clinical features as well as classic and
novel markers of inflammation were evaluated at defined intervals. Anakinra proved to be efficacious and
safe in all MWS patients studied, with a rapid clinical
response after only 2 weeks. At the primary end point (2
weeks), anakinra therapy resulted in complete resolution of fever, fatigue, and musculoskeletal symptoms. In
fact, the vast majority of MWS organ manifestations had
resolved. The mean DAS for MWS also significantly
improved, reflecting excellent disease control. The treatment response was sustained in the majority of patients,
as documented at the last followup visit. Disease sequelae, including hearing loss and amyloidosis, were
shown to be reversible in individual patients. All patientderived measures of disease activity, mood, and performance improved significantly at 2 weeks as compared to
baseline and, at the last followup visit, had continued to
The short-term efficacy of anakinra was documented after 2 weeks of therapy. Rapid resolution of all
constitutional symptoms, most importantly, the diseaseassociated severe fatigue, was seen in all individuals.
MWS patients consistently reported that the
inflammation-associated fatigue negatively affected
their performance and mood. With resolution of the
constitutional features of the disease, scores on the
patient-derived health status, performance, and mood
measures improved in all patients. Organ manifestations
were equally responsive to anakinra therapy. Musculoskeletal symptoms completely resolved, and skin and eye
symptoms significantly improved, following IL-1 blockade. This rapid response to anakinra was first reported
by Hawkins et al (5), who studied 3 severely ill family
members carrying the NALP3 V198M mutation. In that
patient series, clinical features of rash, fever, conjunctivitis, and arthralgia improved within 4 hours after the
first injection, and serologic remission was achieved
within 1 week (5). Leslie et al (18) described 22 patients
with CAPS, 15 of whom were treated with anakinra. The
authors reported that the clinical features resolved
within 4–12 hours, and the laboratory markers normalized within 1 week (18). Similar observations were
reported by Hoffman et al (19) for FCAS patients,
Goldbach-Mansky et al (20) for NOMID patients, and
Maksimovic et al (21) for MWS/FCAS overlap patients.
The long-term efficacy of anakinra therapy was
determined at the last followup visit. There was a
sustained response to anakinra in the majority of patients. Adults did not require any dosage adjustment to
maintain disease control; however, all patients had mild
features of MWS at the last followup. In contrast, 2 of 5
children needed a significant dosage augmentation, to 8
mg/kg/day. One child who did not have a dosage adjustment had severe disease including fever at the last
followup (score of 13 on the DAS for MWS). It appeared that younger children required higher doses of
anakinra as compared to adults.
Recurrence of MWS organ manifestations was
observed in 50% of our patients, comparing the data at
the primary study end point at 2 weeks with the data at
the last followup visit. These symptoms were mainly
conjunctivitis and arthralgia, less commonly rash. Improvement and/or stability of organ manifestations was
seen in the other 50% of patients. The latter group
included the 2 children, who had a dosage adjustment.
Headaches, oral ulcers, abdominal pain, and renal disease, including proteinuria and hematuria, remained
well controlled in all patients.
Sensorineural hearing loss was reversible in 1
patient, who was 15 years old at the start of therapy. One
adult, who was 44 years of age, had a gradual improvement. In 2 other adult patients, hearing worsened during
anakinra therapy. In all of the remaining patients,
anakinra appeared to stabilize the hearing loss. The two
children who required dosage adjustment never developed hearing loss.
Long-term followup data for anakinra therapy in
children and adults with MWS are limited. Leslie et al
(18) reported the outcome of 15 MWS patients, including 2 children, who were followed up for a median of 17
months (range 1–39 months). All patients showed a
sustained response to drug therapy. No dosage adjustment was needed to prevent the recurrence of symptoms. Significant improvement in renal disease, as determined by proteinuria and amyloidosis (measured by
scintigraphic scan for amyloidosis), was recorded (5).
Three patients described by Hawkins et al (5) in 2004
were followed up for 3 months and were also reported to
have experienced a sustained response to anakinra.
Single cases of MWS in whom hearing loss was
reversed following anakinra treatment have recently
been described (22–24). These patients were ages 8–22
years, similar to the individuals in our cohort. These data
suggest that there may be a window of opportunity at a
younger age for reversing hearing loss, although Rynne
et al (25) reported reversibility of sensorineural deafness
in a 59-year-old woman with MWS.
Classic markers of inflammation improved in the
majority of patients. The ESR normalized in all but 1
patient (92%) and the CRP value in 45% of those who
had an elevation at baseline. While significant improvement in the ESR was detectable as early as 2 weeks and
then plateaued, CRP levels improved further until the
last followup visit. Hematologic abnormalities also completely resolved and did not recur as of the last followup
The novel markers of inflammation in patients
with MWS had distinct kinetics. The SAA levels mirrored the CRP and IL-6 concentrations, improving at 2
weeks and significantly decreasing over the long term.
The S100A12 levels, in contrast, rapidly decreased at 2
weeks (P ⫽ 0.05), but had increased again by the time of
the last followup visit. These data indicate that MWS
may be associated with abnormal activation of neutrophils, which is not completely alleviated by IL-1␤ blockade. In this cohort, serum levels of IL-1␤ and TNF␣ did
not correlate significantly with clinical features and
other markers of inflammation.
Classic markers of inflammation have been measured in previous series of MWS patients treated with
anakinra. Hawkins et al (5) and Leslie et al (18) reported
a rapid decrease in CRP levels and a resolution of
hematologic abnormalities in all patients. Lovell et al
(26), in contrast, noted an improvement in the ESR in 2
NOMID patients; however, the CRP levels appeared to
be “unstable” and remained abnormal at all times.
Goldbach-Mansky et al (20) reported significantly decreased SAA, CRP, and ESR values in NOMID patients
at month 3, all of which remained low at month 6. The
novel markers of inflammation have not been systematically studied in most series. Goldbach-Mansky et al
(20), Hawkins et al (5), and Leslie et al (18) reported
SAA levels. Goldbach-Mansky also reported IL-1, Il-6,
and TNF␣ concentrations in NOMID patients, which
have not been reported in MWS patients until now.
The most promising biomarker of MWS in our
series was S100A12, a neutrophil-specific protein belonging to the group of damage-associated molecular
patterns. This marker may indicate subclinical disease
activity, as has already been shown in other inflammatory disorders (27) and may possibly be associated with
subclinical disease progression and risk of the development of disease sequelae such as amyloidosis.
Subcutaneous injections of anakinra were reasonably well tolerated in all patients, including the children.
Local injection site reactions, including itchiness, swelling, and redness, occurred in 42% of the patients.
Similar rates of local reactions in other series of patients
have been reported (5,18,20). Increasing the dosages
and the corresponding drug volumes resulted in increased local discomfort and pain, particularly in small
children. However, the benefit of clinical improvement
outweighed the injection site discomfort in all participating MWS patients.
The overall safety of anakinra in our cohort was
excellent. No serious adverse events were observed. No
discontinuation of therapy was necessary. Hyperactivity,
which was seen in 4 individuals, may be a result of the
increased energy level reported by all patients. Weight
gain was observed in 4 female MWS patients (33%).
This study has limitations, however. It was an
observational cohort study, which inevitably suffers from
incompleteness of the data. Since the patients were
followed up according to a standardized protocol, however, the percentage of missing data was ⬍5%, indicating robustness of the results. Only 12 MWS patients
were recruited. Nevertheless, since MWS is a newly
recognized, rare disease, this study reflects the largest
experience with IL-1 blockade in patients with severe
MWS published to date. Also, no previous study has
enrolled a comparable number of children with MWS,
making this the largest pediatric experience with anakinra thus far.
In conclusion, anakinra was an effective and safe
therapy for children and adults with severe MWS. Rapid
resolution of constitutional symptoms and organ manifestations was observed. Most noticeably, anakinra had a
significant and sustained positive impact on the quality
of life, as documented by all patient-derived measures.
Disease sequelae were possibly prevented and even
reversed in some patients. Novel markers of inflammation, such as the S100A12, appear to be promising,
sensitive measures of disease activity.
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. Dr. Benseler had full access to all of
the data in the study and takes responsibility for the integrity of the
data and the accuracy of the data analysis.
Study conception and design. Kuemmerle-Deschner, Tyrrell, Koetter,
Wittkowski, Tzaribachev, Lohse, Koitchev, Benseler.
Acquisition of data. Kuemmerle-Deschner, Tyrrell, Koetter, Wittkowski, Bialkowski, Tzaribachev, Lohse, Koitchev, Deuter, Foell,
Analysis and interpretation of data. Kuemmerle-Deschner, Tyrrell,
Koetter, Wittkowski, Lohse, Koitchev, Foell, Benseler.
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DOI 10.1002/art.27655
Article Withdrawn Prior to Final Publication
An article entitled “Inhibition of JNK Enhances Chondrogenesis of Mesenchymal Progenitor Cells by
Increasing Autocrine TGF␤ Signaling” (Caerteling SB, van der Kraan PM, Vitters EL, Dechering KJ, van
Zoelen EJ, Piek E) was accepted by Arthritis & Rheumatism in July 2010 and published online in the journal’s
Accepted Articles section. Prior to publication in final form in an issue of the journal, the article was withdrawn
at the authors’ request.
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adults, efficacy, patients, syndrome, autoinflammatory, muckle, anakinra, safety, pediatrics, therapy, well
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