Expert Review of Clinical Pharmacology

ISSN: 1751-2433 (Print) 1751-2441 (Online) Journal homepage: http://www.tandfonline.com/loi/ierj20

Pharmacological treatment options for cryopyrin-

associated periodic syndromes

Emmanuelle C. Landmann & Ulrich A. Walker

To cite this article: Emmanuelle C. Landmann & Ulrich A. Walker (2017) Pharmacological
treatment options for cryopyrin-associated periodic syndromes, Expert Review of Clinical
Pharmacology, 10:8, 855-864, DOI: 10.1080/17512433.2017.1338946

To link to this article: http://dx.doi.org/10.1080/17512433.2017.1338946

Accepted author version posted online: 06

Jun 2017.
Published online: 20 Jun 2017.

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 EXPERT REVIEW OF CLINICAL PHARMACOLOGY, 2017
VOL. 10, NO. 8, 855–864
https://doi.org/10.1080/17512433.2017.1338946

REVIEW

Pharmacological treatment options for cryopyrin-associated periodic syndromes

Emmanuelle C. Landmann and Ulrich A. Walker
Department of Rheumatology, University Hospital Basel, Basel, Switzerland

ABSTRACT ARTICLE HISTORY

Introduction: Cryopyrin-associated periodic syndromes (CAPS) are rare monogenic autoinflammatory dis- Received 3 April 2017
eases, comprising a spectrum of phenotypes of varying severity. CAPS are associated with gain-of-function Accepted 2 June 2017
mutations in the NLRP3 inflammasome, a multiprotein complex critical for the activation of IL-1ß, and are KEYWORDS
characterized by episodes of fever, urticaria-like rash, musculoskeletal, ocular, and neurological symptoms. Anakinra; autoinflammatory;
Areas covered: Accounting for the pivotal role of IL-1ß in the pathogenesis of CAPS, three therapeutic canakinumab;
options, all blocking the action of IL-1ß, are currently approved: anakinra, a recombinant IL-1 receptor Cryopyrin-associated
antagonist, the IL-1 trap rilonacept and canakinumab, a monoclonal anti-IL-1ß antibody. All agents reduce periodic syndrome; Familial
Downloaded by [University of New England] at 03:08 08 November 2017

or even resolve clinical symptoms, biochemical activity markers and improve quality of life in CAPS. This Cold Autoinflammatory
review also covers pharmacokinetic, pharmacodynamic and safety aspects of the approved drugs and the Syndrome; interleukin-1;
Muckle-Wells Syndrome;
potential utility of IL-1β blockers in a wide range of other conditions with an autoinflammatory component. Neonatal Onset Multisystem
Expert commentary: Due to the success story of current pharmaceutics, the therapeutic options in Inflammatory Disease;
CAPS are not expected to expand in the near future. Prospective observational studies are needed to NLRP3 inflammasome;
confirm long-term efficacy and sustained benefit. New IL-1ß blockers will likely address unmet clinical rilonacept
needs in other autoinflammatory conditions.

1. Introduction along with the precursors of a number of other IL-1 cytokine family
members [2]. The NLRP3 inflammasome is activated by various
Cryopyrin-associated periodic syndromes (CAPS) are a spectrum of
pathogen-associated molecules, but also by danger signals
rare monogenic autoinflammatory syndromes arising from an
released by stressed and damaged cells [3,4].
overactive NLRP3 inflammasome in innate immune cells and are
characterized by periodic fever episodes and systemic inflamma-
tion. Autoantibodies or autoreactive effectors of the acquired 3. Cryopyrin-associated periodic syndromes
immune system have no role in the pathogenesis of CAPS [1].
CAPS are a group of autoinflammatory diseases, which com-
Current therapeutic approaches of CAPS target IL-1ß with a highly
prises familial cold autoinflammatory syndrome (FCAS),
successful outcome, emphasizing the crucial role of IL-1ß in the
Muckle–Wells syndrome (MWS), and chronic infantile neurolo-
pathogenesis of CAPS. This review aims to provide an overview of
gical cutaneous and articular syndrome (CINCA), also called
the currently licensed drugs for CAPS and to discuss future
neonatal onset multisystem inflammatory disease (NOMID).
developments.
The spectrum of disease severity ranges from FCAS being
the mildest presentation, to MWS as an intermediate, and
2. NLRP3 inflammasome CINCA as the most severe form [5,6].
At the molecular level, CAPS are characterized by missense
IL-1ß is a potent proinflammatory cytokine, mainly originating
single-nucleotide substitutions in the NLRP3-gene on the long
from cells of the innate immune system [2]. Its inactive precursor
arm of chromosome 1 leading to a gain-of-function mutation in
pro-IL-1ß is cleaved intracellularly by the nucleotide-binding oli-
cryopyrin, the NLRP3-gene product [7–10]. The majority of the 181
gomerization domain-like receptor family, pyrin domain contain-
[11] so far identified sequence variants are located in exon 3, which
ing 3 (NLRP3) inflammasome, a multiprotein complex. NLRP3 (also
encodes the NACHT-domain, and its flanking regions [7,9–11]. In
referred to as cryopyrin) is a member of the nucleotide-binding
more than half of the cases, the mutations are inherited in an
oligomerization domain (NOD)-like receptor (NLR) family, and is
autosomal-dominant fashion but somatic mutations are described
composed of a nucleotide-binding NACHT domain, which is
in around 20–35% of patients, particularly in CINCA [7–9,12].
flanked by a leucine-rich repeat (LRR)-sequence on the C’-terminus
Moreover, a number of patients are mutation negative, and may
and a pyrin (PYD)-domain on the N’-Terminus. In order to form the
harbor currently unknown mutation variants, or feature low-level
NLRP3-inflammasome, cryopyrin binds to the intracellular protein
somatic mosaicism [12–15]. Despite the common molecular back-
apoptosis-associated speck-like protein (ASC), that in turn links to
ground, the diagnosis of CAPS is however based on clinical char-
caspase-1 [3]. The latter then cleaves IL-1ß into its active form,
acteristics and the verification of a NLRP3 mutation is not

CONTACT Ulrich A. Walker ulrich.walker@usb.ch Department of Rheumatology, University Hospital Basel, Petersgraben 4, Basel CH-4031, Switzerland
© 2017 Informa UK Limited, trading as Taylor & Francis Group
 856 E. C. LANDMANN AND U. A. WALKER
mandatory [16]. Due to the identification of the NLRP3 mutations,
CAPS are now understood as a continuum of phenotypes rather
than three distinct entities.
The cryopyrin variants elicit systemic inflammation
through a constitutive gain of activity of cryopyrin and the
inflammasome, although details are still elusive. In vitro
studies demonstrate that the mutated cryopyrin confers an
excessive and dysregulated secretion of active IL-1ß in the
innate immune system. Monocytes of patients with FCAS
[17], MWS [18], and CINCA [19] excessively secrete IL-1ß
[18–22] spontaneously, after stimulation with lipopolysac-
charide, or at mild hypothermia. Similarly, CAPS-patients
feature approximately five-fold higher serum levels of IL-1ß
than healthy controls [23].
The prevalence of CAPS may be higher in Caucasians than
in other ethnicities, but generally is very low, with an estimate
of 1 case in every 360ʹ000 in France [5,7]. Consistent with the
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autosomal-dominant inheritance, there are no gender differ-
ences in the prevalence of CAPS [5,16,24].
The disease onset of most CAPS is typically in the neo-
natal period or at early childhood [5,7,24] with recurrent
episodes of fever and an urticaria-like rash. Aside from
fever, the urticaria-like rash is considered the key symptom
and generally the first manifestation in all phenotypes [25].
CAPS are also accompanied by signs of IL-1ß-triggered sys-
temic inflammation, such as fatigue, elevated neutrophil
counts, and acute-phase reactants (C-reactive protein
(CRP), erythrocyte sedimentation rate (ESR), and serum amy-
loid A (SAA)) [2,25]. Musculoskeletal symptoms are also
common and tend to increase in severity over time [26].
Ocular, auditory, and neurological manifestations may also
be observed in some phenotypes [16,26].
FCAS is characterized by recurrent, short episodes (hours
to a few days) of fever, rash, and polyarthralgia, that are
triggered by exposure to cold temperatures and may be
associated with conjunctivitis and headache. The intensity
of the cold trigger correlates with symptom severity, but
symptoms follow a circadian rhythm as well, being worse in
the evening [25,27,28].
MWS presents either with recurrent flares or virtually per-
manent symptoms of rash, arthralgia, occasional joint effu-
sions, and conjunctivitis [29]. Again, fever attacks can be
triggered by cold temperature [29] but also be absent [25].
Late complications consist of progressive bilateral sensori-
neural hearing loss, and AA amyloidosis with gradual renal
failure in approximately one-fourth of the patients [29–31].
CINCA, the most severe phenotype is typically associated
with fever, rash, musculoskeletal, ocular and central nervous
manifestations. The musculoskeletal complications are more
severe in CINCA than in the other phenotypes and range from
arthritis in the majority of the cases, to striking skeletal dys-
morphia with cartilage anomalies, and overgrowth of the
patella and the epiphyses of long bones [25,26,32,33].
Central nervous manifestations consist of aseptic meningitis
and increased intracranial pressure leading to morning head-
ache, papilledema, optic disc atrophy [33], ocular disability
[34], and cognitive impairment [33]. Anterior uveitis is also
common [34]. Similar to MWS, perceptive deafness [33] and
amyloidosis [25] develop with disease progression.
4. Therapeutic options for CAPS
CAPS flares tremendously impair the quality of life in both,
its physical and psychological determinants [35–37]. Thus,
treatment is indicated as soon as CAPS has been diagnosed,
also because of the favorable benefit–risk profile of the
currently available agents.
To date, the European Medicines Agency (EMA) and US
FDA approved three different medications in the treatment
for CAPS, all of which block the action of IL-1ß. These drugs
are the short-acting recombinant IL-1 receptor antagonist
anakinra, the IL-1ß trap rilonacept and canakinumab, a mono-
clonal antibody against IL-1ß [38]. The efficacy and safety of
these agents in CAPS were investigated in a number of stu-
dies. Table 1 provides an overview of the approved indica-
tions, dosage, and preliminary use in other conditions.
Prior to the advent of the IL-1 antagonists, the traditional
treatment of CAPS consisted of various immunosuppressive
agents. An anecdotal report describes a benefit with cyclospor-
ine A, high-dose corticosteroids, mycophenolate, and thalido-
mide [61]. Methotrexate was also reported to provide partial
relief [62,63]. Tocilizumab, an anti-IL-6 receptor monoclonal anti-
body [64] and TNFα-blockers [65] failed to reliably suppress
symptoms and to normalize laboratory signs of activity.
Nonsteroidal antirheumatic drugs are however frequently used
to assist in alleviating symptoms [61–63].
4.1. Anakinra (Kineret ) ®
Anakinra was the first IL-1 targeting drug on the market. It was
studied in rheumatoid arthritis since 1993 [66,67], and in CAPS
since 2003 [68]. Anakinra has been approved by the FDA for
CINCA in 2012 [69] and by the EMA in 2013 for all subtypes of
CAPS in persons of at least 8 months of age and a body weight of
at least 10 kg [70]. Anakinra is a recombinant, nonglycosylated
version of the physiological human IL-1 receptor antagonist (IL-
1RA) that competitively inhibits the binding of IL-1ß and IL-1α to
the IL-1 receptor, thereby blocking downstream signaling [70].
Anakinra is produced by recombinant DNA technology in
Escherichia coli. The amino-acid structure of anakinra is identical
to that of the native IL-1RA, except for an additional methionine
residue on its N’-terminus [70]. The half-life of anakinra ranges
from 4 to 6 h [70], therefore anakinra is administered daily by
subcutaneous injection with a recommended dose of 1–2 mg/kg
in children [69,70], and 100 mg in adults [61,71,72]. In severe
cases stepwise dose escalation to 8 mg/kg [69,70], or even to
10 mg/kg [73] is suggested. Since the drug is principally elimi-
nated by the kidney [74], the dose interval should be doubled in
severe renal failure or end-stage renal disease (creatinine clear-
ance below 30 ml/min) [69,70]. Although numerous individuals
with CAPS have developed antibodies against anakinra, no effect
on efficacy or safety was reported [70].
Owing to its early approval for rheumatoid arthritis, anakinra
was the first drug studied in CAPS. In 2003, Hawkins et al. [68]
demonstrated a remarkable response to anakinra in MWS. Over
the years, further studies revealed rapid responses to anakinra, not
only in MWS [29,71,72], but also in FCAS [28], CINCA [65,73,75] and
overlap phenotypes such as CINCA/MWS [36], and MWS/FCAS
[76]. Clinical improvement was observed as early as four hours
 EXPERT REVIEW OF CLINICAL PHARMACOLOGY 857

Table 1. Approved drugs that target IL-1 in CAPS and trials outside licensed indications.
Anakinra Rilonacept Canakinumab
Approved indications FDA: FDA: FDA:
and year of approval - RA ≥18 years (in 2001) - FCAS, MWS ≥12 years (in 2008) - FCAS, MWS ≥4 years (in 2009)
- CINCA (in 2012) EMA: - SJIA ≥2 years (in 2013)
EMA: - CAPS (in 2009, withdrawal in 2012) EMA:
- RA in combination with methotrexate (in - periodic fever syndromes ≥2 years:
2002) CAPS; TRAPS, HIDS/MKD, FMF (in 2009 and
- all subtypes of CAPS ≥8 months or 2016, respectively)
≥10 kg (in 2013) - Still’s disease (in 2013)
- Gout with at least 3 flares per year (in 2013)
Dose CAPS: 1–2 mg/kg s.c. daily CAPS: weekly CAPS: every 8 weeks
RA: 100 mg s.c. daily ≥18 years: loading dose 320 mg s.c., >40 kg 150 mg s.c.
maintenance dose 160 mg s.c. ≥15 kg and ≤40 kg 2 mg/kg s.c.
≥12 and ≤17 years: loading dose ≥7.5 kg and <15 kg 4 mg/kg s.c.
4.4 mg/kg s.c., maintenance dose 2 to <4 years and ≥7.5 kg 4 mg/kg s.c.
2.2 mg/kg s.c. TRAPS, HIDS/MKD, FMF:
every 4 weeks
>40 kg 150 mg s.c.
≥7.5kg and ≤40 kg 2 mg/kg s.c.
Still’s disease: every 4 weeks
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≥7.5 kg 4 mg/kg s.c.

Gout: 150 mg s.c. during attack
Studies outside licensed FMF [39] FMF [50] Schnitzler’s syndrome [55]
indications Still’s disease [40] SJIA [51] Behçet’s disease [56]
Behçet’s disease [41] Schnitzler’s syndrome [52] Polymyalgia rheumatica [57]
Kawasaki disease [42] Gout [53] Diabetes mellitus type 1 [46]
Gout [43], CPPD [44] Atherosclerosis and chronic kidney Diabetes mellitus type 2 [58]
Diabetes mellitus type 1 [45,46] disease [54] Atherosclerosis [59]
Diabetes mellitus type 2 [47] COPD [60]
Myocardial infarction [48]
Pericarditis [49]
CAPS, cryopyrin-associated periodic syndrome; CINCA, chronic infantile neurological cutaneous and articular syndrome; COPD, chronic obstructive pulmonary disease;
CPPD, calcium pyrophosphate deposition disease; EMA, European Medicines Agency; FCAS, familial cold autoinflammatory syndrome; FDA, Food and Drug
Administration; FMF, familial Mediterranean fever; HIDS, hyper-IgD-syndrome; MKD, mevalonate kinase deficiency; MWS, Muckle Wells-syndrome; RA, rheumatoid
arthritis; s.c., subcutaneous; SJIA, systemic juvenile idiopathic arthritis; TRAPS, TNF receptor-associated periodic syndrome.

after injection [29]. Anakinra ameliorated constitutional (fever,
fatigue), musculoskeletal, und cutaneous symptoms
[36,61,65,71–73]. The neurological manifestations of the severe
phenotypes also showed improvement with continued adminis-
tration. In a number of trials, chronic meningitis, and intracranial
pressure improved and papilledema stabilized [36] or regressed
[73,75]. In line with these findings, headache ameliorated or even
resolved [36,65,73,75] and visual acuity improved in the majority
of cases [75]. From a pharmacodynamic perspective, anakinra has
been found to dose dependently cross the blood–brain barrier in
nonhuman primates [77], hence a direct anti-inflammatory action
in the brain is conceivable. Some neurological symptoms may,
however, also benefit from a resolution of systemic inflammation.
No improvement of cognitive function was noted, probably due
to irreversible organ damage seen in magnetic resonance imaging
(MRI) [36,73,75]. Regarding long-term CAPS complications, the
progression of perceptive hearing loss is halted in the majority
of patients. Both, improvement [65,71,73] and aggravation [71,75]
of auditory symptoms have been reported. Amyloidosis improved
in a number of patients [71,73] or even resolved [61]. With regard
to the arthropathy, progression was not unusual [73,75], although
one case of positive development was reported [78].
The positive clinical effects were not only maintained on a
short-term, but also after several months of continuous applica-
tion with the vast majority of patients having sustained disease
control [29,72]. Furthermore, continuous treatment with ana-
kinra improved the quality of life globally and with regard to its
physical and psychological components [36,75]. In addition to
this tremendous improvement of clinical symptoms, serological
markers of inflammation (CRP, ESR, SAA) decreased within hours
after the administration of anakinra [72,75].
The most common adverse event of anakinra is injection
site reaction [36,61,71–73,75,79]. The majority of injection-site
events (65%) occurred within the first month, whereas
approximately three-quarter of the cases (73%) resolved
within one week [79]. An increased rate of infections has
also been observed, particularly of the upper respiratory
tract [72,75,79]. An elevated rate of severe and invasive infec-
tions with Group A Streptococcus was associated with anakinra
treatment, leading to necrotizing fasciitis, sepsis or tissue
abscess [80]. To a lesser extend, headache, arthralgia [69,79],
and gastrointestinal symptoms [36,69] have been observed,
however these adverse events may also reflect uncontrolled
activity of the underlying CAPS. In a long-term cohort study,
the highest number of adverse events was reported in the first
year of treatment with a gradual decrease over time [79].
Anakinra passes the placenta and enters breast milk, this is
however also observed physiologically with respect to the nat-
ural occurring IL-1RA [81]. A small observational study analyzed
the outcome of women with CAPS during pregnancy treated
with anakinra [82]. No complications or negative consequences
on maternal or fetal health were reported, except for one case of
renal agenesis [82,83]. Although no worsening of CAPS-symp-
toms was observed during pregnancy, a dose increase is recom-
mended if the weight gain exceeds 10kg [82,83]. Another
observational report [83] described no development
 858 E. C. LANDMANN AND U. A. WALKER
peculiarities in exposed infants, except for the occurrence of one
renal agenesis as well, but the long-term safety of drug exposure
to the fetus and infant needs to be investigated further.
4.2. Rilonacept (Arcalyst ) ®
Rilonacept has been approved by the FDA in 2008 for adults and
children with FCAS and MWS above the age of 12 years [84]. In
2009, the EMA has also granted approval for the treatment of
CAPS. Due to limited use in the European market, the approval of
Rilonacept has however been withdrawn in 2012 [85].
Rilonacept is an engineered construct of the extracellular
IL-1 receptor domains (IL-1 receptor 1 (IL-1R1) and IL-receptor
accessory protein (IL-1RAP)) fused to a humanized IgG1-Fc
portion. Rilonacept captures IL-1ß, IL-1α, and IL-1RA as a
decoy receptor. Compared with the natural IL-1 receptor, the
affinity of rilonacept to IL-1ß is 100-fold higher [86,87].
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Rilonacept is administered weekly, owing to its approximate
terminal half-life of 7 days. In adults, the initial subcutaneous
loading dose is 320 mg, followed by weekly injections of 160 mg
[84]. In pediatric patients below 17 years of age, the loading dose
is 4.4 mg/kg (to a maximum of 320 mg per injection) with a
maintenance dosage of 2.2 mg/kg (to a maximum of 160 mg per
week) [84]. In patients with renal impairment, dose adjustment is
not needed, however no controlled study has been performed
[86,88]. Approximately one-third of the patients developed anti-
drug antibodies but no influence on the pharmacokinetics or
safety of rilonacept was observed [89,90]
After first trials with rilonacept had shown a positive effect
in patients with rheumatoid arthritis [91], a benefit was also
noted in FCAS [89,92] and MWS [89]. In comparison to pla-
cebo, a clinical and serological response was described within
24 h after drug administration [89,92]. Disease activity and key
symptoms of CAPS (fever, rash, eye redness/pain, fatigue,
arthralgia) decreased significantly after the initiation of treat-
ment [89]. If remission was not achieved, a successful result
was noted after a dose escalation to the maximum of 320 mg
per week [92].
Rilonacept has also sustained benefit on the long term
[90,92]. After 18 months of consecutive treatment, rilonacept
improved key symptoms by half in the vast majority (87%) of
patients and by 70% in three-quarters of patients [90]. The
patient’s as well as the physician’s assessment of disease
activity and daily impairment improved substantially [89,90].
Additionally, rilonacept efficiently prevented disease flares in
comparison to placebo [89]. In line with clinical improvement,
rilonacept also induced a significant decline of serological
markers of CAPS activity (particularly CRP, and SAA) [89,92].
To the author’s knowledge, there are no published data with
regard to the brain penetration of rilonacept. Although rilona-
cept is unlikely to directly cross the blood–brain barrier due to
its high-molecular weight (251 kDa) [88], neurological symp-
toms do improve. During flares of meningitis, leaky meninges
may permit drug entry into the brain. Control of systemic
inflammation may also contribute to the resolution of cerebral
inflammation [88].
The most common adverse events of rilonacept consist of
injection-site reactions [84,89] and upper respiratory tract
infections [84,89,92]. In one trial, approximately half (48%) of
patients treated with rilonacept experienced an infection,
compared to 17% in the placebo group [89]. In another
patient population, however, no significant increase in infec-
tions was reported [88]. Moreover, weight gain [92], generally
decreasing over time [89] and headache [89] was noted.
Importantly, the occurrence of adverse reactions was indepen-
dent of the dose administered [86]. Based on animal experi-
ments, rilonacept may cause an increase of stillbirths and
osseous abnormalities but the fertility was not altered [84].
As there are no controlled data in human pregnancy, rilona-
cept should only be given during pregnancy when benefits
outweigh risks.
4.3. Canakinumab (Ilaris ) ®
Canakinumab was granted approval by the FDA in 2009 in adults
and children above 4 years of age with FCAS and MWS [93], and by
the EMA in 2009 for all CAPS phenotypes in children above 2 years
of age [94]. Canakinumab is a recombinant fully humanized mono-
clonal antibody of the IgG1 isotype, and neutralizes serum IL-1ß
with high selectivity and affinity [95]. Thus, canakinumab blocks
the interaction of IL-1ß with its receptors and inhibits its down-
stream signals [95]. Canakinumab has a mean terminal half-life of
26 days [23], permitting subcutaneous injections every 8 weeks.
The recommended dose is 150 mg in patients above 40 kg of
body weight, 2 mg/kg in patients with a body weight between
15 kg and 40 kg, and 4 mg/kg in patients with a weight of below
15 kg and above 7.5 kg. In infants between 2 and 4 years of age,
the recommended dose is 4 mg/kg [72,93,94]. In renal or hepatic
impairment, no dose adjustment is needed, however, the experi-
ence in these populations is limited [93,94,96]. No immunogenicity
is reported in most trials [96–99].
The efficacy of canakinumab was first described in rheuma-
toid arthritis [100]. In CAPS, clinical and serological improve-
ment was noted as early as 24 h after drug administration
[97,98]. After one week about 89% of patients with CAPS [97]
were in complete remission. The short-term response rates
varied slightly [97–99], possibly due to differences in the
demographic characteristics and CAPS phenotypes included.
The effects were sustained and complete response rates aug-
mented to even 97% after 48 weeks of treatment in one trial
[97], although lower rates (72%) were also reported [101].
Canakinumab was also shown to prevent disease flares in a
placebo-controlled trial [99], with 80% of patients in the pla-
cebo group experiencing recurrence of inflammation after
drug discontinuation [97]. Apart from the clinical responses,
a prompt and long-lasting normalization of acute-phase reac-
tants (CRP and SAA) was shown with continuous administra-
tion of canakinumab [98,99].
With regard to the more severe clinical CAPS presentations,
neurological complications also improved [102], in one trial even
in virtually 50% of patients over a period of 2 years [99]; cognitive
impairment however remained [102]. Similarly, visual acuity,
sensorineural hearing loss, and renal amyloidosis improved or
did not progress [99,102,103]. It is however important to note
that pediatric patients as well as those with the more severe
CAPS phenotypes, particularly with CINCA, may require higher
doses or shorter dosing intervals in order to achieve complete
clinical and serological remission [99,101,102,104]. The necessity

of dose adjustments in some patients is also underlined by
considerably lower complete response rates in patients with
more severe CAPS phenotypes (14%) compared to mild and
moderate subtypes (76% and 85%, respectively) [101], perhaps
owing to the negligible penetrance of the monoclonal antibody
into brain tissue. Therefore, a more aggressive treatment regi-
men is proposed in these severe cases with 4 mg/kg every
4 weeks [104]. This regimen is also recommended for canakinu-
mab in the treatment of systemic juvenile idiopathic arthritis [93].
Similar to other immunosuppressive medications, the most
common adverse event of canakinumab is infections [101],
particularly of the upper respiratory tract, although gastroen-
teritis and urinary tract infections were noted as well [97,99]. In
the beta-confident registry, a registry that prospectively fol-
lows 288 patients treated with canakinumab in 13 countries,
the incidence rate of serious infections was 4.1 per 100 patient
years [105]. A few cases of opportunistic infections (for
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instance aspergillosis, herpes zoster, and atypical mycobac-
teria) were observed [94]. Injection site reactions [98,99,101],
as well as headache and vertigo [93,94,98,99] were also
reported. Remarkably, no additional adverse events appeared
with increased dosage [101].
Monoclonal antibodies are transferred via the placenta in
linear manner, and therefore a fetal exposure in the 2nd and
3rd trimester is likely. A delay in fetal ossification was observed
in animal models [93]. In pregnancy, limited data are available,
abnormalities were not reported [83]. Women of reproductive
age are advised to use contraceptives for up to 3 months after
the last injection of canakinumab [94]. It is not established if
canakinumab is present in breast milk, although IgG is known
to appear physiologically in breast milk [93].
4.4. General remarks with regard to the approved IL-1β
targeting agents
Up to date, no head-to-head trial has directly compared the
three anti-IL-1 drugs. A cohort study however compared the
efficacy of anakinra with that of canakinumab [72]. Both
agents showed good efficacy in clinical and serological disease
control. A greater sustained remission rate was noted in
patients treated with canakinumab (93% versus 75% in
patients treated with anakinra), however, variations in disease
severity were present among the two cohorts prior to treat-
ment [72]. In patients who experienced secondary treatment
failure with anakinra, despite anakinra dose escalation and
excellent treatment adherence, switching to canakinumab
induced a good response [72,98].
A few clinical and serological changes observed in treated
patients, apply to all agents that target IL-1ß, owing to the
resolution of the chronic inflammatory state. Various authors
reported a considerable growth and weight gain in treated
patients, particularly in children, likely as a consequence of the
control of the catabolic state of inflammation [73,75,98].
Similarly, hematological changes were noted, for instance a
rise in hemoglobin, red blood cells, as well as a decrease in
neutrophil granulocytes and platelets [89,90,93,94,98], and a
change in lipid profiles [84,92].
Also noteworthy is the good clinical and serological
response to IL-1ß blocking drugs, regardless of the presence
EXPERT REVIEW OF CLINICAL PHARMACOLOGY 859
or type of gene defect [36,65,75,99]. Although one report
noted an insufficient response in patients without clear
NLRP3 mutations [62]; in the beta-confident registry CAPS
activity was predominantly absent in patients without detect-
able NLRP3 mutations receiving canakinumab [105].
The improved outcome of patients with CAPS treated with
IL-1ß blockers emphasizes the pivotal role of IL-1ß in these
syndromes. IL-1ß blockade is not a cure of CAPS and therefore
disease flares occur after drug discontinuation [23,98]. Up to
date, long-term observations are sparse, however, it is
assumed that early and life-long treatment is essential for a
good prognosis, also because persistent inflammation leads to
progressive and irreversible organ damage.
During infections withdrawal of IL-1 blockers should be con-
sidered carefully due to the risk of CAPS flares triggered by the
infectious agent. Unlike the situation with biologics in autoim-
mune diseases, it is therefore suggested to rather increase the
dosage of the IL-1 inhibitor during infection and surgery [75,79].
5. Conclusion
The treatment of CAPS has evolved tremendously. Three
approved IL-1ß targeting drugs induce a prompt and sus-
tained clinical and serological response in CAPS of varying
phenotype. The outcome of CAPS has improved significantly,
also with regard to quality of life. Generally, the agents are
safe and well tolerated by the patients.
6. Expert commentary
Although the treatment of CAPS with drugs targeting IL-1ß is
a success story, long-term prospective studies are important to
ensure efficacy and safety over decades. Future clinical trials
should also address the association between CAPS pheno-
types, the vast number of genetic variants and response to
treatment. This may allow a more targeted dose regimen.
More work is also needed to better delineate drug safety in
pregnancy, neonates and infants, and to better characterize
the evolution of late complications with early treatment.
Clearly a multinational platform is necessary to generate
robust data in a disease of such low prevalence.
At present, there is no clear unmet need for new IL-1
inhibitors in the particular group of patients with CAPS. The
only new IL-1β blocker developed for CAPS is HL2351 [106]. It
is a recombinant IL-1 receptor antagonist fused to a hybrid Fc
fragment consisting of IgD and IgG4. The hybrid fusion tech-
nology enables a prolonged half-life with a weekly subcuta-
neous administration. A phase II study in individuals with
CAPS was however terminated due to recruitment difficulties
[107]. To our knowledge, no results regarding drug safety or
efficacy are available.
It is particularly important to better understand the role of
IL-1 blockers in promoting bacterial infections, in particular
pneumococci and group A streptococci [80]. Interestingly,
pneumococcal vaccinations were recently found to provoke
substantial local and systemic inflammation in CAPS, even in
those patients who were treated with canakinumab [108,109].
The role of IL-1 blockers in preventing such inflammatory
 860 E. C. LANDMANN AND U. A. WALKER
episodes triggered by bacterial antigens, and their require-
ment during surgery need to be better characterized.
The activated inflammasome is also known to cleave proIL-
18 cytokine to the active IL-18 [2]. In vitro studies have demon-
strated an enhanced IL-18 secretion from leukocytes from
patients with CAPS [19,110]. Although it was hypothesized
that IL-18 may drive early disease processes and skin pathol-
ogy in CAPS [110], the extraordinarily rapid and sustained
resolution of most clinical activity by IL-1ß blockers argues
against such prominent role of IL-18 and rather underlines
the predominant role of IL-1ß. The role of IL-18 in CAPS
needs to be elucidated in more detail, perhaps with the help
of antibodies that target IL-18 [111].
7. Five-year view
The IL-1 blockers currently approved for CAPS are also studied
Downloaded by [University of New England] at 03:08 08 November 2017
in numerous other autoimmune, metabolic and inflammatory
disorders (Table 1). For instance, atherosclerosis is now recog-
nized as a disorder with a strong autoinflammatory compo-
nent [112]. For this reason a number of preliminary trials
investigate anti-IL-1β agents for the primary and secondary
prophylaxis of atherosclerosis [59,113]. The potential utility of
IL-1β blockers in a wide range of conditions with an autoin-
flammatory component justifies the great efforts made to
develop novel agents targeting IL-1ß and its intracellular
synthesis.
Gevokizumab (also referred as Xoma 052) is an engineered
humanized allosteric ligand-modifying antibody of the IgG2 iso-
type [114] which binds IL-1ß with a high affinity [115] and speci-
ficity [114,115]. Gevokizumab modulates the affinity kinetics of IL-
1ß to its receptor IL-1R1 [114–116] without suppressing negative
regulators of IL-1ß in the intent to restore the physiological pro-
and anti-inflammatory balance [116]. Gevokizumab has a half-life
of approximately 23 days [117]. Gevokizumab had promising
results in preliminary studies of Behçet’s disease [118], psoriasis
[119], and diabetes mellitus type 2 [120]. Although gevokizumab
failed to meet the primary end point in some phase III studies
[118], its clinical development will likely continue.
Other antibodies that neutralize IL-1ß are not yet in clinical
use but will likely enter further development. One example is
P2D7KK, a high-affinity anti-IL-1ß-antibody with a 11-fold
higher potency to neutralize IL-1ß than canakinumab, but
with similar affinity and efficacy to block IL-1R1 [121].
Direct NLRP3 inflammasome inhibitors are interesting, as
these agents do not only block the formation of IL-1, IL-18,
and other caspase-1-dependent molecules, but also target
other mechanisms of potential pathophysiological relevance,
such as pyroptosis, a particular mechanism of cell death
mediated by inflammasome activation. One of the endogenous
inhibitors of the NLRP3 inflammasome is pyrin domain-only
protein 1 (POP1). POP1 prevents inflammasome assembly, thus
abating caspase-1 activation and release of IL-1ß and IL-18 [122].
Other small molecules such as MCC950, a NLRP3 inhibitor that
interferes with inflammasome assembly [123], and VX-765, an
orally absorbed prodrug of a competitive caspase-1 inhibitor
[124,125], are currently in experimental use only.
In summary, the therapeutic armamentarium for CAPS can-
not be expected to expand within the next few years but the
principle of IL-1 and NLRP3 inflammasome blockade will likely
be developed for numerous other autoinflammatory condi-
tions. In CAPS future research will focus on a better under-
standing of genotype phenotype correlations, what triggers
CAPS flares, and to monitor long term drug efficacy and safety.
Key issues
● CAPS are a group of rare monogenic autoinflammatory
disorders with a constitutively activated NLRP3-
inflammasome.
● There are three approved agents that target IL-1β in CAPS:
anakinra, a recombinant IL-1 receptor antagonist, the IL-1 trap
rilonacept and canakinumab, a monoclonal anti-IL-1ß antibody.
● IL-1 blockers induce prompt resolution of clinical and bio-
chemical CAPS activity but may require dose escalation,
particularly in children and in severe phenotypes.
● IL-1β targeting drugs are mostly well-tolerated in indivi-
duals with CAPS. The rate of severe infections is about 4.1
per 100 person years.
● Early and life-long treatment is mostly required to maintain
the goal of sustained remission.
Funding
This paper was not funded.
Declaration of interest
UA Walker has served for Novartis in the steering committee of the Beta-
confident (canakinumab) registry. The authors have no other relevant
affiliations or financial involvement with any organization or entity with
a financial interest in or financial conflict with the subject matter or
materials discussed in the manuscript apart from those disclosed.
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