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The cryopyrin-associated periodic syndrome (CAPS) is a very rare disease. It is estimated that there are 1–2 cases for every 1 million people in the US and 1 in every 360,000 in France. However, many patients are diagnosed very late or not at all, meaning the real prevalence is likely to be higher. CAPS encompasses the three entities of familial cold auto-inflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous and articular (CINCA) syndrome. They have in common a causative mutation in the NLRP3 gene. The altered gene product cryopyrin leads to activation of the inflammasome which in turn is responsible for excessive production of interleukin (IL)-1β. IL-1β causes the inflammatory manifestations in CAPS. These appear as systemic inflammation including fever, headache or fatigue, rash, eye disease, progressive sensorineural hearing loss, musculoskeletal manifestations and central nervous system (CNS) symptoms (NOMID/CINCA only). With the advent of IL-1 Inhibitors, safe and effective therapeutic options became available for this devastating disease. To prevent severe and possible life-threatening disease sequelae, early and correct diagnosis and immediate initiation of therapy are mandatory in most patients. Canakinumab is a fully human monoclonal IgG1 anti-IL-1β antibody. It provides selective and prolonged IL-1β blockade and has demonstrated a rapid (within hours), complete and sustained response in most CAPS patients without any consistent pattern of side effects. Long-term follow-up trials have demonstrated sustained efficacy, safety and tolerability. Canakinumab is approved by the US Food and Drug Administration for FCAS and MWS and by European Medicines Agency for treatment of all three phenotypes of CAPS.
Cryopyrin-associated periodic syndrome (CAPS) is a rare disease [Farasat et al. 2008]. It is estimated that there are 1–2 cases for every 1 million inhabitants in the US and 1 in every 360,000 in France [Cuisset et al. 2011]. In Germany, approximately 2–7 patients under the age of 16 are diagnosed with CAPS every year [Lainka et al. 2011]. About 250 adults and children with familial cold auto-inflammatory syndrome (FCAS), but only very few patients with Muckle–Wells syndrome (MWS) are registered in the USA. In contrast in Europe only a few patients with FCAS are documented, whereas significantly more MWS patients are known. Males and females are equally affected. Most of the currently known CAPS patients are White. Owing to the severity of the disease, neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous and articular (CINCA) syndrome is diagnosed quite early, while in FCAS, the mildest manifestation of CAPS, diagnosis is often delayed significantly. The true prevalence of CAPS is likely higher than estimated, as the disease is still not widely known and therefore often not diagnosed correctly. In one study, 44% of CAPS patients carried another diagnosis before CAPS as correct diagnosis was identified [Stych and Dobrovolny, 2008].
However, while 40 years ago the median delay between disease onset and diagnosis was 40 years, due to increased distribution of knowledge regarding CAPS this delay could be reduced to 1 year [Toplak et al. 2012].
Mutations in the NACHT domain of the NLPR3/CIAS1 gene are the genetic cause for CAPS. This was first described in genetic studies in large families with FCAS and MWS [Hoffman et al. 2001a]. To date, about 145 different sequence variants of the NLRP3 gene and approximately 90 variants associated with a CAPS phenotype are known (see http://fmfighcnrsfr/ISSAID/infevers) [Milhavet et al. 2008].
Genotype–phenotype studies indicate that some mutations are associated only with a mild clinical phenotype whereas others lead to severe illness. However, heterogeneous phenotypes with respect to disease severity have been observed in carriers of identical mutations [Aksentijevich et al. 2007; Kuemmerle-Deschner et al. 2011b].
In about 40% of patients with NOMIC/CINCA, the most severe manifestation of CAPS, no genetic mutation can be identified. In 69% of these patients, disease-inducing somatic NLRP3 mosaicisms were identified in one study [Tanaka et al. 2011].
Cryopyrin (NALP3 protein), which is mutated in CAPS, plays a central role in the recognition of danger signals and the ensuing immunological cascade. Cryopyrin is a family member of the intracellular ‘NOD-like’ receptors (NLRs) [Ye and Ting, 2008]. NLRs aggregate to a multiprotein complex, the so-called inflammasome, which, after activation, leads to caspase-1-induced IL-1β secretion [Petrilli et al. 2007]. The inflammasome can be activated by exogenous stimuli or danger signals, such as microbial components or large anorganic crystalline structures, but also by endogenous mediators set free during apoptosis or cell death.
IL-1β is a prototypic alarm cytokine with an important coordinating role in early immune response and binds to the IL-receptor type I for signal transduction.
The balance between IL-1 and IL-1-receptor antagonist (IL-1RA) is important to regulate pro- and anti-inflammatory response.
IL-1β is secreted mostly by monocytes, macrophages, and dendritic cells [Dinarello, 2009]. Dependent on the type of target cells, release of IL-1β induces secretion of more IL-1β, tumor necrosis factor (TNF), inducible nitric oxide synthetase (iNOS) [Aksentijevich et al. 2002], cyclooxygenase type 2 (COX2), and prostaglandin E2 (PGE2).
In 2001, mutations in the gene encoding for cryopyrin were identified. These mutations caused autosomal-dominant inherited diseases such as FCAS or MWS [Hoffman et al. 2001b]. Sporadic mutations in the same gene were identified in the following year in patients with NOMID/CINCA [Aksentijevich et al. 2002; Feldmann et al. 2002]. Today it is acknowledged that FCAS, MWS, and NOMID/CINCA represent a group of diseases with a similar etiology of mutations in the NLRP3 gene and increased IL-1β excretion, and have been termed CAPS (Figure 1).
In most cases CAPS becomes apparent during early childhood. Early onset of disease is therefore a strong indicator for CAPS. Because the disease is rare and some patients present with only mild symptoms, the diagnosis of CAPS is often delayed and therefore has to be considered in the differential diagnosis in adults [Fye et al. 2007]. The suspected diagnosis is frequently supported by family history, the patient’s history, physical examination, and additional examinations such as audiograms or MRI. At the initial presentation, standardized questionnaires and exams may be applied, which can help to identify CAPS and also hidden organ manifestations. The patient’s disease diaries and in some cases diagnostic therapy attempts are used to establish the correct diagnosis.
Owing to the autosomal-dominant inheritance, a conspicuous family history indicates CAPS in many cases. Therefore, a thorough family history is imperative in the diagnosis of auto-inflammatory diseases to identify even oligosymptomatic disease presentations, e.g. unspecified hearing loss or renal failure.
Clinically, if the diagnosis of CAPS appears likely, then molecular genetic testing for mutations in the NLRP3 gene may confirm the CAPS diagnosis. In France, a twofold increase in molecular genetic examinations was registered between 2005 and 2009, but only in 16% of 821 cases was an NLRP3 mutation confirmed [Cuisset et al. 2011]. Therefore, criteria that may be applied to reduce unnecessary genetic screening were suggested: ≥3 recurrent disease episodes, age at disease onset <20 years, elevated C-reactive protein (CRP) level, urticaria, and fever [Cuisset et al. 2011].
In almost half the patients with NOMID/CINCA, no NLRP3 mutation may be identified, although in some somatic mosaicisms are found [Aksentijevich et al. 2002; Goldbach-Mansky, 2011]. Patients with MWS (25%) and FCAS (10%) also do not always show mutations [Aksentijevich et al. 2007]. Therefore, the lack of confirmed genetic mutation may not preclude the diagnosis of CAPS.
Clinical manifestations are as follows:
CAPS symptoms can be separated into daily recurrent ailments (Figure 2(a)) and long-term disease sequelae (Figure 3(a)) due to chronic inflammation. Frequent symptoms in all diseases of the CAPS spectrum are signs of systemic inflammation such as fever, headache, influenza-like muscle ache, and fatigue. In FCAS patients fever usually appears 24 hours after cold exposure and is often accompanied by shivers. In particular, children with MWS often complain about abdominal pain. Chronic fatigue and emotional irritability are exhausting and difficult for the whole family and chronic pain is a major impairment of the patient’s quality of life.
Skin features were originally described as urticaria-like (Figure 2(b)), but may also appear as erythematous and edematous papules or plaques. In some cases, rashes may be itchy and are often sensitive to touch. Usually rashes are not induced by direct contact with cold objects or water, but often appear 2–4 hours after cold exposure in areas not directly exposed to cold, such as upper arm, trunk, bottom cheeks, or thighs. Neutrophil and lymphocyte infiltrations can be detected in skin biopsies [Kastner, 2005].
Muscle and joint involvement reflects phenotype and disease severity. FCAS patients may complain about limb pain and myalgia. Patients suffering from MWS often also experience arthralgia and arthritis. Joints such as wrists, knees, and ankles are often affected. Sometimes painful periarticular swelling occurs [Hoffman et al. 2001a]. In FCAS and MWS, myalgia and arthralgia may be limited to acute flares only. Chronic polyarticular arthritis is seen in severe forms of MWS and in NOMID/CINCA.
Eye involvement may present as keratitis, conjunctivitis (Figure 2(c)), episcleritis, anterior and posterior uveitis. Elevated intracranial pressure (NOMID/CINCA) may cause papillary edema and subsequent optic disc atrophy. In their anterior eye segments, patients with NOMID/CINCA may have dry eyes and chronic conjunctivitis or perilimbal redness. The cornea is involved in 40% of patients. Interstitial keratitis with clouding of corneal stroma, band keratopathy, and corneal neovascularizations may appear. Mild-to-moderate nongranulomatous uveitis is seen in 50% of NOMID/CINCA patients. Inflammation of the posterior eye segments is less frequent, and presents as vitritis, retinal vasculitis, and focal chorioretinitis. In more than 80% of NOMID/CINCA patients the optic nerve head is affected: the most frequent ocular manifestation in this group of patients. Manifestations are observed bilaterally and are often associated with chronic meningitis. Papillary edema and optic disc atrophy may be found. When optic nerve and corneal manifestations are present, moderate-to-severe reduction of visual acuity is reported [Dollfus et al. 2000].
Progressive hearing loss is a major symptom in MWS and NOMID/CINCA. It is a sensorineural, not a conductive, hearing impairment and most likely caused by degeneration of sensoric structures in the organ of Corti. At onset, primarily high frequencies (4–10 kHz) are affected [Ahmadi et al. 2011]. Depending on the type of mutation, hearing loss increases in extent and intensity throughout the course of the disease and with age [Kuemmerle-Deschner et al. 2013]. A reversal or halt in progress of hearing loss may be achieved by timely induction of treatment.
Skeletal deformities are observed almost exclusively in NOMID/CINCA (Figure 3(b)). Characteristic arthropathy is caused by overgrowth and asymmetry of the cartilage, excessive uncontrolled growth of the patella and the epiphysis of the long bones and may be found in 60% of patients [Hill et al. 2007]. Reduced longitudinal growth of affected bones, uneven bone length and joint contractures may result in limited mobility and, in extreme cases, inability to ambulate. Additional features are arthritis, osteitis, osteopenia, short stature, frontal bossing, and, rarely, flattening of the nasal dorsum with saddle nose formation [Goldbach-Mansky, 2011]. In contrast to most other symptoms, abnormal bone formation in NOMID/CINCA is mostly unaffected by IL-1 inhibition [Goldbach-Mansky, 2011].
Central nervous impairment is the most devastating feature of NOMID/CINCA. Aseptic meningitis and increased intracranial pressure occur frequently (Figure 3(c)). MRI reveals leptomeningeal and cochlear enhancement as signs of CNS inflammation. Brain atrophy and enlarged ventricles indicate organ damage due to persistently elevated intracranial pressure. Chronic leptomeningeal inflammation causes arachnoidal adhesions. Depending on the severity of the disease various degrees of cognitive impairment are found. Further CNS symptoms are seizures, stroke, and vascular occlusions [Goldbach-Mansky, 2011].
A quarter of MWS patients may develop amyloidosis [Dode et al. 2003] and up to 20% of NOMID/CINCA patients died from various complications such as infections, vasculitis, and amyloidosis before reaching childhood [Hashkes and Lovell, 1997].
The generalized inflammation is also expressed in elevated inflammatory parameters such as erythrocyte sedimentation rate (ESR), CRP, and serum amyloid A (SAA). SAA is an important biomarker for the development of amyloid A amyloidosis, which may lead to renal insufficiency and early death [Lachmann et al. 2007]. The phagocyte-specific S100 proteins S100 A12 and MRP 8/14 may be used as surrogate parameters for inflammation. For these parameters, increased serum levels in several inflammatory conditions and a good correlation to response to therapy has been demonstrated. Potentially subclinical disease activity might be detected with their help [Foell et al. 2007; Wittkowski et al. 2011].
In addition to differences between the three CAPS phenotypes, disease expression within one phenotype varies, and even carriers of identical mutations display heterogeneous clinical features. In MWS patients carrying the E311K mutation, rash was observed in just 54% and febrile episodes in only 31% [Kuemmerle-Deschner et al. 2011b].
Assessment of disease activity is very important when making decisions about treatment and for monitoring the response to therapy. A semiquantitative disease activity score (MWS-DAS) was developed for patients with MWS. One point is added for every symptom with mild expression and two points for severe disease activity. Items recorded include fatigue, fever, headaches, eye involvement, hearing loss, oral aphthae, abdominal pain, renal disease, muscle pain, and rash, for a combined total of up to 20 points. With the help of this score risk factors for severe MWS disease, such as female gender and hearing loss, have been identified [Kummerle-Deschner et al. 2010].
Early and aggressive treatment for CAPS patients is crucial to avoid end-organ damage. Most CAPS specific symptoms are reversible if treatment is given early. Unfortunately, some manifestations in NOMID/CINCA patients, such as bony overgrowth and bone deformities, are not reversible. Growth retardation, CNS inflammation and hearing loss have been reported to improve with anakinra in some patients [Ahmadi et al. 2011; Neven et al. 2010].
CAPS disease activity is monitored by the patient’s assessment of disease activity, by a physician’s examination and assessment of judged disease activity, and by examination of inflammatory parameters at defined intervals. As CAPS disease activity may fluctuate, it is important for patients to take notes of their symptoms in a designated diary. Fatigue and general disease activity may be scored by using a visual analog scale (VAS).
The frequency of visits to the physician depends on the age of the patient, his individual set of symptoms and the therapeutic regimen. At each visit CAPS disease activity should be assessed and recorded by the physician.
Laboratory parameters such as CRP, ESR, and SAA should be monitored. Laboratory remission is defined as CRP, SAA, and ESR within normal range. The blood count is examined to monitor anemia and leukocytosis; urinalysis is performed to rule out proteinuria.
If the skeletal bones are affected, lesions should be monitored on an annual basis. If the CNS is involved, MRI with fluid-attenuated inversion recovery (FLAIR) imaging is recommended and children under five should be monitored by spinal tap and analysis.
For the evaluation of quality of life at diagnosis and during treatment, children can be examined by the PedsQL questionnaire and adults with the Functional Assessment of Chronic Illness Therapy (FACIT)-fatigue, 36-item Short Form Health Survey (SF-36), and Health Assessment Questionnaire Disability Index (HAQ-DI) questionnaires. An IQ test may be performed according to individual needs. In some cases, patients who rated their own state of health as ‘normal’ only realize with therapy how much they had been impaired before treatment.
CAPS patients should be followed by medical centers specialized in the care of patients with auto-inflammatory diseases.
Some NLRP3 mutations are present in the general population without essential association to CAPS symptoms, e.g. the V198M or Q703K sequence variants [Aganna et al. 2002]. However, when patients carrying these polymorphisms display clinical symptoms, their response to IL-1β inhibition is less favorable, meaning that dosage and frequency of application have to be increased [Kuemmerle-Deschner et al. 2011a]. Reliable diagnosis and appropriate therapy for patients with NLRP3 polymorphisms is subject to ongoing studies.
Before the identification of the underlying pathological mechanisms for CAPS and the development of targeted IL-1 inhibition, therapeutic options were scarce. In addition to cold avoidance, anti-inflammatory drugs were recommended: these decreased symptoms but could not change the underlying pathogenesis, namely excessive IL-1 secretion. Nonsteroidal anti-inflammatory drugs (NSAIDs) were often used, as were high-dose corticosteroids, which had severe side effects, and antirheumatics such as methotrexate (MTX), which somewhat suppressed symptoms. TNF antagonists were also applied showing improvement in some patients [Glaser and Goldbach-Mansky, 2008]. The goal in CAPS treatment is to suppress the persistent auto-inflammatory state, improve functionality, and avoid organ and other damage by controlling inflammation.
As IL-1 plays the central role in CAPS pathogenesis, blocking of IL-1 is the main therapeutic approach. Currently, three IL-1 inhibitors, anakinra, rilonacept, and canakinumab (Table 1), are available. Their safety and effectiveness has been examined in several studies [Goldbach-Mansky et al. 2006; Hawkins et al. 2003; Hoffman et al. 2008; Lachmann et al. 2009a].
The focus of this review is on the use of canakinumab in CAPS.
Canakinumab was originally developed by Novartis as a potential treatment for asthma but is no longer listed for that indication [Church and McDermott, 2010]. Subsequently, canakinumab has been studied in disorders such as CAPS, chronic obstructive pulmonary disease, and type 2 diabetes mellitus [Cook et al. 2010]. In 2008, canakinumab was granted orphan drug status for the treatment of systemic onset juvenile idiopathic arthritis (SoJIA) and CAPS in the EU and USA [Church and McDermott, 2010]. In 2009 canakinumab was approved by the US Food and Drug Administration (FDA) for the treatment of FCAS and MWS and by European Medicines Agency (EMA) for the treatment of CAPS.
Canakinumab is a fully human immunoglobulin IgG1k monoclonal antibody against IL-1β. It has been developed using Medarex Inc’s (NJ, USA) UltiMab™ technology [Church and McDermott, 2010]. It is now produced using genetically engineered murine Sp2/0 myeloma cells. The drug is available in a sterile, single-use 6 ml vial containing 150 mg of a lyophilized powder for reconstitution with 1 ml preservative-free sterile water, to be administered subcutaneously.
Canakinumab binds to soluble human IL-1β and neutralizes the biological function of the cytokine by blocking its interaction with the IL-1 receptor (Figure 4). In patients with CAPS, IL-1β production is elevated fivefold compared with healthy individuals, leading to an increase in inflammatory markers (CRP and SAA). The inhibition of IL-1β interrupts its positive feedback mechanism and leads to the normalization of IL-1β-production. Consequently, levels of inflammatory markers are also normalized [Lachmann et al. 2009b]. Canakinumab neither binds to nor inactivates IL-1α or IL-1Ra.
A phase I safety study assessed canakinumab (1, 3, and 10 mg/kg intravenously on days 1 and 15) in healthy volunteers (n = 24). The pharmacokinetics (PK) were found to be linear and typical for an IgG-type antibody. A PK/pharmacodynamic (PD) model predicted that following a single dose of 10 mg/kg of canakinumab, free IL-1β would be reduced by more than 90% for more than 60 days [Bonner et al. 2006].
In a phase II clinical trial, the PK of canakinumab (150 mg subcutaneously) were assessed in NLRP3 mutation-positive clinically affected CAPS patients (n = 7). According to prediction models the application of 150 mg every 8 weeks was expected to maintain a concentration of 1.1 µg/ml in patients with a body mass of more than 40 kg [Lachmann et al. 2009b].
Phase I/IIa dose-titration study [Lachmann et al. 2009b]. Patients with proven NLRP3 gene mutations, the clinical phenotype of CAPS, and the need for treatment were enrolled. Canakinumab was administered at 10 mg/kg intravenously. At relapse these patients were retreated with 1 mg (3 or 5 mg/kg) intravenously (Figure 5). Within 1 day urticarial rashes had disappeared and within 1 week a complete clinical response by an absence of symptoms (skin rash, absence of joint or muscle pain, improvement in arthralgia, normal body temperature, and normal serum values of CRP and SAA) was observed. The complete remission was long-lasting with a median duration of 185 days.
This study also examined the relationship between the duration of clinical remission and IL-1β neutralization. The model took advantage of the fact that when complexed with canakinumab the half-life of IL-1β is extended from its normal 3.5 hours to that of the antibody (30 days). This means that levels of IL-1β previously undetectable in the sera of patients could now be measured accurately.
As IL-1β has been shown to stimulate its own production, in this study canakinumab interfered with this positive feedback mechanism reducing IL-1β production to a normal and constitutive IL-1β-independent rate by suppressing IL-1β.
The pivotal multicenter 48-week phase III trial in CAPS patients consisted of three parts [Lachmann et al. 2009a]. Part 1 was an open-label run-in phase: canakinumab 150 mg in patients weighing >40 kg or 2 mg/kg in patients weighing <40 kg body weight was administered once every 8 weeks. In part 2 (double-blind withdrawal phase), 15 patients received canakinumab and 16 patients received placebo for 24 weeks. Part 3 (open-label treatment phase) had a duration of 16 weeks and 31 patients were included. The primary endpoint of the trial was the proportion of patients with relapse during part 2 [Lachmann et al. 2009a].
In part 1, a complete response to a single dose of canakinumab occurred in 97% of patients by week 8. The response was rapid (within 24 hours) and a complete response occurred by day 8 in 71% of patients. In part 2, all 15 canakinumab recipients remained in remission, compared to 81% of patients in the placebo group who had a relapse (p < 0.001). CRP and SAA levels remained within a normal range in treated patients, but were elevated in the patients who received a placebo (p < 0.001). The median time until disease relapse was 100 days from the start of part 2. All canakinumab recipients compared with 25% of placebo recipients had no or only minimal physician-assessed disease activity (p < 0.001) at the end of part 2. In part 3, the clinical and biochemical remission was reported in 97% of canakinumab-treated patients. No antibodies against canakinumab were detected [Lachmann et al. 2009a].
In a subsequent long-term phase III extension trial, 166 adult and pediatric CAPS patients received canakinumab. Patients with residual symptoms after the first dose received an increased dose of up to 600 mg or 8 mg/kg and/or an increased drug application frequency [Kuemmerle-Deschner et al. 2011a].
Upward dose and frequency adjustments were needed in 24.1% of patients, mostly in children and in patients with severe CAPS phenotypes. Complete response was achieved in 78% (85/109) of canakinumab-naïve patients. Most complete responses (79/85) occurred within 8 days. No relapse was reported in 90% (127/141) patients who underwent a relapse assessment (Figure 6).
Quality of life in canakinumab-treated CAPS patients [Kone-Paut et al. 2011]: In this study the effects of canakinumab on health-related quality of life (HRQoL) in patients with CAPS was determined in addition to efficacy regarding CAPS symptoms. At baseline the HRQoL scores were considerably below those of the general population. Improvement in the SF-36 domain scores was evident by day 8. HRQoL approached or exceeded those of the general US population by week 8 and remained stable throughout canakinumab therapy. Improvement in bodily pain and role-physical were particularly marked.
It has been demonstrated that patients with a more severe phenotype had higher concentrations of IL-1. Therefore, it may be speculated that these patients require higher doses of IL-1 inhibitor for the same clinical effects. This is supported by the fact that the median time for relapse after canakinumab treatment was shortest in the more severe phenotypes [Kuemmerle-Deschner et al. 2011a].
In one study with six NOMID/CINCA patients (aged 11–34 years), patients received 150 mg (2 mg/kg) or 300 mg (4 mg/kg) every 4–8 weeks. A dose increase up to 600 mg (8 mg/kg) was allowed if needed. In 5 out of 6 patients remission was experienced according to patient’s disease activity diaries. However, CRP remained elevated in 1/6 patients and CNS leukocytosis persisted in 5/6 patients. Visual acuity and visual field remained stable throughout the course of the trial. Hearing loss progressed in 1/10 ears by 15–30 dB. In all patients the canakinumab dose had to be increased to the maximum of 600 mg (8 mg/kg), which however was well tolerated by adults and children alike. In 6 patients, 12 infection-associated adverse events (AEs) were recorded. One serious adverse event (SAE) was an abscess due to methicillin-resistant Staphylococcus aureus (MRSA) infection [Goldbach-Mansky et al. 2012].
Caorsi and colleagues recently published results from 13 CAPS patients and demonstrated that in daily practice the use of canakinumab is associated with a persistent satisfactory control of disease activity but needs progressive dose adjustments in more severely affected patients [Caorsi et al. 2013]. The clinical phenotype, rather than age, represented the main variable by which the need for more frequent administrations of the drug at a higher dosage was determined.
The thorough measurement of clinical and laboratory disease activity by using patient diaries, physician’s assessment, and novel and traditional inflammatory markers may show whether the therapeutic goal of controlling disease activity is reached. If not, dose adjustment is needed (Figures 7 and and88).
In one study, the prevalence of patients with NLRP3 polymorphisms in the general population was determined [Aksentijevich et al. 2007]. Many of these patients do not show signs of disease. If, however, patients with NLRP3 polymorphisms become clinically apparent, IL-1 inhibition seems not to be as effective as in other CAPS patients. Various phenotypes have also been described as carriers of identical mutations.
For treatment decisions it has to be considered whether the often unspecific symptoms are indeed related to CAPS. This is particularly challenging in patients without a confirmed genetic mutation. In some patients diagnostic therapy attempts may be undertaken using short-acting IL-1 inhibitors. Clinical response to IL-1 inhibition indicates CAPS disease (Figure 9)
The effects of canakinumab treatment on hearing loss were studied in 63 CAPS patients. Improvement was recorded in 13, no progression of hearing loss was found in 29 patients, and no patient complained about decreased hearing ability [Kuemmerle-Deschner et al. 2011a] (Figure 10). No information is available regarding the ability of canakinumab therapy to affect features such as arthropathy, ocular or CNS damage, or to reverse amyloidosis.
At this point no information regarding canakinumab in pregnancy is available. However, it has been documented that IL-1 inhibition increases fertility. For inclusion in canakinumab trials, women of child-bearing age had been informed not to get pregnant during treatment with canakinumab. During the canakinumab in CAPS trials three pregnancies were recorded. Two patients decided to have the pregnancy terminated. One patient discontinued canakinumab treatment and had a healthy child.
Canakinumab manufacturer’s information recommends starting canakinumab therapy after the course of routine vaccinations has been completed including pneumococci and influenza [Novartis Pharmaceuticals Corporation, 2009]. During the therapy no vaccination involving live vaccines should be applied. It is recommended that canakinumab therapy should not be used 3 months before and after the application of live vaccines, which is a problem in children with active CAPS disease. Currently one trial on vaccinations in children <4 years on canakinumab therapy is being conducted. General recommendations regarding vaccination in patients with biologics treatment state that vaccination with dead vaccines may be applied (evidence level C).
No data from controlled trials are available regarding intervals between canakinumab application and scheduled elective surgery. In general, it is recommended to wait out the duration of two plasma half-lives for biologicals. For the long-lasting canakinumab this would amount to an interval of 8 weeks. Our practical approach is to switch IL-1 inhibition to the short-acting anakinra when surgery is scheduled, in order to avoid disease flares in a long treatment-free interval. After wound-healing is finished we would restart treatment with the long-acting IL-1 inhibitor canakinumab. In one case, the interval between canakinumab application and surgery was only 4 weeks but no complications were recorded. We would also recommend a liberal application of a perioperative antibiotic prophylaxis.
The safety of canakinumab in a large cohort of patients with CAPS was demonstrated using data from the β-confident registry [Hoffman et al. 2012].
Of the 234 patients registered, 65 (27.8%) reported a total of 136 AEs. The incidence rate of AEs in these patients was 101.03/100 patient-years. Infections were the most common AE (45 events) reported in 31 patients (13.2%) with an incidence rate of 33.4/100 patient years. Nasopharyngitis, pneumonia, and urinary tract infections were the most common infections reported. Cumulatively, a total of 20 SAEs with an incidence rate of 9.7/100 patient years were reported in 13 (8.5%) patients.
Further events, such as malignancies, infections, vertigo, and hypersensitivity reactions, were as follows:
CAPS is a rare autosomal-dominant inherited auto-inflammatory disease which encompasses the three entities of FCAS, MWS, and NOMID/CINCA syndrome. In most cases, CAPS is caused by mutations in the NLRP3 gene. The altered gene product cryopyrin activates the inflammasome which leads to excessive production of IL-1β. IL-1β causes the inflammatory manifestations in CAPS: systemic inflammation including fever, headache or fatigue, rash, eye disease, progressive sensorineural hearing loss, musculoskeletal manifestations, and CNS symptoms (NOMID/CINCA only). IL-1 inhibitors are safe and effective therapeutic options and treatment of CAPS should be started early to prevent long-term sequelae.
Canakinumab is a fully human monoclonal antibody against IL-1β. It is generally well tolerated and has a low incidence of side effects. In patients with CAPS, the recommended dose of canakinumab is 150 mg in patients weighing >40 kg or 2 mg/kg in patients weighing <40 kg once every 8 weeks. In the EU second injections of canakinumab (150 mg or 2 mg/kg) can be given within 7 days if no clinical response is achieved. If full response is then achieved, the patient should be maintained on a dosage of 300 mg or 4 mg/kg once every 8 weeks. In the US the manufacturer recommends increasing the initial dosage to 3 mg/kg in children weighing 15–40 kg who have an inadequate response. In patients who respond to the increased dose of 300 mg or 4 mg/kg but develop disease activity after 3–4 weeks, the application interval should also be shortened to dosing every 4 weeks. Patients treated with canakinumab should be carefully monitored for infections including tuberculosis. If possible, patients should be vaccinated prior to canakinumab treatment. No live vaccination during treatment is recommended.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflicts of interest statement: JKD has received grant support and honoraria from Novartis, the manufacturer of canakinumab. IH has nothing to disclose.
Jasmin B. Kuemmerle-Deschner, Division of Pediatric Rheumatology, Department of Pediatrics, University Children’s Hospital Tuebingen, Hoppe-Seyler-Strasse 1, 72076 Tuebingen, Germany.
Iris Haug, Division of Pediatric Rheumatology, Department of Pediatrics, University Hospital, Tuebingen, Germany.