Cryopyrin-associated Periodic Syndrome Patients Research Articles

Efficacy and safety analysis of off-label treatment with biologics in autoinflammatory diseases : Experiences from aGerman registry(GRAID2)

To evaluate the safety and efficacy of therapy with biologics in patients with autoinflammatory diseases (AIF) or macrophage activating syndrome (MAS) in areal-life setting in Germany. The German Register of Autoimmune Diseases2 (GRAID2) is aretrospective, non-interventional, multicenter registry collecting data from all patients with inflammatory rheumatic diseases refractory to conventional therapy and treated with initial off-label biologics between August 2006 and December 2013. Patients with MAS could be included without prior treatment with abiologic agent. Data from 26patients with AIF and 5with MAS were collected. Of the AIF patients 13(50%) were diagnosed with adult onset Still's disease (AOSD), 6(23%) with familial Mediterranean fever (FMF), 4(15.4%) with tumor necrosis factor-associated periodic syndrome (TRAPS), 1(3.8%) patient with cryopyrin-associated periodic syndrome (CAPS) and 2(8%) with undifferentiated fever syndromes. The 5MAS patients suffered from rheumatoid arthritis (RA) with chronic myeloid leukemia, systemic lupus erythematosus and in 2cases AOSD. In 1patient achronic neurological disease was documented without further differentiaton. All patients with TRAPS were primarily treated with etanercept and all CAPS patients with canakinumab. The AOSD and FMF patients were treated with anakinra as the first line off-label biologic in 6 out of 13 and 5 out of 6cases, respectively. The MAS patients responded very well or well to therapy in 40% and 60% had amoderate response. There were no non-responders. Within the group of AIF patients the physicians documented avery effective or effective treatment in 38.5%, amoderate response in 30.8% and no response in 30.7%. The tolerance was very good in 5 out of 5of the MAS and in 92% of the AIF patients. The data of this retrospective register provide indications for an effective and safe treatment with off-label biologic medication in patients with AIF and MAS in daily practice.

Real-World Experience and Impact of Canakinumab in Cryopyrin-Associated Periodic Syndrome: Results From a French Observational Study.

The ENVOL study was designed to assess the psychosocial impact of disease and therapy in a French cohort of cryopyrin-associated periodic syndromes (CAPS) patients (and caregivers) treated with canakinumab. The ENVOL study was a multicenter, observational study of CAPS patients given ≥1 canakinumab dose. Data were collected before treatment, at 6 and 12 months afterward, and at the last visit. Patients and caregivers completed questionnaires assessing changes from the 12 months of pretreatment to 12 months prior to interview. Data were analyzed retrospectively. The study included 10 physicians and 68 patients (53 adults, 15 children). Sixty-five patients (95.6%) were still receiving canakinumab at the last visit (median 5 years after starting therapy). The mean ± SD score for patient-reported general health increased from 7 ± 2.9 before canakinumab to 2.7 ± 2.7 after treatment (P < 0.001). Physical and emotional symptoms resolved or improved in a substantial proportion of patients, including bodily pain (38 of 46 patients), fever (32 of 39), skin disease (35 of 41), fatigue (31 of 47), self-confidence (29 of 46), and energy (34 of 47). Social activity, relationships, sexuality, and energy measures improved in >40% of respondents. Caregivers spent a median of 3 versus 0.5 hours/week on care in the 12 months of pretreatment versus 12 months prior to interview (P < 0.001). Following treatment, patients required fewer consultations with general practitioners (mean ± SD per patient per year: 5.2 ± 7.4 versus 8.5 ± 7.2 pretreatment), internists/rheumatologists/dermatologists (2.0 ± 2.1 versus 3.7 ± 3.9), and pediatricians (1.8 ± 1.5 versus 4.4 ± 4.2). Long-term treatment with canakinumab achieves a highly relevant improvement in the physical, emotional, and social lives of patients with CAPS, accompanied by a marked reduction in support required from caregivers and in health care consultations.

Safety of vaccinations in patients with cryopyrin-associated periodic syndromes: a prospective registry based study.

Pneumococcal, tetanus and influenza vaccinations are recommended for patients with cryopyrin-associated periodic syndromes (CAPS) when treated with immunosuppressive medication. The aim of this publication is to report the safety of pneumococcal and other vaccinations in CAPS patients. All CAPS patients followed in the β-CONFIDENT (Clinical Outcomes and Safety Registry study of Ilaris patients) registry were analysed if they had received a vaccination. The β-CONFIDENT registry is a global, long-term, prospective, observational registry, capturing and monitoring patients treated with canakinumab. Sixty-eight CAPS patients had received a total of 159 vaccine injections, 107 injections against influenza, 19 pneumococcal vaccinations, 12 against tetanus/diphtheria antigens and 21 other vaccinations. Fourteen per cent of injections had elicited at least one vaccine reaction. All five vaccine-related serious adverse events were associated with pneumococcal vaccination. Vaccine reactions were observed in 70% of pneumococcal vaccinations, compared with 7% in influenza and 17% in tetanus/diphtheria vaccinations. The odds ratios to react to the pneumococcal vaccines compared with influenza and tetanus/diphtheria vaccines were 31.0 (95% CI: 8, 119) and 10.8 (95% CI: 2, 74). Vaccine reactions after pneumococcal vaccinations were more severe and lasted significantly longer (up to 3 weeks) compared with other vaccinations. In two patients, pneumococcal vaccination also elicited symptoms consistent with systemic inflammation due to CAPS reactivation. Pneumococcal vaccines, unlike other vaccines, frequently trigger severe local and systemic inflammation in CAPS patients. Clinicians must balance potential benefits of pneumococcal immunization against safety concerns. The 13-valent pneumococcal conjugate vaccine might be favourable over the polysaccharide vaccine in CAPS patients.

Induction of Myeloid-Derived Suppressor Cells in Cryopyrin-Associated Periodic Syndromes

Cryopyrin-associated periodic syndromes (CAPS) are caused by mutations in the NLRP3 gene leading to overproduction of IL-1β and other NLRP3 inflammasome products. Myeloid-derived suppressor cells (MDSCs) represent a novel innate immune cell subset capable of suppressing T-cell responses. As inflammasome products were previously found to induce MDSCs, we hypothesized that NLRP3 inflammasome-dependent factors induce the generation of MDSCs in CAPS. We studied neutrophilic MDSCs, their clinical relevance, and MDSC-inducing factors in a unique cohort of CAPS patients under anti-IL-1 therapy. Despite anti-IL-1 therapy and low clinical disease activity, CAPS patients showed significantly elevated MDSCs compared to healthy controls. MDSCs were functionally competent, as they suppressed polyclonal T-cell proliferation, as well as Th1 and Th17 responses. In addition, MDSCs decreased monocytic IL-1β secretion. Multiplex assays revealed a distinct pattern of MDSC-inducing cytokines, chemokines, and growth factors. Experimental analyses demonstrated that IL-1 cytokine family members and autoinflammation-associated alarmins differentially induced human MDSCs. Increased MDSCs might represent a novel autologous anti-inflammatory mechanism in autoinflammatory conditions and may serve as a future therapeutic target.

Real-life effectiveness of canakinumab in cryopyrin-associated periodic syndrome.

Cryopyrin-associated periodic syndrome (CAPS) is a heterogeneous group of diseases characterized by excessive IL-1β release resulting in severe systemic and organ inflammation. Canakinumab targets IL-1β and is approved at standard dose for children and adults with all CAPS phenotypes. Limited data are available for the real-life effectiveness of canakinumab in patients living with CAPS. Therefore the aim of the study was to evaluate the real-life dosing and effectiveness of canakinumab in CAPS. A multi-centre study of consecutive children and adults with CAPS treated with canakinumab was performed. Demographics, CAPS phenotype and disease activity, inflammatory markers and canakinumab treatment strategy were recorded. Treatment response was assessed using CAPS disease activity scores, CRP and/or serum amyloid A levels. Comparisons between age groups, CAPS phenotypes and centres were conducted. A total of 68 CAPS patients at nine centres were included. All CAPS phenotypes were represented. Thirty-seven (54%) patients were females, the median age was 25 years and 27 (40%) were children, and the median follow-up was 28 months. Overall, complete response (CR) was seen in 72% of CAPS patients, significantly less often in severe (14%) than in mild CAPS phenotypes (79%). Only 53% attained CR on standard dose canakinumab. Dose increase was more commonly required in children (56%) than in adults (22%). Centres with a treat-to-target approach had significantly higher CR rates (94 vs 50%). Real-life effectiveness of canakinumab in CAPS was significantly lower than in controlled trials. Treat-to-target strategies may improve the outcome of children and adults living with CAPS.

Cryopyrin associated periodic syndromes (CAPS): immunological characterization of knock-in mouse model to exploit novel approaches for the modulation of the NLRP3 inflammasome.

Question CAPS are autoinflammatory diseases characterized by recurrent episodes of fever and systemic inflammation, subdivides into three different severity phenotypes (FCAS, MWS, CINCA). These syndromes are caused by mutations of NLRP3 gene coding for an intracellular multiprotein complex that mediates IL-1b processing and secretion. These mutations are gain-of-function, resulting in an inflammasome hyperactivity and IL-1b hypersecretion. We aimed to: increase the knowledge on pathologic consequences of NLRP3 mutations in CAPS patients; understand the molecular and regulatory mechanisms of CAPS disease; identify novel molecular targets for the treatment of cryopyrin/NLRP3 related disorders.

Various inflammatory phenotypes in V200M NLRP3 carriers

Background Cryopyrin-associated periodic syndrome (CAPS) is a very rare auto-inflammatory syndrome. CAPS is caused by mutations of the NLRP3 gene that encodes crypopyrin protein that is a part of inflammasome complex. CAPS patients can present with different phenotypes of the disease Familial cold urticaria, Muckle-Wells syndrome, and the most severe phenotype neonatal onset multisystem inflammatory disease (NOMID). CAPS patients experience symptoms of systemic inflammation, intense fatigue and have poor quality of life. In the most severe forms, they may develop serious organ damage such as visual and hearing impairment, arthritis, neurological deterioration and renal insufficiency. However, V200M mutation has been associated with mild inflammatory phenotype and its pathogenic role is even questioned by some. We report two families of V200M mutation carriers, with variable inflammatory phenotypes. In all cases mutations of MEFV, MVK, TNFRSF1A genes were excluded.

Whole Exome Sequencing reveals a NLRP3 mutation in exon 5 in a patient with CINCA

Cryopyrin-associated periodic Syndromes (CAPS) are caused by heterozygous mutations in the NLRP3 gene. More than 80 disease causing mutations have been identified, mostly clustered in NLRP3 exon 3, but also described in exons 4 and 6. However, up to 50% of clinically diagnosed CAPS patients (with identical clinical features and response to anti-IL-1 treatment) show no mutation in NLRP3 detected by conventional DNA sequencing analysis of exons 3, 4 and 6. Recently somatic NLRP3 mosaicism has been shown to account for up to 70% of these mutation negative CAPS patients.

Tr1 Cells, but Not Foxp3+ Regulatory T Cells, Suppress NLRP3 Inflammasome Activation via an IL-10-Dependent Mechanism.

The two best-characterized types of CD4(+) regulatory T cells (Tregs) are Foxp3(+) Tregs and Foxp3(-) type 1 regulatory (Tr1) cells. The ability of Foxp3(+) Tregs and Tr1 cells to suppress adaptive immune responses is well known, but how these cells regulate innate immunity is less defined. We discovered that CD44(hi)Foxp3(-) T cells from unmanipulated mice are enriched in Tr1 cell precursors, enabling differentiation of cells that express IL-10, as well as Tr1-associated cell surface markers, CD49b and LAG-3, and transcription factors, cMaf, Blimp-1, and AhR. We compared the ability of Tr1 cells versus Foxp3(+) Tregs to suppress IL-1β production from macrophages following LPS and ATP stimulation. Surprisingly, Tr1 cells, but not Foxp3(+) Tregs, inhibited the transcription of pro-IL-1β mRNA, inflammasome-mediated activation of caspase-1, and secretion of mature IL-1β. Consistent with the role for IL-10 in Tr1 cell-mediated suppression, inhibition of inflammasome activation and IL-1β secretion was abrogated in IL-10R-deficient macrophages. Moreover, IL-1β production from macrophages derived from Nlrp3(A350V) knockin mice, which carry a mutation found in cryopyrin-associated periodic syndrome patients, was suppressed by Tr1 cells but not Foxp3(+) Tregs. Using an adoptive transfer model, we found a direct correlation between Tr1 cell engraftment and protection from weight loss in mice expressing a gain-of-function NLRP3. Collectively, these data provide the first evidence for a differential role of Tr1 cells and Foxp3(+) Tregs in regulating innate immune responses. Through their capacity to produce high amounts of IL-10, Tr1 cells may have unique therapeutic effects in disease-associated inflammasome activation.

How to Diagnose and Manage Systemic Autoinflammatory Diseases in Childhood

Systemic autoinflammatory diseases (sAIDs) are severe disabling conditions associated with a significant morbidity and limited awareness. Cryopyrin-associated periodic syndrome (CAPS) and systemic juvenile idiopathic arthritis (sJIA) are two prototype sAIDs that present with chronic urticarial or maculo-papular rash in early childhood. A diagnosis of sAID relies on combined clinical symptoms, a positive family history, where applicable, and typical laboratory results. Treatment with anti-cytokine blockers targeting interleukin-1 (IL-1) or IL-6 is effective in reducing clinical symptoms and inflammatory markers and approved for the treatment of CAPS and/or sJIA. In order to prevent severe complications such as amyloidosis, destructive arthropathy or macrophage activation syndrome (MAS), it is important to diagnose patients early and to initiate anti-IL-1 blockade in symptomatic CAPS patients and anti-IL-1 or anti-IL-6 blockade in therapy-refractive sJIA patients without delay.

A functional inflammasome activation assay differentiates patients with pathogenic NLRP3 mutations and symptomatic patients with low penetrance variants

Cryopyrin-associated periodic syndromes (CAPS) are characterized by recurrent episodes of systemic inflammation caused by mutations in the NLRP3 gene. Besides confirmed pathogenic NLRP3 mutations, patients with CAPS-like symptoms frequently show low penetrance variants in NLRP3. The disease relevance of these variants is inconsistent. In this study, we investigated if an inflammasome activation assay differentiates between patients with confirmed pathogenic CAPS mutations, patients with low penetrance NLRP3 variants (V198M and Q703K) and healthy controls. The release of mature IL-1β, IL-18, and caspase-1 into cell culture supernatants after 4h of inflammasome stimulation was significantly increased in patients with confirmed pathogenic CAPS mutations compared to low penetrance NLRP3 variants and controls. IL-1β secretion in CAPS patients correlated with disease severity. This inflammasome activation assay differentiates between autoinflammation patients with confirmed pathogenic CAPS mutations and patients with low penetrance NLRP3 variants, and points towards alternative pathophysiological mechanisms in low penetrance NLRP3 variants.

The interleukin 1 inhibitor canakinumab in the treatment of cryopyrin-associated periodic syndromes (CAPS): clinical experience

Interleukin (IL) 1β is a major mediator of cryopyrin-associated periodic syndrome (CAPS). In this connection, the experience with IL-1 inhibitors used in patents with CAPS is being accumulated worldwide. Canakinumab was approved by FDA and EMEA in 2009 to treat CAPS and registered in the Russian Federation for this in 2011. The drug has been shown to be highly effective and well tolerated by patients with CAPS. Objective : to present Russia's experience in using the IL-1 inhibitor canakinumab in children with CAPS. Subjects and methods. The trial enrolled 6 CAPS patients, including 4 with Muckle-Wells Syndrome (MWS) and 4 with chronic infantile onset neurologic cutaneous articular/neonatal onset multisystem inflammatory disease (CINCA/NOMID), among whom there were 5 female patients aged 3.5 to 40 years and 1 male patient aged 17 years. Two patients (a 17-year-old daughter and her 40-year-old mother) were stated to have a familial MWS case. The duration of the disease was 3.5 to 33 years. All the patients underwent a molecular genetic analysis for mutations in the NLRP3 (CIAS1) gene. Four patients with MWS were found to have Thr436Ile and Thr438Ile mutations; the mother and her daughter had Thr350Met mutations; no mutations were detected in 2 patients with CINCA/NOMID. At the study, one female patient with MWS took gluco-corticoids (GC) in a dose of 0.1 mg/kg; the others received symptomatic therapy with nonsteroidal antiinflammatory drugs. Canakinumab was injected subcutaneously every 8 weeks in a dose of 4 mg/kg for patients with a body weight of &lt;15 kg and in a dose of 2 mg/kg for those with a body weight of &gt;15 kg. By now, 2 patients with MWS received 7 injections of the drug (a 48-week follow-up); 2 patients with CINCA/NOMID had its 6 injections (a 40-week follow-up) and 2 patients with MWS had 2 injections (a 10-week follow-up). Results . All the patients showed a significant clinical improvement: recovery; elimination of fever, rash, and eye symptoms; and a reduction in the levels of acute-phase markers. The effect retained throughout the follow-up. GC could be completely discontinued in the female patient with MWS. No adverse events were observed in any case. Conclusion . The experience in using canakinumab in the patients with CAPS showed the high efficacy and good tolerability of the drug. The decrease in acute-phase markers was slower in the patients with CINCA/NOMID, the most severe form of CAPS.

Interleukine-6 and TNFα blockers provide only partial and short-term temporal improvement in cryopyrin-associated periodic syndrome

Cryopyrin-associated periodic syndrome (CAPS) is an inherited disease which is caused by gain-of function mutations in CIAS1 gene function resulting in increased secretion of active IL-1β. IL-1β also can stimulate the production of other proinflammatory cytokines, such as IL-6, TNFα and so on (downstream cascade). The use of IL-1 blockers dramatically controls inflammation in CAPS patients and provide a persistent amelioration of the inflammatory manifestations. The data about using of IL-6 or TNFα blockers in CAPS are very limited.

The IL-1 receptor antagonist anakinra (kineret®) stabilizes the NLRP3 mutation-specific risk for hearing loss in patients with severe cryopyrin-associated periodic syndromes (CAPS)

CAPS is a rare monogenic autoinflammatory syndrome consisting of a spectrum of three conditions: Familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and the most severe form, NOMID/CINCA. Progressive hearing loss is a characteristic of severe CAPS [1]. Previous analyses showed that long-term anakinra treatment stabilized the progression of hearing loss [2,3]. CAPS patients with different NLRP3 mutations have distinctly different trajectories of hearing loss, suggesting a mutation-specific risk that should be considered when making treatment decisions [4].

The role of somatic NLRP3 mosaicism and new gene discovery in mutation negative cryopyrin-associated periodic syndrome patients

Cryopyrin associated periodic syndromes (CAPS) are caused by autosomal dominant gain of function mutations in the NLRP3 gene. However, up to 50% of clinically diagnosed CAPS patients with typical clinical features and good response to anti-IL-1b treatment have no mutation detected by conventional Sanger DNA sequencing. Recent studies suggest that somatic NLRP3 mosaicism may account for a proportion of these apparently “mutation-negative” patients. Another possible explanation is that CAPS can be caused by other genetic mutations.

Impaired cytokine responses in patients with cryopyrin-associated periodic syndrome (CAPS).

Cryopyrin-associated periodic syndrome (CAPS) is characterized by dysregulated inflammation with excessive interleukin (IL)-1β activation and secretion. Neonatal-onset multi-system inflammatory disease (NOMID) is the most severe form. We explored cytokine responses in 32 CAPS patients before and after IL-1β blocking therapy. We measured cytokines produced by activated peripheral blood monuclear cells (PBMCs) from treated and untreated CAPS patients after stimulation for 48 h with phytohaemagglutinin (PHA), PHA plus IL-12, lipopolysaccharide (LPS) or LPS plus interferon (IFN)-γ. We measured IL-1β, IL-6, IL-10, tumour necrosis factor (TNF), IL-12p70 and IFN-γ in the supernatants. PBMCs from three untreated CAPS patients were cultured in the presence of the IL-1β blocker Anakinra. Fifty healthy individuals served as controls. CAPS patients had high spontaneous production of IL-1β, IL-6, TNF and IFN-γ by unstimulated cells. However, stimulation indexes (SIs, ratio of stimulated to unstimulated production) of these cytokines to PHA and LPS were low in NOMID patients compared to controls. Unstimulated IL-10 and IL-12p70 production was normal, but up-regulation after PHA and LPS was also low. LPS plus IFN-γ inadequately up-regulated the production of IL-1β, IL-6, TNF and IL-10 in CAPS patients. In-vitro but not in-vivo treatment with Anakinra improved SIs by lowering spontaneous cytokine production. However, in-vitro treatment did not improve the low stimulated cytokine levels. Activating mutations in NLRP3 in CAPS are correlated with poor SIs to PHA, LPS and IFN-γ. The impairment in stimulated cytokine responses in spite of IL-1β blocking therapy suggests a broader intrinsic defect in CAPS patients, which is not corrected by targeting IL-1β.

A case of cryopyrin-associated periodic syndrome with kidney transplant failure.

The cryopyrin-associated periodic syndrome (CAPS) is an autosomal dominant autoinflammatory disease characterized by fever, skin rash, and joint involvement with acute inflammatory response. The genetic defect involves the NLRP3 gene that encodes cryopyrin and leads to an abnormal production of interleukin-1 (IL-1). Therefore, anti-IL-1 treatment represents an effective therapy. One of the most severe manifestations of the disease is secondary amyloidosis that causes renal failure. We present a patient with CAPS who underwent renal transplantation for renal insufficiency caused by amyloidosis. The function of the transplanted kidney deteriorated because of the late administration of IL-1 receptor antagonist, anakinra. This case may indicate the importance of early initiation of anti-IL-1 treatment in CAPS patients who have undergone kidney transplantation.

PReS-FINAL-2240: Serum amyloid protein a concentration in CAPS patients treated with anti IL1Β

Although all patients with chronic inflammatory conditions are at risk for developing type AA amyloidosis, the incidence varies widely between the different Autoinflammatory syndromes. The reported incidence is about 35% of patients with CAPS (cryopyrin-associated periodic syndrome) which comprises familial cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome and CINCA (chronic infantile neurological cutaneous, articular inflammatory syndrome). CAPS is associated with mutations in NLRP3/CIAS1 on chromosome 1q44, found only in about 50% of patients. Previous studies have demonstrated that IL-1β inhibitors are able to induce complete remission of clinical manifestations and suppression of markers of inflammation in the majority of patients.

Canakinumab in patients with cryopyrin-associated periodic syndrome: an update for clinicians

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.

Methodological challenges in monitoring new treatments for rare diseases: lessons from the cryopyrin-associated periodic syndrome registry

BackgroundThe Cryopyrin-Associated Periodic Syndromes (CAPS) are a group of rare hereditary autoinflammatory diseases and encompass Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS), and Neonatal Onset Multisystem Inflammatory Disease (NOMID). Canakinumab is a monoclonal antibody directed against IL-1 beta and approved for CAPS patients but requires post-approval monitoring due to low and short exposures during the licensing process. Creative approaches to observational methodology are needed, harnessing novel registry strategies to ensure Health Care Provider reporting and patient monitoring.MethodsA web-based registry was set up to collect information on long-term safety and effectiveness of canakinumab for CAPS.ResultsStarting in November 2009, this registry enrolled 241 patients in 43 centers and 13 countries by December 31, 2012. One-third of the enrolled population was aged < 18; the overall population is evenly divided by gender. Enrolment is ongoing for children.ConclusionsInnovative therapies in orphan diseases require post-approval structures to enable in depth understanding of safety and natural history of disease. The rarity and distribution of such diseases and unpredictability of treatment require innovative methods for enrolment and follow-up. Broad international practice-based recruitment and web-based data collection are practical.