The cryopyrin-associated periodic syndrome (CAPS) is a severity spectrum of rare diseases. CAPS comprises the three conditions previously described as familial cold autoinflammatory syndrome (FCAS), ...Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disorder (NOMID), also known as chronic infantile neurologic, cutaneous, and articular (CINCA) syndrome. The clinical phenotype of CAPS is characterized by systemic inflammation. General symptoms are fatigue and fever. Local manifestations affect multiple tissues such as skin, joints, muscles, eyes, and the central nervous system. Distinct clinical features are characteristic for each subphenotype. In FCAS, these are cold-induced urticaria and fever, in MWS systemic amyloidosis and hearing loss and in NOMID/CINCA central nervous system inflammation and bone deformities. CAPS is caused by single heterozygous germline or somatic gain of function mutations in the
NLRP3
gene encoding the protein cryopyrin. Cryopyrin nucleates an NLRP3 inflammasome, which regulates the activation and cleavage of caspase-1 that cleaves the pro-inflammatory cytokines, IL-1β and IL-18. IL-1β plays the key role in the induction of inflammation in CAPS. This has been confirmed by the application of IL-1 blocking agents, which lead not only to a rapid and sustained reversal of daily symptoms but also to some extent of long-term disease sequelae. To prevent CAPS-induced organ damage, early diagnosis and swift initiation of effective treatment are mandatory.
Objective
To evaluate the efficacy and safety of etanercept in patients with enthesitis‐related arthritis (ERA) in juvenile idiopathic arthritis (JIA).
Methods
This was a 2‐phase study in JIA ...patients with active, refractory ERA. Phase I was an open‐label, uncontrolled 24‐week study period in which all patients were administered etanercept. Patients considered to be treatment responders at week 24 according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) criteria for improvement in juvenile arthritis entered the second phase, a 24‐week randomized, double‐blind, placebo‐controlled withdrawal study, for an additional 24 weeks, for evaluation of the primary end point, occurrence of a disease flare from week 24 to week 48, based on the ACR preliminary definition of disease flare in juvenile arthritis.
Results
Forty‐one patients were enrolled. At week 24, treatment with etanercept resulted in response rates of 93%, 93%, 80%, 56%, and 54% based on the ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and Pedi 100 criteria, respectively. In addition, a marked decrease in all disease activity measures was observed. The mean number of tender joints, swollen joints, and joints with active arthritis decreased by 91%, 97%, and 94%, respectively. Physician's global assessment of disease activity, parent's assessment of patient's overall well‐being, and the Childhood Health Assessment Questionnaire disability index improved by 91%, 80%, and 86%, respectively. The number of tender enthesis sites and total scores for back pain, nocturnal pain, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, and Juvenile Arthritis Disease Activity Score based on 10‐joint counts (JADAS10) decreased by 75%, 72%, 81%, 72%, 85%, and 87%, respectively. In phase II, 38 patients were randomly assigned to receive placebo (n = 18) or to continue receiving etanercept (n = 20). Up to week 48, 12 disease flares occurred, in 9 patients receiving placebo and 3 patients receiving etanercept (odds ratio 6.0, P = 0.02). There were no serious infections, malignancies, or deaths.
Conclusion
In this study of patients with the ERA category of JIA, etanercept proved effective, as indicated by high ACR Pedi response rates and JADAS10 response rates at week 24. Patients who continued treatment with etanercept had significantly fewer flares than those who received placebo, although 50% of patients in the placebo group did not experience a flare. Treatment suspension may be a consideration for patients with the ERA category of JIA who achieve remission.
Cryopyrin-associated periodic syndrome (CAPS) is a rare, heterogeneous disease entity associated with
gene mutations and increased interleukin-1 (IL-1) secretion. Early diagnosis and rapid initiation ...of IL-1 inhibition prevent organ damage. The aim of the study was to develop and validate diagnostic criteria for CAPS. An innovative process was followed including interdisciplinary team building, item generation: review of CAPS registries, systematic literature review, expert surveys, consensus conferences for item refinement, item reduction and weighting using 1000Minds decision software. Resulting CAPS criteria were tested in large cohorts of CAPS cases and controls using correspondence analysis. Diagnostic models were explored using sensitivity analyses. The international team included 16 experts. Systematic literature and registry review identified 33 CAPS-typical items; the consensus conferences reduced these to 14. 1000Minds exercises ranked variables based on importance for the diagnosis. Correspondence analysis determined variables consistently associated with the diagnosis of CAPS using 284 cases and 837 controls. Seven variables were significantly associated with CAPS (p<0.001). The best diagnosis model included: Raised inflammatory markers (C-reactive protein/serum amyloid A) plus ≥two of six CAPS-typical symptoms: urticaria-like rash, cold-triggered episodes, sensorineural hearing loss, musculoskeletal symptoms, chronic aseptic meningitis and skeletal abnormalities. Sensitivity was 81%, specificity 94%. It performed well for all CAPS subtypes and regardless of
mutation. The novel approach integrated traditional methods of evidence synthesis with expert consensus, web-based decision tools and innovative statistical methods and may serve as model for other rare diseases. These criteria will enable a rapid diagnosis for children and adults with CAPS.
The cryopyrin-associated periodic syndromes (CAPS) are usually caused by heterozygous
gene variants, resulting in excessive inflammasome activation with subsequent overproduction of interleukin ...(IL)-1β. The CAPS spectrum includes mild, moderate, and severe phenotypes. The mild phenotype is called familial cold autoinflammatory syndrome (FCAS), the moderate phenotype is also known as Muckle-Wells syndrome (MWS), and the neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic cutaneous articular syndrome (CINCA) describes the severe phenotype. The CAPS phenotypes display unspecific and unique clinical signs. Dermatologic, musculoskeletal, ocular, otologic, and neurologic disease symptoms combined with chronic systemic inflammation are characteristic. Nevertheless, making the CAPS diagnosis is challenging as several patients show a heterogeneous multi-system clinical presentation and the spectrum of genetic variants is growing. Somatic mosaicisms and low-penetrance variants lead to atypical clinical symptoms and disease courses. To avoid morbidity and to reduce mortality, early diagnosis is crucial, and a targeted anti-IL-1 therapy should be started as soon as possible. Furthermore, continuous and precise monitoring of disease activity, organ damage, and health-related quality of life is important. This review summarizes the current evidence in diagnosis and management of patients with CAPS.
Background
The interleukin‐1 (IL‐1) mediated systemic autoinflammatory diseases, including the cryopyrin‐ associated periodic syndromes (CAPS), tumour necrosis factor receptor‐associated periodic ...syndrome (TRAPS), mevalonate kinase deficiency (MKD) and deficiency of the IL‐1 receptor antagonist (DIRA), belong to a group of rare immunodysregulatory diseases that primarily present in early childhood with variable multiorgan involvement. When untreated, patients with severe clinical phenotypes have a poor prognosis, and diagnosis and management of these patients can be challenging. However, approved treatments targeting the proinflammatory cytokine IL‐1 have been life changing and have significantly improved patient outcomes.
Objective
To establish evidence‐based recommendations for diagnosis, treatment and monitoring of patients with IL‐1 mediated autoinflammatory diseases to standardise their management.
Methods
A multinational, multidisciplinary task force consisting of physician experts, including rheumatologists, patients or caregivers and allied healthcare professionals, was established. Evidence synthesis, including systematic literature review and expert consensus (Delphi) via surveys, was conducted. Consensus methodology was used to formulate and vote on statements to guide optimal patient care.
Results
The task force devised five overarching principles, 14 statements related to diagnosis, 10 on therapy, and nine focused on long‐term monitoring that were evidence and/or consensus‐based for patients with IL‐1 mediated diseases. An outline was developed for disease‐specific monitoring of inflammation‐induced organ damage progression and reported treatments of CAPS, TRAPS, MKD and DIRA.
Conclusion
The 2021 EULAR/American College of Rheumatology points to consider represent state‐of‐the‐art knowledge based on published data and expert opinion to guide diagnostic evaluation, treatment and monitoring of patients with CAPS, TRAPS, MKD and DIRA, and to standardise and improve care, quality of life and disease outcomes.
Objective
To assess long‐term efficacy and safety of canakinumab and the response to vaccination in children ages ≤5 years with cryopyrin‐associated periodic syndrome (CAPS).
Methods
CAPS patients ...(ages ≤5 years) received 2 mg/kg canakinumab subcutaneously every 8 weeks; patients with neonatal‐onset multisystem inflammatory disease (NOMID) received a starting dose of 4 mg/kg in this open‐label trial. Efficacy was evaluated using physician global assessment of disease activity and serum levels of C‐reactive protein (CRP) and amyloid A (SAA). Adverse events (AEs) were recorded. Vaccination response was evaluated using postvaccination antibody titers at 4 and 8 weeks after immunization.
Results
Of the 17 patients enrolled, 12 (71%) had Muckle‐Wells syndrome, 4 (24%) had NOMID, and 1 (6%) had familial cold autoinflammatory syndrome. All 17 patients had a complete response to canakinumab. Disease activity improved according to the physician global assessment, and for 65% of the patients autoinflammatory disease was characterized as “absent” at the end of the study. Median CRP levels decreased over time. No such change was evident in SAA levels. During the extension study, postvaccination antibody titers increased above protective levels in 16 (94%) of 17 assessable vaccinations. Ten of the patients (59%) had AEs suspected to be related to canakinumab; 8 (47%) experienced at least 1 serious AE (SAE). None of the AEs or SAEs required interruption of canakinumab therapy.
Conclusion
Our findings indicate that canakinumab effectively maintains efficacy through 152 weeks and appears to have no effect on the ability to produce antibodies against standard childhood non‐live vaccines. The safety profile of canakinumab was consistent with previous studies, supporting long‐term use of canakinumab for CAPS in children ≤5 years of age.
Abstract Autoinflammatory disorders are characterized by usually unprovoked recurrent episodes of features of inflammation caused by activation of the innate immune system. Many autoinflammatory ...disorders – the monogenetic defects in particular – are associated with alterations of inflammasomes. Inflammasomes are complex multimolecular structures, which respond to “danger” signals by activation of cytokines. Among these, IL-1 is the key player of the innate immune response and inflammation. Consequently, IL-1 blocking strategies are specific pathway targeting therapies in autoinflammatory diseases and applied in CAPS, colchicine-resistant FMF, TRAPS, HIDS and DIRA. A number of rare genetic disorders involve inflammasome malfunction resulting in enhanced inflammatory response. IL-1 inhibition to date is the most successful specific therapy in autoinflammatory disorders. Here, current treatment strategies in autoinflammatory disorders are reviewed with a focus on inflammasome and cytokine inhibition.
The cryopyrin-associated periodic syndrome (CAPS) is associated with an overproduction of interleukin-1. Canakinumab, an anti–interleukin-1β monoclonal antibody, was given to 35 patients with CAPS ...and was found to induce remission in most of the patients.
The cryopyrin-associated periodic syndrome (CAPS) is associated with an overproduction of interleukin-1. Canakinumab, an anti–interleukin-1β monoclonal antibody, was given to patients with CAPS and was found to induce remission in most of the patients.
The cryopyrin-associated periodic syndrome (CAPS) comprises a spectrum of apparently distinct, rare, inherited inflammatory disorders of increasing severity, including the familial cold autoinflammatory syndrome, the Muckle–Wells syndrome, and neonatal-onset multisystem inflammatory disorder (also known as the chronic infantile neurologic, cutaneous, and articular syndrome). Patients with these disorders have severe fatigue, fever, and influenza-like myalgia from infancy, together with chronic anemia and inflammation of the skin, eyes, bones, joints, and meninges. Clinical features include rash, conjunctivitis, arthritis, chronic meningitis, sensorineural deafness, and intellectual impairment. Systemic AA amyloidosis that causes renal failure and usually results in death within 5 to 10 years . . .
: Autoinflammatory diseases are characterised by fever and systemic inflammation, with potentially serious complications. Owing to the rarity of these diseases, evidence-based guidelines are lacking. ...In 2012, the European project Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate regimens for the management of children and young adults with rheumatic diseases, facilitating the clinical practice of paediatricians and (paediatric) rheumatologists. One of the aims of SHARE was to provide evidence-based recommendations for the management of the autoinflammatory diseases cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) and mevalonate kinase deficiency (MKD). These recommendations were developed using the European League Against Rheumatism standard operating procedure. An expert committee of paediatric and adult rheumatologists was convened. Recommendations derived from the systematic literature review were evaluated by an online survey and subsequently discussed at a consensus meeting using Nominal Group Technique. Recommendations were accepted if more than 80% agreement was reached. In total, four overarching principles, 20 recommendations on therapy and 14 recommendations on monitoring were accepted with ≥80% agreement among the experts. Topics included (but were not limited to) validated disease activity scores, therapy and items to assess in monitoring of a patient. By developing these recommendations, we aim to optimise the management of patients with CAPS, TRAPS and MKD.
Objective
Periodic fever syndrome (PFS) conditions are characterized by recurrent attacks of fever and localized inflammation. This study examined the diagnostic pathway and treatments at tertiary ...centers for familial Mediterranean fever (FMF), tumor necrosis factor receptor–associated periodic syndrome (TRAPS), and mevalonate kinase deficiency (MKD)/hyperimmunoglobulinemia D syndrome (HIDS).
Methods
PFS specialists at medical centers in the US, the European Union, and the eastern Mediterranean participated in a retrospective chart review, providing de‐identified data in an electronic case report form. Patients were treated between 2008 and 2012, with at least 1 year of followup; all had clinical and/or genetically proven disease and were on/eligible for biologic treatment.
Results
A total of 134 patients were analyzed: FMF (n = 49), TRAPS (n = 47), and MKD/HIDS (n = 38). Fever was commonly reported as severe across all indications. Other frequently reported severe symptoms were serositis for FMF patients and elevated acute‐phase reactants and gastrointestinal upset for TRAPS and MKD/HIDS. A long delay from disease onset to diagnosis was seen within TRAPS and MKD/HIDS (5.8 and 7.1 years, respectively) compared to a 1.8‐year delay in FMF patients. An equal proportion of TRAPS patients first received anti–interleukin‐1 (anti‐IL‐1) and anti–tumor necrosis factor (anti‐TNF) biologic agents, whereas IL‐1 blockade was the main choice for FMF patients resistant to colchicine and MKD/HIDS patients. For TRAPS patients, treatment with anakinra versus anti‐TNF treatments as first biologic agent resulted in significantly higher clinical and biochemical responses (P = 0.03 and P < 0.01, respectively). No significant differences in responses were observed between biologic agents among other cohorts.
Conclusion
Referral patterns and diagnostic delays highlight the need for greater awareness and improved diagnostics for PFS. This real‐world treatment assessment supports the need for further refinement of treatment practices.
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