ABSTRACT
Introduction: Despite its high potential, patient feedback does not always result in learning. For feedback to be effective students must engage with it, which partly depends on their perceptions of feedback. To better understand student engagement with patient feedback in a clinical context, this study explored the following research questions: 1) What are medical students' general beliefs about patient feedback and what are their specific perceptions of feedback messages? 2) What is the difference between these general beliefs and feedback message perceptions before and after patient feedback training? Methods: The study context was a 12-week clerkship combining Pediatrics and Gynecology, which included feedback training for students and asking for patient feedback. Ninety 4th-year medical students completed pre- and post-clerkship questionnaires. The questionnaires (Beliefs about Patient Feedback Questionnaire, Feedback Perception Questionnaire) were adapted from validated peer-feedback questionnaires. Questionnaires were quantitatively analyzed. Results: Both pre- and post-clerkship, students had positive general beliefs about patient feedback and positive perceptions of the feedback messages they received. However, paired t-tests showed that students' general beliefs and feedback message perceptions became less positive after feedback training and experience. Discussion: Patient feedback is not an easy means to learn and students do not become feedback literate in terms of patient feedback overnight. We suggest that future researchers further explore reasons for the decline in positive perceptions of patient feedback. We suggest implementing longitudinal feedback training in medical curricula, where students are guided and supported in the complex task of learning from patients through feedback.
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Clinical Clerkship , Feedback , Students, Medical , Humans , Students, Medical/psychology , Students, Medical/statistics & numerical data , Surveys and Questionnaires , Clinical Clerkship/methods , Female , Male , Perception , Adult , Education, Medical, Undergraduate/methodsABSTRACT
Background: Developing theoretical courses for post-graduate medical training that are aligned to current workplace-based learning practices and adaptive to change in the field is challenging, especially in (sub) specialties where time for re-design is limited and needs to be performed while education continues. Approach: An instructional design method was applied based on flexible co-design to improve post-graduate theoretical courses in child and adolescent psychiatry (CAP) in the Netherlands. In four phases over a period of three years, courses were re-designed at a national level. Evaluation: Once common vision and learning goals were agreed upon and the prototype was developed (phases 1 and 2), the first courses could be tested in daily practice (phase 3). Phase 4 refined these courses in brief iterative cycles and allowed for designing additional courses building on and adding to previous experiences in brief iterative cycles. The resulting national theoretical courses re-allocated resources previously spent on a local level using easily accessible online tools. This allowed trainees to align content with their clinical rotations, personal preferences and training schedules. Reflection: The development of theoretical courses for post-graduate medical training in smaller medical (sub-)specialties with limited resources may profit from a flexible instructional design method. We consider the potential merit of such a method to other medical specialties and other (inter-)national efforts to develop theoretical teaching courses. A longer-term implementation evaluation is needed to show to what extent the investment made in the re-design proves to be future-proof and enables rapid adaptation to changes in the field.
Subject(s)
Education, Medical, Graduate , Humans , Education, Medical, Graduate/methods , Netherlands , Curriculum/trends , Adolescent Psychiatry/education , Adolescent Psychiatry/methods , Child Psychiatry/education , Child Psychiatry/methodsABSTRACT
OBJECTIVES: The study is aimed to evaluate the impact of safety events in the Eurofever registry for Autoinflammatory diseases. METHODS: This was a retrospective and longitudinal observational multicentre study. Data were retrieved from the international registry Eurofever, starting patients' enrolment since 2009. All moderate, severe, or very severe AEs reported by treating physician in Eurofever were analyzed regardless of a possible suspected causal relationship to any therapies and according to the latest release of the Medical Dictionary for Regulatory Activities. RESULTS: Complete information on safety were available in 2464 patients enrolled in the registry. In 1499 of them retrospective data encompassing the period from disease onset to enrolment were available, whereas 965 consecutive patients entered in the longitudinal part of the study. A total of 479 AEs have been reported in 275 patients. Eighty-two AEs were reported as serious and 99 were drug-related according to the physicians. Infections or infestations (94; 19.6%), gastrointestinal disorders (66; 13.8%), nervous system disorders (41; 8.6%) and systemic disorders or administration site reactions (35; 7.3%) were the most frequent reported events. The highest absolute number of drug-related AEs were related to biologic DMARDs (40/99 reports, 40,4%) and colchicine (31/99 reports, 31.3%). CONCLUSIONS: Present study shows the importance of a longitudinal and homogeneous registration of the AEs in rare conditions, with a particular focus on the safety profile of the treatments used in these conditions.
Subject(s)
Registries , Humans , Female , Male , Adult , Retrospective Studies , Adolescent , Longitudinal Studies , Young Adult , Middle Aged , Child , Child, Preschool , Aged , Hereditary Autoinflammatory Diseases/epidemiology , Infant , Drug-Related Side Effects and Adverse Reactions/epidemiology , Europe/epidemiology , Adverse Drug Reaction Reporting Systems/statistics & numerical dataABSTRACT
INTRODUCTION: Given the complexity of teaching clinical reasoning to (future) healthcare professionals, the utilization of serious games has become popular for supporting clinical reasoning education. This scoping review outlines games designed to support teaching clinical reasoning in health professions education, with a specific emphasis on their alignment with the 8-step clinical reasoning cycle and the reflective practice framework, fundamental for effective learning. METHODS: A scoping review using systematic searches across seven databases (PubMed, CINAHL, ERIC, PsycINFO, Scopus, Web of Science, and Embase) was conducted. Game characteristics, technical requirements, and incorporation of clinical reasoning cycle steps were analyzed. Additional game information was obtained from the authors. RESULTS: Nineteen unique games emerged, primarily simulation and escape room genres. Most games incorporated the following clinical reasoning steps: patient consideration (step 1), cue collection (step 2), intervention (step 6), and outcome evaluation (step 7). Processing information (step 3) and understanding the patient's problem (step 4) were less prevalent, while goal setting (step 5) and reflection (step 8) were least integrated. CONCLUSION: All serious games reviewed show potential for improving clinical reasoning skills, but thoughtful alignment with learning objectives and contextual factors is vital. While this study aids health professions educators in understanding how games may support teaching of clinical reasoning, further research is needed to optimize their effective use in education. Notably, most games lack explicit incorporation of all clinical reasoning cycle steps, especially reflection, limiting its role in reflective practice. Hence, we recommend prioritizing a systematic clinical reasoning model with explicit reflective steps when using serious games for teaching clinical reasoning.
Subject(s)
Clinical Reasoning , Humans , Health Occupations/education , Clinical Competence , Video Games , TeachingABSTRACT
OBJECTIVES: To describe the clinical phenotype and response to treatment of autoinflammatory disease (AID) patients with the TNFRSF1A-pR92Q variant compared to patients with tumour necrosis factor receptor-associated periodic syndrome (TRAPS) due to pathogenic mutations in the same gene and patients diagnosed with other recurrent fever syndromes including periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA) and syndrome of undefined recurrent fever (SURF). METHODS: Clinical data from pR92Q variant associated AID, classical TRAPS, PFAPA and SURF patients were obtained from the Eurofever registry, an international, multicentre registry enabling retrospective collection of data on AID patients. RESULTS: In this study, 361 patients were enrolled, including 77 pR92Q variant, 72 classical TRAPS, 152 PFAPA and 60 SURF patients. pR92Q carriers had an older age of disease onset than classical TRAPS and PFAPA patients. Compared to pR92Q variant patients, classical TRAPS patients had more relatives affected and were more likely to have migratory rash and AA-amyloidosis. Despite several differences in disease characteristics and symptoms between pR92Q variant and PFAPA patients, part of the pR92Q variant patients experienced PFAPA-like symptoms. pR92Q variant and SURF patients showed a comparable clinical phenotype. No major differences were observed in response to treatment between the four patient groups. Steroids were most often prescribed and effective in the majority of patients. CONCLUSIONS: Patients with AID carrying the TNFRSF1A-pR92Q variant behave more like SURF patients and differ from patients diagnosed with classical TRAPS and PFAPA in clinical phenotype. Hence, they should no longer be diagnosed as having TRAPS and management should differ accordingly.
Subject(s)
Hereditary Autoinflammatory Diseases , Lymphadenitis , Pharyngitis , Stomatitis, Aphthous , Humans , Retrospective Studies , Fever/genetics , Fever/diagnosis , Hereditary Autoinflammatory Diseases/diagnosis , Hereditary Autoinflammatory Diseases/genetics , Hereditary Autoinflammatory Diseases/complications , Pharyngitis/diagnosis , Lymphadenitis/diagnosis , Stomatitis, Aphthous/diagnosis , Stomatitis, Aphthous/genetics , Receptors, Tumor Necrosis Factor, Type I/geneticsABSTRACT
Mevalonate kinase (MK) deficiency is a rare autosomal recessive metabolic disorder caused by pathogenic variants in the MVK gene with a broad phenotypic spectrum including autoinflammation, developmental delay and ataxia. Typically, neurological symptoms are considered to be part of the severe end of the phenotypical spectrum and are reported to be in addition to the autoinflammatory symptoms. Here, we describe a patient with MK deficiency with severe neurological symptoms but without autoinflammation and we found several similar patients in the literature. Possibly, the non-inflammatory phenotype is related to a specific genotype: the MVK p.(His20Pro)/p.(Ala334Thr) variant. There is probably an underdetection of the neurological MK deficient phenotype without inflammatory symptoms as clinicians may not test for MK deficiency when patients present with only neurological symptoms. In conclusion, although rare, neurological symptoms without hyperinflammation might be more common than expected in MK deficiency. It seems relevant to consider MK deficiency in patients with psychomotor delay and ataxia, even if there are no inflammatory symptoms.
ABSTRACT
Moving towards person-centered care, with equal partnership between healthcare professionals and patients, requires a solid role for the patient in the education of students and professionals. Patients can be involved as teachers, assessors, curriculum developers, and policy-makers. Yet, many of the initiatives with patients are isolated, small events for targeted groups and there is a lack of patient involvement at the institutional level. To support educators in involving patients, both at the institutional level and at single educational encounters, we offer twelve practical tips. This paper came about through an innovative collaboration between healthcare professionals, educators, teachers, and patients. These tips can be used as a tool to start or reinforce patient involvement in health professions education and provide guidance on how to make it a sustainable part of the curriculum. The article involves organizational conditions for success, tips for sustainable partnerships, ideas for curriculum design and proposes concrete teaching strategies. Finally, besides practical tips, we stress that involving patients in education is not business as usual, and paradoxically this needs to be acknowledged before it can become business as usual.
Subject(s)
Curriculum , Patient Participation , Humans , Students , Health Personnel , Health OccupationsABSTRACT
OBJECTIVES: Mevalonate kinase deficiency (MKD) is a rare autoinflammatory syndrome. Several reports have described allogeneic hematopoietic stem cell transplantation in severely affected patients, sometimes with promising results. In view of the scarcity of data, this study aims to analyse the efficacy and safety of allogeneic hematopoietic stem cell transplantation (HSCT) to give a more complete overview of this treatment. METHODS: This multicentre retrospective study on behalf of the European Society for Blood and Marrow Transplantation aimed to include all MKD patients who had undergone allogeneic HSCT. All centres related to EMBT and centres that have reported cases of allogeneic HSCT in the literature were contacted via the EBMT data office. RESULTS: We analyzed 9 patients (5 male). Treosulfan based conditioning was the most frequently used conditioning regimen. Engraftment occurred in all but one patient. Source of stem cells was cord blood (n = 2), peripheral blood stem cells (n = 4) and bone marrow (n = 5). Two patients needed a second transplantation due to an incomplete response or primary graft failure. Seven patients went into complete remission after stem cell transplantation. At final follow-up these patients reported no symptoms of MKD. Four patients suffered from grade II-IV acute graft-versus-host disease (GvHD). During follow-up two patients died due to transplantation related complications. CONCLUSION: In conclusion, allogeneic stem cell transplantation represents an effective treatment for the most severely affected MKD patients. However, treatment-related morbidity and mortality are significant. Transplantation may be justified in patients with a severe disease course on conservative therapy.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Mevalonate Kinase Deficiency , Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Humans , Male , Mevalonate Kinase Deficiency/therapy , Retrospective Studies , Transplantation Conditioning/adverse effects , Transplantation Conditioning/methodsABSTRACT
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.
Subject(s)
Cryopyrin-Associated Periodic Syndromes , Hereditary Autoinflammatory Diseases , Mevalonate Kinase Deficiency , Rheumatology , Cryopyrin-Associated Periodic Syndromes/diagnosis , Cryopyrin-Associated Periodic Syndromes/drug therapy , Fever , Hereditary Autoinflammatory Diseases/diagnosis , Hereditary Autoinflammatory Diseases/drug therapy , Hereditary Autoinflammatory Diseases/genetics , Humans , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Interleukin-1 , Mevalonate Kinase Deficiency/diagnosis , Mevalonate Kinase Deficiency/drug therapy , Quality of Life , Receptors, Interleukin-1/therapeutic useABSTRACT
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.
Subject(s)
Cryopyrin-Associated Periodic Syndromes , Hereditary Autoinflammatory Diseases , Mevalonate Kinase Deficiency , Rheumatology , Child, Preschool , Cryopyrin-Associated Periodic Syndromes/diagnosis , Cryopyrin-Associated Periodic Syndromes/drug therapy , Fever , Hereditary Autoinflammatory Diseases/diagnosis , Hereditary Autoinflammatory Diseases/drug therapy , Hereditary Autoinflammatory Diseases/genetics , Humans , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Interleukin-1 , Mevalonate Kinase Deficiency/diagnosis , Mevalonate Kinase Deficiency/drug therapy , Quality of Life , Receptors, Interleukin-1 , United StatesABSTRACT
OBJECTIVES: To evaluate the long-term efficacy and safety of canakinumab in patients with mevalonate kinase deficiency during the open label extension (weeks 41-113) of the randomized controlled CLUSTER trial. METHODS: During a 72-week period, patients received open-label canakinumab 150 or 300 mg, every 4 or 8 weeks. The disease activity was evaluated every 8 weeks using physician global assessment and counting the number of flares. Concentrations of CRP and serum amyloid A protein were measured. The safety was studied by determination and classification of observed adverse events. The safety and efficacy were analysed separately in three subgroups of patients receiving a cumulative dose of less than <35 mg/kg, ≥35 to <70 mg/kg or ≥70 mg/kg. RESULTS: Of the 74 patients who started the CLUSTER study, 66 entered Epoch 4 and 65 completed it. During the 72-week period, 42 (64%) patients experienced no flares, while 13 (20%) had one flare, as compared with a median of 12 flares per year reported at baseline. Low physician global assessment scores were seen at the end of the study for all groups with >90% reporting minimal disease activity or none at all. Median CRP concentrations were consistently equal or lower than 10 mg/l, while median serum amyloid A concentrations remained only slightly above the normal range of 10 mg/l. The study showed no new or unexpected adverse events. CONCLUSION: Canakinumab proved effective to control disease activity and prevent flares in mevalonate kinase deficiency during the 72-week study period. No new safety concerns were reported. TRIAL REGISTRATION: NCT02059291. https://clinicaltrials.gov.
Subject(s)
Mevalonate Kinase Deficiency , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized/adverse effects , Double-Blind Method , Humans , Mevalonate Kinase Deficiency/drug therapy , Serum Amyloid A Protein , Treatment OutcomeABSTRACT
BACKGROUND: Although a number of successful handoff interventions have been reported, the handoff process remains vulnerable because it relies on memory. The aim of this study was to investigate the effect of deliberate cognitive processing (i.e., analytical, conscious, and effortful thinking) on recall of information from a simulated handoff. METHODS: This two-phased experiment was executed in the Netherlands in 2015. A total of 78 pediatric residents were randomly divided into an intervention group (nâ¯=â¯37) and a control group (nâ¯=â¯41). In phase 1, participants received written handoffs from 8 patients. The intervention group was asked to develop a contingency plan for each patient, deliberately processing the information. The control group received no specific instructions. In phase 2, all participants were asked to write down as much as they recalled from the handoffs. The outcome was the amount and accuracy of recalled information, calculated by scoring for idea units (single information elements) and inferences (conclusions computed by participants based on two or more idea units). RESULTS: Participants in the intervention group recalled significantly more inferences (7.24 vs. 3.22) but fewer correct idea units (21.1% vs. 25.3%) than those in the control group. There was no difference with regard to incorrectly recalled information. CONCLUSION: Our study revealed that deliberate cognitive processing leads to creation of more correct inferences, but fewer idea units. This suggests that deliberate cognitive processing results in interpretation of the information into higher level concepts, rather than remembering specific pieces of information separately. This implies better understanding of patients' problems.
Subject(s)
Internship and Residency , Patient Handoff , Child , Cognition , Humans , NetherlandsABSTRACT
BACKGROUND: TNF receptor-associated periodic syndrome (TRAPS) is a rare autoinflammatory disease caused by dominant mutation of the TNF super family receptor 1A (TNFRSF1A) gene. Data regarding long-term treatment outcomes are lacking. OBJECTIVE: To assess correlations of genotype-phenotypes in patients with TRAPS, as defined by the International Study Group for Systemic Autoinflammatory Diseases (INSAID) classification and Eurofever criteria, with treatment responses. METHODS: Data from 226 patients with variants of the TNFRSF1A gene and enrolled in the Eurofever registry were classified according to the INSAID classification in groups A (pathogenic or likely pathogenic variants), B (variants of uncertain significance or not classified variants), and C (benign or likely benign variants) and screened for Eurofever criteria. RESULTS: In group A (127 of 226 patients, 56%), all fulfilled Eurofever criteria and 20 of 127 patients (16%) developed AA amyloidosis. In group B (78 of 226 patients, 35%), 40 of 78 patients (51%) did not fulfill Eurofever criteria, displaying a lower incidence of abdominal pain (P < .02) and higher efficacy rate of on-demand nonsteroidal anti-inflammatory drugs (P < .02) and colchicine (P < .001). Group C (21 of 226 patients, 9%) presented a milder disease (P < .02) and none fulfilled Eurofever criteria. Anti-IL-1 drugs were the most frequently used in patients fulfilling Eurofever criteria, with the highest efficacy rate (>85% complete response). No patients on anti-IL-1 treatments developed AA amyloidosis, and 7 women with a history of failure to conceive had successful pregnancies. CONCLUSION: Anti-IL-1 drugs are the best maintenance treatment in patients with TRAPS. The diagnosis of TRAPS should be considered very carefully in patients of group B not fulfilling Eurofever criteria and group C, and colchicine may be preferable as the first maintenance treatment.
Subject(s)
Hereditary Autoinflammatory Diseases , Abdominal Pain , Colchicine , Female , Hereditary Autoinflammatory Diseases/diagnosis , Hereditary Autoinflammatory Diseases/drug therapy , Hereditary Autoinflammatory Diseases/epidemiology , Humans , Mutation , RegistriesABSTRACT
Background: Mevalonate kinase deficiency (MKD) is an inborn error of metabolism leading to a syndrome characterized by recurrent inflammation. This clinically manifests itself as fever and can be accompanied by gastrointestinal symptoms, oral ulcers, cervical lymphadenopathy, and skin rash. Methods: We searched Pubmed, Embase, Cochrane, and CINAHL for relevant articles. All articles were screened by both authors. Relevant articles were included in this review. Results: The interleukin-1 antagonist canakinumab is the only well-studied and effective treatment for MKD patients with 35% of patients reaching complete remission in a large randomized controlled trial. Other therapeutic options include glucocorticoids and the IL-1 antagonist anakinra, although the level of evidence for these treatments is weaker. If patients fail to these treatments, the biologicals etanercept or tocilizumab can be used. Mildly affected patients might benefit from cheaper, less invasive treatments such as paracetamol and NSAIDs. Conclusion: Canakinumab is the only evidence-based treatment for mevalonate kinase deficiency. However, the costs limit availability for many patients. Cheaper and more readily available options include glucocorticoids, anakinra, etanercept, and tocilizumab, although there is limited evidence supporting these treatments.
Subject(s)
Mevalonate Kinase Deficiency/therapy , Child , Child, Preschool , Female , Humans , Immunologic Factors/therapeutic use , MaleABSTRACT
BACKGROUND AND OBJECTIVE: Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease (AID) worldwide. The disease is caused by mutations in the MEFV gene encoding the inflammasome sensor Pyrin. Clinical diagnosis of FMF is complicated by overlap in symptoms with other diseases, and interpretation of genetic testing is confounded by the lack of a clear genotype-phenotype association for most of the 340 reported MEFV variants. In this study, the authors designed a functional assay and evaluated its potential in supporting FMF diagnosis. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from patients with Pyrin-associated autoinflammation with an FMF phenotype (n=43) or with autoinflammatory features not compatible with FMF (n=8), 10 asymptomatic carriers and 48 healthy donors. Sera were obtained from patients with distinct AIDs (n=10), and whole blood from a subset of patients and controls. The clinical, demographic, molecular genetic factors and other characteristics of the patient population were assessed for their impact on the diagnostic test read-out. Interleukin (IL)-1ß and IL-18 levels were measured by Luminex assay. RESULTS: The ex vivo colchicine assay may be performed on whole blood or PBMC. The functional assay robustly segregated patients with FMF from healthy controls and patients with related clinical disorders. The diagnostic test distinguished patients with classical FMF mutations (M694V, M694I, M680I, R761H) from patients with other MEFV mutations and variants (K695R, P369S, R202Q, E148Q) that are considered benign or of uncertain clinical significance. CONCLUSION: The ex vivo colchicine assay may support diagnosis of FMF and functional subtyping of Pyrin-associated autoinflammation.
Subject(s)
Familial Mediterranean Fever/diagnosis , Immunophenotyping/methods , Pyrin/blood , Adolescent , Adult , Aged , Aged, 80 and over , Case-Control Studies , Child , Child, Preschool , Colchicine/analysis , Familial Mediterranean Fever/genetics , Female , Genetic Association Studies , Humans , Leukocytes, Mononuclear , Male , Middle Aged , Mutation , Phenotype , Pyrin/genetics , Young AdultABSTRACT
Diagnosis of systemic autoinflammatory diseases (SAIDs) is often difficult to achieve and can delay the start of proper treatments and result in irreversible organ damage. In several patients with dominantly inherited SAID, postzygotic mutations have been detected as the disease-causing gene defects. Mutations with allele frequencies <5% have been detected, even in patients with severe phenotypes. Next-generation sequencing techniques are currently used to detect mutations in SAID-associated genes. However, even if the genomic region is highly covered, this approach is usually not able to distinguish low-grade postzygotic variants from background noise. We, therefore, developed a sensitive deep sequencing assay for mosaicism detection in SAID-associated genes using single-molecule molecular inversion probes. Our results show the accurate detection of postzygotic variants with allele frequencies as low as 1%. The probability of calling mutations with allele frequencies ≥3% exceeds 99.9%. To date, we have detected three patients with mosaicism, two carrying likely pathogenic NLRP3 variants and one carrying a likely pathogenic TNFRSF1A variant with an allele frequency of 1.3%, confirming the relevance of the technology. The assay shown herein is a flexible, robust, fast, cost-effective, and highly reliable method for mosaicism detection; therefore, it is well suited for routine diagnostics.
Subject(s)
Hereditary Autoinflammatory Diseases/genetics , High-Throughput Nucleotide Sequencing/methods , Molecular Probes/genetics , Mosaicism , Case-Control Studies , False Positive Reactions , Gene Frequency , Humans , Mutation , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Polymerase Chain Reaction/methods , Receptors, Tumor Necrosis Factor, Type I/geneticsABSTRACT
OBJECTIVES: To describe the clinical characteristics, treatment response and genetic findings in a large cohort of patients with undefined systemic autoinflammatory diseases (SAIDs). METHODS: Clinical and genetic data from patients with undefined SAIDs were extracted from the Eurofever registry, an international web-based registry that retrospectively collects clinical information on patients with autoinflammatory diseases. RESULTS: This study included 187 patients. Seven patients had a chronic disease course, 180 patients had a recurrent disease course. The median age at disease onset was 4.3 years. Patients had a median of 12 episodes per year, with a median duration of 4 days. Most commonly reported symptoms were arthralgia (n=113), myalgia (n=86), abdominal pain (n=89), fatigue (n=111), malaise (n=104) and mucocutaneous manifestations (n=128). In 24 patients, relatives were affected as well. In 15 patients, genetic variants were found in autoinflammatory genes. Patients with genetic variants more often had affected relatives compared with patients without genetic variants (p=0.005). Most patients responded well to non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, colchicine and anakinra. Complete remission was rarely achieved with NSAIDs alone. Notable patterns were found in patients with distinctive symptoms. Patients with pericarditis (n=11) were older at disease onset (33.8 years) and had fewer episodes per year (3.0/year) compared with other patients. Patients with an intellectual impairment (n=8) were younger at disease onset (2.2 years) and often had relatives affected (28.6%). CONCLUSION: This study describes the clinical characteristics of a large cohort of patients with undefined SAIDs. Among these, patients with pericarditis and intellectual impairment appear to comprise distinct subsets.
Subject(s)
Genetic Variation/genetics , Hereditary Autoinflammatory Diseases/genetics , Adolescent , Adrenal Cortex Hormones/therapeutic use , Adult , Age of Onset , Antirheumatic Agents/therapeutic use , Child , Child, Preschool , Chronic Disease , Colchicine/therapeutic use , Europe , Female , Hereditary Autoinflammatory Diseases/drug therapy , Hereditary Autoinflammatory Diseases/pathology , Humans , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Male , Pedigree , Registries , Retrospective Studies , Young AdultABSTRACT
BACKGROUND: Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)-familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)-and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA. METHODS: Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients' diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria. RESULTS: The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94-1 and specificity of 0.95-1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98). CONCLUSION: Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.
Subject(s)
Genetic Predisposition to Disease/epidemiology , Hereditary Autoinflammatory Diseases/classification , Hereditary Autoinflammatory Diseases/genetics , Mevalonate Kinase Deficiency/classification , Registries , Consensus , Cross-Sectional Studies , Europe , Familial Mediterranean Fever/classification , Familial Mediterranean Fever/epidemiology , Familial Mediterranean Fever/genetics , Female , Hereditary Autoinflammatory Diseases/epidemiology , Humans , Male , Mevalonate Kinase Deficiency/diagnosis , Mevalonate Kinase Deficiency/epidemiology , Mevalonate Kinase Deficiency/genetics , Prevalence , Risk Assessment , Sensitivity and SpecificityABSTRACT
OBJECTIVE: Provisional evidence-based classification criteria for hereditary periodic fever (HPF) have been recently developed. However, no consensus on how to combine clinical criteria, laboratory tests, and results of molecular analysis has been reached. The objective of this study is to understand which variables physicians consider important for the classification of patients with HPF. METHODS: Two Delphi surveys were sent to health professionals in the field of autoinflammation. In the first open survey, 124 researchers could list all the variables they consider useful for the diagnosis of each monogenic periodic fever. The variables could be of any type and each researcher could complete the survey for 1 or more diseases. In the second survey, 162 researchers were asked to select, from a list of items coming from the first survey, the 10 top variables and to rank them by assigning a score from 10 to 1. RESULTS: The response rates to the Delphi surveys were 85% for the first session and 87% for the second. The variables selected for each disease (corresponding to the third quartile, considering the total score obtained by the variables after the second Delphi survey) were 21 for mevalonate kinase deficiency, 22 for cryopyrinopathies, 18 for familial Mediterranean fever, and 20 for tumor necrosis factor receptor-associated periodic fever syndrome. A positive genetic test reached the top rank in all the HPF. CONCLUSION: Our process led to the identification of those features considered the most important as candidate variables to be included in a new set of evidence-based classification criteria for HPF.