Influenza vaccine uptake in juvenile idiopathic arthritis: a multi-centre cross-sectional study.

While most countries provide safe and effective influenza vaccines for at-risk groups, influenza vaccine coverage among children with rheumatic diseases remains uncertain. This study investigated influenza vaccination rates in children with juvenile idiopathic arthritis (JIA) during the 2019-2020 season and assessed the knowledge and attitudes of caregivers of children with JIA regarding influenza vaccination. The secondary aims were to identify barriers to vaccination and explore strategies to improve vaccination rates. A multi-centre, cross-sectional anonymous survey was conducted in 7 countries during the 2019-2020 influenza season to assess the uptake history of influenza vaccination. Among 287 participants, only 87 (30%) children with JIA received the influenza vaccine during the 2019-2020 season. Children who were more likely to be vaccinated were those with systemic juvenile idiopathic arthritis (sJIA), a history of previous vaccination and those aware of the vaccination recommendations. Conversely, children who previously experienced adverse vaccine-related events reported the lowest uptake. The primary reason for non-vaccination was lack of awareness about the necessity of influenza vaccination.  Conclusion: Despite variations among countries, the uptake of influenza vaccines remains low in children with JIA. Improving awareness among families about the importance of influenza vaccination may increase vaccination rates in children with rheumatic diseases. What is Known: • Rheumatic children are at increased risk for influenza infection due to immunosuppressive therapy and immune dysregulation. • Influenza vaccine is formally recommended to children with rheumatic diseases. What is New: • This multicentre study showed that influenza vaccine uptake rates remain suboptimal among children with Juvenile Idiopathic Arthritis despite formal recommendations. • Factors like previous experience with vaccination and information provided by medical professionals via different ways play essential roles in increasing vaccination rates and can contribute to improved health outcomes for these vulnerable children.

EULAR/PRES recommendations for vaccination of paediatric patients with autoimmune inflammatory rheumatic diseases: update 2021.

OBJECTIVES: Recent insights supporting the safety of live-attenuated vaccines and novel studies on the immunogenicity of vaccinations in the era of biological disease-modifying antirheumatic drugs in paediatric patients with autoimmune/inflammatory rheumatic diseases (pedAIIRD) necessitated updating the EULAR recommendations. METHODS: Recommendations were developed using the EULAR standard operating procedures. Two international expert committees were formed to update the vaccination recommendations for both paediatric and adult patients with AIIRD. After a systematic literature review, separate recommendations were formulated for paediatric and adult patients. For pedAIIRD, six overarching principles and seven recommendations were formulated and provided with the level of evidence, strength of recommendation and Task Force level of agreement. RESULTS: In general, the National Immunisation Programmes (NIP) should be followed and assessed yearly by the treating specialist. If possible, vaccinations should be administered prior to immunosuppressive drugs, but necessary treatment should never be postponed. Non-live vaccines can be safely given to immunosuppressed pedAIIRD patients. Mainly, seroprotection is preserved in patients receiving vaccinations on immunosuppression, except for high-dose glucocorticoids and B-cell depleting therapies. Live-attenuated vaccines should be avoided in immunosuppressed patients. However, it is safe to administer the measles-mumps-rubella booster and varicella zoster virus vaccine to immunosuppressed patients under specific conditions. In addition to the NIP, the non-live seasonal influenza vaccination should be strongly considered for immunosuppressed pedAIIRD patients. CONCLUSIONS: These recommendations are intended for paediatricians, paediatric rheumatologists, national immunisation agencies, general practitioners, patients and national rheumatology societies to attain safe and effective vaccination and optimal infection prevention in immunocompromised pedAIIRD patients.

High incidence of multisystem inflammatory syndrome and other autoimmune diseases after SARS-CoV-2 infection compared to COVID-19 vaccination in children and adolescents in south central Europe.

OBJECTIVES: To estimate the incidence and describe the spectrum of inflammatory and autoimmune diseases linked to SARS-CoV-2 infection and COVID-19 vaccination in children from two neighbouring south central European countries. METHODS: We performed a multi-centre prospective cohort study of children under 18 years diagnosed with inflammatory/autoimmune diseases linked to SARS-CoV-2 infection or COVID-19 vaccination, who were admitted to the paediatric tertiary care hospitals in Slovenia and Friuli Venezia Giulia, Italy, from January 1, 2020, to December 31, 2021. Disease incidence was calculated based on laboratory-confirmed cases only. RESULTS: Inflammatory and autoimmune diseases linked to SARS-CoV-2 were diagnosed in 192 children (127 laboratory-confirmed), of whom 112 had multisystem inflammatory syndrome (MIS-C), followed by vasculitis, neurological and cardiac diseases. Calculated risk of MIS-C was 1 in 860 children after SARS-CoV-2 infection and cumulative incidence of MIS-C was 18.3/100,000 of all children. Fifteen children had severe COVID-19. Two patients with MIS-C and a patient with myositis presented after COVID-19 vaccination. All 3 had at presentation also a serologically proven recent SARS-CoV-2 infection. After MIS-C, nine patients were vaccinated against COVID-19 and 25 patients had a SARS-CoV-2 reinfection, without recurrence of MIS-C. CONCLUSIONS: Autoimmune diseases following SARS-CoV-2 infection in children were 8.5 times as common as severe COVID-19. MIS-C was the most common manifestation and its incidence in this predominantly white population was higher than previously reported. MIS-C does not seem to recur after SARS-CoV-2 reinfection or COVID-19 vaccination. Autoimmune diseases were much more common after SARS-CoV-2 infection than after COVID-19 vaccination.

Safety and immunogenicity of BNT162b2 mRNA COVID-19 vaccine in adolescents with rheumatic diseases treated with immunomodulatory medications.

OBJECTIVES: Adolescents with juvenile-onset autoimmune inflammatory rheumatic diseases (AIIRDs) could be at risk for disease flare secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or to withholding anti-inflammatory therapy. While vaccination can protect against coronavirus disease 2019 (COVID-19), safety and immunogenicity data regarding anti-SARS-CoV-2 vaccines among adolescents with AIIRDs are limited. This international, prospective, multicentre study evaluated the safety and immunogenicity of the BNT162b2 anti-SARS-CoV-2 vaccine among adolescents and young adults with juvenile-onset AIIRDs, 80% of whom are on chronic immunomodulatory therapy. METHODS: Vaccine side effects, disease activity and short-term efficacy were evaluated after 3 months in 91 patients. Anti-spike S1/S2 IgG antibody levels were evaluated in 37 patients and 22 controls 2-9 weeks after the second dose. RESULTS: A total of 91 patients and 40 healthy controls were included. The safety profile was good, with 96.7% (n = 88) of patients reporting mild or no side effects and no change in disease activity. However, three patients had transient acute symptoms: two following the first vaccination (renal failure and pulmonary haemorrhage) and one following the second dose (mild lupus flare vs viral infection). The seropositivity rate was 97.3% in the AIIRD group compared with 100% among controls. However, anti-S1/S2 antibody titres were significantly lower in the AIIRD group compared with controls [242 (s.d. 136.4) vs 387.8 (57.3) BAU/ml, respectively; P < 0.0001]. No cases of COVID-19 were documented during the 3 month follow-up. CONCLUSION: Vaccination of juvenile-onset AIIRD patients demonstrated good short-term safety and efficacy and a high seropositivity rate but lower anti-S1/S2 antibody titres compared with healthy controls. These results should encourage vaccination of adolescents with juvenile-onset AIIRDs, even while on immunomodulation.

Consensus-based recommendations for the management of juvenile systemic sclerosis.

Juvenile systemic sclerosis (JSSc) is a rare disease of childhood and currently no international consensus exists with regard to its assessment and treatment. This SHARE (Single Hub and Access point for paediatric Rheumatology in Europe) initiative, based on expert opinion informed by the best available evidence, provides recommendations for the assessment and treatment of patients with JSSc with a view to improving their outcome. Experts focused attention not only on the skin assessment but also on the early signs of internal organ involvement whose proper treatment can significantly affect the long-term outcome. A score for disease severity is proposed in order to perform a structured assessment of outcome over time but a validation in a wider patient population is recommended. Finally, a stepwise treatment approach is proposed in order to unify the standard of care throughout Europe with the aim to reduce morbidity and mortality in this disease.

Childhood-onset of primary Sjögren's syndrome: phenotypic characterization at diagnosis of 158 children.

OBJECTIVES: To characterize the phenotypic presentation at diagnosis of childhood-onset primary SS. METHODS: The Big Data Sjögren Project Consortium is an international, multicentre registry using worldwide data-sharing cooperative merging of pre-existing clinical SS databases from the five continents. For this study, we selected those patients in whom the disease was diagnosed below the age of 19 years according to the fulfilment of the 2002/2016 classification criteria. RESULTS: Among the 12 083 patients included in the Sjögren Big Data Registry, 158 (1.3%) patients had a childhood-onset diagnosis (136 girls, mean age of 14.2 years): 126 (80%) reported dry mouth, 111 (70%) dry eyes, 52 (33%) parotid enlargement, 118/122 (97%) positive minor salivary gland biopsy and 60/64 (94%) abnormal salivary US study, 140/155 (90%) positive ANA, 138/156 (89%) anti-Ro/La antibodies and 86/142 (68%) positive RF. The systemic EULAR Sjögren's syndrome disease activity index (ESSDAI) domains containing the highest frequencies of active patients included the glandular (47%), articular (26%) and lymphadenopathy (25%) domains. Patients with childhood-onset primary SS showed the highest mean ESSDAI score and the highest frequencies of systemic disease in 5 (constitutional, lymphadenopathy, glandular, cutaneous and haematological) of the 12 ESSDAI domains, and the lowest frequencies in 4 (articular, pulmonary, peripheral nerve and CNS) in comparison with patients with adult-onset disease. CONCLUSIONS: Childhood-onset primary SS involves around 1% of patients with primary SS, with a clinical phenotype dominated by sicca features, parotid enlargement and systemic disease. Age at diagnosis plays a key role in modulating the phenotypic expression of the disease.

Vaccination coverage in children with rheumatic diseases.

OBJECTIVES: To assess vaccination status in a cohort of children with rheumatic diseases followed at the University Children's Hospital Ljubljana and to evaluate the most common reasons for vaccination dropout. METHODS: Patients with rheumatic diseases who were evaluated at the rheumatology outpatient clinic between January 2015 and January 2017 received a questionnaire about their vaccination status and reasons for potential vaccination dropout. Vaccination coverage for individual vaccines was determined at 5, 10, 18 years and at the time of their last clinic visit. RESULTS: Data were received from 187 out of 424 enrolled patients (44.1%). Majority of included patients had juvenile idiopathic arthritis (n=165), followed by childhood-onset systemic lupus erythematosus (n=6), juvenile dermatomyositis (n=5), mixed connective tissue disease (n=3), chronic recurrent multifocal osteomyelitis, juvenile systemic sclerosis, Takayasu's arteritis (n=2 each), granulomatous polyangiitis and fibromyalgia (n=1 each). Vaccination coverage was complete in 91.9%, 70.3%, 66.7% and 64.7% of patients at 5, 10, 18 years and at their last clinic visit, respectively. Most commonly omitted vaccines were hepatitis B and second dose of measles, mumps and rubella vaccine. Most common additional vaccine was against rotavirus. Most common reason for vaccination dropout was suggestion of the treating rheumatologist. CONCLUSIONS: Thirty-five percent of our patients remain incompletely vaccinated and thus susceptible to vaccine-preventable diseases. Physicians play a crucial role in the decision to vaccinate.

Chronic non-bacterial osteomyelitis: a retrospective international study on clinical manifestations and response to treatment.

OBJECTIVES: Chronic non-bacterial osteomyelitis (CNO) is a rare non-infectious bone inflammatory disorder; when multifocal, it is referred to as Chronic Recurrent Multifocal Osteomyelitis (CRMO). This study evaluates the demographic, clinical and radiological characteristics of a multi-centre cohort of patients with CNO/CRMO. METHODS: Demographic and clinical data of patients with an established diagnosis of CNO/CRMO followed at paediatric rheumatology centres across Europe (Italy, France, Slovenia) and India were retrospectively collected. RESULTS: There were no demographic differences across countries, but time to diagnosis was significantly longer in India (p=0.041). Pain was almost invariably present at disease onset; functional impairment was more frequent among Italian and Slovenian patients (p=0.001). The number of sites of bone involvement was similar between genders and countries, with long bone metaphises being the most common site. Raised acute phase reactants, detected in >50% of patients, were not associated with clinical manifestations or response to treatment. Comorbidities, evinced in 37% of patients, were equally distributed between genders and nationalities. Imaging approach was similar across countries, without any association between radiological findings and clinical manifestations. NSAIDs were almost invariably used as first-line treatment, but response rate was significantly lower in Italy (p=0.02). Methotrexate was used in 28% of case, with an overall rate of response of 82%. Health conditions and rate of permanent deformities were similar across different countries. CONCLUSIONS: The differences in clinical presentation, radiological features and response to treatment described in this multinational cohort of CNO/CRMO might provide novel insights into this still elusive disease.

Vaccination for Children on Biologics.

PURPOSE OF REVIEW: Several biologic drugs are available for treatment of immune-mediated diseases, and the number of children treated with biologics is increasing. This review summarises current knowledge about the safety and immunogenicity of vaccines in children treated with biologic therapy. RECENT FINDINGS: A recent retrospective, multicentre study reported that the booster dose of live-attenuated vaccine (MMR/V) was safe for patients with rheumatic diseases treated with biologic therapy. Recent publications revealed that immunogenicity of vaccines in children treated with biologics was lower than in the healthy population, especially on long-term follow-up. Children treated with biologic therapy are at greater danger of infections, compared to the healthy population. Therefore, they should be vaccinated according to national guidelines. Regardless of the therapy, non-live vaccines are recommended. However, it is common practice to advise postponing vaccination with live-attenuated vaccines in children while they are on immunosuppressive therapy. Newly published data suggest that booster dose MMR/V is safe for children treated with biologic therapy.

Consensus-based recommendations for the management of juvenile localised scleroderma.

In 2012, a European initiative called Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases. Juvenile localised scleroderma (JLS) is a rare disease within the group of paediatric rheumatic diseases (PRD) and can lead to significant morbidity. Evidence-based guidelines are sparse and management is mostly based on physicians' experience. This study aims to provide recommendations for assessment and treatment of JLS. Recommendations were developed by an evidence-informed consensus process using the European League Against Rheumatism standard operating procedures. A committee was formed, mainly from Europe, and consisted of 15 experienced paediatric rheumatologists and two young fellows. Recommendations derived from a validated systematic literature review were evaluated by an online survey and subsequently discussed at two consensus meetings using a nominal group technique. Recommendations were accepted if ≥80% agreement was reached. In total, 1 overarching principle, 10 recommendations on assessment and 6 recommendations on therapy were accepted with ≥80% agreement among experts. Topics covered include assessment of skin and extracutaneous involvement and suggested treatment pathways. The SHARE initiative aims to identify best practices for treatment of patients suffering from PRDs. Within this remit, recommendations for the assessment and treatment of JLS have been formulated by an evidence-informed consensus process to produce a standard of care for patients with JLS throughout Europe.

Classification criteria for autoinflammatory recurrent fevers.

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.

Identification of novel reassortant mammalian orthoreoviruses from bats in Slovenia.

BACKGROUND: Recently, mammalian orthoreoviruses (MRVs) were detected for the first time in European bats, and the closely related strain SI-MRV01 was isolated from a child with severe diarrhoea in Slovenia. Genetically similar strains have also been reported from other mammals, which reveals their wide host distribution. The aim of this study was to retrospectively investigate the occurrence and genetic diversity of MRVs in bats in Slovenia, from samples obtained throughout the country in 2008 to 2010, and in 2012 and to investigate the occurrence of the novel SI-MRV01 MRV variant in Slovenian bats. RESULTS: The detection of MRVs in bat guano was based on broad-range RT-PCR and specific bat MRV real-time RT-PCR. Subsequently, MRV isolates were obtained from cell culture propagation, with detailed molecular characterisation through whole-genome sequencing. Overall, bat MRVs were detected in 1.9% to 3.8% of bats in 2008, 2009 and 2012. However, in 2010 the prevalence was 33.0%, which defined an outbreak of the single SI-MRV01 strain. Here, we report on the identification of five MRV isolates of different serotypes that are designated as SI-MRV02, SI-MRV03, SI-MRV04, SI-MRV05 and SI-MRV06. There is high genetic variability between these characterised isolates, with evident genome reassortment seen across their genome segments. CONCLUSIONS: In conclusion, we have confirmed the presence of the SI-MRV01 strain in a Slovenian bat population. Moreover, according to genetic characterisation of S1 genome segment, all three MRV serotypes were present in the bat population. In this study, five independent MRV isolates were obtained and detailed whole genome analysis revealed high diversity between them. This study generates new information about the epidemiology and molecular characteristics of emerging bat MRV variants, and provides important molecular data for further studies of their pathogenesis and evolution.

The Slovene version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR).

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Slovene language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the 3 Likert assumptions, floor/ceiling effects, internal consistency, Cronbach's alpha, interscale correlations, test-retest reliability, and construct validity (convergent and discriminant validity). A total of 100 JIA patients (7.0% systemic, 47.0% oligoarticular, 22.0% RF negative polyarthritis, 24.0% other categories) and 120 healthy children, were enrolled. The JAMAR components discriminated well healthy subjects from JIA patients, except for the Health-Related Quality of Life, Psychosocial Health subscales. All JAMAR components revealed good psychometric performances. In conclusion, the Slovene version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.

Antiadhesion activity of juniper (Juniperus communis L.) preparations against Campylobacter jejuni evaluated with PCR-based methods.

The food-borne pathogen Campylobacter jejuni can cause bacterial gastrointestinal infections. Biofilm formation amplifies the risk of human infection by improving survival and persistence of C. jejuni in food processing environments and its transmission through the food chain. We aimed to control C. jejuni using an alternative strategy of low doses of Juniperus communis fruit preparations to target bacterial adhesion properties in the first step of biofilm formation. First, we defined the anti-Campylobacter activity of a juniper fruit crude extract and its fractionated biflavonoids, flavone glycosides, and purified amentoflavone, of juniper fruit essential oil and of juniper fruit postdistillation waste material extract. For accurate quantification of adherent C. jejuni, we optimised digital Polymerase Chain Reaction (PCR) and quantitative real-time PCR for construction of standard curves and quantification. We show for the first time that juniper fruit formulations can effectively inhibit adhesion of C. jejuni to polystyrene. Furthermore, ≥94% of the antiadhesion activity of juniper fruit crude extract and juniper fruit essential oil remained under food-related conditions: modified culture medium with glucose, or a stainless steel surface, or mixed co-cultures of C. jejuni and Listeria monocytogenes. This study indicates that addition of juniper fruit formulations can control growth and adhesion of C. jejuni and thus limit food chain transmission of campylobacters.

Acute rheumatic fever outbreak in southern central European country.

A decline in the incidence of acute rheumatic fever (ARF) in developed countries over the past century can be attributed to the improved public hygiene and to widespread use of antibiotics. ARF seemed to be a rare disease in southern central European country, Slovenia, up to 2010 when we noticed an increase in the number of patients with ARF. In order to assess the current incidence of ARF, we performed a retrospective study of all patients with ARF treated at the University Children's Hospital Ljubljana from January 2008 until the end of December 2014. In a period of 7 years, 19 patients with ARF were identified. The estimated annual incidence of ARF during the study period was 1.25 cases per 100,000 children. Carditis was present in all patients, arthritis in 37 % and Sydenham chorea in 32 %. CONCLUSION: Recent ARF outbreak in Slovenia revealed that this disease is still present in southern central Europe with an estimated annual incidence of 1.25 cases per 100,000 children. Unrecognized or inadequately treated ARF could be the cause of acquired heart disease and must be even nowadays included among the differential diagnoses in a febrile child with arthritis, heart murmur or movement disorder. What is Known: • Acute rheumatic fever (ARF) is diagnosed based on the major and minor Jones Criteria. • A decline in the incidence of ARF in developed countries over the past century can be attributed to the improved public hygiene and to widespread use of antibiotics. What is New: • In the last decade, an increase in the incidence of ARF was observed in Slovenia which has a central European geographic position. • Our paper highlights the importance of including ARF in the differential diagnosis of a febrile child with arthritis/arthralgia and/or heart murmur and/or acute chorea.

Autoimmune and Inflammatory Manifestations in 247 Patients with Primary Immunodeficiency-a Report from the Slovenian National Registry.

An abnormal regulation of immune responses leads to autoimmune and inflammatory manifestations in patients with primary immunodeficiencies (PIDs). The objective of our study was to evaluate the frequency of non-infectious and non-malignant manifestations in a large cohort of patients included in the Slovenian national PID registry and to assess the time of manifestation onset with respect to the time of PID diagnosis. Medical records of registered patients were reviewed. Data on autoimmunity, lymphoproliferation, autoinflammation, allergies, PID diagnosis, and underlying genetic defects were collected and analyzed. The time of each manifestation onset was determined and compared with the time of PID diagnosis. As of May 2015, 247 patients with 50 different PIDs were registered in the Slovenian national PID registry (147 males, 100 females; mean age 20 years). Mean disease duration was 14 years; 78 % of patients were younger than 18 years; and 22 % of patients were adults. Diagnosis of PID was genetically confirmed in 51 % of patients. Non-infectious and non-malignant manifestations were present in 69/235 (29 %) patients, including autoimmune manifestations in 52/235 (22 %), lymphoproliferative/granulomatous in 28/235 (12 %), autoinflammatory in 12/247 (5 %), and allergic manifestations in 10/235 (4 %) of all registered patients. Autoimmune manifestations were present in all patients whose PIDs were classified as diseases of immune dysregulation, 47 % of patients with chronic granulomatous disease, and 38 % of patients with predominantly antibody immune deficiencies. A high prevalence of non-infectious and non-malignant manifestations among patients in the Slovenian national PID registry suggests common genetic factors of autoimmunity, inflammation, and immunodeficiency. Patients with PID should be routinely screened for autoimmune and inflammatory manifestations at the time of PID diagnosis and during the long-term follow up.

Raynaud's syndrome in children: systematic review and development of recommendations for assessment and monitoring.

OBJECTIVES: To develop recommendations for investigation and monitoring of children with Raynaud's syndrome, based on paediatric evidence collated by a systematic review. METHODS: A systematic review was undertaken to establish the paediatric evidence for assessment and monitoring of Raynaud's syndrome. An expert panel including members of the Paediatric Rheumatology European Society (PRES) Scleroderma Working Group, were invited to a consensus meeting where recommendations were developed based on evidence graded by the systematic review and where evidence was lacking, consensus opinion. A nominal technique was used where 75% consensus was taken as agreement. RESULTS: The expert panel recommended testing anti-nuclear antibody (ANA), more specific antibodies associated with connective tissue disease and nail-fold capillaroscopy in all children presenting with Raynaud's syndrome as data suggests these can be risk factors for evolution into a connective tissue disease. The frequency of follow-up recommended depends on presence of these risk factors with the aim to detect evolving connective tissue disease early in high risk individuals. Those with no abnormalities on capillaroscopy and negative autoantibodies were deemed low risk of progression, whereas those with ANA positivity, specific autoantibodies and/or nailfold capillary changes were deemed high risk and more frequent follow-up was recommended. CONCLUSIONS: Recommendations, primarily based on consensus opinion, were agreed regarding investigation and monitoring of children who present with Raynaud's syndrome. Further prospective studies are needed to better define the risk factors for progression to connective tissue disease.

The carrier rate and spectrum of MEFV gene mutations in central and southeastern European populations.

OBJECTIVES: Familial Mediterranean fever (FMF) is an autosomal-recessive disorder caused by mutations in MEFV gene. Eastern Mediterranean populations have the highest number of carriers, whereas western Mediterranean populations are less frequently affected. The aim of this study was to determine the carrier rate and spectrum of MEFV gene mutations in apparently healthy populations and in suspected FMF patients from central and southeastern European (CSEE) countries. METHODS: We screened 507 apparently healthy persons from 5 CSEE countries. Exons 2 and 10 of the MEFV gene were PCR amplified and subsequently sequenced with ABI prism310 genetic analyser. Six most common mutations in the MEFV gene were tested: V726A, K695R, M694V, M694I, M680I in exon 10, and E148Q in exon 2. In suspected FMF patients we screened all MEFV exons in selected cases. RESULTS: The overall carrier frequency of all MEFV mutations was higher than expected (9.3%). In the whole cohort we did not find any apparently healthy persons with two mutations. Heterozygous mutations were found in apparently healthy subjects from different CSEE countries as follows: Macedonia 16%, Serbia 11%, Bosnia and Herzegovina 8%, Slovenia 6% and Hungary 5%. The most common mutation in healthy controls was K695R, appearing in 40% of mutated alleles. The most common mutation in suspected FMF patients was M694V, followed by K695R. CONCLUSIONS: We found a higher than expected carrier rate of MEFV gene mutations in populations from CSEE countries. It is interesting to note that 40% of detected carriers carry the K695R mutation.

Clinical features and genetic background of the periodic Fever syndrome with aphthous stomatitis, pharyngitis, and adenitis: a single center longitudinal study of 81 patients.

PFAPA syndrome is the most common autoinflammatory disorder in childhood with unknown etiology. The aim of our study was clinical evaluation of PFAPA patients from a single tertiary care center and to determine whether variations of AIM2, MEFV, NLRP3, and MVK genes are involved in PFAPA pathogenesis. Clinical and laboratory data of consecutive patients with PFAPA syndrome followed up at the University Children's Hospital, Ljubljana, were collected from 2008 to 2014. All four genes were PCR amplified and directly sequenced. Eighty-one patients fulfilled criteria for PFAPA syndrome, 50 (63%) boys and 31 (37%) girls, with mean age at disease onset of 2.1 ± 1.5 years. Adenitis, pharyngitis, and aphthae were present in 94%, 98%, and 56%, respectively. Family history of recurrent fevers in childhood was positive in 78%. Nineteen variants were found in 17/62 (27%) patients, 4 different variants in NLRP3 gene in 13 patients, and 6 different variants in MEFV gene in 5 patients, and 2 patients had 2 different variants. No variants of clinical significance were found in MVK and AIM2 genes. Our data suggest that PFAPA could be the result of multiple low-penetrant variants in different genes in combination with epigenetic and environmental factors leading to uniform clinical picture.

IgA-dominant acute poststreptococcal glomerulonephritis with concomitant rheumatic fever successfully treated with steroids: a case report.

There are only a few reports of the co-occurrence of acute poststreptococcal glomerulonephritis (APGN) and acute rheumatic fever. We report an unusual case of a 3-year-old boy with nephrotic syndrome and acute renal failure with the transitional need for peritoneal dialysis, biopsy-proven atypical IgA-dominant APGN, and concomitant acute rheumatic fever, successfully treated by steroids. Aggressive treatment with pulses of methylprednisolone proved to be successful and we recommend its use in this type of cases.