Treat-to-target strategies for the management of familial Mediterranean Fever in children.

BACKGROUND: The objective of this initiative was to develop a treat-to-target (T2T) approach for the management of patients with Familial Mediterranean Fever (FMF), including the definition of a complex treatment target, and establish strategies that improve patient care and long-term outcome. METHODS: An initial set of statements as well as a flow chart visualising the proposed concept was developed. To adapt the preliminary statements to the current state of knowledge, a systematic literature search was performed and the modified statements were subject to a Delphi approach. To ensure the applicability of the statements in daily practice, an online survey was conducted among paediatric rheumatologists in Germany. In addition, data from the national AID-NET registry were analysed with respect to therapeutic response. RESULTS: This T2T initiative yielded a total of 26 statements guiding FMF management with respect to diagnosis, treatment targets, treatment strategies and monitoring. The online survey identified cut-off values for inflammatory markers indicating treatment intensification and appropriate measures in case of colchicine intolerance or non-adherence. The analysis of data derived from the national AID-NET showed that colchicine therapy was successfully terminated in 61% of patients (27 out of 44) with heterozygous MEFV mutations. Multidimensional treatment targets incorporating objective and subjective reported outcome measures were developed. These provide the basis for stratifying patients into the following treatment paths: continue colchicine, persisting attacks / inflammation, colchicine intolerance, persisting arthritis, colchicine reduction and adjustment/reduction of biologics. CONCLUSIONS: The proposed consensus treatment plan for the management of FMF incorporates multidimensional targets allowing transparent treatment decisions, which will promote personalised disease management and increase adherence to therapy.

Increased Prevalence of NLRP3 Q703K Variant Among Patients With Autoinflammatory Diseases: An International Multicentric Study.

Background: The NLRP3 inflammasome has been recognized as one of the key components of innate immunity. Gain-of-function mutations in the exon 3 of NLRP3 gene have been implicated in inflammatory diseases suggesting the presence of functionally important sites in this region. Q703K (c.2107C>A, p.Gln703Lys, also known in the literature as Q705K) is a common variant of NLRP3, that has been considered to be both clinically unremarkable or disease-causing with a reduced penetrance. Objectives: We aimed to investigate the potential genetic impact of the NLRP3 variant Q703K in patients with recurrent fever presenting with two autoinflammatory diseases: PFAPA (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) and CAPS (cryopyrin-associated periodic syndrome), as well as with undefined autoinflammatory disease (uAID). Methods: This is an international multicentric observational retrospective study characterizing the clinical phenotype of patients presenting with recurrent fever suspected to be of auto-inflammatory origin and where the Q703K NLRP3 variant was found. Monocytes of parents of 6 Q703K+ PFAPA patients were studied and levels of pro-inflammatory cytokines produced by monocytes of Q703K+ and Q703K- parents have been compared by ELISA. Results: We report 42 patients with the Q703K NLRP3 genetic variant: 21 were PFAPA patients, 6 had a CAPS phenotype, and 15 had an uAID. The phenotypes of PFAPA, CAPS and uAID were quite similar between Q703K positive and negative patients with the exception of increased prevalence of pharyngitis in the Q703K positive CAPS population compared to the negative one. The in vitro production of IL-1ß was not significantly different between Q703K+ and Q703K- monocytes from asymptomatic parents. Conclusion: The evidence we report in our study shows an increased prevalence of NLRP3 Q703K in patients with autoinflammatory diseases, suggesting an association between the Q703K variant and the risk of PFAPA, CAPS and uAID syndromes. However, we did not show a functional effect of this mutation on the inflammasome basal activity.

Correction to: Age dependent ultrasound B-mode findings of the elbow joint in healthy children and adolescents.

The Second author's name was incorrectly published in the original article. The correct name is Hartwig Wilhelm Lehmann.

Age dependent ultrasound B-mode findings of the elbow joint in healthy children and adolescents.

Due to maturation of joints, various changes take place, not only in the field of paediatric rheumatology but also in paediatric orthopaedics musculoskeletal ultrasound plays an important role in both the diagnosis and the follow-up of diseases in this field. To differentiate between physiological and pathological findings, the knowledge of reference values of joint structures is indispensable. The objective was to define B-mode ultrasound age- and sex-related reference values for the elbow joint in healthy children and adolescents during maturation. In a cross-sectional, multicentre ultrasound study we examined both sides of the elbow joints of 437 healthy children and adolescents (194 boys/243 girls) being between one and less than 18 years old. The children were classified into six equal age groups and divided according to their gender. We measured the distance between the outer margin of the joint capsule and the bone surface to define the bone-capsule distance (BCD), the thickness of the joint cartilage as well as the thickness of the joint capsule. The bone-capsule junction zone and the shape of the joint capsule were analysed qualitatively. The bone capsule distance and the capsule thickness increased with age. In contrast, the joint cartilage thickness decreased. In most cases the junction zone was peaked. The joint capsule showed mostly a concave shape. Intra- and interobserver reliabilities were good. We propose B-mode ultrasound age- and sex-related reference values for the elbow joint in a large number of healthy children and adolescents for the first time. By applying these standard values to the ultrasound examination of the elbow joint, it may be possible to achieve greater certainty in the diagnosis of pathological processes.

Arthrosonographic Reference Values of the Shoulder Joint in Healthy Children and Adolescents: A Cross-Sectional Multicentre Ultrasound Study.

Background Defining of gray scale ultrasound standard reference values of the shoulder joint in childhood and adolescence during maturation. PATIENTS: We examined 445 healthy girls and boys between 1 year and 18 years of age. Method A cross-sectional multicentre grey-scale ultrasound study was performed to examine the shoulder joint on both sides. The children were divided according to their gender and were further classified into six age groups, which constituted three-year age ranges, to record anatomical development changes. We measured the capsule-bone distance (BCD) as a representation of the intracapsular cavity, as well as the thickness of the joint capsule and joint cartilage. Values were expressed in mean±standard deviation (SD) and minimum-maximum (min-max). The shape of the joint capsule and capsule-bone junction zone was qualitatively analysed. Results The joint cartilage thickness decreased with increasing age in all joints independently from sex and body side. However, the BCD and the capsule thickness increased with age. There was no intraarticular fluid visible. The joint capsule had a predominantly concave form, whereas the capsule-bone junction was mostly sharp. Discussion This study is the first describing age-related normal values of the intracapsular cavity, joint capsule and cartilage thickness as well as their respective shape in a large cohort of healthy children. Conclusion The findings could be helpful to differentiate between physiological and pathological joint conditions and thereby distinguishing age-related variations from alterations caused by inflammation.

Age-dependent arthrosonographic reference values of the hip joint in healthy children and adolescents - a cross-sectional multicenter ultrasound study.

BACKGROUND: Musculoskeletal US is a noninvasive imaging method for diagnosing and monitoring inflammatory rheumatic diseases. OBJECTIVES: To develop age- and gender-related arthrosonographic reference intervals for the hip joint of healthy children and adolescents. MATERIALS AND METHODS: In a cross-sectional US study, we examined both hip joints of 445 children and adolescents with an age range of 1 year to 18 years. We measured the distance between the bone surface and the outer margin of the joint capsule to define the bone-capsule distance, the joint capsule and cartilage thickness, and the capsule layer thickness. Reference values were calculated. The shape of the joint capsule and bone-capsule junction zone were analyzed qualitatively. An intraobserver analysis was performed. RESULTS: Bone-capsule distance, capsule thickness and the anterior capsule layer increase with age. In contrast, joint cartilage decreases. The posterior capsule layer exhibited constant thickness across all age groups. The difference between both body sides and gender was collectively less than 0.5 mm. The intraobserver variations were within the calculated reference intervals. The insertion of the capsule to the bone was mostly a peaked one. The capsule shape had a convex or straight configuration in a neutral position and a concave position during outward rotation. The intraobserver analysis revealed good to very good concordance. CONCLUSION: We propose age- and gender-related reference intervals for the bone-capsule distance, joint capsule and cartilage thickness of the hip.

Pediatric musculoskeletal ultrasound: age- and sex-related normal B-mode findings of the knee.

Musculoskeletal ultrasound (MSUS) is an important tool for evaluating disease activity, therapeutic progress, and remission status of rheumatic diseases in children. Knowledge of age-related normal findings is essential when interpreting pathological findings such as those seen in juvenile idiopathic arthritis. To evaluate normal findings of the knee joint, we recorded age-related stages of musculoskeletal development in the knee of 435 healthy children between 1 and 18 years of age using high-resolution B-mode MSUS. We determined approximate age- and sex-related norms for the suprapatellar recess size, ossified patella size, and distal femoral intercondylar cartilage thickness. In almost all age-groups, over 64 % of children had visible fluid accumulation in the suprapatellar recess. Significant correlations were found between chronological age and the suprapatellar recess size and ossified patella length (p < 0.05). An age-dependent decrease in intercondylar cartilage thickness of the distal femoral epiphysis was found in children between 10 and 18 years of age. High-resolution B-mode MSUS is an excellent tool for assessing joint and skeletal development in children. Our reference data can be used to discriminate better between normal physiological findings and pathological abnormalities.