Gabriella Giancane

Evidence-based recommendations for genetic diagnosis of familial Mediterranean fever

Familial Mediterranean fever (FMF) is a disease of early onset which can lead to significant morbidity. In 2012, Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) was launched with the aim of optimising and disseminating diagnostic and management regimens for children and young adults with rheumatic diseases. The objective was to establish recommendations for FMF focusing on provision of diagnostic tools for inexperienced clinicians particularly regarding interpretation of MEFV mutations. Evidence-based recommendations were developed using the European League against Rheumatism standard operating procedure. An expert committee of paediatric rheumatologists defined search terms for the systematic literature review. Two independent experts scored articles for validity and level of evidence. Recommendations derived from the literature were evaluated by an online survey and statements with less than 80% agreement were reformulated. Subsequently, all recommendations were discussed at a consensus meeting using the nominal group technique and were accepted if more than 80% agreement was reached. The literature search yielded 3386 articles, of which 25 were considered relevant and scored for validity and level of evidence. In total, 17 articles were scored valid and used to formulate the recommendations. Eight recommendations were accepted with 100% agreement after the consensus meeting. Topics covered were clinical versus genetic diagnosis of FMF, genotype–phenotype correlation, genotype–age at onset correlation, silent carriers and risk of amyloid A (AA) amyloidosis, and role of the specialist in FMF diagnosis. The SHARE initiative provides recommendations for diagnosing FMF aimed at facilitating improved and uniform care throughout Europe.

EULAR recommendations for the management of familial Mediterranean fever

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease, but many rheumatologists are not well acquainted with its management. The objective of this report is to produce evidence-based recommendations to guide rheumatologists and other health professionals in the treatment and follow-up of patients with FMF. A multidisciplinary panel, including rheumatologists, internists, paediatricians, a nurse, a methodologist and a patient representative, was assembled. Panellists came from the Eastern Mediterranean area, Europe and North America. A preliminary systematic literature search on the pharmacological treatment of FMF was performed following which the expert group convened to define aims, scope and users of the guidelines and established the need for additional reviews on controversial topics. In a second meeting, recommendations were discussed and refined in light of available evidence. Finally, agreement with the recommendations was obtained from a larger group of experts through a Delphi survey. The level of evidence (LoE) and grade of recommendation (GR) were then incorporated. The final document comprises 18 recommendations, each presented with its degree of agreement (0–10), LoE, GR and rationale. The degree of agreement was greater than 7/10 in all instances. The more controversial statements were those related to follow-up and dose change, for which supporting evidence is limited. A set of widely accepted recommendations for the treatment and monitoring of FMF is presented, supported by the best available evidence and expert opinion. It is believed that these recommendations will be useful in guiding physicians in the care of patients with FMF.

Clinical outcome measures in juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA), as a chronic condition, is associated with significant disease- and treatment-related morbidity, thus impacting children’s quality of life. In order to optimize JIA management, the paediatric rheumatologist has begun to regularly use measurements of disease activity developed, validated and endorsed by international paediatric rheumatology professional societies in an effort to monitor the disease course over time and assess the efficacy of therapeutic interventions in JIA patients.A literature review was performed to describe the main outcome measures currently used in JIA patients to determine disease activity status.The Juvenile Disease Activity Score (JADAS), in its different versions (classic JADAS, JADAS-CRP and cJADAS) and the validated definitions of disease activity and response to treatment represent an important tool for the assessment of clinically relevant changes in disease activity, leading more and more to a treat-to-target strategy, based on a tight and thorough control of the patient condition. Moreover, in recent years, increasing attention on the incorporation of patient-reported or parent-reported outcomes (PRCOs), when measuring the health state of patients with paediatric rheumatic diseases has emerged.We think that the care of JIA patients cannot be possible without taking into account clinical outcome measures and, in this regard, further work is required.

Temporomandibular Joint Involvement is Associated with Quality of Life, Disability and High Disease Activity in Juvenile Idiopathic Arthritis

To evaluate the demographic, disease activity, disability, and health‐related quality of life (HRQOL) differences between children with juvenile idiopathic arthritis (JIA) and their healthy peers, and between children with JIA with and without clinical temporomandibular joint (TMJ) involvement and its determinants.

IL-1 inhibition in systemic juvenile idiopathic arthritis

Systemic juvenile idiopathic arthritis (sJIA) is the form of childhood arthritis whose treatment is most challenging. The demonstration of the prominent involvement of interleukin (IL)-1 in disease pathogenesis has provided the rationale for the treatment with biologic medications that antagonize this cytokine. The three IL-1 blockers that have been tested so far (anakinra, canakinumab, and rilonacept) have all been proven effective and safe, although only canakinumab is currently approved for use in sJIA. The studies on IL-1 inhibition in sJIA published in the past few years suggest that children with fewer affected joints, higher neutrophil count, younger age at disease onset, shorter disease duration, or, possibly, higher ferritin level may respond better to anti-IL-1 treatment. In addition, it has been postulated that use of IL-1 blockade as first-line therapy may take advantage of a “window of opportunity,” in which disease pathophysiology can be altered to prevent the occurrence of chronic arthritis. In this review, we analyze the published literature on IL-1 inhibitors in sJIA and discuss the rationale underlying the use of these medications, the results of therapeutic studies, and the controversial issues.

Primary Hypertrophic Osteoarthropathy: An Update on Patient Features and Treatment

To the Editor: Hypertrophic osteoarthropathy (HO) is a disorder characterized by changes to the skin and bones, and occurs either in a rare familial primary form [primary hypertrophic osteoarthropathy, (PHO)], also called pachydermoperiostosis (PDP), with a 9:1 male:female prevalence ratio, or more commonly secondary to an underlying pathology1. Key features include digital clubbing, periostosis with bone and joint enlargement, and skin changes, such as pachydermia, abnormal furrowing, seborrhea, and hyperhidrosis. Specific developmental abnormalities have been found in some patients with PHO, such as wide cranial sutures, Wormian bones, and patent ductus arteriosus 2. In adults, when all major clinical features are present, PHO is relatively easy to diagnose. However, for the pediatrician, who often has to contend with an incomplete clinical presentation3, diagnosis may be a challenge. The discovery of mutations in 2 prostaglandin pathway genes HPGD and SLCO2A1 has clarified the autosomal recessive inheritance [Mendelian Inheritance in Man (MIM) #259100, MIM #614441] of this genetically heterogeneous condition4,5,6,7. Here we present 4 previously undescribed patients who exemplify the gene-dependent presentations of PHO and provide diagnostic and treatment advice. The subjects’ written consent was obtained in conformance to the Declaration of Helsinki. Key clinical features are listed in Table 1. Secondary causes of HO were excluded8, and DNA sequence analysis (Supplementary Data available online at jrheum.org) confirmed the clinical diagnoses of PHO/PDP. View this table: Table 1. Patients’ clinical features. A 20-year-old male patient had begun limping at the age of 14 months. At 3 years old, chronic arthritis of both knees was investigated by arthroscopy, with nonspecific chronic synovial inflammation at biopsy. Oligoarticular juvenile idiopathic arthritis (JIA) was diagnosed, and the patient was treated with nonsteroidal antiinflammatory drugs (NSAID), with clinical improvement. At age 5, coarse facies was noted. … Address correspondence to Dr. Gabriella Giancane, Department of Pediatric Immunology, University Medical Centre Utrecht, 3508 AB, Utrecht, the Netherlands. E-mail: gabriella.giancane{at}gmail.com, ggiancan{at}umcutrecht.nl

Evidence based recommendations for genetic diagnosis of Familial Mediterranean Fever.

Familial Mediterranean Fever (FMF) is a disease that starts in childhood and can lead to significant morbidity. In 2012, a European initiative called SHARE (Single Hub and Access point for pediatric Rheumatology in Europe) has been launched to optimize and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases. For FMF, attention was focused on genetics.

Frequency of Radiographic Damage and Progression in Individual Joints in Children With Juvenile Idiopathic Arthritis

To evaluate the presence and progression of radiographic joint damage, as assessed with the adapted Sharp/van der Heijde score (SHS), in individual joints in the hand and wrist in patients with juvenile idiopathic arthritis (JIA) and to compare progression of damage among different JIA categories.

Current Research in Outcome Measures for Pediatric Rheumatic and Autoinflammatory Diseases

A rational management of children and adolescents with rheumatic and autoinflammatory diseases requires the regular assessment of the level of disease activity and of child health and well-being through the use of well-validated outcome measures. Ideally, such instruments should be simple and feasible and easily applicable in standard clinical practice. In recent years, a number of novel outcome measures have been developed and validated for use in pediatric patients with rheumatic and autoinflammatory illnesses. Furthermore, there has been an increased focus on the appraisal of child and parent perception of the disease impact. The new tools have markedly enlarged the spectrum of disorders and health domains that can be assessed in a standardized way. This progress will help to enhance the reliability of research studies and clinical trials. The aim of the present review is to provide an update of the recent advances in this field of research.

Update on the pathogenesis and treatment of juvenile idiopathic arthritis

Purpose of review To provide an overview of recently published studies on pathogenesis and management of juvenile idiopathic arthritis (JIA). Recent findings In the past year, the potential role of network analysis in the understanding of the molecular phenotype of individual JIA subgroups has been highlighted. In addition, potential new targets for pharmacologic interventions have been identified through the elucidation of mechanisms that modulate the function of cells involved in the inflammatory process. There is a growing interest for the role of the gut microbiome in disease pathogenesis, which may open the way to future therapeutic manipulations of fecal microbial population. Recent therapeutic studies have provided important information in large patient samples on the effectiveness and toxicity profile of biologic medications used in JIA. Concomitant administration of methotrexate was found to increase the effectiveness of intra-articular corticosteroid therapy in children with oligoarticular JIA. Summary A great deal of work is being conducted to better define the molecular phenotype of the individual subsets of JIA and to identify potential new targets for therapeutic interventions. The results of the ongoing large-scale international data collections will help establish the long-term safety profiles of biologic medications, in particular the risk of malignancy.