Sylvain Breton

Ultrasonography for detecting enthesitis in juvenile idiopathic arthritis.

Enthesitis is a major feature of juvenile idiopathic arthritis (JIA) but is difficult to diagnose clinically. Our objective was to compare the accuracy of ultrasonography with power Doppler (US‐PD) versus clinical examination for diagnosing enthesitis in patients with JIA and healthy controls.

Comparison of Clinical and Ultrasonographic Evaluations for Peripheral Synovitis in Juvenile Idiopathic Arthritis

OBJECTIVES The characteristics of synovitis in juvenile idiopathic arthritis (JIA) are important to evaluate, as they define several clinical categories. The metacarpophalangeal (MCP) and metatarsophalangeal (MTP) joints are frequently involved. Few studies have investigated peripheral joint evaluation using ultrasonography, a sensitive tool for detecting subclinical synovitis. Our objectives here were to compare clinical and ultrasound evaluations of MCP and MTP joint synovitis and to determine the prevalence of predefined ultrasound abnormalities in JIA patients and healthy controls. METHODS Standardized physical and ultrasound assessments of the same joints were done in 31 consecutive patients with JIA and 41 healthy volunteers. Joint pain, motion limitation, and swelling were recorded. Ultrasonography was performed on the same joints by 2 trained sonographers who recorded synovial fluid, synovial hypertrophy, erosion, and power Doppler signal. Intraobserver reproducibility of ultrasonography was assessed. RESULTS Of 558 peripheral joints examined in JIA patients, 69 (12.5%) had ultrasonographic synovitis and 83 (15%) had abnormal physical findings. All the physical abnormalities were significantly associated with ultrasonographic synovitis (P < 0.0001) but agreement was low between ultrasonographic and physical findings. Ultrasonographic synovitis was most common at the feet (59.4%), where it was detected clinically in only 25% of cases. Ultrasonographic synovitis was associated with the presence of synovial fluid. Cartilage vascularization was found in 2 (4.2%) healthy controls. CONCLUSION Ultrasonography is useful for monitoring synovitis in JIA. Subclinical involvement of the MTP joints is common. Clinicians should be aware of the specific ultrasonographic findings in children.

LRBA deficiency with autoimmunity and early onset chronic erosive polyarthritis.

LRBA (lipopolysaccharide-responsive and beige-like anchor protein) deficiency associates immune deficiency, lymphoproliferation, and various organ-specific autoimmunity. To date, prevalent symptoms are autoimmune cytopenias and enteropathy, and lymphocytic interstitial lung disease. In 2 siblings from a consanguineous family presenting with early onset polyautoimmunity, we presumed autosomal recessive inheritance and performed whole exome sequencing. We herein report the first case of early-onset, severe, chronic polyarthritis associated with LRBA deficiency. A novel 1bp insertion in the LRBA gene, abolishing protein expression, was identified in this family. Among the 2 brothers homozygous for LRBA mutation, one developed Evans syndrome and deceased at age 8.5 from complications of severe autoimmune thrombocytopenia. His brother, who carried the same homozygous LRBA mutation, early-onset erosive polyarthritis associated with chronic, bilateral, anterior uveitis and early onset type 1 diabetes mellitus. This report widens the clinical spectrum of LRBA deficiency and, in lights of the variable phenotypes described so far, prompts us to screen for this disease in patients with multiple autoimmune symptoms in the family, including severe, erosive, polyarticular juvenile arthritis.

Heterogeneity of mutational mechanisms and modes of inheritance in auriculocondylar syndrome

Background Auriculocondylar syndrome (ACS) is a rare craniofacial disorder consisting of micrognathia, mandibular condyle hypoplasia and a specific malformation of the ear at the junction between the lobe and helix. Missense heterozygous mutations in the phospholipase C, β 4 (PLCB4) and guanine nucleotide binding protein (G protein), α inhibiting activity polypeptide 3 (GNAI3) genes have recently been identified in ACS patients by exome sequencing. These genes are predicted to function within the G protein-coupled endothelin receptor pathway during craniofacial development. Results We report eight additional cases ascribed to PLCB4 or GNAI3 gene lesions, comprising six heterozygous PLCB4 missense mutations, one heterozygous GNAI3 missense mutation and one homozygous PLCB4 intragenic deletion. Certain residues represent mutational hotspots; of the total of 11 ACS PLCB4 missense mutations now described, five disrupt Arg621 and two disrupt Asp360. The narrow distribution of mutations within protein space suggests that the mutations may result in dominantly interfering proteins, rather than haploinsufficiency. The consanguineous parents of the patient with a homozygous PLCB4 deletion each harboured the heterozygous deletion, but did not present the ACS phenotype, further suggesting that ACS is not caused by PLCB4 haploinsufficiency. In addition to ACS, the patient harbouring a homozygous deletion presented with central apnoea, a phenotype that has not been previously reported in ACS patients. Conclusions These findings indicate that ACS is not only genetically heterogeneous but also an autosomal dominant or recessive condition according to the nature of the PLCB4 gene lesion.

Imaging approaches for evaluating peripheral joint abnormalities in juvenile idiopathic arthritis.

OBJECTIVES To assess the usefulness of imaging studies for peripheral joint assessment in children with juvenile idiopathic arthritis (JIA), based on a systematic literature review. METHODS We used PubMed to identify relevant articles published between 2000 and 2011. RESULTS Plain radiography is still the reference imaging study for monitoring joint destruction in patients with JIA, and the results correlate well with the clinical findings. Radiographs should be obtained routinely during follow-up and in therapeutic trials. Available scoring methods have been validated in children, but no recommendations are available on the intervals between radiographic assessments. Ultrasonography and magnetic resonance imaging (MRI) can detect inflammatory changes that precede bone destruction. Ultrasonography features in JIA are still being studied. Ultrasonography can detect clinically silent synovitis, which has major implications for determining the JIA subtype. MRI is the only imaging study capable of showing bone marrow edema, which predicts joint destruction. CONCLUSIONS Although radiography remains the reference standard imaging study for assessing peripheral joint destruction in JIA, ultrasonography and MRI allow the early detection of predestructive changes, the presence of which affects treatment decisions. Much more work is needed to determine the optimal imaging protocols, the best interval between imaging evaluations during follow-up, and the therapeutic implications of imaging study findings.

The identification of MAFB mutations in eight patients with multicentric carpo–tarsal osteolysis supports genetic homogeneity but clinical variability

Multicentric carpo–tarsal osteolysis (MCTO) with or without nephropathy is a rare osteolysis disorder beginning in early childhood and involving mainly carpal and tarsal bones. Renal disease appears later in life in the majority of cases and evolves quickly to end stage renal failure. Autosomal dominant (AD) inheritance has been demonstrated, with a high frequency of sporadic cases. Recently, mutations in a highly conserved region of the MAFB gene (v‐maf musculoaponeurotic fibrosarcoma oncogene ortholog B) have been identified in MCTO patients by exome sequencing. MafB, known as a regulator of various developmental processes, is essential for osteoclastogenesis and renal development. We report here the molecular screening of MAFB in eight MCTO patients from six families. We identified MAFB mutations in all, including three novel missense mutations clustering within the hot spot mutation region. Among the eight patients, six only presented renal disease. Our report confirms the genetic homogeneity of MCTO and provides data underlying the clinical variability of this disorder.

Mutation in MMP2 gene may result in scleroderma-like skin thickening

We read with interest the paper by Banka et al 1 who identify microduplications of chromosome 8q22 as the cause of Leri’s pleonostosis, a disease belonging to the ‘transforming growth factor beta (TGF-beta)-pathies’ group of musculoskeletal disorders. We have been involved in the identification of rare monogenic systemic lupus erythematosus (SLE), especially inherited interferonopathies,2 ,3 and we agree with the authors that the common phenotype of autoimmune diseases, such as SLE and systemic sclerosis (SSc), could be explained by involvement of different disease-associated genes in related physiological pathways. Herein we aim to report for the first time that mutation in matrix metalloproteinase-2 (MMP-2) may result in scleroderma-like skin thickening. A 12-year-old girl was referred because of distal osteoporosis revealed by several pathological appendicular fractures since the age of 8 years. There was no family history. Physical evaluation revealed mildly coarse face, hypertrophic scars and keloids, …

Bone involvement in monogenic autoinflammatory syndromes

Until recently the most common autoinflammatory diseases (AIDs) associated with bone disease in childhood included a few genetically complex (chronic non-bacterial osteomyelitis, synovitis, acne, pustulosis, hyperostosis and osteitis syndrome) and monogenic (Majeed syndrome, deficiency of IL-1 receptor antagonist, cherubism) AIDs. However, the spectrum of monogenic AIDs associated with bone manifestations has markedly expanded to include both recently identified diseases such as the type I interferonopathies and also newly recognized bone dysplasias in already established AIDs. In addition, we propose that some known bone dysplasia syndromes, especially those presenting with hyperostosis and associated systemic inflammation, be classified as AIDs. Collectively, we provide an overview of the diverse bone manifestations identified in the genetically defined AIDs, discuss the hypotheses of the underlying pathophysiological mechanisms and highlight potential novel therapeutic strategies.

Fibrous Arthropathy Associated With Morphea: A New Cause of Diffuse Acquired Joint Contractures

Through 2 demonstrative cases, we describe a new entity associating circumscribed morphea and diffuse articular fibrosis, extending the list of etiologies for diffuse acquired joint contractures. Etiologies for childhood-onset diffuse joint contractures encompass a large group of inherited disorders and acquired diseases, in particular a subtype of juvenile idiopathic arthritis called “dry polyarthritis,” dermatomyositis, and systemic sclerosis. We report on 2 boys, aged 5 and 8 years, who developed acquired symmetric painless joint contractures preceding the development of superficial plaques of morphea by 7 to 13 months. There was no other clinical involvement, biological inflammation, or autoantibodies. No urinary mucopolysaccharidosis was seen. In both patients, wrist MRI showed no joint effusion, no bone erosion, and no or mild synovial thickening with slight enhancement after gadolinium infusion. One patient underwent a synovial biopsy, which showed dense fibrosis with a sparse inflammatory infiltrate, similar to the pathologic pattern observed in the skin biopsy. With methotrexate and systemic steroids, joint contractures slowly improved in the first patient and remained stable in the second. These 2 cases suggest that fibrous synovitis should be considered in children with acquired diffuse, symmetric, painless contractures and without elevation of acute-phase reactants, even in the absence of cutaneous manifestations. Articular MRI with gadolinium and careful cutaneous examination at onset and during follow-up should provide clues for diagnosing this entity.

Conventional radiography in juvenile idiopathic arthritis: Joint recommendations from the French societies for rheumatology, radiology and paediatric rheumatology

BackgroundJuvenile idiopathic arthritis (JIA) can cause structural damage. However, data on conventional radiography (CR) in JIA are scant.ObjectiveTo provide pragmatic guidelines on CR in each non-systemic JIA subtype.MethodsA multidisciplinary task force of 16 French experts (rheumatologists, paediatricians, radiologists and one patient representative) formulated research questions on CR assessments in each non-systemic JIA subtype. A systematic literature review was conducted to identify studies providing detailed information on structural joint damage. Recommendations, based on the evidence found, were evaluated using two Delphi rounds and a review by an independent committee.Results74 original articles were included. The task force developed four principles and 31 recommendations with grades ranging from B to D. The experts felt strongly that patients should be selected for CR based on the risk of structural damage, with routine CR of the hands and feet in rheumatoid factor-positive polyarticular JIA but not in oligoarticular non-extensive JIA.ConclusionThese first pragmatic recommendations on CR in JIA rely chiefly on expert opinion, given the dearth of scientific evidence. CR deserves to be viewed as a valuable tool in many situations in patients with JIA.Key Points• CR is a valuable imaging technique in selected indications.• CR is routinely recommended for peripheral joints, when damage risk is high.• CR is recommended according to the damage risk, depending on JIA subtype.• CR is not the first-line technique for imaging of the axial skeleton.