Galeazzi M

Diagnosis of calcium pyrophosphate dihydrate crystal deposition disease: ultrasonographic criteria proposed

Objective: To investigate by high frequency ultrasonography the appearance of calcium pyrophosphate dihydrate (CPPD) calcifications, in the most commonly affected sites in CPPD disease, and the relationship between ultrasonographic CPPD deposits and the presence of CPPD crystals in synovial fluid. Methods: Three ultrasonographic patterns of CPPD calcification were identified and 11 patients enrolled. A control group comprised 13 patients with no evidence of CPPD deposits. Synovial fluid was aspirated from all patients and controls and examined for identification of crystals. All patients underwent a standard radiography examination at the same sites investigated by ultrasound. Results: In all patients with ultrasonographically defined CPPD deposits, CPPD crystals were found in the synovial fluid. In two cases, standard radiographic examination did not show evidence of the calcific deposits that were identified by ultrasonography. CPPD crystals were not found in the synovial fluid of controls. In four control group patients, ultrasonography identified calcifications defined as deposits of another nature. Conclusions: The ultrasonographic pattern used in this study for the diagnosis of CPPD disease demonstrated a very high correlation with the presence of CPPD crystals in synovial fluid. Ultrasonography demonstrated a sensitivity and specificity at least equal to that of radiography in identifying CPPD crystal calcifications.

Effectiveness and tuberculosis-related safety profile of interleukin-1 blocking agents in the management of Behçet's disease

Behçets disease (BD) is a multi-systemic disorder of unknown etiology characterized by relapsing oral-genital ulcers, uveitis, and involvement of the articular, gastrointestinal, neurologic, and vascular systems. Although the primum movens of this condition remains unknown, a tangled plot combining autoimmune and autoinflammatory pathways has been hypothesized to explain its start and recurrence. In-depth analysis of BD pathogenetic mechanisms, involving dysfunction of multiple proinflammatory molecules, has opened new modalities of treatment: different agents targeting interleukin-1 have been studied in recent years to manage the most difficult and multi-resistant cases of BD. Growing experience with anakinra, canakinumab and gevokizumab is discussed in this review, highlighting the relative efficacy of each drug upon the protean BD clinical manifestations. Safety and tolerability of interleukin-1 antagonists in different doses have been confirmed by numerous observational studies on both large and small cohorts of patients with BD. In particular, the potential for Mycobacterium tuberculosis reactivation and tuberculosis development appears to be significantly lower with interleukin-1 blockers compared to tumor necrosis factor-α inhibitors, thus increasing the beneficial profile of this approach.

Idiopathic recurrent pericarditis refractory to colchicine treatment can reveal tumor necrosis factor receptor-associated periodic syndrome

Recurrences develop in up to 20–50% of patients with acute pericarditis. Although different causes of recurrent pericarditis have been identified, the etiology remains obscure in most cases which are therefore labelled as idiopathic. Autoinflammatory syndromes include familial Mediterranean fever (FMF), due to mutations in the MEFV gene, and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), due to mutations in the TNFRSF1A gene. Recurrent pericarditis is a common feature of both conditions, but it rarely occurs alone. Colchicine is the standard treatment for FMF, while patients with TRAPS do not respond to colchicine therapy, but are responsive to corticosteroids. Based on the proven efficacy of colchicine in preventing polyserositis in FMF, colchicine has been proposed for the treatment of recurrent pericarditis and is able to decrease the recurrence rate. Our aim was to investigate the possible involvement of TNFRSF1A mutations in a group of patients with idiopathic recurrent pericarditis who were refractory to colchicine treatment. Thirty consecutive patients (17 males, 13 females) diagnosed with idiopathic recurrent pericarditis, who were characterized by a poor response to colchicine treatment, were enrolled in the study. Mutations of the TNFRSF1A gene were searched for by amplifying, using polymerase chain reaction (PCR), genomic DNA, and direct sequencing. TNFRSF1A mutations were found in 4 of the 30 patients. None of these 4 patients had a family history of recurrent inflammatory syndromes or history of pericarditis. One of the 4 patients had a novel heterozygous deletion (ΔY103-R104) and three patients carried a heterozygous low-penetrance R92Q mutation. Our data suggest that TRAPS should be kept in mind in the differential diagnosis of recurrent pericarditis, and mutation analysis of the TNFRSF1A gene should be considered, in addition to MEFV analysis, in patients of Mediterranean origin. A poor response to colchicine treatment and/or a steroid-dependence may be the clue to investigate TNFRSF1A mutations in patients with idiopathic recurrent pericarditis.

Role of etanercept in the treatment of tumor necrosis factor receptor-associated periodic syndrome: personal experience and review of the literature

Tumor necrosis factor-α receptor (TNFRl)—associated periodic syndrome (TRAPS) is the most common autosomal-dominant autoinflammatory condition and is caused by mutations in the TNFRSF1A gene. TRAPS is characterized by recurrent attacks of fever typically lasting from 1 to 3 weeks; in addition to fever, common clinical features include mainly periorbital oedema, conjunctivitis, a migratory erythematous plaque simulating erysipela with underlying myalgia, and arthritis or arthralgia; serosal membrane inflammation is also possible. The identification of TNFRSF1A mutations as the genetic cause of TRAPS coincided with the wider use of biological agents in medicine and raised the possibility that blocking TNF could potentially represent the primary therapeutic goal in TRAPS, thus disclosing new treatment choices for this complex disease. In the past few years, isolated reports and case-series have been published suggesting that inhibition of TNF-α might represent a promising therapeutic approach in TRAPS. We present here our experience with etanercept in the treatment of patients affected with TRAPS, and we also add a review of the literature.

Treatment strategies for childhood noninfectious chronic uveitis: an update

Background: Uveitis is an inflammatory disorder involving inflammation of the uveal tract. It is classified as anterior, intermediate, posterior or panuveitis, depending on the part of eye affected by the inflammatory process. In children, noninfectious, chronic uveitis is a relatively uncommon but serious disease, with the potential for significant long-term complications and possible blindness. Although frequently associated with an underlying systemic disease, for example, juvenile idiopathic arthritis, a significant number of cases in children show no associated signs or symptoms and are labeled as idiopathic. Results: We reviewed the available literature. Taking into account this evidence, an anti-inflammatory therapy based on an immunomodulatory approach seems a reasonable strategy for noninfectious chronic uveitis, in children as well as in adults. Due to a lack of controlled studies regarding uveitis in children, immunosuppressive strategy is supported only at evidence level III. Our aim is to review the currently available medical strategies for the treatment of childhood sight-threatening chronic uveitis. Conclusion: Uveitis in children can be severe. Methotrexate is the drug of choice for recalcitrant cases, and biologic therapies can be useful in selected situations.

Hyperhomocysteinemia: a cardiovascular risk factor in autoimmune diseases?

Epidemiological studies conducted over the past 25 years have provided ample support for the association of mild hyperhomocysteinemia (HHcy) with an elevated risk of atherothrombosis. Since autoimmune disorders (AD) are frequently associated with relevant and early signs of atherothrombotic damage not adequately explained by the traditional risk factors involved in the onset of cardiovascular disease (CVD), a large interest has been shown to the putative role of mild HHcy in this setting. On the basis of such considerations, we focused the attention on the relationship between homocysteine (Hcy) and CVD in patients affected with autoimmune diseases, reviewing the most recent literature data and also providing our original experience. Although the large amount of available studies clearly shows that HHcy represents a common finding in patients affected with several autoimmune diseases, the actual role of Hcy in the development of CVD in the course of AD is not clear yet, perhaps, with the only exception of the systemic lupus erythematosus. In the other conditions, the role of Hcy in the pathogenesis of vascular complications is still a matter of debate, as the result of conflicting reports and/or lack of an adequate body of investigation. Lupus (2007) 16, 852—862.

Tendon involvement in patients with ochronosis: an ultrasonographic study

Ochronosis is the musculoskeletal manifestation of alcaptonuria, a rare autosomal recessive disorder with an estimated prevalence of below 1:250 000.1 Alcaptonuria is associated with deficient homogentisate 1,2-dioxygenase (HGO) activity in the liver,2 causing production of large quantities of homogentisic acid (HGA). In urine and tissues, HGA oxidises to benzoquinones, which in turn form melanin-like polymers. Tendons are sites of ochronotic pigment deposition because of their high collagen content.3 Several cases of tendon and ligament ruptures in alcaptonuria have been reported.1 4 5 To our knowledge, no studies have been carried out regarding tendon pathology in ochronosis. Ultrasonography (US) is an inexpensive, repeatable, non-invasive exam that permits accurate visualisation of tendons and ligaments. Our …

SAT0625 Ultrasound assessment of joints and enthesis in a cohort of patients affected by ochronosis: how common is inflammation?

Background Ochronosis, the musculoskeletal manifestation of alcaptonuria (AKU), is characterized by alterations of the spine and large joints of the limbs similar to those of osteoarthritis. However, some cases of spinal involvement that resembles spondiloarthritis (SpA) have been describe, suggesting a prevalent inflammatory involvement of the joints. Objectives To evaluate the prevalence of inflammatory abnormalities in peripheral joints and enthesis of a cohort of patients affected by AKU. Methods consecutive patients with definite diagnosis of AKU (with or without clinical manifestations) referred at our clinic from 2014 to 2016 were enrolled. All patients underwent a US examination of the following sites bilaterally: metacarpo-phalangeal joints (MCP), proximal interphalangeal joints (PIP), radiocarpal/mid carpal joints, elbow, gleno-humeral, hip, knee, ankle and metatarso-phalangeal (MTP) joints; flexor and extensor tendons of fingers and wrist and the ankle tendons. Further, the enthesis of the rotator cuff of the shoulder, triceps, quadriceps, patellar and Achilles tendon were assessed. Joints and tendons with a synovial sheath were assessed for effusion, synovial hypertrophy and power Doppler (PD) signal while enthesis were evaluated for the presence of PD signal, enthesophytes and calcifications. All the US lesions were scored using a dichotomous scale (presence/absence). All US exams were performed by an expert sonographer blind to clinical history, using an Esaote MyLab70 scanner equipped with high resolution linear probes. Results 11 patients (6 women) were enrolled in this study with a mean age of 57 yo (SD±11,50). the mean number of joints with effusion was 3,9 for each patient (median 3, range 2–8) while the mean number of joints with synovial hypertrophy was of 2,9 (median 2, range 2–7). =0,18 joints (median 0, range 0–2) presented also PD signal. I The mean number of exudative tenosynovitis was0,81 (median 2, range 0–3) while proliferative tenosynovitis (mean 0,54, median 0, range 0–2) and PD in tendons with sheaths (mean 0,27, median 0, range 0–2) were rare. Finally, the mean number of enthesis with PD was 1,27 (median 1, range 0–7), the mean number of enthesophytes was 0,63 (median 0, range 0–3) and for calcifications 4,27 (median 5, range 1–8). Conclusions Ochronotic arthropathy is believed to be characterized by a widespread articular damage, correlated mainly to degenerative processes due to the deposition of Homogentisinic Acid in the joints. The results of this US study showed that joint inflammation is common in ochronotic patients, associated in some cases with peripheral enthesis involvement confirming previously published data (1). The prevalence and the characteristics of the inflammatory manifestations should be further studied in larger cohorts of patients as they could play an important role in the joint damage process in these patients and provide a rationale for the use of new drugs. References Filippou G, Frediani B, Selvi E et al, Tendon involvement in patients with ochronosis: an ultrasonographic study. Ann Rheum Dis 2008 Dec;67(12):1785–6. Disclosure of Interest None declared

AB0037 Serum cytokine signature in mucocutaneous and ocular behÇet's disease

Background Behçets disease (BD) is a multi-systemic inflammatory disorder consisting of recurrent oral aphthosis, genital ulcers, and chronic relapsing bilateral uveitis. However, many other organs including the vascular, gastrointestinal, neurological, and musculoskeletal systems can be affected. Pathogenetically, both innate and adaptive immunity have shown to play a pivotal role, and several proinflammatory cytokines derived from Th1 and Th17 lymphocytes seem to be involved in different pathogenic pathways leading to development of the clinical manifestations. Objectives The primary aim of our study was to compare a core set of proinflammatory cytokines between patients with BD and healthy control (HC). The secondary aim was to evaluate potential correlations between these putative circulating biomarkers, the status of disease activity, and the specific organ involvement at the time of sample collection. Methods Fifty-four serum samples were collected from 46 BD patients (17 males, 29 females, mean age 45,5±11,3 years), and 19 HC (10 males, 9 females, mean age 43±8.3 years). Twenty-five serum cytokines (APRIL/TNFS13, BAFF/TNFSF13B, sCD30/TNFRSF8, sCD163, Chitinase3-like1, gp130/sIL-6Rb, IFNb, sIL-6Ra, IL-10, IL-11, IL-19, IL-20, IL-26, IL-27 (p28), IL-28A/IFN-lambda2, IL-29/IFN-lambda1, IL-32, IL-34, IL-35, LIGHT/TNFSF-14, Pentraxin-3, sTNF-R1, sTNF-R2, TSLP and TWEAK/TNFSF-12) were simultaneously quantified using a Bio-Rad cytokine bead arrays. Results Serum levels of Chitinase3-like1, gp130/sIL-6Rb, IL-11, IL-26, sTNF-R1, sTNF-R2 were significantly higher in BD patients than in HC. Specifically, serum concentration of sTNF-R1 (p<0.01) and sTNF-R2 (p<0.01) resulted higher in both active- and inactive-BD than HC, whilst Chi-tinase3-like1 (p<0.05) and gp130/sIL-6Rb (p<0.01) serum levels were significantly higher in in-active-BD, and IL-26 (p<0.01) in active-BD than HC. No differences were observed between inactive- and active- BD group. In addition, comparing cytokines levels in patients affected by mucocutenous manifestations with (MO-BD) or without (M-BD) ocular involvement we observed that gp130/sIL-6Rb, sIL-6Ra, IL-35, and TSLP serum levels were significant enhanced in MO-BD compared to M-BD subgroup. Conclusions Our findings showed a signature of IL-6, TNF-α as well as of Th17 response in BD patients due to increased levels of gp130/sIL-6Rb, sTNF-R1, sTNF-R2, IL-26 respectively. This evidence could contribute to improve the knowledge regarding the role of these citokines in the induction of specific BD clinical features References Lopalco G, Lucherini OM, Vitale A, Talarico R, Lopalco A, Galeazzi M, et al. Putative Role of Serum Amyloid-A and Proinflammatory Cytokines as Biomarkers for Behcets Disease. Medicine (Baltimore) (2015) 94(42):e1858. Lucherini OM, Lopalco G, Cantarini L, Vitale A, Rotondo C, Lopalco A, et al. Correlation between serum amyloid-A and serum levels of proinflammatory cytokines in patients with Behçets disease. Pediatric Rheumatology Online Journal (2015) 13(Suppl 1):P6. Turan B, Pfister K, Diener PA, Hell M, Möller B, Boyvat A, et al. Soluble tumour necrosis factor receptors sTNFR1 and sTNFR2 are produced at sites of inflammation and are markers of arthritis activity in Behçets disease. Scand J Rheumatol (2008) 37(2):135–41. Disclosure of Interest None declared

FRI0533 Ultrasonographic Features of Joints and Entheses in Healty Children

Background Musculoskeletal Ultrasound (MSUS) is an emerging tool in pediatric rheumatology, particularly in the diagnosis and monitoring of Juvenile Idiopathic Arthritis. Its wide use is still limited by the lack of definitions of normal and pathologic US features in the pediatric population; few studies evaluated US features of healthy joints in children and US definitions for some joint components have only recently been proposed. Objectives To describe the normal US findings of joints and entheses frequently involved in rheumatic diseases, in a population of healthy children Methods We enrolled consecutive healthy children (age range 1-14y) reaching a pediatric outpatient clinic for routinary visit between October and November 2014. US exams was performed by an operator expert in adult MSUS and with a two years experience in pediatric MSUS, with a 8-13 MHz linear transducer (Esaote MyLab Alpha). 18 joints (wrists, MCF, hips, knees, ankles) and 8 entheses (knee entheses and Achilles tendon) were evaluated in children older than 3 yo, using a stardardized technique as described for adults; for children younger than 3yo the evaluation was limited to hip and knee joints and entheses of the lower limbs. Grey scale (GS) and power Doppler (PD) US exam was performed to evaluate the presence of joint effusion, synovitis and PD, classified with a dicotomic and a semiquantitative (grade 0-1-2-3) score. PD exam, with dynamic scans of joints and entheses, was also used to identify the presence of vascular flow within the structures suggestive of normal vascularization. Data were collected about childrens sport activity Results We evaluated 788 joints and 416 entheses from 53 children. 42 children (24 girls) were older than 3 yo (744 joints and 328 entheses): in this group we observed a mild effusion (grade 1) in 62 joints (8,3%): 27 knees, 24 ankles, 8 wrists and 3 MCF. In one child we observed a mild synovitis (grade 1) and presence PD signal within the articular fat pad of 3 MCF joints; in this case we supposed a possible correlation with joint overuse in sport activity. PD exam revealed a flow signal in 290 joints (39%) and 133 entheses (40,5%), notably in younger children; the most frequent findings were the presence of nutritive vessels above quadriceps enthesis and through patellar cartilage (82% and 87% of children), and flow signal of wrist (94%) and ankle (79,5%) joints. 11 children <3yo (6 girls) were evaluated (44 joints and 88 entheses): a grade 1 joint effusion was found in 1 knee (2,3%). Flow PD signal was observed within the hip joints capsule in 3 cases and at 13 entheseal sites (11,4%); the most frequent finding was the presence of vessels within patellar cartilage. However, PD evaluation in these subjects was limited by children movements. Conclusions PD US exam found a mild joint effusion in 8% of healty joints in children and PD abnormalities in a single child among our cohort; a flow PD signal was detected in a large number of joints and entheses, notably in younger children. Our observation, together with other recent acquisitions from the literature, could be very relevant in order to describe normal US features and vascular patterns of growing joints, and to better recognize and interpret abnormal findings in children with inflammatory diseases Disclosure of Interest None declared