Estíbaliz Iglesias

Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes

UNLABELLED : Familial cold autoinflammatory syndrome, Muckle-Wells syndrome (MWS), and chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome are dominantly inherited autoinflammatory diseases associated to gain-of-function NLRP3 mutations and included in the cryopyrin-associated periodic syndromes (CAPS). A variable degree of somatic NLRP3 mosaicism has been detected in ≈35% of patients with CINCA. However, no data are currently available regarding the relevance of this mechanism in other CAPS phenotypes. OBJECTIVE To evaluate somatic NLRP3 mosaicism as the disease-causing mechanism in patients with clinical CAPS phenotypes other than CINCA and NLRP3 mutation-negative. METHODS NLRP3 analyses were performed by Sanger sequencing and by massively parallel sequencing. Apoptosis-associated Speck-like protein containing a CARD (ASC)-dependent nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB) activation and transfection-induced THP-1 cell death assays determined the functional consequences of the detected variants. RESULTS A variable degree (5.5-34.9%) of somatic NLRP3 mosaicism was detected in 12.5% of enrolled patients, all of them with a MWS phenotype. Six different missense variants, three novel (p.D303A, p.K355T and p.L411F), were identified. Bioinformatics and functional analyses confirmed that they were disease-causing, gain-of-function NLRP3 mutations. All patients treated with anti-interleukin1 drugs showed long-lasting positive responses. CONCLUSIONS We herein show somatic NLRP3 mosaicism underlying MWS, probably representing a shared genetic mechanism in CAPS not restricted to CINCA syndrome. The data here described allowed definitive diagnoses of these patients, which had serious implications for gaining access to anti-interleukin 1 treatments under legal indication and for genetic counselling. The detection of somatic mosaicism is difficult when using conventional methods. Potential candidates should benefit from the use of modern genetic tools.

Treatment of Uveitis Associated with Juvenile Idiopathic Arthritis

Chronic anterior uveitis affects 10–30 % of patients with juvenile idiopathic arthritis (JIA) and is still a cause of blindness in childhood. In most patients it is asymptomatic, bilateral, and recurrent, so careful screening and early diagnosis are important to obtain the best long-term prognosis. The treatment of chronic uveitis associated with JIA is challenging. Initial treatment is based on topical steroids and mydriatic drops. Methotrexate is the most common first-line immunomodulatory drug used. For refractory patients, biologicals, mainly the anti-tumor-necrosis-factor (TNF) drugs adalimumab and infliximab, have been revealed to be effective and have changed the outcome for these patients. Collaboration between pediatric rheumatologists and ophthalmologists is important for the successful diagnosis and treatment of patients with uveitis associated with JIA.

Disease Phenotype and Outcome Depending on the Age at Disease Onset in Patients Carrying the R92Q Low-Penetrance Variant in TNFRSF1A Gene

Background Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal-dominant autoinflammatory disease caused by mutations in the TNFRSF1A gene. R92Q, a low-penetrance variant, is usually associated with a milder TRAPS phenotype than structural or pathogenic mutations. No studies differentiating R92Q-related disease in patients with pediatric and adult onset have been performed to date. Objective To analyze clinical features and disease outcomes in patients diagnosed with TRAPS associated with R92Q variant and to investigate differences between patients with pediatric and adult disease onset. Methods A retrospective review of patients with R92Q-related disease from four reference centers for autoinflammatory diseases was performed. Clinical and laboratory features, family history of autoinflammatory diseases, treatments received, and outcomes during follow-up were recorded and separately analyzed in pediatric and adult patients. Our results were included in the analysis with other reported pediatric and adult R92Q-related disease series. Results Our series encompassed 18 patients (9 females and 9 males) with R92Q variant. In 61% of patients, disease onset occurred during infancy and in 39%, during adulthood, with a median diagnostic delay of 5 years and a follow-up of 5.4 years. A positive family history of autoinflammatory disease was detected in 28% of patients. All patients presented with febrile recurrent episodes. Other common symptoms included arthralgia/arthritis (61%), myalgia (39%), asthenia/fatigue (44%), abdominal pain (39%), headache (33%), odynophagia (33%), skin rash (28%), and chest pain (22%). During attacks, 80% of patients increased acute phase reactants levels. No patient had developed amyloidosis during the study period. At the end of follow-up, 28% of patients were asymptomatic and treatment free, 50% were receiving non-steroidal anti-inflammatory drugs or glucocorticoids on demand, and 22% were being treated with biologic agents. When differences between pediatric and adult patients were globally analyzed, adults tended to have longer attacks duration and presented more frequently with chest pain and headache, while abdominal pain, vomiting, cervical adenitis, and pharyngitis predominated in pediatric patients. No differences in outcomes and treatment requirements were observed in both age groups. Conclusion This study has contributed to characterize R92Q-related disease by identifying trends in disease phenotypes depending on the age at disease onset.

Open-label, Phase II Study to Assess Efficacy and Safety of Canakinumab Treatment in Active Hyperimmunoglobulinemia D with Periodic Fever Syndrome

To evaluate the efficacy and safety of canakinumab treatment in active hyperimmunoglobulinemia D with periodic fever syndrome (HIDS).

MR Imaging of the Temporomandibular Joint in Juvenile Idiopathic Arthritis: Technique and Findings

The term juvenile idiopathic arthritis (JIA) encompasses a group of arthritides of unknown cause that begin before 16 years of age and last for at least 6 weeks. Temporomandibular joint (TMJ) involvement has been described in up to 87% of children with JIA and has been associated with all JIA subtypes. TMJ involvement is difficult to detect clinically. In one study, 71% of JIA patients with active TMJ synovitis were asymptomatic and 63% had normal physical examination results. Moreover, the main growth center of the mandible is located in the condyle, separated from the joint space by only a thin layer of fibrocartilage. This makes mandibular growth vulnerable to arthritic changes, eventually resulting in facial asymmetry and retrognathia. Therefore, early detection and treatment of TMJ arthritis are paramount to preserving motility and preventing deformity. As clinical symptoms and physical examination results are not good markers of TMJ involvement, imaging plays a key role in diagnosis and treatment monitoring. Magnetic resonance imaging is the technique of choice for the study of TMJ arthritis. It has the advantages of displaying both soft tissue and bone, is the most sensitive technique for detecting acute synovitis, and is the only one able to demonstrate bone marrow edema. In addition, it allows the assessment of changes to the joint over time and evaluation of the effectiveness of therapeutic interventions. ©RSNA, 2017.

Incidence and clinical features of kawasaki disease in Catalonia (Spain)

between onset of the disease and diagnostic was 7.2±5.3 days. Ethnic distribution was: Caucasian 279 patients(69.9%), North African 26 (6.5%), Amerindian 21 (5.2%), Asian 14 (3.5%) and Sub-Saharan 4 (1%). Ethnicity was not available in 55 (13.8%) patients. Distribution of classical manifestations for KD was: fever in 100% of patients, changes in extremities 40.3% (desquamation in 31% of them), exanthema 84.2%, conjunctival injection 79.7%, changes in lips and oral cavity 55.6% and lymphadenopathy 28.8%. Other clinical findings reported were: sterile pyuria in 80(20%) patients, nausea and vomiting in 96(24%), abdominal pain in 85(21.3%), gallbladder distention in 14 (3.5%), transaminase elevation in 120(30%), jaundice in 21(5.1%), irritability in 118(29.5%), aseptic meningitis in 16(4%), sensorineural hearing loss in 2 patients, uveitis in 11(2.7%) and arthritis or arthralgia in 55(13.8%). Cardiologic findings were: perivascular brightness of the coronary wall in 42(10.5%) patients, pericarditis in 9(2.3%), myocarditis in 4(1%), mitral regurgitation in 28 (7%) and CA in 53 patients(13.3%), 26(49%) of them disappearing before the 2 nd month after the onset of KD. 4 patient had giant CA. Intravenous immunoglobulin (IVIG) was administered in 389(97.5%) patients with response to the 1 st dose in 332(83.2%). Day of IVIG administration was 7.5±3.1. Other treatment plans were: 2 nd (69% response) and 3 rd IVIG doses, oral or iv corticosteroids and abciximab (administered in 3 of the patients with giant CA). 97.7% of patients received anti-platelet dose aspirin in the convalescent phase. Conclusion

The Ecuadorian Spanish 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 Colombian Spanish language. The reading comprehension of the questionnaire was tested in ten 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 three Likert assumptions, floor/ceiling effects, internal consistency, Cronbach’s alpha, interscale correlations, and construct validity (convergent and discriminant validity). A total of 22 JIA patients (9.1% systemic, 27.3% RF-negative polyarthritis, 36.4% enthesitis-related arthritis, 27.2% other categories) were enrolled in the paediatric centre of Bogota. All JAMAR components revealed good psychometric performances. In conclusion, the Colombian Spanish 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.

Pediatric cryoglobulinemic vasculitis successfully managed with rituximab

Cryoglobulinemia is a small and medium vessel vasculitis due to deposit of immune-complexes containing cryoglobulins. It could be associated with malignancy, viral infections, and rheumatic diseases (RamosCasals, Stone, Cid, & Bosch, 2012). Rituximab, anti-CD20 monoclonal antibody, has demonstrated to be a good clinical option for severe cryoglobulinemic vasculitis in adult patients (Ferri et al., 2011; Terrier et al., 2012). A 10-year-old girl presented with palpable purpura and skin ulcers at lower limbs was transferred to our center for ongoing care. There was neither family nor personal background of autoimmune disorders. She had a history of intermittent fever, abdominal pain, vomits, and paresthesia on lower limbs. She appeared cachectic. Skin ulcers of lower limbs were present with severe involvement on both heels (Figure 1a,b). Leukocytoclastic vasculitis without small vessel thrombosis had been detected on skin biopsy. A series of laboratory investigations were performed detecting cryocrit composed by monoclonal immunoglobulin (Ig) M kappa and polyclonal IgG with rheumatoid factor (RF) activity (180 UI/L). With clinical suspicious of cryoglobulinemic vasculitis, studies were extended to rule out potential infectious, neoplastic, and systemic etiologies (Table 1). We detected isolated antinuclear antibodies (1/160) with no extractable nuclear antigen specificity. Neurological assessment demonstrated mononeuritis of the right peroneal

AB0973 Temporomandibular Joint Arthroscopy in Juvenile Idiopathic Arthritis. Successfully Treatment with Synovial Electrocoagulation

Background Temporomandibular joint (TMJ) is affected in approximately 80% of Juvenile Idiopathic Arthritis (JIA) patients, usually asymptomatic. Magnetic Resonance Imaging (MRI) with contrast remains as the gold standard for its diagnosis. Main objectives of management are to control active synovitis and prevent chronic damage but nowadays there is not a consensus on how to treat these patients. TMJ arthroscopy seems to be a non-invasive technique that allows direct examination and local treatment. Objectives To review our JIA patients who have been treated with TMJ arthroscopy because of local active synovitis. Assess clinical and MRI with contrast outcome after 6 and 12 months. Methods We made a retrospective charts review of our JIA patients in whom TMJ arthroscopy had been done. Clinical symptoms and signs were evaluated as pain, maximum interincisal opening, mouth opening deviation and/or presence of microretrognatia. MRI with contrast of TMJ was done before and after arthroscopy. Activity and damage was evaluated with Cron et al score. Arthroscopy was made under general anesthesia and nasotracheal intubation. We used a 1.9 mm glass lens arthroscope for small joints. If synovitis was detected local electrocoagulation was done. We made local infiltration with 1 ml of triamcinolone hexacetonide and sodic hialuronidate. Results 12 patients were included. Clinical symptoms and imaging score improved after arthroscopy in all patients. We have not complications. Not local relapse have been identified. Conclusions TMJ arthroscopy is a complex technique that allows direct joint examination. Electrocoagulation produces a synovial scar that reduce relapse with low index of complications. This technique seems to be promising in patients with TMJ active synovitis despite of systemic treatment. References Stoll ML, Sharpe T, Beukelman T, Good J, Young D, Cron RQ. Risk factors for temporomandibular joint arthritis in children with juvenile idiopathic arthritis. J Rheumatol 2012;39(9)1880-87 Vaid YN, Dunnavant FD, Royal SA, Beukelman T, Stoll ML, Cron RQ. Imaging of the temporomandibular joint in juvenile idiopathic arthritis. Arthritis Care Res 2014;66(1):47-54 Disclosure of Interest None declared

Efficacy and safety of TNF-alpha antagonists in children with juvenile idiopathic arthritis who started treatment under 4 years of age

The experience in the use of tumour necrosis factor (TNF) antagonists in children below 4 years is limited, although there are some trials in the literature which support safety and efficacy under this age.