M. Kostik

Higher-dose canakinumab therapy for refractory macrophage activation syndrome in children with systemic juvenile idiopathic arthritis: two case reports

Macrophage activation syndrome (MAS) is a life-threatening, potentially fatal complication of systemic juvenile idiopathic arthritis (sJIA) appears in non-remitted fever, cytopenia, coagulopathy, liver and CNS dysfunctions. Triggers of MAS could be disease activity, infections and medications. Known IL-1 is the key cytokine in pathogenesis of MAS and SJIA, and disease flare associated with increased amounts of different cytokines, especially IL-1β. Many cases of MAS are medically-refractory to traditional doses of cytokine inhibition and may require increased dosing of biologic cytokine blockade. Interleukin-1 (IL-1) is typically a key cytokine in the pathogenesis of sJIA and associated MAS. When MAS occurs in the setting of sJIA treated with IL-1 inhibitors, then increased dosing of IL-1 blockers may be beneficial. This has been shown for anakinra, an IL-1 receptor antagonist, but this drug is currently not available worldwide. Another IL-1 blocker, canakinumbab (CKB), is a monoclonal antibody that blocks IL-1β, but does not also block IL-1α like anakinra. Herein, we describe 2 sJIA patients who developed MAS on standard doses of CKB (4 mg/kg). Both patients received an increased dose of CKB: 150 mg (7.5 and 12.5 mg/kg, respectively) with rapid and complete resolution of MAS. Later the CKB doses was tapered to normal regimen. No side effects or adverse events were noticed during usage of increased CKB doses. Increased dosing of CKB should be considered for CKB-treated sJIA patients who develop MAS on standard dosing.

Proteomic Profile of Tears for the Diagnosis of Uveitis Associated with Juvenile Idiopathic Arthritis: Setting Targets to Achieve Results

The paper presents epidemiologic and pathophysiological aspects of the problem statement for early recognition of Uveitis (Uv) associated with Juvenile Idiopathic Arthritis (JIA) in terms of the proteomic profile of tears as well as the results of an attempt to solve this problem by means of the Tandem Mass-Spectrometry (TMS). The solution of this problem is of the highest relevance due to revolutionary changes in treatment strategies after introducing highly effective biologics. Content analysis of literature reviews reveals the following: 1. the incidence of JIA-Uv in the Northwest Federal District of Russian Federation averages 0.5-0.7 per 100 000 of children with the prevalence being ten-fold higher than incidence, 2. without Methotrexate treatment 4-7 years after the diagnosis of JIA-Uv cataract is revealed in 35-40% of children and in 5% – glaucoma as well, 3. even with Methotrexate in 28-40% of children the complications of JIA-Uv inevitably will be revealed with blurred vision in 10-36% of children, 4. timely diagnosis of JIA-Uv and adequate treatment reduce the risk of complications by 4% per year, 5. current medical care system reveals in one third of children already the complications of JIA-Uv. Revelation in tears of the motif mode for protein interaction network, triggering mobilization/inhibition of cells which moderate Uv would contradict the traditional point of view on existing natural anatomic and physiologic barriers, isolating the intraocular space, but however seems to be possible since JIA is a systemic disease and Uv leads to damage of the blood-retinal barriers. To reveal protein biomarkers of JIA-Uv tears of 31 children aged 2-17 years were studied: 17 – chronic JIA-Uv, 4 – JIA without Uv, 4 – idiopathic Uv, 3 – systemic vasculitis, 3 – healthy children. We used the current clinical guidelines and standards to diagnose the pathology and TMS with hierarchical clustering methodology for protein identification: nano C18 column attached to Shimadzu nano LC coupled in-line to LTQ Orbitrap XL tandem mass spectrometer, data-dependent 4-event scan method, a survey FT-MS parent scan followed by sequential data dependent FT-MS/MS scans on the three most abundant peptide ions. Proteins were identified from the mass spectra results with Proteome Discoverer 1.2 software for protein database search using the International Protein Index (IPI) and Human Protein Database. Quantification was conducted using SIEVE 2.0 after normalization to albumin keeping in mind the validity of proportional change of its concentration after stimulation of lacri-mation. Data from SIEVE were exported to IPA (Ingenuity Pathway Analysis) for filtering. The extracellular proteins selected in Ingenuity were further analyzed for disease relation and networks formation. TMS revealed more than 3000 proteins in tears and 300 of them have been considered to be the first row candidates to be biomarkers of JIA-Uv. The top two proteins, lactoferrin and lipocalin were upregulated over ten-fold in children with Uv. Pathway analysis placed these proteins into the inflammation-related IL-1 and TNF-α related networks which also included proteins involved in the development of endothelial dysfunction, inflammation and retinopathy. In addition, IL-23, which was previously linked to Uveitis, was found to be upregulated. Taken together, our proof-of-principle study presents a novel and yet untested approach for detection of early biomarkers of Uveitis and identified several candidate proteins.

Measures in assessment of pediatric systemic lupus erythematosus

Systemic lupus erythematosus in children is aggressive disease with an unpredictable course and a more severe phenotype compared to adults. An appropriate monitoring of disease activity, damage and effectiveness of therapy is reqired. The first part of this artcle is review of indices and scales validated by international community for assessment of disease activity, flares, damage and response to therapy in clinical research, trials and usual clinical care; their strengths, restrictions and ability to detect changes are evaluated. We characterized different versions and modifications of standard indices, their advantages and disadvantages. Conclusion: The set of indices including ECLAM, SELENA-SLEDAI, SFI and Ped-SDI can be recommended for retrospective pediatric clinical studies, as they are simple for use and validated by international community.

Measures in assessment of pediatric systemic lupus erythematosus: an experience of retrospective observational study

Systemic lupus erythematosus in children (juvenile-onset SLE, jSLE) is a multisystemic disease with an unpredictable course and a more severe phenotype compared to adults. The patterns of jSLE are extremely heterogeneous, so an enrollment to controlled studies may be rather complicated. Due to this problem and some additional ones, there are no standards for treatment of jSLE yet. The attending physician is fully responsible for the induction and maintenance therapeutical options including durability and aggressiveness. Objectives: finding of jSLE individual course’s features prognostically connected with the disease outcome. Methods: 45 children admitted to the SPbGPMU hospital with the systemic lupus erythematosus diagnosed at the age of 4-17 years were enrolled in this retrospective study. Primary SLE manifestations, the activity of disease according to SELENA-SLEDAI and ECLAM scales during initial treatment period and flares after it, the fact of remission achievement in 6 months were evaluated in each patient. Results: a few organ involvements were considered to be connected with outcome’s characteristics, for example lupus nephritis and early disease oncet are unfavorable predictive factors. The positive connection of favorable outcome with cyclophosphamide, intravenous methylprednisolone and mycophenolate mofetil was found; the negative connection between initial disease activity and flares after induction treatment was also noticed. Conclusion: the patient with initially high disease activity treated aggressively with high cumulative doses of cyclophosphamide, intravenous methylprednisolone and mycophenolate mofetil has more chances of the favorable outcome (the achievement of remission without further flares).

AB0962 Clinical and laboratory characteristics of non-bacterial osteomyelitis: data analysis of 91 patients

Background Non-bacterial Osteomyelitis (NBO) is a sterile inflammatory bone disorder of unknown etiology. It typically affects children and most commonly presents with bone pain and/or swelling. Objectives The aim of study is to evaluate clinical and laboratory features of non-bacterial osteomyelitis in children. Methods Our retrospective – prospective study was included 91 patients with NBO. A routine blood test (WBC, platelets, ESR, C-reactive protein (CRP) and hemoglobin levels), a radiological examination and a bone biopsy with evaluation bacteriological and morphological data were performed in all patients. Results The mean age of onset NBO was 7.3 years (2.5; 10.6). We did not reveal any gender peculiarities in our study. Family history of immune-mediated diseases is found in 5/75 (6.7%) in prospective group. Concomitant immune-mediated diseases were noted in 62/89 (68.1%). Diagnostic delay was 6.3 (2.0; 17.8) months. The radiological examination was performed in the following ratio: X-rays - 91 (100.0%), CT - 79 (86.8%), MRI - 66 (72.5), including MRI “whole body” with 15 pts, bone scintigraphy - 54 (59.3%). Monofocal form was registered in 1/3 cases. 2/3 cases was presented as a typical multifocal process with predominant involvement femur - 37 (40.7%), bone of foot - 36 (39.6%), tibia - 33 (36.3%), spine – 29 (31.9%). The number of foci is 3.0 (1.0; 6.0). We did not revealed any significant differences in quantity of WBC, platelets, hemoglobin level, ESR, CRP). Evidence confirming NBO was a negative bone biopsy in 100.0% cases. However, morphological data were as non-specific, as granulomatous inflammation. Conclusions NBO is determined as a primarily chronic multifocal process without specific clinical and laboratory peculiarities, associated with immune-mediated diseases. Diagnose must be established on morphological and bacteriological data bone biopsy. Disclosure of Interest None declared

THU0226 Outcomes of Treatment of Juvenile Idiopathic Arthritis Related Uveitis with TNF-Alpha Inhibitors

Background Uveitis is the inflammation of the uvea by definition, but for a rather long time the term “uveitis” was used to identify inflammation in any part of the eye (retinitis, chorioretinitis, scleritis, episcleritis). According to some authors one of the most common causes of uveitis in childhood is Juvenile Idiopathic Arthritis (JIA). Patients with JIA associated uveitis are usually asymptomatic at early stages. In 20–30% of cases uveitis may occur a few years before joint manifestation. As the result of those two factors we often see the delay in the treatment or not adequate treatment. Early and aggressive treatment of JIA associated uveitis can help better control inflammation and can help to eliminate inflammation before development of irreversible ophthalmic pathology. Objectives The goal of the study was to evaluate the efficacy of two anti-TNF-alpha biological agents: Adalimumab (ADA, humanized monoclonal anti-TNF-alpha antibody) and Infliximab (INF, chimeric monoclonal antibody that binds both circulating and membrane-bound TNF-alpha receptors) in the treatment of uveitis, associated with Juvenile idiopathic Arthritis (JIA). The incidence of eye involvement in JIA can be as high as 10–20%. Methods Thirty-seven children with aggressive forms of JIA with uveitis who failed immunosuppressive agents were enrolled in the study. The age of the patients at the beginning of anti-TNF-alpha treatment ranged from 5 to 17 years. All patients were divided into two groups: one group received ADA (40 mg sc every 2 weeks), and the other group was received INF (iv 5–6 mg/kg at week 0–2-6 and after every 8 weeks). Duration of treatment was 3–48 months. The efficacy of treatment was assessed by reduction of flare-ups, reduction of topical and systemic steroids, immunosuppressive drugs and reduction of activity of uveitis. Results In ADA group the remission was observed in 61% of cases, reduction of number of flare-ups was in 18% and in 14% we saw worsening of the disease due to discontinuation of non-biological drug. In INF group remission was in 78% and in 22% of the cases no improvement. The remission of uveitis was achieved in 0.5 - 4 months from the starting of ADA. Topical steroids was tapered within 1.5–3 months and none of the patient required regional injections of steroids. Therapy with ADA permitted to cease non-biological immunosuppressive agents, especially in children who received simultaneously 2 non-biological agents. Conclusions Our experience in ADA treatment of uveitis shows good result in control of uveitis independent from the severity of the disease and despite it was used as a first-, second- or third-line agent among the biologics. The speed of remission in patients with JIA associated uveitis treated with ADA and INF depends on the severity of uveitis, the time between the beginning of the disease and administration of immunosuppressive therapy. This study needs to be continued to enroll more patients and to increase the follow-up time to evaluate the long-term efficacy and safety of anti-TNF-alpha agents in JIA associated uveitis. Disclosure of Interest None declared

SAT0257 Update on The Juvenile Systemic Sclerosis Inception Cohort Project. Characteristics of The First 74 Patients at First Assessment

Background Juvenile systemic sclerosis (jSSc) is an orphan autoimmune disease. Currently just retrospective data exist regarding evolvement of organ involvement. In the retrospective studies assessment of the organ involvement is not standardized. Our project is the first one, where prospectively and with a standardized assessment data of jSSc patients are collected. Objectives to learn about the characteristics and evolvement of jSSc Methods Patients with jSSc were recruited worldwide and were prospectively assessed, using the proposed standardized patient assessment protocol. Results 26 centers from 17 countries applied to participate on the project. The assent and consent forms were translated into the local native languages. Up till now 74 patients were enrolled. Sixty (81%) of the 74 patients were female. The mean age of the onset of Raynaud symptomatic was 9.2 years (0.2 – 15.9). The mean age at the onset of the non-Raynaud symptomatic were 9,7 years (0.3 -15.9). 56 (76%) of the 74 have diffuse subtype, 10 (14%) of them have an overlap symptomatic. At the time of the inclusion the mean modified Rodnan Skin Score was 16.0. ANA positive were 55/71 (77%), 24/70 (34%) of them were anti-Scl 70 positive and 3/42 (7%) was anticentromere positive. 43/74 (58%) had already capillary changes and 36/72 (50%) inactive ulcerations, 13/72 (18%) had active ulceration at the time of the inclusion. 38/74 (51%) had cardiopulmonary involvement, 19/38 (50%) of had signs of interstitial lung disease on imaging, 18/42 (43%) had FVC <80% and 12/21 (57%) had DLCO <80%. 6/38 (16%) patients had pulmonary hypertension. 5/74 (7%) had renal involvement. 26/74 (35%) had gastrointestinal involvement, and 23/26 (88%) of them esophageal involvement. 46/73 (63%) had musculoskeletal involvement. 2/74 (3%) showed neurologic involvement. The mean CHAQ score was 0.4 (0–2.5). Patient global disease activity on VAS (0–100) was 44.9 and disease damage 41.6. Physician global of disease activity on VAS (0–100) was 39.7 and physician global of disease damage was 34.6. Conclusions The current recruitment data confirms that pediatric patients are different from the adult patients, there is a significantly higher proportion of diffuse subset patients with 81%. 14% of the patients have overlap features. Disclosure of Interest None declared

AB0876 Achievement Remission in Different Juvenile Idiopathic Arthritis Categories during Adalimumab Therapy: Data of Retrospective Analysis

Background Juvenile idiopathic arthritis (JIA) is a chronic rheumatic disease with onset before 16 years. According ILAR classification there are several categories based on number of joints, clinical and laboratorial features. Patients with JIA without systemic features who fall or not tolerated to methotrexate (MTX) or sulfasalasine (SSZ) usually treated by biologics, especially TNFα-inhibitors. Currently only 2 TNFα-inhibitors approved in JIA: etanercept and adalimumab (ADA). Objectives The aim of study was to evaluate the efficacy of ADA in children with JIA without systemic features and ability to induce remission. Methods In the retrospective observation study were included 53 children (67.9% girls) with active JIA without systemic features, who were resistant to previous therapy with MTX alone (or SSZ in enthesytis-related arthritis) or with combination with other non-biologic DMARDs and were treated with subcutaneous ADA injections every 2 weeks. The onset age was 3.9 (1.7–7.8) years, the interval between onset of JIA and start of ADA was 4.2 (0.3–15.2). Uveitis was detected in 32 (60.3%) patients. According number of active joints and clinical features all patients were divided into 3 groups: oligoarthicular course (OA) – 4 active joints or less, polyarthricular course (PA) – 5 active joints or more and enthesitis-related arthritis (ERA) with any active joints. We evaluated routine clinical and laboratorial test for JIA and ability and time to achieve inactive disease, according to C. Wallace criteria (2004). Results Number of active joints (NAJ) and erythrocyte sedimentation rates significantly decreased, while levels of C-reactive protein, WBC, Hb and platelets still unchanged. In 12 months after start of ADA median of NAJ was equal 0. During the trial 44 (84.6%) patients reached the status of inactive disease (ID) according the C. Wallace criteria in median time 122.0 (36.5–220.0). We have not found any significant differences of initial JIA parameters between patients who achieved and not achieved status of ID. We have found differences in JIA groups in achievement ID: patients with OA similar to PA faster and frequently get into remission than patients with ERA (p=0.03, Log-Rank test, OA vs ERA). During the trial 26 (50.0%) have experienced the flare throw the median time 551.0 (317.0–809.0) days after 1st ADA injection. Patients with flare had less NAJ [1.0 (0,0; 2,0) vs 4.0 (1,0; 8,0), p=0.007]. The main predictors of JIA flare during the ADA trial were calculated with Cox-regression models: JIA duration ≥4 years before start of ADA (HR=2.4, p=0.055), presence of concomitant uveitis (HR=4.8, p=0.0008) and discontinuation of MTX (HR=3.2, p=0.19). During the trial 1 SAE was detected: disseminated tuberculosis in patient who received ADA near 3 years (unrecognized family contact). Conclusions In our study the efficacy of ADA was shown. Further trials required for evaluation long-term outcomes. Disclosure of Interest None declared

SAT0261 Different Treatment Strategies for Chronic Non-Bacterial Osteomyelitis: The Experince of 52 Patients

Background Chronic non-bacterial osteomyelitis (CNO) is a heterogenous group of immune-mediated inflammatory bone diseases, often co-exist with other rheumatic diseases. There are no approved treatments for CNO except non-steroid anti-inflammatory drugs (NSAID). The efficacies of methotrexate (MTX), sulfasalazine, pamidronate (PAM), anti-IL1 and TNFα-inhibitors (TNFα-inh) were shown in different reports. Objectives The aim of study: to compare the efficacy of non-randomized different treatment approaches in pediatric patient CNO cohort. Methods 52 children (25 M and 27 F) with CNO has average age at the onset of disease 8.4 years (5.4÷11.0), the number of foci - 3.0 (2.0÷6.0, incl. multifocal cases in 80.8%), fever at the onset – 38.5%, spine involvement - 34.6%, positive family autoimmune diseases (AID) history - 7.7%, concomitant AID - 67.3%. NSAID was the first-line treatment for non-vertebral cases, as well as PAM for vertebral involvement. Second-line treatment includes MTX, PAM and TNFα-inh. Dynamics of pain, patients (PVAS) and physicians (MDVAS) assessment and ability to each medication to achieve remission of CNO activity we evaluated. Results According to the NSAID, MTX, SSZ, PAM and TNFα-inh groups next data were registered: PVAS: -14.2% (p=0.05), -50.0% (p=0.04), -23.1 (p=0.89), -83.3% (p=0.0001), -73.6% (p=0.0007); pain: -21.9% (p=0.01), -18.6% (p=0.13), +36,4 (p=0.89), -79.7% (p=0.00016), -74.1%, (p=0.0015); MDVAS: -13.8% (p=0.13); -56.4% (p=0.09), +30.8% (p=0.89), -74.7%, (p=0.0001), -82.1 (p=0.0015) respectively. The ability of each treatment strategy to achieve the CNO remission was 52.6%, 44.4%, 57,1%, 88.8% and 73.3% respectively (log-rank test, p=0,001, figure). TNFα-inh usually used as second-third line treatment in cases where other options, especially PAM were fall. Conclusions The most effective treatment approaches for CNO were PAM and TNFα-inh. The randomized controlled trials for assessment efficacy and safety of these medications is mandatory to confirm these results. Disclosure of Interest None declared

Differences in disease activity in cryopyrin-associated periodic syndrome in mutation-positive and mutation-negative patients.

Cryopyrin-associated periodic syndrome (CAPS) is an inherited disease which is caused by gain-of function mutations in CIAS1 gene function resulting in increased secretion of active IL-1β. As known more than 40% of patients with CAPS are genetic negative in CIAS1 gene. One of theories explains this is a fact is a somatic mozaicism.