Irina A. Chikova

Farber lipogranulomatosis with predominant joint involvement mimicking juvenile idiopathic arthritis

The case of a 10-year-old boy with Farber lipogranulomatosis with predominant joint involvement, subacute, laryngeal and tongue granulomas, microcytic anemia, elevated ESR and CRP, is presented. The boy had no signs of CNS and internal organ involvement. The disease manifested at 6 months; at 11 months the boy had widespread granulomatous polyarthritis with contractures, and juvenile idiopathic arthritis (JIA) was suggested. All antirheumatic therapies failed. Immunologic assessment revealed elevated serum interleukin-1β, increased T-helper, NK and CD25-positive cells, and circulating immune complexes. Our case with predominant rheumatologic manifestations illustrates a differential diagnosis of JIA.

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.

Identification of the best cut-off points and clinical signs specific for early recognition of macrophage activation syndrome in active systemic juvenile idiopathic arthritis

Macrophage activation syndrome (MAS) – is a severe life-threatening hematological condition, mostly complicated systemic juvenile idiopathic arthritis (SJIA). Early detection of MAS can lead to appropriate therapeutic interventions and change the outcomes. There are no strict criteria for early MAS detection in SJIA. Currently applied HLH criteria can determinate only advanced stage of MAS, which lead to delay diagnosis, late start of specific treatment and associated with poor outcomes. There are several sets of preliminary criteria of MAS in SJIA.

РЕЗУЛЬТАТЫ ЛЕЧЕНИЯ ЭТАНЕРЦЕПТОМ ДЕТЕЙ С НЕСИСТЕМНЫМИ ВАРИАНТАМИ ЮВЕНИЛЬНОГО ИДИОПАТИЧЕСКОГО АРТРИТА: ДОСТИЖЕНИЕ РЕМИССИИ, РАЗВИТИЕ ОБОСТРЕНИЙ И НЕЖЕЛАТЕЛЬНЫХ ЯВЛЕНИЙ. РЕТРОСПЕКТИВНОЕ КОГОРТНОЕ ИССЛЕДОВАНИЕ

Background. Etanercept is a biological drug most commonly used in patients with juvenile idiopathic arthritis (JIA). The results of its use are showed in local studies. Objective. Our aim was to evaluate the efficacy and safety of the use of etanercept in children with non-systemic JIA, to determine the predictors of remission and the risk factors for the development of exacerbations. Methods. In a retrospective cohort study, the results of etanercept treatment (remission, exacerbations, adverse events) in children with non-systemic JIA were analyzed. The minimum follow-up period was 6 months. Results. The period of remission within 6–36 months occurred in 77/131 (58.8%), exacerbations developed in 18/129 (14.0%) patients. Predictors of achieving remission were the age of JIA onset < 8 years [relative risk (RR) 2.05; 95% confidence interval (CI) 1.27–3.23], the age of prescribing etanercept ≤ 10 years (RR 1.7, 95% CI 1.22–2.38), the time of the disease prior to etanercept prescription < 2.5 years (RR 2.4, 95% CI 1.4–4.4), the presence of HLA-B27 antigen (RR 2.15, 95% CI 0.98–4.75; p = 0.06). The risk of exacerbations was higher in children with polyarticular JIA (RR 2.7, 95% CI 0.9–8.2; p = 0.08), whereas methotrexate therapy reduced the risk of exacerbations (RR 0.32, 95% CI 0.1–1.15; p = 0.05). Etanercept was discontinued due to primary (improvement by the ACRpedi criteria after 3 months of therapy <30%) or secondary (loss of previously achieved ≥ 30% improvement) failure in 14/152 (9.2%) patients; de novo uveitis developed in 8/152 (5.3%) patients; reactions at the injection site — in 6/152 (4.0%) patients. Conclusion. Therapy involving etanercept is more likely to induce remission in younger patients with JIA onset at the age of 8 years and a history of less than 2.5 years. A high risk of exacerbations was noted in patients with polyarticular JIA, and low one — in those receiving methotrexate as a part of combined therapy.

Evaluation of the efficiency and safety of tocilizumab therapy in patients with systemic-onset juvenile idiopathic arthritis: results of a retrospective follow-up

Objective: to study the efficiency and safety of tocilizumab (TCZ) therapy in patients with systemic-onset juvenile idiopathic arthritis (sJIA). Patients and methods. The retrospective study included 48 children with active sJIA in whom TCZ therapy was initiated because of the inefficiency of using different anti-rheumatic drugs. The investigators studied the time course of changes in the main indicators of sJOA activity, as well as the possibility of achieving remission in accordance with the Wallace criteria (2004). Results and discussion. The main demographic characteristics of the study group (median [25th and 75th percentiles]) included the age of the patients (9.9 [5.0; 12.7] years) and the duration of TCZ therapy (27.0 [5.9; 89.7] months). 40 (83.3%) patients achieved remission; the median of its achievement was 138.5 [56.0; 255.0] days. The patients who had achieved remission had milder sJOA: hepatosplenomegaly, pulmonary and cardiac involvements, and macrophage activation syndrome were less frequently observed. At baseline, they also had higher hemoglobin values and a lower erythrocyte sedimentation rate, and decreased levels of leukocytes, granulocytes, C-reactive protein (CRP), lactate dehydrogenase (LDH) and ferritin. The main predictors for achieving remission, which were estimated using the analysis of sensitivity and specificity, as well as Cox regression models, were CRP ≤82.0 mg/l (OR – 7.9; HR – 1.17); ESR ≤32 mm/h (OR – 17.0; HR – 0.85), ferritin ≤273 ng/ml (OR – 56.5; HR – 2.6), hemoglobin >113 g/l (OR – 17.0; HR – 1.33), LDH ≤676 U/l (OR – 113.6; HR – 3.2), platelets >335⋅109 /l (OR – 5.0; HR – 2.5), and a decline in white blood cells two weeks after the first infusion by more than 11% (OR – 13.0; HR – 6.0) and in granulocytes by more than 12% (OR – 14.0; HR – 4.7). Conclusion. Children with a less severe course of sJIA more promptly reached remission during TCZ therapy. Male gender, high inflammatory activity, previous glucocorticoid therapy, long time to achieve remission, and TCZ dosing regimen deviations were the main factors for an exacerbation of sJOA. Male sex, signs of the high disease activity, preceding CS treatment, long time to achievement of inactive disease and treatment protocol deviations increased risk of sJIA flare.

Применение тоцилизумаба у 40 пациентов с полиартикулярным вариантом ювенильного идиопатического артрита: результаты ретроспективного исследования

The issue of a therapy of children with juvenile idiopathic arthritis (JIA) with intolerance or insufficient effectiveness of methotrexate remains actual. Objective: Our aim was to study the efficacy and safety of tocilizumab in patients with polyarticular JIA. Methods. In a retrospective study, we studied the results of the use of tocilizumab in patients with active polyarticular JIA ( 5 active joints) resistant to prior therapy with methotrexate or a combination of methotrexate with other nonbiologic disease-modifying antiinflammatory drugs. Results. The data of 40 children (83% girls) with the onset median of polyarticular JIA of 4.8 (2.9, 8.1) years and the interval between the disease onset and the initiation of tocilizumab therapy of 5.7 (1.8, 8.5) years was analyzed. Tocilizumab was used as an intravenous infusion of 8 mg/kg (with a weight 30 kg) or 10 mg/kg (with a weight < 30 kg) every 4 weeks. The duration of tocilizumab monotherapy in 5 (13%) children was 1,109 days (452; 1,542). The stages of inactive disease (according to the criteria of C. Wallace, 2004) in 6 months of tocilizumab therapy reached 6 (15%) patients, in 42 months — 32 (80%) patients. In 3 patients, tocilizumab was canceled due to persistent remission. After 6 months of treatment, there was a marked decrease in erythrocyte sedimentation rate, C-reactive protein concentration, number of leukocytes and platelets (in all cases, p < 0.001) to normal values, which persisted throughout the whole period of drug administration. Predictors for achieving inactive disease were the initial (at the onset of tocilizumab therapy) number of peripheral blood leukocytes < 9.0X109/l [relative risk (RR) 1.92; 95% confidence interval (CI) 0.9–4.6)] and the absence of prior biological therapy (RR 1.92, 95% CI 0.9–4.6). The most frequent side effects of tocilizumab therapy were transient hypercholesterolemia (in 13), hypertriglyceridemia (in 4), transient grade II neutropenia (in 1). Conclusion. The long-term efficacy and relative safety of tocilizumab in children with polyarticular JIA have been showed.

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

Comparison of different treatment approaches in chronic non-bacterial osteomyelitis.

Chronic non-bacterial osteomyelitis (CNO) is a heterogenous group of immune-mediated inflammatory bone diseases, which often co-exist with other rheumatic diseases. There are no approved treatments for CNO, except non-steroid anti-inflammatory drugs (NSAID). The efficacy of methotrexate (MTX), sulfasalazine, pamidronate (PAM), anti-IL1 and TNFα-inhibitors was shown in different reports, but there are some concerns about safety of pamidronate due to long-term accumulation and persistation in bone. The aim of our study was to compare the efficacy of non-randomized different treatment approaches in pediatric patient cohort with CNO.

THU0521 The Methotrexate Treatment can Prevent Uveitis Onset in Juvenile Idiopathic Arthritis: The Experience in Cohort with Increased Proportion of Methotrexate

Background Uveitis is the most common extra-articular manifestation of juvenile idiopathic arthritis (JIA), often entirely asymptomatic but could be sight-threatening. The main predictors of uveitis in JIA are oligoarticular (OA) subtype, ANA-positivity and younger age at the JIA onset. Methotrexate (MTX) has been able to decrease the incidence of uveitis in JIA up to 2 times [1]. Treatment of JIA depends on number of active joints: NSAID and intra-articular (IAC) steroid injection are the first line-therapy for OA subtype of JIA. In Russia there is a restricted access to prolonged intra-articular steroids, such as triamcinolone hexacetamide. In the cases of relapse after short-term IAC followed by start of MTX therapy, which lead to higher proportion of patients with JIA, treated with MTX then in Europe and North America. Objectives To re-evaluate the possibility of MTX to prevent the onset of uveitis in Russian JIA cohort patients with increased proportion of applying of MTX. Methods The clinical charts of all consecutive patients who had received a stable management for at least 2 years with or without MTX were reviewed. Patients who were given systemic medications other than MTX (except NSAID) were excluded. Patients with systemic arthritis, rheumatoid factor-positive arthritis, or enthesitis-related arthritis were also excluded. In each patient, the al least 2-year follow-up period after first visit was examined to establish whether uveitis had occurred. Results A total of 281 patients with a median disease duration of 3.8 year were included. One hundred and ninety one patients (68%) were treated with MTX compare to 33.9% in previous study [1]. During the at least 2-year follow-up, 64 patients (22.8%) developed uveitis, a median of 1.6 year after the disease onset. The frequency of uveitis was lower in MTX-treated than in MTX-untreated patients (11.5% vs 46.7%, respectively, OR=6.7 (95%CI:3.7-12.3), p=0.0000001). In previous study the frequency of uveitis was 10.5 in MTX-treated vs 20.2 in MTX-untreated patients [1]. Survival analysis confirmed that patients treated with MTX had a lower probability of developing uveitis (HR=4.35, p=0.000001) (Fig.). In subgroup analysis was shown that MTX more preventive in boys (HR=6.7, p=0.0007) than in girls (HR=3.6, p=0.000001); in patient with onset age more than 5 years (HR=22.2, p=0.000001) than whom disease onset less 5 years (HR=2.3, p=0.003). The data of survival analysis of MTX prevention not shown benefits depend on number of active joints: in OA (HR=4.0, p=0.000001) similar to polyarthritis (HR=3.7, p=0.02) and ANA status: ANA-positive (HR=4.4, p=0.00002) similar to ANA-negative (HR=3.6, p=0.003). Conclusions MTX therapy may prevent the onset of uveitis in children with JIA. Further randomized controlled trial required to confirmation our results. References Papadopoulou C, Kostik M, Bohm M, Nieto-Gonzalez JC, Gonzalez-Fernandez MI, Pistorio A, Martini A, Ravelli A. Methotrexate Therapy May Prevent the Onset of Uveitis in Juvenile Idiopathic Arthritis. J Pediatr 2013;163:879-84 Disclosure of Interest None declared