Tatyana Likhacheva

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.

A130: Is the CCR5‐delta32 Mutation Protective Against Systemic‐Onset Juvenile Idiopathic Arthritis?

The CCR5 protein is a chemokine receptor, and is known to be expressed on T cells, macrophages, dendritic and microglia cells. It is believed that different prevalence of HLA and CCR5‐ delta32—a 32 base pair deletion in the coding region—in various ethnic groups is associated with the severity and prevalence of chemokine‐mediated autoimmune diseases, systemic‐onset Juvenile Idiopathic Arthritis (soJIA) being among them (Del Rincon et al., 2003). Since the end of the last century the protective role of the CCR5‐delta32 mutation against JIA is discussed (Hinks et al., 2010), though it seems the role of this mutation is less simple than was hitherto thought. The purposes of the study was to compare the prevalence of the CCR5‐delta32 mutation in children with and without soJIA, to assess the association of this mutation with the severity of the disease and thus to evaluate its protective role.

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.

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.

Efficacy of golimumab in children with polyarticular juvenile idi-opathic arthritis

Golimumab is a human anti- monoclonal antibody against tumor necrosis factor alpha (TNF-α) TNF-α is one of the main proinflammatory cytokines taking part in JRA’s (juvenile idiopathic arthritis) pathogenesis. To compare with currently used tumor necrosis factor inhibitors golimumab therapy has high compliance because of low pain in the site of injection and long half-life period. The efficacy of golimumab was demonstrated earlier in adults with rheumatoid arthritis, spondyloarthritis and psoriatic arthritis. 10 children with active polyarticular JRA despite previous methotrexate treatment were enrolled in randomized study. All patients received subcutaneous golimumab 30 mg/kg every 4 weeks. At week 16 patients were randomly assigned to one of two treatment arms: 4 of them received placebo, others continued subcutaneous golimumab at the same dose. 3 of 4 children who received placebo later continued golimumab because of confirmed flare. Assessments were performed at week 24 and at the moment of last visit available for assessment (week 96-week 116) Dynamics of main clinical and laboratory disease activity measures were evaluated, including JA-DAS and CDAI dynamics and ACRPedi response criteria. During this study the majority of patients showed significant improvement of disease activity measures and their components with good ACR-Pedi response without serious adverse events and significant changes in blood count (erythrocytes, leukocytes and hemoglobin). According study results, golimumab can be evaluated as effective and quite safe therapy of polyarticular JRA.

Anemia in children with JIA: is it really driven by hepcidin level, or by a set of factors of a chronic disease

Hepcidin - 25-amino acid peptide - is known to be a key regulator of systemic iron metabolism [Ganz T., Nemeth E., 2012]. Hepcidin acts indirectly through ferroportin, which is both a receptor for hepcidin and the only known exporter of iron in the human body [De Falco L. et. al., 2013]. Hyperproduction of hepcidin due to the influence of pro-inflammatory cytokines, especially IL-6, triggers to transport of iron from circulation to the storage, consequently, limiting iron accessibility for erythropoiesis [Weiss G., Goodnought T., 2005]. Thus, overproduction of hepcidin seems to be the leading mechanism of development of anemia in children with Juvenile Idiopathic Arthritis (JIA). A set of negative factors of a chronic disease, particularly disbalance of vitamins, proteins, amino acids and minerals, which are also the known causes, of anemia can weaken control of iron metabolism by hepcidin.

A98: Rescue Treatment by Increased Doses of IL-1 Inhibitors for Macrophage Activation Syndrome in Children With Systemic Juvenile Idiopathic Arthritis.

macrophage activation syndrome (MAS) is a life‐threatening complication of systemic juvenile idiopathic arthritis (SJIA). More than half cases of MAS are steroid‐resistant and required to use second‐line agents, such as cyclosporine A (CsA), intravenous immunoglobulin (IVIG) and biologic agents. Known interleukin‐1 (IL‐1) is the key cytokine in pathogenesis of MAS and SJIA, so anti‐IL‐1 treatment considered as potential effective treatment. There are several publication about efficacy of increased doses of anakinra during the MAS episodes. Data about efficacy others new IL‐1 blockers (canakinumab and rilonacept) for MAS in SJIA are limited. There are only several cases of MAS during and after canakinumab (CNKB) treatment of SJIA in randomized controlled trials.

A124: Hepcidin as a Predictor of Evolution of Anemia of Chronic Disease to a Macrophage Activation Syndrome in Children With Juvenile Idiopathic Arthritis

Anemia of chronic disease (ACD), also referred to as anemia of inflammatory response, is an anemia seen in chronic illnesses, particularly—in JIA. Now it is suggested to be mostly the result of the hyperproduction of hepcidin which in turn is a result of influence of proinflammatory cytokines, primarily—IL‐6 considered to be the primary cause of anemia in patients with JIA (Tanaka, Kishimoto, 2012). However, IL‐6 blockers itself may provoke the onset of Macrophage Activation Syndrome (MAS) (Kobayashi et al., 2011), manifesting, particularly, also with anemia. In view of the fact that macrophages involved in MAS express CD163—a scavenger receptor that binds hemoglobin‐haptoglobin complexes—and trigger the pathways which are important for adaptation to oxidative stress induced by free iron (Grom, Mellins, 2010) we can consider hepcidin as a welcome challenge to predict the development of MAS early in the course of the disease. Objective of this study was to assess the possibility to use the serum hepcidin level for predict development of MAS in children with JIA.

FRI0551 Successful Treatment with TOCILIZUMAB Every 4 Weeks Distinguishes Low Disease Activity Group and Possibility to Achieve Drug-Free Remission in Patients with Systemic-Onset Juvenile Idiopathic Arthritis

Background Systemic-onset juvenile idiopathic arthritis (SoJIA) is one of the most striking forms of juvenile arthritis, which can lead to severe joint disability, organ involvement and potentially could be life-threatening. Objectives The aim of our study was to evaluate clinical response to IL-6 blockade, according to different tocilizumab (TCZ) treatment, outcomes and possibility to achieve drug-free remission. Methods Our retrospective study was included 37 active SJIA children who fall corticosteroids (CS) and DMARDs and their combination and in whom TCZ was initiated in standard dosage. We used TCZ in 2 branches: every 2 weeks (Q2W) and every 4 weeks (Q4W), depended on the severity of disease, steroid-dependence, presence of MAS and organ involvement. Patients with milder SJIA course (CS≤0.2-0.3 mg/kg, no signs of MAS and no organ involvement) were considered as suitable for Q4W treatment. Only patients who had no signs of flare, exacerbation, side effects and signs of TCZ inefficacy during 4 weeks and received TCZ Q4W (n=26). Patients who successfully treated with TCZ Q4W were recognized as group of low disease activity (LDA). If any signs of inefficacy during first 4 weeks were occurred the patient was treated with TCZ Q2W (n=11). Also if patient later had any signs of insufficient efficacy of TCZ Q4W this patient was re-assessed as HDA patient and referred to appropriate group. Results From 37 children included in the trial 33 (89.1%) successfully completed it. TCZ was discontinued in 10 patients during the trial: 6 children achieved inactive disease, allowed to stop TCZ, 4 had severe adverse events. Currently 6 patients have TCZ-free remission (3/6 remission off-medication, 3/6 still on MTX) with median duration 661 days. Patients who treated Q4W had milder SJIA course: higher hemoglobin, total protein, albumin, lower WBC, granulocytes, CRP, ESR, ferritin, LDH, no new cases of macrophage activation syndrome (MAS), lower frequency of organ involvement and relapses during TCZ treatment. No patients, who required TCZ every 2 weeks, experienced TCZ-free remission by now. All cases of MAS relapses during TCZ course were only in Q2W group. Q4W patients decreased the granulocytes number intensively than Q2W. Hb>10.3 g/dl, granulocytes≤9792 cells in 1 μl, granulocytes in 1 week≤8142 cells in 1 μl, WBC in 2 weeks≤7.5*109/l, granulocytes in 2 weeks≤3975 cells in 1 μl, platelets>208*109/l, ESR≤26 mm/h, ferritin≤605 mg/ml, LDH≤571 U/l, total protein>7.2 g/dl, albumin>2.8 g/dl, absence of hepatosplenomegaly, coagulopathy, cardiorespiratory, CNS and kidney involvement, no MAS during TCZ were factors increased possibility to use TCZ Q4W and referred the patient to LDA group. Fever before and MAS after TCZ initiation, lymphadenopathy, coagulopathy, CNS dysfunction and treatment Q2W decreased possibility to achieve TCZ-off remission. Conclusions Different response to IL-6 blockade distinguishes two different subsets of SJIA. We offer the provisional criteria distinguish patients with LDA and HDA and provisional criteria probability to rich TCZ-free remission. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.2273